Study With AG-013736 Combined With Chemotherapy And Bevacizumab In Patients With Metastatic Colorectal Cancer

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00460603
• Collaborator: (none)
• Enrollment: 187
• Locations: 107
• Arms: 3
• Duration (Months): 82
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

To determine the safety and efficacy of AG-013736 in combination with other standard of care medication in patients with first line metastatic colorectal cancer.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Neoplasms	Drug: bevacizumab; Drug: AG-013726; Drug: AG-013736 (axitinib)	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 187 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase 2 Study Of The Anti-Angiogenesis Agent AG-013736 In Combinations With Chemotherapy And Bevacizumab In Patients With Metastatic Colorectal Cancer Preceded By A Phase 1 Portion
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: B bevacizumab 5 mg/kg every 2 weeks + FOLFOX	Drug: bevacizumab; bevacizumab 5 mg/kg every 2 weeks
Experimental: C AG-013726 5 mg bid+ bevacizumab 2 mg/kg every 2 weeks + FOLFOX	Drug: AG-013726; AG-013726 5 mg bid every 2 weeks
Experimental: A AG-013736 5 mg bid starting dose + FOLFOX	Drug: AG-013736 (axitinib); AG-013736 5 mg bid starting dose

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Objective Response: Phase 2 [Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)]

   Percentage of participants with objective response (OR) based assessment of confirmed complete response(CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR defined as disappearance of all lesions and no appearance of new lesions. Confirmed PR defined as >=30 percent (%) decrease in sum of the longest dimensions (LD) of the target lesions taking as reference the baseline sum LD , without progression of nontarget lesions and no appearance of new lesions. Confirmed responses are those that persist on repeat imaging study >=4 weeks after initial documentation of response.

Secondary Outcome Measures

1. Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Axitinib: Phase 1 [Predose, 1, 2, 2.5, 4, 6 and 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1]

   Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). Pharmacokinetic (PK) parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. AUClast for axitinib in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data. Results were normalized to axitinib 5 mg dose.

2. Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Axitinib: Phase 1 [Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1]

   AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. AUC (t - ∞] for axitinib in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data. Results were normalized to axitinib 5 mg dose.

3. Maximum Observed Plasma Concentration (Cmax) For Axitinib: Phase 1 [Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1]

   PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3.Cmax for axitinib (AG-013736) in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data. Results were normalized to axitinib 5 mg dose.

4. Minimum Observed Plasma Trough Concentration (Cmin) For Axitinib: Phase 1 [Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1]

5. Apparent Oral Clearance (CL/F) For Axitinib: Phase 1 [Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1]

   Clearance (CL) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed (F). Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. CL/F for axitinib (AG-013736) in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data.

6. Plasma Decay Half-Life (t1/2) For Axitinib: Phase 1 [Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1]

   Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. t1/2 for axitinib in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data.

7. Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Oxaliplatin: Phase 1 [Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

   Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. AUClast for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 oxaliplatin dose.

8. Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Oxaliplatin: Phase 1 [Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

   AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. AUC (0 - ∞) for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 oxaliplatin dose.

9. Maximum Observed Plasma Concentration (Cmax) For Oxaliplatin: Phase 1 [Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

   PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. Cmax for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 oxaliplatin dose.

10. Minimum Observed Plasma Trough Concentration (Cmin) For Oxaliplatin: Phase 1 [Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

11. Clearance (CL) For Oxaliplatin: Phase 1 [Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    CL is a quantitative measure of the rate at which a drug substance is removed from the body. PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. CL for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.

12. Plasma Decay Half-Life (t1/2) For Oxaliplatin: Phase 1 [Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. t1/2 for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.

13. Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For 5-Fluorouracil: Phase 1 [Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. AUClast for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 5-FU dose.

14. Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For 5-Fluorouracil: Phase 1 [Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. AUC (0 - ∞) for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 5-FU dose.

15. Maximum Observed Plasma Concentration (Cmax) For 5-Fluorouracil: Phase 1 [Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. Cmax for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 5-FU dose.

16. Minimum Observed Plasma Trough Concentration (Cmin) For 5-Fluorouracil: Phase 1 [Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

17. Clearance (CL) For 5-Fluorouracil: Phase 1 [Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    CL is a quantitative measure of the rate at which a drug substance is removed from the body. PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. CL for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.

18. Plasma Decay Half-Life (t1/2) For 5-Fluorouracil: Phase 1 [Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. t1/2 for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.

19. Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Irinotecan: Phase 1 [Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). AUClast for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 irinotecan dose.

20. Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Irinotecan: Phase 1 [Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). AUC (0 - ∞) for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 irinotecan dose.

21. Maximum Observed Plasma Concentration (Cmax) For Irinotecan: Phase 1 [Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    Cmax for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 irinotecan dose.

22. Minimum Observed Plasma Trough Concentration (Cmin) For Irinotecan: Phase 1 [Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

23. Clearance (CL) For Irinotecan: Phase 1 [Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    CL is a quantitative measure of the rate at which a drug substance is removed from the body. CL for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.

24. Plasma Decay Half-Life (t1/2) For Irinotecan: Phase 1 [Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. t1/2 for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.

25. Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Bevacizumab: Phase 1 [Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. AUClast for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. The bevacizumab pharmacokinetic parameters were normalized to 1 mg/kg dose.

26. Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Bevacizumab: Phase 1 [Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. AUC (0 - ∞) for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. The bevacizumab pharmacokinetic parameters were normalized to 1 mg/kg dose.

27. Maximum Observed Plasma Concentration (Cmax) For Bevacizumab: Phase 1 [Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. Cmax for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. The bevacizumab pharmacokinetic parameters were normalized to 1 mg/kg dose.

28. Minimum Observed Plasma Trough Concentration (Cmin) For Bevacizumab: Phase 1 [Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

29. Clearance (CL) For Bevacizumab: Phase 1 [Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    CL is a quantitative measure of the rate at which a drug substance is removed from the body. PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. CL for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.

30. Plasma Decay Half-Life (t1/2) For Bevacizumab: Phase 1 [Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1]

    Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. t1/2 for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.

31. Duration of Response (DR): Phase 2 [Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)]

    Time in days from the first documentation of objective tumor response to objective tumor progression or death due to any cancer. Duration of tumor response was calculated as the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR that was subsequently confirmed plus 1. DR was calculated for the subgroup of participants with a confirmed objective tumor response. CR: disappearance of all lesions and no appearance of new lesions. PR: >=30% decrease in sum of LD of target lesions taking as reference the baseline sum LD, without progression of nontarget lesions and no appearance of new lesions. Progression: >=20% increase in sum of LD of target lesions taking as references the smallest sum LD recorded since treatment start, unequivocal progression of existing nontarget lesions, or appearance of new lesions, occurrence of pleural effusion/ascites, substantiated by cytologic investigation.

32. Progression-Free Survival (PFS): Phase 2 [Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)]

    Time in days from date of randomization to first documentation of objective tumor progression or death due to any cause. PFS was calculated as first event date minus the date of first dose of study medication plus 1. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from adverse event (AE) data (where the outcome was "Death"). Progression: >=20% increase in sum of LD of target lesions taking as references the smallest sum LD recorded since treatment start, unequivocal progression of existing nontarget lesions, or appearance of new lesions, occurrence of pleural effusion/ascites, substantiated by cytologic investigation.

33. Time to Treatment Failure (TTF): Phase 2 [Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)]

    TTF is defined as the time from the randomization to the date of the first documentation of PD, symptomatic deterioration, death due to any cause, or treatment discontinuation due to adverse event, refusal or other reasons. Progression: >=20% increase in sum of LD of target lesions taking as references the smallest sum LD recorded since treatment start, unequivocal progression of existing nontarget lesions, or appearance of new lesions, occurrence of pleural effusion/ascites, substantiated by cytologic investigation.

34. Overall Survival (OS): Phase 2 [Every 3 months after discontinuation of study treatment until death due to any cause or 1 year after randomization of the last participant]

    Time in days from randomization date to date of death due to any cause. OS was calculated as the death date minus the date of first dose of study medication plus 1. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death).

35. Change From Baseline in M.D. Anderson Symptom Assessment Inventory - Diarrhea (MDASI-D) Symptom Severity and Interference Subscale Scores at Day 1 of Cycle 2 Through Day 1 Cycle 42 and Follow-up: Phase 2 [Cycle 1 Day 1 (baseline), every 2 weeks for the first 2 months (Cycle 2 Day 1 [C2D1], Cycle 3 Day 1, and Cycle 4 Day 1) then monthly thereafter starting Cycle 6 Day 1, and 28 days after the last dose]

    PROs included assessment of symptom severity and interference which were measured using M.D. Anderson Symptom Assessment Inventory-Diarrhea (MDASI-D), 20-item questionnaire which assesses the severity of 14 symptoms over the past 24 hours, as well as symptoms interference with 6 areas of function (e.g., walking, work, mood), when the symptom was "at its worst". Each item is scored from 0 to 10, with '0' indicating that the symptom was either not present or did not interfere with their activities, and '10' indicating that the symptom was "as bad as you can imagine" or "interfered completely" with their life. The 2 subscales, symptom severity score and symptom interference score were average of respective items and ranged from 0 to 10, higher score indicating greater severity or interference of symptoms.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• (Phase 1) Patients with any solid/GI tumor who have had no more than 1 previous chemotherapy for greater than 3 months prior to enrollment

• (Phase 2) Patients with locally advanced or metastatic colorectal cancer (CRC) previously untreated with any systemic therapy.

• Patients treated with adjuvant chemotherapy (with radiation) will be eligible if last treatment was > 12 months prior to enrollment,

• Patients must have measurable disease by RECIST and if any history of hypertension, it must be controlled with medication.

Exclusion Criteria:

• Prior system therapy for advanced CRC (Ph 2 portion only)

• Prior treatment with anti-angiogenesis agent such as bevacizumab or VEGF inhibitors.

• Prior irradiation of greater than 25% of bone marrow (whole pelvis = 25%)

• Prior radiation, major surgery, or investigational agent within 4 weeks of study entry except palliative radiotherapy to non-target, metastatic lesions. Minor surgeries should be completed > 2 weeks of enrollment and be fully recovered from any procedure.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pfizer Investigational Site	Daphne	Alabama	United States	36526
2	Pfizer Investigational Site	Huntsville	Alabama	United States	35801
3	Pfizer Investigational Site	Huntsville	Alabama	United States	35805
4	Pfizer Investigational Site	Mobile	Alabama	United States	36608
5	Pfizer Investigational Site	Antioch	California	United States	94531
6	Pfizer Investigational Site	Colton	California	United States	92324
7	Pfizer Investigational Site	Corona	California	United States	92879
8	Pfizer Investigational Site	Gilroy	California	United States	95020
9	Pfizer Investigational Site	Glendora	California	United States	91741
10	Pfizer Investigational Site	La Jolla	California	United States	92037
11	Pfizer Investigational Site	La Jolla	California	United States	92093
12	Pfizer Investigational Site	LaJolla	California	United States	92093
13	Pfizer Investigational Site	Pasadena	California	United States	91105
14	Pfizer Investigational Site	Pleasant Hill	California	United States	94523
15	Pfizer Investigational Site	Pomona	California	United States	91767
16	Pfizer Investigational Site	Rancho Cucamonga	California	United States	91730
17	Pfizer Investigational Site	Rancho Mirage	California	United States	92270
18	Pfizer Investigational Site	Redlands	California	United States	92374
19	Pfizer Investigational Site	San Diego	California	United States	92103
20	Pfizer Investigational Site	San Diego	California	United States	92121
21	Pfizer Investigational Site	San Leandro	California	United States	94578
22	Pfizer Investigational Site	West Covina	California	United States	91790
23	Pfizer Investigational Site	Auroa	Colorado	United States	80012
24	Pfizer Investigational Site	Boulder	Colorado	United States	80303
25	Pfizer Investigational Site	Colorado Springs	Colorado	United States	80909
26	Pfizer Investigational Site	Denver	Colorado	United States	80218
27	Pfizer Investigational Site	Denver	Colorado	United States	80220
28	Pfizer Investigational Site	Lakewood	Colorado	United States	80228
29	Pfizer Investigational Site	Littleton	Colorado	United States	80120-4413
30	Pfizer Investigational Site	Lone Tree	Colorado	United States	80124
31	Pfizer Investigational Site	Longmont	Colorado	United States	80501
32	Pfizer Investigational Site	Parker	Colorado	United States	80138
33	Pfizer Investigational Site	Thornton	Colorado	United States	80260
34	Pfizer Investigational Site	Ocala	Florida	United States	34471
35	Pfizer Investigational Site	Stuart	Florida	United States	34994
36	Pfizer Investigational Site	Atlanta	Georgia	United States	30318
37	Pfizer Investigational Site	Beech Grove	Indiana	United States	46107
38	Pfizer Investigational Site	Indianapolis	Indiana	United States	46237
39	Pfizer Investigational Site	Jeffersonville	Indiana	United States	47130
40	Pfizer Investigational Site	Muncie	Indiana	United States	47303
41	Pfizer Investigational Site	Kansas City	Kansas	United States	66112
42	Pfizer Investigational Site	Overland Park	Kansas	United States	66210
43	Pfizer Investigational Site	Louisville	Kentucky	United States	40202
44	Pfizer Investigational Site	Louisville	Kentucky	United States	40207
45	Pfizer Investigational Site	Louisville	Kentucky	United States	40217
46	Pfizer Investigational Site	Louisville	Kentucky	United States	40241
47	Pfizer Investigational Site	Shelbyville	Kentucky	United States	40065
48	Pfizer Investigational Site	Baton Rouge	Louisiana	United States	70809
49	Pfizer Investigational Site	Brownstone	Michigan	United States	48183
50	Pfizer Investigational Site	Dearborn	Michigan	United States	48126
51	Pfizer Investigational Site	Detroit	Michigan	United States	48202
52	Pfizer Investigational Site	West Bloomfield	Michigan	United States	48322
53	Pfizer Investigational Site	Kansas City	Missouri	United States	64111
54	Pfizer Investigational Site	Kansas City	Missouri	United States	64131
55	Pfizer Investigational Site	Kansas City	Missouri	United States	64154
56	Pfizer Investigational Site	Lee's Summit	Missouri	United States	64064
57	Pfizer Investigational Site	St. Louis	Missouri	United States	63110
58	Pfizer Investigational Site	Grand Island	Nebraska	United States	68803
59	Pfizer Investigational Site	Las Vegas	Nevada	United States	89135
60	Pfizer Investigational Site	Summit	New Jersey	United States	07902
61	Pfizer Investigational Site	Albany	New York	United States	12206
62	Pfizer Investigational Site	Albany	New York	United States	12208
63	Pfizer Investigational Site	Amsterdam	New York	United States	12010
64	Pfizer Investigational Site	Hudson	New York	United States	12534
65	Pfizer Investigational Site	Latham	New York	United States	12110-0610
66	Pfizer Investigational Site	Rexford	New York	United States	12148
67	Pfizer Investigational Site	Troy	New York	United States	12180
68	Pfizer Investigational Site	Kernersville	North Carolina	United States	27284
69	Pfizer Investigational Site	Lexington	North Carolina	United States	27295
70	Pfizer Investigational Site	Mount Airy	North Carolina	United States	27030
71	Pfizer Investigational Site	North Wilkesboro	North Carolina	United States	28659
72	Pfizer Investigational Site	Pollocksville	North Carolina	United States	28573
73	Pfizer Investigational Site	Winston Salem	North Carolina	United States	27103
74	Pfizer Investigational Site	Oregon City	Oregon	United States	97045
75	Pfizer Investigational Site	Portland	Oregon	United States	97213
76	Pfizer Investigational Site	Portland	Oregon	United States	97225
77	Pfizer Investigational Site	Portland	Oregon	United States	97227
78	Pfizer Investigational Site	Tualatin	Oregon	United States	97062
79	Pfizer Investigational Site	West Reading	Pennsylvania	United States	19611
80	Pfizer Investigational Site	Charleston	South Carolina	United States	29406
81	Pfizer Investigational Site	Easley	South Carolina	United States	29640
82	Pfizer Investigational Site	Greenville	South Carolina	United States	29605
83	Pfizer Investigational Site	Greenville	South Carolina	United States	29615
84	Pfizer Investigational Site	Seneca	South Carolina	United States	29672
85	Pfizer Investigational Site	Spartanburg	South Carolina	United States	29307
86	Pfizer Investigational Site	Chattanooga	Tennessee	United States	37403
87	Pfizer Investigational Site	Franklin	Tennessee	United States	37067
88	Pfizer Investigational Site	Gallatin	Tennessee	United States	37066
89	Pfizer Investigational Site	Hermitage	Tennessee	United States	37076
90	Pfizer Investigational Site	Lebanon	Tennessee	United States	37087
91	Pfizer Investigational Site	Nashville	Tennessee	United States	37203
92	Pfizer Investigational Site	Nashville	Tennessee	United States	37205
93	Pfizer Investigational Site	Nashville	Tennessee	United States	37207
94	Pfizer Investigational Site	Nashville	Tennessee	United States	37211
95	Pfizer Investigational Site	Smyrna	Tennessee	United States	37167
96	Pfizer Investigational Site	Dallas	Texas	United States	75235
97	Pfizer Investigational Site	Dallas	Texas	United States	75237
98	Pfizer Investigational Site	Dallas	Texas	United States	75246
99	Pfizer Investigational Site	Dallas	Texas	United States	75390
100	Pfizer Investigational Site	Fort Worth	Texas	United States	76177
101	Pfizer Investigational Site	Houston	Texas	United States	77090
102	Pfizer Investigational Site	Tyler	Texas	United States	75702
103	Pfizer Investigational Site	Ogden	Utah	United States	84403-3274
104	Pfizer Investigational Site	Everett	Washington	United States	98201
105	Pfizer Investigational Site	Kennewick	Washington	United States	99336
106	Pfizer Investigational Site	Vancouver	Washington	United States	98684
107	Pfizer Investigational Site	Vancouver	Washington	United States	98686

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT00460603
• Other Study ID Numbers: A4061020
• First Posted: Apr 16, 2007
• Last Update Posted: Dec 6, 2013
• Last Verified: Nov 1, 2013

• Keywords provided by Pfizer: GI neoplasms (phase 1)
• Additional relevant MeSH terms: Colorectal Neoplasms; Bevacizumab; Axitinib

Study Results

Participant Flow

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1)	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 2)	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 3)	Phase 1: Axitinib + FOLFIRI (Cohort 4)	Phase 1: Axitinib + FOLFOX (Cohort 5)	Phase 1: Axitinib + FOLFIRI (Cohort 6)	Phase 1: Axitinib + FOLFOX (Cohort 7)	Phase 1: Axitinib + FOLFIRI (Cohort 8)	Phase 1: Axitinib + FOLFIRI (Cohort 9)	Phase 2: Axitinib + FOLFOX	Phase 2: Bevacizumab + FOLFOX	Phase 2: Axitinib + Bevacizumab + FOLFOX
Arm/Group Description	Bevacizumab 1 milligram per kilogram (mg/kg) intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 milligram per square meter (mg/m^2) intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-fluorouracil (5-FU) 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily from Day 3 to Day 12 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 to Day 12 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Axitinib (AG-13736) tablet 7 mg orally twice daily for 7 days in 2-week lead-in period prior to Day 1 Cycle 1. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 7 mg to 10 mg orally twice daily from Day 3 to Day 9 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Axitinib (AG-13736) tablet 7 mg orally twice daily for 7 days in 2-week lead-in period prior to Day 1 Cycle 1. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 10 mg orally twice daily from Day 3 to Day 9 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Period Title: Phase 1
STARTED	6	6	4	8	6	4	6	3	18	0	0	0
COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0
NOT COMPLETED	6	6	4	8	6	4	6	3	18	0	0	0
Period Title: Phase 1
STARTED	0	0	0	0	0	0	0	0	0	42	43	41
Treated	0	0	0	0	0	0	0	0	0	39	43	41
COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0
NOT COMPLETED	0	0	0	0	0	0	0	0	0	42	43	41

Baseline Characteristics

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1)	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 2)	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 3)	Phase 1: Axitinib + FOLFIRI (Cohort 4)	Phase 1: Axitinib + FOLFOX (Cohort 5)	Phase 1: Axitinib + FOLFIRI (Cohort 6)	Phase 1: Axitinib + FOLFOX (Cohort 7)	Phase 1: Axitinib + FOLFIRI (Cohort 8)	Phase 1: Axitinib + FOLFIRI (Cohort 9)	Phase 2: Axitinib + FOLFOX	Phase 2: Bevacizumab + FOLFOX	Phase 2: Axitinib + Bevacizumab + FOLFOX	Total
Arm/Group Description	Bevacizumab 1 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily from Day 3 to Day 12 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 to Day 12 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Axitinib (AG-13736) tablet 7 mg orally twice daily for 7 days in 2-week lead-in period prior to Day 1 Cycle 1. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 7 mg to 10 mg orally twice daily from Day 3 to Day 9 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Axitinib (AG-13736) tablet 7 mg orally twice daily for 7 days in 2-week lead-in period prior to Day 1 Cycle 1. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 10 mg orally twice daily from Day 3 to Day 9 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Total of all reporting groups
Overall Participants	6	6	4	8	6	4	6	3	18	42	43	41	187
Age, Customized (Number) [Number]
Less than (<) 18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
18 to 44 years	1 16.7%	2 33.3%	0 0%	1 12.5%	1 16.7%	1 25%	0 0%	0 0%	1 5.6%	2 4.8%	4 9.3%	8 19.5%	21 11.2%
45 to 64 years	2 33.3%	1 16.7%	3 75%	3 37.5%	2 33.3%	1 25%	5 83.3%	3 100%	13 72.2%	22 52.4%	18 41.9%	23 56.1%	96 51.3%
Greater than or equal to (>=) 65 years	3 50%	3 50%	1 25%	4 50%	3 50%	2 50%	1 16.7%	0 0%	4 22.2%	18 42.9%	21 48.8%	10 24.4%	70 37.4%
Sex: Female, Male (Count of Participants)
Female	3 50%	1 16.7%	2 50%	2 25%	1 16.7%	2 50%	2 33.3%	0 0%	7 38.9%	17 40.5%	15 34.9%	15 36.6%	67 35.8%
Male	3 50%	5 83.3%	2 50%	6 75%	5 83.3%	2 50%	4 66.7%	3 100%	11 61.1%	25 59.5%	28 65.1%	26 63.4%	120 64.2%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Objective Response: Phase 2
Description	Percentage of participants with objective response (OR) based assessment of confirmed complete response(CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed CR defined as disappearance of all lesions and no appearance of new lesions. Confirmed PR defined as >=30 percent (%) decrease in sum of the longest dimensions (LD) of the target lesions taking as reference the baseline sum LD , without progression of nontarget lesions and no appearance of new lesions. Confirmed responses are those that persist on repeat imaging study >=4 weeks after initial documentation of response.
Time Frame	Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population included all randomized participants, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

Arm/Group Title	Phase 2: Axitinib + FOLFOX	Phase 2: Bevacizumab + FOLFOX	Phase 2: Axitinib + Bevacizumab + FOLFOX
Arm/Group Description	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	42	43	41
Number (95% Confidence Interval) [Percentage of participants]	28.6 476.7%	48.8 813.3%	39.0 975%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Axitinib + FOLFOX, Phase 2: Bevacizumab + FOLFOX
	Comments	One-sided Cochran-Mantel-Haenszel test of treatment stratified by prior adjuvant chemotherapy (yes versus [vs.] no) and prior pelvic irradiation (yes vs. no) was used for the analysis.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9726
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.585
	Confidence Interval	(2-Sided) 95%; 0.332 to 1.031
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Axitinib + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
	Comments	One-sided Cochran-Mantel-Haenszel test of treatment stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no) was used for the analysis.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8391
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.735
	Confidence Interval	(2-Sided) 95%; 0.399 to 1.352
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Bevacizumab + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
	Comments	One-sided Cochran-Mantel-Haenszel test of treatment stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no) was used for the analysis.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8192
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Risk Ratio (RR)
	Estimated Value	0.797
	Confidence Interval	(2-Sided) 95%; 0.489 to 1.299
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Axitinib: Phase 1
Description	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). Pharmacokinetic (PK) parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. AUClast for axitinib in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data. Results were normalized to axitinib 5 mg dose.
Time Frame	Predose, 1, 2, 2.5, 4, 6 and 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFIRI (Cohort 4)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	12	6	6
Cycle 1 Day 8	119.02	106.76	97.05
Cycle 2 Day 1	95.70	143.68	117.47

3. Secondary Outcome

Title	Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Axitinib: Phase 1
Description	AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. AUC (t - ∞] for axitinib in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data. Results were normalized to axitinib 5 mg dose.
Time Frame	Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFIRI (Cohort 4)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	8	4	3
Cycle 1 Day 8	190.51	113.20	205.41
Cycle 2 Day 1	224.46	168.07	178.46

4. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) For Axitinib: Phase 1
Description	PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3.Cmax for axitinib (AG-013736) in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data. Results were normalized to axitinib 5 mg dose.
Time Frame	Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFIRI (Cohort 4)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	12	6	6
Cycle 1 Day 8	35.57	27.14	24.23
Cycle 2 Day 1	27.51	42.48	32.62

5. Secondary Outcome

Title	Minimum Observed Plasma Trough Concentration (Cmin) For Axitinib: Phase 1
Time Frame	Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK assessments were done only for cohort 1 to 5, as per planned analysis. Results for Cmin are not reported because Cmin could not be assessed from the data obtained from the study.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFIRI (Cohort 4)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	0	0	0

6. Secondary Outcome

Title	Apparent Oral Clearance (CL/F) For Axitinib: Phase 1
Description	Clearance (CL) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed (F). Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. CL/F for axitinib (AG-013736) in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data.
Time Frame	Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFIRI (Cohort 4)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	8	4	3
Cycle 1 Day 8	30.01	47.10	28.49
Cycle 2 Day 1	30.08	33.33	28.90

7. Secondary Outcome

Title	Plasma Decay Half-Life (t1/2) For Axitinib: Phase 1
Description	Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of axitinib (AG-013736) were combined for Cohorts 1, 2, and 3. t1/2 for axitinib in absence of bevacizumab + FOLFOX was estimated from Cycle 1 Day 8 data and in presence of bevacizumab + FOLFOX was estimated from Cycle 2 Day 1 data.
Time Frame	Predose, 1, 2, 2.5, 4, 6, 8 hours postdose on Cycle 1 Day 8, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFIRI (Cohort 4)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1,2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	8	4	3
Cycle 1 Day 8	3.26 (3.943)	2.23 (0.702)	3.47 (2.820)
Cycle 2 Day 1	6.12 (7.450)	3.09 (0.889)	1.73 (0.456)

8. Secondary Outcome

Title	Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Oxaliplatin: Phase 1
Description	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. AUClast for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 oxaliplatin dose.
Time Frame	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1,2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	15	5
Cycle 1 Day 1	4814.87	4308.71
Cycle 2 Day 1	5231.71	5303.66

9. Secondary Outcome

Title	Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Oxaliplatin: Phase 1
Description	AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. AUC (0 - ∞) for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 oxaliplatin dose.
Time Frame	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	15	5
Cycle 1 Day 1	5955.70	5137.31
Cycle 2 Day 1	6744.06	6430.67

10. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) For Oxaliplatin: Phase 1
Description	PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. Cmax for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 oxaliplatin dose.
Time Frame	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	15	5
Cycle 1 Day 1	278.81	265.05
Cycle 2 Day 1	318.99	374.03

11. Secondary Outcome

Title	Minimum Observed Plasma Trough Concentration (Cmin) For Oxaliplatin: Phase 1
Time Frame	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK assessments were done only for cohort 1 to 5, as per planned analysis. Results for Cmin are not reported because Cmin could not be assessed from the data obtained from the study.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	0	0

12. Secondary Outcome

Title	Clearance (CL) For Oxaliplatin: Phase 1
Description	CL is a quantitative measure of the rate at which a drug substance is removed from the body. PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. CL for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	15	5
Cycle 1 Day 1	27.51	30.74
Cycle 2 Day 1	24.29	24.56

13. Secondary Outcome

Title	Plasma Decay Half-Life (t1/2) For Oxaliplatin: Phase 1
Description	Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of oxaliplatin, assessed by estimating total platinum in plasma ultrafiltrate, were combined for Cohorts 1, 2, and 3. t1/2 for oxaliplatin in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	15	5
Cycle 1 Day 1	20.63 (6.513)	18.38 (3.004)
Cycle 2 Day 1	23.30 (14.975)	19.86 (4.110)

14. Secondary Outcome

Title	Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For 5-Fluorouracil: Phase 1
Description	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. AUClast for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 5-FU dose.
Time Frame	Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFIRI (Cohort 4)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	14	7	5
Cycle 1 Day 1	39212.03	40955.29	52164.28
Cycle 2 Day 1	45087.71	36533.84	95123.13

15. Secondary Outcome

Title	Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For 5-Fluorouracil: Phase 1
Description	AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. AUC (0 - ∞) for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 5-FU dose.
Time Frame	Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFIRI (Cohort 4)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	9	7	5
Cycle 1 Day 1	36314.14	41460.50	52430.15
Cycle 2 Day 1	38983.80	36776.79	96632.41

16. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) For 5-Fluorouracil: Phase 1
Description	PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. Cmax for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 5-FU dose.
Time Frame	Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFIRI (Cohort 4)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	14	7	5
Cycle 1 Day 1	16160.85	34436.94	19622.74
Cycle 2 Day 1	16249.77	39730.46	34180.87

17. Secondary Outcome

Title	Minimum Observed Plasma Trough Concentration (Cmin) For 5-Fluorouracil: Phase 1
Time Frame	Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK assessments were done only for cohort 1 to 5, as per planned analysis. Results for Cmin are not reported because Cmin could not be assessed from the data obtained from the study.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFIRI (Cohort 4)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	0	0	0

18. Secondary Outcome

Title	Clearance (CL) For 5-Fluorouracil: Phase 1
Description	CL is a quantitative measure of the rate at which a drug substance is removed from the body. PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. CL for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame	Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFIRI (Cohort 4)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	9	7	5
Cycle 1 Day 1	147.43	128.28	99.36
Cycle 2 Day 1	137.34	144.62	53.92

19. Secondary Outcome

Title	Plasma Decay Half-Life (t1/2) For 5-Fluorouracil: Phase 1
Description	Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of 5-FU were combined for Cohorts 1, 2, and 3. t1/2 for 5-FU in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame	Pre-5-FU bolus, 5 min (post-5-FU bolus), 0.25, 0.5, 0.75, 2, 4, 6, 22, 34-46 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)	Phase 1: Axitinib + FOLFIRI (Cohort 4)	Phase 1: Axitinib + FOLFOX (Cohort 5)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	9	7	5
Cycle 1 Day 1	0.26 (0.218)	0.19 (0.069)	0.39 (0.291)
Cycle 2 Day 1	0.25 (0.142)	0.14 (0.029)	0.24 (0.131)

20. Secondary Outcome

Title	Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Irinotecan: Phase 1
Description	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). AUClast for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 irinotecan dose.
Time Frame	Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + FOLFIRI (Cohort 4)
Arm/Group Description	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	7
Cycle 1 Day 1	12081.58
Cycle 2 Day 1	11496.32

21. Secondary Outcome

Title	Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Irinotecan: Phase 1
Description	AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). AUC (0 - ∞) for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 irinotecan dose.
Time Frame	Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + FOLFIRI (Cohort 4)
Arm/Group Description	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	7
Cycle 1 Day 1	13055.88
Cycle 2 Day 1	12459.89

22. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) For Irinotecan: Phase 1
Description	Cmax for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. Results were normalized to Cycle 1 Day 1 irinotecan dose.
Time Frame	Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + FOLFIRI (Cohort 4)
Arm/Group Description	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	7
Cycle 1 Day 1	1910.25
Cycle 2 Day 1	1788.69

23. Secondary Outcome

Title	Minimum Observed Plasma Trough Concentration (Cmin) For Irinotecan: Phase 1
Time Frame	Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK assessments were done only for cohort 1 to 5, as per planned analysis. Results for Cmin are not reported because Cmin could not be assessed from the data obtained from the study.

Arm/Group Title	Phase 1: Axitinib + FOLFIRI (Cohort 4)
Arm/Group Description	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	0

24. Secondary Outcome

Title	Clearance (CL) For Irinotecan: Phase 1
Description	CL is a quantitative measure of the rate at which a drug substance is removed from the body. CL for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame	Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + FOLFIRI (Cohort 4)
Arm/Group Description	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	7
Cycle 1 Day 8	26.09
Cycle 2 Day 1	27.34

25. Secondary Outcome

Title	Plasma Decay Half-Life (t1/2) For Irinotecan: Phase 1
Description	Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. t1/2 for irinotecan in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame	Predose, 1, 2, 2.5, 4, 6, 8, 24 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + FOLFIRI (Cohort 4)
Arm/Group Description	FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	7
Cycle 1 Day 1	6.45 (1.406)
Cycle 2 Day 1	6.75 (0.886)

26. Secondary Outcome

Title	Area Under the Concentration-Time Curve From Time Zero to Last Quantifiable Concentration (AUClast) For Bevacizumab: Phase 1
Description	Area under the plasma concentration time-curve from zero to the last measured concentration (AUClast). PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. AUClast for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. The bevacizumab pharmacokinetic parameters were normalized to 1 mg/kg dose.
Time Frame	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	9
Cycle 1 Day 1	3394758.83
Cycle 2 Day 1	3554899.52

27. Secondary Outcome

Title	Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] For Bevacizumab: Phase 1
Description	AUC (0 - ∞)= Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It was obtained from AUC (0 - t) plus AUC (t - ∞). PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. AUC (0 - ∞) for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. The bevacizumab pharmacokinetic parameters were normalized to 1 mg/kg dose.
Time Frame	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	9
Cycle 1 Day 1	4987528.96
Cycle 2 Day 1	5114888.84

28. Secondary Outcome

Title	Maximum Observed Plasma Concentration (Cmax) For Bevacizumab: Phase 1
Description	PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. Cmax for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data. The bevacizumab pharmacokinetic parameters were normalized to 1 mg/kg dose.
Time Frame	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	9
Cycle 1 Day 1	26460.05
Cycle 2 Day 1	26850.12

29. Secondary Outcome

Title	Minimum Observed Plasma Trough Concentration (Cmin) For Bevacizumab: Phase 1
Time Frame	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK assessments were done only for cohort 1 to 5, as per planned analysis. Results for Cmin are not reported because Cmin could not be assessed from the data obtained from the study.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	0

30. Secondary Outcome

Title	Clearance (CL) For Bevacizumab: Phase 1
Description	CL is a quantitative measure of the rate at which a drug substance is removed from the body. PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. CL for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	9
Cycle 1 Day 1	0.01
Cycle 2 Day 1	0.02

31. Secondary Outcome

Title	Plasma Decay Half-Life (t1/2) For Bevacizumab: Phase 1
Description	Plasma decay half-life (t1/2) is the time measured for the plasma concentration to decrease by one half. PK parameters of bevacizumab were combined for Cohorts 1, 2, and 3. t1/2 for bevacizumab in absence of axitinib was estimated from Cycle 1 Day 1 data and in presence of axitinib was estimated from Cycle 2 Day 1 data.
Time Frame	Predose, 1, 2, 2.25, 2.5, 4, 6, 8, 24, 36-48 hours postdose on Cycle 1 Day 1, Cycle 2 Day 1

Outcome Measure Data

Analysis Population Description

PK parameter analysis set included all treated participants who had at least 1 estimated PK parameters of primary interest. PK assessments were done only for cohort 1 to 5, as per planned analysis. Here 'N' (Number of participants analyzed) signifies those participants who were evaluable for this measure.

Arm/Group Title	Phase 1: Axitinib + Bevacizumab + FOLFOX (Cohort 1-3)
Arm/Group Description	Bevacizumab 1, 2 or 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently with oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	9
Cycle 1 Day 1	205.97 (46.454)
Cycle 2 Day 1	210.22 (55.317)

32. Secondary Outcome

Title	Duration of Response (DR): Phase 2
Description	Time in days from the first documentation of objective tumor response to objective tumor progression or death due to any cancer. Duration of tumor response was calculated as the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR that was subsequently confirmed plus 1. DR was calculated for the subgroup of participants with a confirmed objective tumor response. CR: disappearance of all lesions and no appearance of new lesions. PR: >=30% decrease in sum of LD of target lesions taking as reference the baseline sum LD, without progression of nontarget lesions and no appearance of new lesions. Progression: >=20% increase in sum of LD of target lesions taking as references the smallest sum LD recorded since treatment start, unequivocal progression of existing nontarget lesions, or appearance of new lesions, occurrence of pleural effusion/ascites, substantiated by cytologic investigation.
Time Frame	Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized. 'N' (Number of participants analyzed)= those participants who were evaluable for this measure.

Arm/Group Title	Phase 2: Axitinib + FOLFOX	Phase 2: Bevacizumab + FOLFOX	Phase 2: Axitinib + Bevacizumab + FOLFOX
Arm/Group Description	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	12	21	16
Median (95% Confidence Interval) [days]	434.0	NA	343.0

33. Secondary Outcome

Title	Progression-Free Survival (PFS): Phase 2
Description	Time in days from date of randomization to first documentation of objective tumor progression or death due to any cause. PFS was calculated as first event date minus the date of first dose of study medication plus 1. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from adverse event (AE) data (where the outcome was "Death"). Progression: >=20% increase in sum of LD of target lesions taking as references the smallest sum LD recorded since treatment start, unequivocal progression of existing nontarget lesions, or appearance of new lesions, occurrence of pleural effusion/ascites, substantiated by cytologic investigation.
Time Frame	Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

Arm/Group Title	Phase 2: Axitinib + FOLFOX	Phase 2: Bevacizumab + FOLFOX	Phase 2: Axitinib + Bevacizumab + FOLFOX
Arm/Group Description	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	42	43	41
Median (95% Confidence Interval) [days]	336	485	381

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Axitinib + FOLFOX, Phase 2: Bevacizumab + FOLFOX
	Comments	Hazard ratio and corresponding 95% confidence interval (CI) was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5699
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 95%; 0.47 to 2.45
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Axitinib + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
	Comments	Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2167
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.33 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Bevacizumab + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
	Comments	Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8746
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.49
	Confidence Interval	(2-Sided) 95%; 0.75 to 2.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

34. Secondary Outcome

Title	Time to Treatment Failure (TTF): Phase 2
Description	TTF is defined as the time from the randomization to the date of the first documentation of PD, symptomatic deterioration, death due to any cause, or treatment discontinuation due to adverse event, refusal or other reasons. Progression: >=20% increase in sum of LD of target lesions taking as references the smallest sum LD recorded since treatment start, unequivocal progression of existing nontarget lesions, or appearance of new lesions, occurrence of pleural effusion/ascites, substantiated by cytologic investigation.
Time Frame	Baseline (Phase 2) until disease progression, assessed every 6 weeks up to Week 148 (Phase 2) or follow-up (every 6 weeks after last dose of study drug until progression or start of alternate therapy)

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

Arm/Group Title	Phase 2: Axitinib + FOLFOX	Phase 2: Bevacizumab + FOLFOX	Phase 2: Axitinib + Bevacizumab + FOLFOX
Arm/Group Description	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	42	43	41
Median (95% Confidence Interval) [days]	187.0	241.0	238.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Axitinib + FOLFOX, Phase 2: Bevacizumab + FOLFOX
	Comments	Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8884
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.40
	Confidence Interval	(2-Sided) 95%; 0.81 to 2.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Axitinib + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
	Comments	Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6648
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Bevacizumab + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
	Comments	Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8065
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.25
	Confidence Interval	(2-Sided) 95%; 0.75 to 2.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

35. Secondary Outcome

Title	Overall Survival (OS): Phase 2
Description	Time in days from randomization date to date of death due to any cause. OS was calculated as the death date minus the date of first dose of study medication plus 1. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death).
Time Frame	Every 3 months after discontinuation of study treatment until death due to any cause or 1 year after randomization of the last participant

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants , with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

Arm/Group Title	Phase 2: Axitinib + FOLFOX	Phase 2: Bevacizumab + FOLFOX	Phase 2: Axitinib + Bevacizumab + FOLFOX
Arm/Group Description	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	42	43	41
Median (95% Confidence Interval) [days]	552.0	659.0	601.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Axitinib + FOLFOX, Phase 2: Bevacizumab + FOLFOX
	Comments	Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6904
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.155
	Confidence Interval	(2-Sided) 95%; 0.656 to 2.033
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Axitinib + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
	Comments	Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7364
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.203
	Confidence Interval	(2-Sided) 95%; 0.676 to 2.141
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Phase 2: Bevacizumab + FOLFOX, Phase 2: Axitinib + Bevacizumab + FOLFOX
	Comments	Hazard ratio and corresponding 95% CI was calculated based on the Cox proportional hazards model stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no). One-sided p-value was derived from the log-rank test stratified by prior adjuvant chemotherapy (yes vs. no) and prior pelvic irradiation (yes vs. no).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4140
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.941
	Confidence Interval	(2-Sided) 95%; 0.535 to 1.653
	Parameter Dispersion	Type: Value:
	Estimation Comments

36. Secondary Outcome

Title	Change From Baseline in M.D. Anderson Symptom Assessment Inventory - Diarrhea (MDASI-D) Symptom Severity and Interference Subscale Scores at Day 1 of Cycle 2 Through Day 1 Cycle 42 and Follow-up: Phase 2
Description	PROs included assessment of symptom severity and interference which were measured using M.D. Anderson Symptom Assessment Inventory-Diarrhea (MDASI-D), 20-item questionnaire which assesses the severity of 14 symptoms over the past 24 hours, as well as symptoms interference with 6 areas of function (e.g., walking, work, mood), when the symptom was "at its worst". Each item is scored from 0 to 10, with '0' indicating that the symptom was either not present or did not interfere with their activities, and '10' indicating that the symptom was "as bad as you can imagine" or "interfered completely" with their life. The 2 subscales, symptom severity score and symptom interference score were average of respective items and ranged from 0 to 10, higher score indicating greater severity or interference of symptoms.
Time Frame	Cycle 1 Day 1 (baseline), every 2 weeks for the first 2 months (Cycle 2 Day 1 [C2D1], Cycle 3 Day 1, and Cycle 4 Day 1) then monthly thereafter starting Cycle 6 Day 1, and 28 days after the last dose

Outcome Measure Data

Analysis Population Description

ITT population included all randomized participants, with study drug assignment designated according to initial randomization, regardless of whether participants received study drug or received a different drug from that to which they were randomized.

Arm/Group Title	Phase 2: Axitinib + FOLFOX	Phase 2: Bevacizumab + FOLFOX	Phase 2: Axitinib + Bevacizumab + FOLFOX
Arm/Group Description	FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.	Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
Measure Participants	42	43	41
Severity Scale: Baseline (n=41,43,40)	1.62 (1.57)	2.20 (1.93)	2.18 (2.06)
Severity Scale: C2D1 (n=37,37,37)	0.63 (1.22)	0.04 (1.16)	0.80 (1.32)
Severity Scale: C3D1 (n=32,38,32)	0.68 (1.29)	-0.22 (1.17)	0.63 (1.61)
Severity Scale: C4D1 (n=23,37,30)	0.88 (1.41)	-0.40 (1.27)	0.64 (1.68)
Severity Scale: C5D1 (n=23,34,29)	0.72 (1.37)	-0.34 (1.59)	0.60 (2.13)
Severity Scale: C6D1 (n=15,38,26)	0.70 (1.80)	0.09 (1.44)	0.96 (1.60)
Severity Scale: C7D1 (n=12,30,22)	0.28 (1.51)	-0.16 (1.55)	0.26 (1.22)
Severity Scale: C8D1 (n=17,29,22)	0.28 (1.45)	-0.13 (1.56)	0.42 (1.74)
Severity Scale: C9D1 (n=11,24,21)	-0.15 (1.55)	-0.03 (1.67)	0.76 (1.50)
Severity Scale: C10D1 (n=14,27,21)	0.28 (1.37)	0.06 (1.52)	0.77 (1.52)
Severity Scale: C11D1 (n=10,20,19)	0.15 (1.57)	-0.05 (1.59)	0.57 (1.33)
Severity Scale: C12D1 (n=11,23,16)	0.32 (1.40)	0.47 (1.37)	0.38 (1.14)
Severity Scale: C13D1 (n=8,13,12)	-0.09 (1.43)	0.10 (1.35)	0.73 (1.55)
Severity Scale: C14D1 (n=8,17,14)	0.03 (0.81)	0.38 (1.48)	-0.05 (1.44)
Severity Scale: C15D1 (n=7,11,9)	0.28 (1.50)	0.42 (1.49)	0.71 (1.34)
Severity Scale: C16D1 (n=7,17,14)	-0.30 (0.88)	0.11 (1.46)	0.05 (2.08)
Severity Scale: C17D1 (n=5,11,6)	-0.20 (0.70)	0.21 (1.69)	0.72 (1.07)
Severity Scale: C18D1 (n=6,14,9)	0.02 (0.85)	0.31 (1.15)	0.61 (1.55)
Severity Scale: C19D1 (n=4,8,16)	-0.18 (0.54)	0.34 (1.42)	0.81 (2.32)
Severity Scale: C20D1 (n=5,14,8)	-0.06 (0.54)	0.15 (1.21)	-0.06 (1.67)
Severity Scale: C21D1 (n=4,5,5)	-0.25 (0.71)	0.27 (1.90)	1.20 (1.35)
Severity Scale: C22D1 (n=3,11,8)	0.57 (0.45)	0.81 (0.95)	0.09 (1.37)
Severity Scale: C23D1 (n=4,5,3)	0.30 (0.80)	0.64 (1.32)	1.05 (1.11)
Severity Scale: C24D1 (n=5,11,7)	0.91 (2.07)	0.37 (1.10)	-0.20 (1.62)
Severity Scale: C25D1 (n=4,5,5)	0.25 (0.96)	-0.03 (1.12)	-0.30 (1.63)
Severity Scale: C26D1 (n=4,6,7)	-0.05 (0.76)	0.46 (0.72)	-0.13 (1.79)
Severity Scale: C27D1 (n=4,3,4)	-0.21 (0.65)	0.07 (0.99)	0.34 (2.70)
Severity Scale: C28D1 (n=4,5,7)	0.12 (0.82)	0.74 (1.01)	-0.43 (2.00)
Severity Scale: C29D1 (n=2,3,4)	3.00 (2.12)	-0.14 (0.58)	-0.09 (2.51)
Severity Scale: C30D1 (n=3,6,3)	1.05 (1.70)	0.45 (1.05)	0.64 (0.68)
Severity Scale: C31D1 (n=1,1,3)	-0.50 (NA)	-0.64 (NA)	1.55 (1.69)
Severity Scale: C32D1 (n=2,4,4)	0.11 (0.25)	0.80 (0.93)	1.29 (1.03)
Severity Scale: C33D1 (n=0,0,2)	NA (NA)	NA (NA)	0.89 (1.26)
Severity Scale: C34D1 (n=2,4,3)	0.04 (0.15)	0.75 (0.89)	0.43 (0.74)
Severity Scale: C35D1 (n=0,0,1)	NA (NA)	NA (NA)	0.79 (NA)
Severity Scale: C36D1 (n=2,3,2)	0.29 (0.51)	1.24 (1.22)	-0.18 (0.25)
Severity Scale: C37D1 (n=0,1,0)	NA (NA)	0.86 (NA)	NA (NA)
Severity Scale: C38D1 (n=2,2,1)	0.13 (0.28)	1.68 (1.97)	0.86 (NA)
Severity Scale: C39D1 (n=0,1,0)	NA (NA)	0.86 (NA)	NA (NA)
Severity Scale: C40D1 (n=2,2,2)	0.18 (0.35)	1.29 (1.11)	0.43 (0.61)
Severity Scale: C42D1 (n=2,2,1)	0.18 (0.35)	1.25 (1.26)	0.00 (NA)
Severity Scale: Follow_Up (n=4,15,14)	1.29 (2.75)	-0.00 (1.66)	0.29 (1.72)
Interference Scale: Baseline (n=41,43,40)	2.50 (2.70)	2.79 (2.57)	2.47 (2.66)
Interference Scale: C2D1 (n=37,37,36)	0.46 (1.80)	-0.08 (1.74)	0.78 (2.55)
Interference Scale: C3D1 (n=31,38,30)	0.60 (2.37)	-0.57 (1.88)	1.09 (2.37)
Interference Scale: C4D1 (n=23,36,30)	0.92 (2.16)	-0.54 (1.89)	1.15 (2.37)
Interference Scale: C5D1 (n=23,34,29)	0.65 (2.20)	-0.59 (1.98)	1.19 (2.90)
Interference Scale: C6D1 (n=15,38,26)	0.32 (2.01)	-0.18 (2.33)	0.99 (2.54)
Interference Scale: C7D1 (n=12,30,22)	0.43 (1.25)	-0.59 (2.13)	0.55 (2.05)
Interference Scale: C8D1 (n=17,29,22)	0.01 (1.58)	-0.10 (2.00)	0.48 (1.87)
Interference Scale: C9D1 (n=11,24,21)	-0.14 (1.08)	-0.39 (2.31)	0.75 (1.76)
Interference Scale: C10D1 (n=14,27,21)	-0.18 (1.80)	0.15 (2.06)	0.99 (2.12)
Interference Scale: C11D1 (n=10,20,19)	0.42 (1.23)	-0.51 (1.75)	0.84 (2.50)
Interference Scale: C12D1 (n=10,23,16)	0.03 (0.78)	0.17 (2.23)	0.38 (1.51)
Interference Scale: C13D1 (n=8,13,12)	-0.50 (1.56)	-0.31 (2.49)	0.31 (1.70)
Interference Scale: C14D1 (n=8,17,14)	-0.10 (0.84)	0.15 (2.57)	0.29 (2.12)
Interference Scale: C15D1 (n=7,11,9)	-0.52 (0.85)	0.27 (1.91)	0.70 (2.36)
Interference Scale: C16D1 (n=7,17,14)	-0.02 (0.33)	-0.48 (2.31)	-0.01 (2.38)
Interference Scale: C17D1 (n=5,11,6)	-0.90 (1.31)	-0.29 (3.16)	1.17 (1.28)
Interference Scale: C18D1 (n=6,14,9)	0.06 (0.34)	0.04 (2.38)	1.00 (2.26)
Interference Scale: C19D1 (n=4,8,6)	0.04 (0.34)	0.54 (2.25)	1.04 (1.84)
Interference Scale: C20D1 (n=5,14,8)	0.27 (0.65)	-0.08 (2.34)	0.35 (2.07)
Interference Scale: C21D1 (n=4,5,5)	-0.04 (0.86)	-0.97 (3.50)	1.83 (1.28)
Interference Scale: C22D1 (n=3,11,8)	0.44 (0.84)	0.74 (1.71)	0.83 (2.05)
Interference Scale: C23D1 (n=4,5,3)	0.21 (0.42)	1.13 (2.58)	1.28 (1.80)
Interference Scale: C24D1 (n=5,11,7)	2.00 (3.25)	0.30 (2.65)	0.55 (2.33)
Interference Scale: C25D1 (n=4,5,5)	0.00 (0.41)	0.10 (2.45)	0.90 (0.88)
Interference Scale: C26D1 (n=4,6,7)	0.33 (0.85)	0.67 (1.80)	0.33 (2.11)
Interference Scale: C27D1 (n=4,3,4)	0.04 (0.52)	0.11 (1.13)	1.63 (2.44)
Interference Scale: C28D1 (n=4,5,7)	0.71 (1.19)	0.97 (1.81)	0.19 (2.40)
Interference Scale: C29D1 (n=2,3,4)	3.25 (3.89)	-0.56 (0.96)	1.33 (2.97)
Interference Scale: C30D1 (n=3,6,3)	0.94 (1.49)	1.08 (2.16)	1.06 (1.83)
Interference Scale: C31D1 (n=1,1,3)	0.00 (NA)	-0.17 (NA)	2.33 (2.08)
Interference Scale: C32D1 (n=2,4,4)	0.08 (0.12)	1.50 (2.26)	2.17 (1.81)
Interference Scale: C33D1 (n=0,0,2)	NA (NA)	NA (NA)	1.92 (2.71)
Interference Scale: C34D1 (n=2,4,3)	0.17 (0.24)	1.25 (1.89)	1.11 (1.51)
Interference Scale: C35D1 (n=0,0,1)	NA (NA)	NA (NA)	1.67 (NA)
Interference Scale: C36D1 (n=2,3,2)	0.17 (0.24)	1.89 (2.18)	1.33 (1.89)
Interference Scale: C37D1 (n=0,1,0)	NA (NA)	0.83 (NA)	NA (NA)
Interference Scale: C38D1 (n=2,2,1)	0.08 (0.12)	2.25 (2.47)	-0.17 (NA)
Interference Scale: C39D1 (n=0,1,0)	NA (NA)	0.50 (NA)	NA (NA)
Interference Scale: C40D1 (n=2,2,2)	0.42 (0.59)	2.50 (2.12)	0.25 (0.35)
Interference Scale: C42D1 (n=2,2,1)	0.25 (0.35)	2.58 (2.24)	0.00 (NA)
Interference Scale: Follow Up (n=4,15,14)	1.33 (2.48)	-0.21 (2.44)	0.91 (1.65)

Adverse Events

Adverse Event Reporting Description	The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 1)		Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 2)		Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 3)		Phase 1: Axitinib + FOLFIRI (Cohort 4)		Phase 1: Axitinib + FOLFOX (Cohort 5)		Phase 1: Axitinib + FOLFIRI (Cohort 6)		Phase 1: Axitinib + FOLFOX (Cohort 7)		Phase 1: Axitinib + FOLFIRI (Cohort 8)		Phase 1: Axitinib + FOLFOX (Cohort 9)		Phase 2: Axitinib + FOLFOX		Phase 2: Bevacizumab + FOLFOX		Phase 2: Axitinib + Bevacizumab + FOLFOX
Arm/Group Description	Bevacizumab 1 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.		Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.		Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.		FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to irinotecan infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.		FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 in Cycle 1 and starting from Day 1 in all subsequent cycles administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.		FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily from Day 3 to Day 12 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.		FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily starting from Day 3 to Day 12 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.		Axitinib (AG-13736) tablet 7 mg orally twice daily for 7 days in 2-week lead-in period prior to Day 1 Cycle 1. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 7 mg to 10 mg orally twice daily from Day 3 to Day 9 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.		Axitinib (AG-13736) tablet 7 mg orally twice daily for 7 days in 2-week lead-in period prior to Day 1 Cycle 1. FOLFIRI combination chemotherapy on Day 1 of each 14-day cycle consisting of irinotecan 180 mg/m^2 intravenous infusion over 90 minutes, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by irinotecan, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 10 mg orally twice daily from Day 3 to Day 9 in each 14-day cycle administered following completion of 5-FU infusion on Day 3. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.		FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered prior to oxaliplatin infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.		Bevacizumab 5 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.		Bevacizumab 2 mg/kg intravenous infusion over 90 minutes on Day 1 of each 14-day cycle followed by FOLFOX combination chemotherapy on Day 1 of each 14-day cycle consisting of oxaliplatin 85 mg/m^2 intravenous infusion over 2 hours, leucovorin 400 mg/m^2 intravenous infusion over 2 hours administered concurrently or followed by oxaliplatin, then 5-FU 400 mg/m^2 intravenous bolus injection and a subsequent 5-FU 2400 mg/m^2 intravenous infusion over 46 to 48 hours. Axitinib (AG-013736) tablet 5 mg orally twice daily in each 14-day cycle administered following bevacizumab infusion on Day 1. Dose adjustment for any drug in the combination was done for individual participants who experienced drug-related toxicity, as per investigator's discretion.
All Cause Mortality
	Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 1)		Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 2)		Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 3)		Phase 1: Axitinib + FOLFIRI (Cohort 4)		Phase 1: Axitinib + FOLFOX (Cohort 5)		Phase 1: Axitinib + FOLFIRI (Cohort 6)		Phase 1: Axitinib + FOLFOX (Cohort 7)		Phase 1: Axitinib + FOLFIRI (Cohort 8)		Phase 1: Axitinib + FOLFOX (Cohort 9)		Phase 2: Axitinib + FOLFOX		Phase 2: Bevacizumab + FOLFOX		Phase 2: Axitinib + Bevacizumab + FOLFOX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 1)		Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 2)		Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 3)		Phase 1: Axitinib + FOLFIRI (Cohort 4)		Phase 1: Axitinib + FOLFOX (Cohort 5)		Phase 1: Axitinib + FOLFIRI (Cohort 6)		Phase 1: Axitinib + FOLFOX (Cohort 7)		Phase 1: Axitinib + FOLFIRI (Cohort 8)		Phase 1: Axitinib + FOLFOX (Cohort 9)		Phase 2: Axitinib + FOLFOX		Phase 2: Bevacizumab + FOLFOX		Phase 2: Axitinib + Bevacizumab + FOLFOX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/6 (50%)		2/6 (33.3%)		2/4 (50%)		3/8 (37.5%)		5/6 (83.3%)		1/4 (25%)		1/6 (16.7%)		1/3 (33.3%)		8/18 (44.4%)		15/39 (38.5%)		17/43 (39.5%)		23/41 (56.1%)
Blood and lymphatic system disorders
Neutropenia	0/6 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Anaemia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		2/43 (4.7%)		0/41 (0%)
Febrile neutropenia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		1/43 (2.3%)		1/41 (2.4%)
Cardiac disorders
Bradycardia	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Cardiac failure congestive	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Cardiomyopathy	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Left ventricular dysfunction	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Myocardial infarction	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		1/43 (2.3%)		1/41 (2.4%)
Sinus bradycardia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Eye disorders
Blindness	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Gastrointestinal disorders
Abdominal pain	1/6 (16.7%)		1/6 (16.7%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		2/39 (5.1%)		1/43 (2.3%)		2/41 (4.9%)
Constipation	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Diarrhoea	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		1/43 (2.3%)		0/41 (0%)
Diverticular perforation	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Dysphagia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Enteritis	0/6 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Gastric ulcer	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Gastric ulcer haemorrhage	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Gastrointestinal haemorrhage	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		2/43 (4.7%)		0/41 (0%)
Gastrointestinal stenosis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Haemorrhoids	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Melaena	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Nausea	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		3/41 (7.3%)
Intestinal obstruction	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Oesophagitis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Proctalgia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Small intestinal obstruction	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Stomatitis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Vomiting	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		1/43 (2.3%)		3/41 (7.3%)
General disorders
Asthenia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		4/39 (10.3%)		1/43 (2.3%)		1/41 (2.4%)
Chest discomfort	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Chest pain	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		2/41 (4.9%)
Disease progression	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Fatigue	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Mucosal inflammation	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		1/41 (2.4%)
Non-cardiac chest pain	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Pain	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Pyrexia	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		3/43 (7%)		0/41 (0%)
Hepatobiliary disorders
Cholangitis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Cholecystitis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Cholecystitis acute	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Cholelithiasis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Immune system disorders
Hypersensitivity	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Infections and infestations
Abscess intestinal	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Abdominal abscess	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Bacteraemia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Bacterial sepsis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Device related infection	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Pneumonia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		3/43 (7%)		0/41 (0%)
Rectal abscess	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Sepsis	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		1/43 (2.3%)		1/41 (2.4%)
Sepsis syndrome	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Septic shock	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Staphylococcal infection	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		1/18 (5.6%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Urinary tract infection	0/6 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		3/43 (7%)		0/41 (0%)
Injury, poisoning and procedural complications
Lower limb fracture	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Procedural haemorrhage	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Toxicity to various agents	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Wound dehiscence	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Investigations
Aspartate aminotransferase increased	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Hepatic enzyme increased	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Haemoglobin decreased	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
International normalised ratio increased	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Metabolism and nutrition disorders
Dehydration	0/6 (0%)		2/6 (33.3%)		0/4 (0%)		0/8 (0%)		2/6 (33.3%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		3/39 (7.7%)		2/43 (4.7%)		7/41 (17.1%)
Decreased appetite	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Hyponatraemia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Malnutrition	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Musculoskeletal and connective tissue disorders
Fistula	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Musculoskeletal pain	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Nervous system disorders
Convulsion	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		2/41 (4.9%)
Altered state of consciousness	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Cerebral haemorrhage	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Cerebrovascular accident	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Encephalopathy	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Haemorrhage intracranial	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Headache	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		2/41 (4.9%)
Hemiparesis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Peripheral motor neuropathy	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Speech disorder	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Syncope	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Psychiatric disorders
Confusional state	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Mental status changes	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Renal and urinary disorders
Dysuria	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Renal failure	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Renal failure acute	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		1/41 (2.4%)
Reproductive system and breast disorders
Testicular pain	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Acute respiratory failure	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Chronic obstructive pulmonary disease	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Dyspnoea	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Pulmonary embolism	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		3/39 (7.7%)		1/43 (2.3%)		1/41 (2.4%)
Respiratory failure	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Pneumothorax	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Pleural effusion	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Pulmonary fibrosis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Vascular disorders
Aortic thrombosis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Deep vein thrombosis	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		2/39 (5.1%)		1/43 (2.3%)		2/41 (4.9%)
Flushing	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Hypertension	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		2/41 (4.9%)
Hypotension	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		2/43 (4.7%)		0/41 (0%)
Jugular vein thrombosis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Orthostatic hypotension	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Shock haemorrhagic	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Subclavian vein thrombosis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Superior vena cava syndrome	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Other (Not Including Serious) Adverse Events
	Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 1)		Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 2)		Phase 1: Axitinib + FOLFOX + Bevacizumab (Cohort 3)		Phase 1: Axitinib + FOLFIRI (Cohort 4)		Phase 1: Axitinib + FOLFOX (Cohort 5)		Phase 1: Axitinib + FOLFIRI (Cohort 6)		Phase 1: Axitinib + FOLFOX (Cohort 7)		Phase 1: Axitinib + FOLFIRI (Cohort 8)		Phase 1: Axitinib + FOLFOX (Cohort 9)		Phase 2: Axitinib + FOLFOX		Phase 2: Bevacizumab + FOLFOX		Phase 2: Axitinib + Bevacizumab + FOLFOX
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		6/6 (100%)		4/4 (100%)		8/8 (100%)		6/6 (100%)		4/4 (100%)		6/6 (100%)		3/3 (100%)		18/18 (100%)		39/39 (100%)		42/43 (97.7%)		39/41 (95.1%)
Blood and lymphatic system disorders
Anaemia	2/6 (33.3%)		0/6 (0%)		2/4 (50%)		1/8 (12.5%)		2/6 (33.3%)		3/4 (75%)		1/6 (16.7%)		1/3 (33.3%)		5/18 (27.8%)		9/39 (23.1%)		9/43 (20.9%)		12/41 (29.3%)
Anaemia megaloblastic	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Febrile neutropenia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Hypercoagulation	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Leukocytosis	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Leukopenia	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		4/18 (22.2%)		2/39 (5.1%)		3/43 (7%)		3/41 (7.3%)
Lymph node pain	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		2/18 (11.1%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Lymphopenia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Microcytosis	0/6 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Neutropenia	1/6 (16.7%)		1/6 (16.7%)		3/4 (75%)		3/8 (37.5%)		1/6 (16.7%)		1/4 (25%)		1/6 (16.7%)		2/3 (66.7%)		9/18 (50%)		15/39 (38.5%)		21/43 (48.8%)		19/41 (46.3%)
Pancytopenia	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Thrombocytopenia	2/6 (33.3%)		1/6 (16.7%)		2/4 (50%)		2/8 (25%)		2/6 (33.3%)		1/4 (25%)		1/6 (16.7%)		0/3 (0%)		6/18 (33.3%)		11/39 (28.2%)		12/43 (27.9%)		16/41 (39%)
Cardiac disorders
Angina pectoris	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Atrial fibrillation	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		1/43 (2.3%)		0/41 (0%)
Bradycardia	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		2/41 (4.9%)
Left ventricular dysfunction	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Tachycardia	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		2/18 (11.1%)		3/39 (7.7%)		1/43 (2.3%)		2/41 (4.9%)
Ear and labyrinth disorders
Deafness	2/6 (33.3%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Ear discomfort	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Ear pain	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		1/43 (2.3%)		0/41 (0%)
Hypoacusis	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Tinnitus	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		1/18 (5.6%)		0/39 (0%)		1/43 (2.3%)		1/41 (2.4%)
Vertigo	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Endocrine disorders
Hypothyroidism	1/6 (16.7%)		0/6 (0%)		2/4 (50%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		2/6 (33.3%)		2/3 (66.7%)		3/18 (16.7%)		7/39 (17.9%)		2/43 (4.7%)		7/41 (17.1%)
Eye disorders
Blepharospasm	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Conjunctival haemorrhage	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Cataract	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		2/41 (4.9%)
Dry eye	0/6 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		1/41 (2.4%)
Eye discharge	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Eye irritation	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		2/18 (11.1%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Eye pain	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Lacrimation increased	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		2/39 (5.1%)		0/43 (0%)		1/41 (2.4%)
Photophobia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Retinal vein occlusion	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Vision blurred	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		3/39 (7.7%)		3/43 (7%)		3/41 (7.3%)
Gastrointestinal disorders
Abdominal discomfort	0/6 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		2/39 (5.1%)		0/43 (0%)		4/41 (9.8%)
Abdominal pain	2/6 (33.3%)		1/6 (16.7%)		3/4 (75%)		3/8 (37.5%)		2/6 (33.3%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		5/18 (27.8%)		8/39 (20.5%)		5/43 (11.6%)		14/41 (34.1%)
Abdominal distension	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		2/43 (4.7%)		2/41 (4.9%)
Abdominal pain lower	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		1/41 (2.4%)
Abdominal pain upper	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		1/4 (25%)		1/6 (16.7%)		0/3 (0%)		1/18 (5.6%)		2/39 (5.1%)		1/43 (2.3%)		12/41 (29.3%)
Abdominal rigidity	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Abdominal tenderness	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		1/3 (33.3%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Flatulence	0/6 (0%)		1/6 (16.7%)		1/4 (25%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		1/43 (2.3%)		3/41 (7.3%)
Gastrooesophageal reflux disease	1/6 (16.7%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		4/43 (9.3%)		4/41 (9.8%)
Gastrointestinal sounds abnormal	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Glossitis	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Glossodynia	1/6 (16.7%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		1/43 (2.3%)		1/41 (2.4%)
Haematochezia	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Haemorrhoids	1/6 (16.7%)		1/6 (16.7%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		1/3 (33.3%)		2/18 (11.1%)		3/39 (7.7%)		1/43 (2.3%)		3/41 (7.3%)
Hypoaesthesia oral	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Lip blister	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Loose tooth	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		2/43 (4.7%)		0/41 (0%)
Mesenteric vein thrombosis	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		1/41 (2.4%)
Mouth ulceration	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Nausea	6/6 (100%)		4/6 (66.7%)		3/4 (75%)		5/8 (62.5%)		5/6 (83.3%)		3/4 (75%)		5/6 (83.3%)		3/3 (100%)		13/18 (72.2%)		22/39 (56.4%)		23/43 (53.5%)		23/41 (56.1%)
Oesophageal stenosis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Oesophagitis	2/6 (33.3%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Oral pain	1/6 (16.7%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		2/18 (11.1%)		1/39 (2.6%)		4/43 (9.3%)		7/41 (17.1%)
Paraesthesia oral	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Proctalgia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		2/18 (11.1%)		0/39 (0%)		3/43 (7%)		7/41 (17.1%)
Rectal haemorrhage	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		3/39 (7.7%)		3/43 (7%)		3/41 (7.3%)
Retching	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Salivary hypersecretion	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Stomatitis	2/6 (33.3%)		0/6 (0%)		1/4 (25%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		2/6 (33.3%)		1/3 (33.3%)		2/18 (11.1%)		4/39 (10.3%)		5/43 (11.6%)		9/41 (22%)
Swollen tongue	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Toothache	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		4/43 (9.3%)		0/41 (0%)
Tongue disorder	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Vomiting	3/6 (50%)		3/6 (50%)		1/4 (25%)		5/8 (62.5%)		0/6 (0%)		1/4 (25%)		2/6 (33.3%)		3/3 (100%)		6/18 (33.3%)		12/39 (30.8%)		12/43 (27.9%)		15/41 (36.6%)
General disorders
Adverse drug reaction	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		2/41 (4.9%)
Asthenia	1/6 (16.7%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		3/6 (50%)		0/3 (0%)		1/18 (5.6%)		8/39 (20.5%)		5/43 (11.6%)		4/41 (9.8%)
Axillary pain	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Catheter site erythema	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Catheter site haematoma	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Catheter site pain	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		2/39 (5.1%)		0/43 (0%)		1/41 (2.4%)
Chest discomfort	0/6 (0%)		0/6 (0%)		1/4 (25%)		1/8 (12.5%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		2/43 (4.7%)		3/41 (7.3%)
Chest pain	1/6 (16.7%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		3/43 (7%)		4/41 (9.8%)
Chills	1/6 (16.7%)		0/6 (0%)		2/4 (50%)		0/8 (0%)		1/6 (16.7%)		1/4 (25%)		0/6 (0%)		1/3 (33.3%)		1/18 (5.6%)		3/39 (7.7%)		1/43 (2.3%)		2/41 (4.9%)
Device dislocation	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Device occlusion	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		2/41 (4.9%)
Early satiety	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Face oedema	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Fatigue	5/6 (83.3%)		4/6 (66.7%)		4/4 (100%)		4/8 (50%)		3/6 (50%)		4/4 (100%)		4/6 (66.7%)		2/3 (66.7%)		14/18 (77.8%)		24/39 (61.5%)		29/43 (67.4%)		31/41 (75.6%)
Gait disturbance	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Hernia pain	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Impaired healing	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Influenza like illness	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		2/41 (4.9%)
Local swelling	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Malaise	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		1/18 (5.6%)		2/39 (5.1%)		2/43 (4.7%)		4/41 (9.8%)
Mucosal inflammation	6/6 (100%)		2/6 (33.3%)		1/4 (25%)		2/8 (25%)		4/6 (66.7%)		2/4 (50%)		1/6 (16.7%)		1/3 (33.3%)		6/18 (33.3%)		7/39 (17.9%)		9/43 (20.9%)		15/41 (36.6%)
Nodule	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Non-cardiac chest pain	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Oedema	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Oedema peripheral	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		2/4 (50%)		0/6 (0%)		0/3 (0%)		4/18 (22.2%)		5/39 (12.8%)		4/43 (9.3%)		3/41 (7.3%)
Pain	2/6 (33.3%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/18 (0%)		2/39 (5.1%)		6/43 (14%)		4/41 (9.8%)
Pyrexia	0/6 (0%)		0/6 (0%)		2/4 (50%)		1/8 (12.5%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		1/3 (33.3%)		4/18 (22.2%)		3/39 (7.7%)		6/43 (14%)		8/41 (19.5%)
Temperature intolerance	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		5/39 (12.8%)		10/43 (23.3%)		9/41 (22%)
Thrombosis in device	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Hepatobiliary disorders
Cholangitis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Cholelithiasis	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Hepatic pain	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		1/41 (2.4%)
Hyperbilirubinaemia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		1/43 (2.3%)		3/41 (7.3%)
Jaundice	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Portal vein thrombosis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		2/43 (4.7%)		0/41 (0%)
Immune system disorders
Hypersensitivity	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		1/43 (2.3%)		2/41 (4.9%)
Infections and infestations
Arthropod-borne disease	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Bronchitis	0/6 (0%)		0/6 (0%)		2/4 (50%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		2/39 (5.1%)		1/43 (2.3%)		1/41 (2.4%)
Candidiasis	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		1/43 (2.3%)		5/41 (12.2%)
Catheter site infection	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		2/41 (4.9%)
Enterobacter sepsis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Escherichia urinary tract infection	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Eye infection	0/6 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Furuncle	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Fungal skin infection	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Gastroenteritis viral	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Gastrointestinal viral infection	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Herpes virus infection	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Incision site infection	0/6 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Infection	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Influenza	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		2/41 (4.9%)
Laryngitis	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		2/41 (4.9%)
Nasopharyngitis	1/6 (16.7%)		1/6 (16.7%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/4 (0%)		1/6 (16.7%)		1/3 (33.3%)		0/18 (0%)		1/39 (2.6%)		2/43 (4.7%)		3/41 (7.3%)
Oral candidiasis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		2/6 (33.3%)		0/3 (0%)		1/18 (5.6%)		2/39 (5.1%)		0/43 (0%)		2/41 (4.9%)
Oral herpes	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		2/41 (4.9%)
Pneumonia	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Rectal abscess	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Sinusitis	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		2/6 (33.3%)		0/4 (0%)		2/6 (33.3%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		2/43 (4.7%)		1/41 (2.4%)
Subcutaneous abscess	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Tinea infection	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Tooth infection	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		2/39 (5.1%)		0/43 (0%)		0/41 (0%)
Upper respiratory tract infection	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		1/3 (33.3%)		0/18 (0%)		2/39 (5.1%)		4/43 (9.3%)		3/41 (7.3%)
Urinary tract infection	3/6 (50%)		0/6 (0%)		0/4 (0%)		2/8 (25%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		3/18 (16.7%)		5/39 (12.8%)		3/43 (7%)		7/41 (17.1%)
Urosepsis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Viral infection	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Vulvovaginal mycotic infection	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Wound dehiscence	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		2/41 (4.9%)
Tooth abscess	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		2/39 (5.1%)		0/43 (0%)		0/41 (0%)
Injury, poisoning and procedural complications
Anal injury	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Burns second degree	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Contusion	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		2/41 (4.9%)
Excoriation	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		0/43 (0%)		2/41 (4.9%)
Lower limb fracture	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Procedural pain	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		2/39 (5.1%)		0/43 (0%)		1/41 (2.4%)
Procedural site reaction	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		2/39 (5.1%)		0/43 (0%)		0/41 (0%)
Skeletal injury	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Tooth fracture	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Wound	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Wound complication	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		2/41 (4.9%)
Investigations
Alanine aminotransferase increased	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		2/18 (11.1%)		1/39 (2.6%)		1/43 (2.3%)		2/41 (4.9%)
Aspartate aminotransferase increased	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		2/18 (11.1%)		1/39 (2.6%)		2/43 (4.7%)		2/41 (4.9%)
Blood alkaline phosphatase increased	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		3/18 (16.7%)		2/39 (5.1%)		1/43 (2.3%)		2/41 (4.9%)
Blood bilirubin increased	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		2/18 (11.1%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Blood creatinine increased	0/6 (0%)		1/6 (16.7%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		1/3 (33.3%)		2/18 (11.1%)		1/39 (2.6%)		1/43 (2.3%)		0/41 (0%)
Blood lactate dehydrogenase increased	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Blood magnesium decreased	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		2/41 (4.9%)
Blood potassium decreased	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Blood pressure diastolic decreased	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Blood pressure increased	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		4/39 (10.3%)		1/43 (2.3%)		1/41 (2.4%)
Blood testosterone decreased	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Blood thyroid stimulating hormone increased	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		2/39 (5.1%)		0/43 (0%)		0/41 (0%)
Blood uric acid increased	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Breath sounds abnormal	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		1/4 (25%)		1/6 (16.7%)		0/3 (0%)		3/18 (16.7%)		0/39 (0%)		1/43 (2.3%)		1/41 (2.4%)
Cardiac enzymes increased	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Haemoglobin decreased	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
International normalised ratio increased	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		2/43 (4.7%)		0/41 (0%)
Neutrophil count decreased	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Platelet count decreased	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		2/43 (4.7%)		0/41 (0%)
Weight decreased	0/6 (0%)		2/6 (33.3%)		1/4 (25%)		2/8 (25%)		1/6 (16.7%)		0/4 (0%)		1/6 (16.7%)		2/3 (66.7%)		2/18 (11.1%)		7/39 (17.9%)		6/43 (14%)		17/41 (41.5%)
White blood cell count decreased	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		2/43 (4.7%)		0/41 (0%)
Metabolism and nutrition disorders
Cachexia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Decreased appetite	5/6 (83.3%)		4/6 (66.7%)		2/4 (50%)		4/8 (50%)		4/6 (66.7%)		0/4 (0%)		3/6 (50%)		1/3 (33.3%)		5/18 (27.8%)		10/39 (25.6%)		10/43 (23.3%)		20/41 (48.8%)
Dehydration	5/6 (83.3%)		0/6 (0%)		0/4 (0%)		4/8 (50%)		3/6 (50%)		0/4 (0%)		1/6 (16.7%)		1/3 (33.3%)		3/18 (16.7%)		7/39 (17.9%)		8/43 (18.6%)		12/41 (29.3%)
Diabetes mellitus	2/6 (33.3%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Hyperglycaemia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		2/6 (33.3%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		3/43 (7%)		2/41 (4.9%)
Hyperkalaemia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		1/43 (2.3%)		0/41 (0%)
Hypernatraemia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Hyperuricaemia	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Hypoalbuminaemia	0/6 (0%)		0/6 (0%)		1/4 (25%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		2/39 (5.1%)		1/43 (2.3%)		3/41 (7.3%)
Hypocalcaemia	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		1/43 (2.3%)		2/41 (4.9%)
Hypoglycaemia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Hypokalaemia	1/6 (16.7%)		1/6 (16.7%)		1/4 (25%)		3/8 (37.5%)		1/6 (16.7%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		5/18 (27.8%)		7/39 (17.9%)		7/43 (16.3%)		5/41 (12.2%)
Hypomagnesaemia	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		2/6 (33.3%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		2/39 (5.1%)		4/43 (9.3%)		1/41 (2.4%)
Hyponatraemia	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		3/18 (16.7%)		0/39 (0%)		4/43 (9.3%)		3/41 (7.3%)
Hypophosphataemia	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Hypovolaemia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		2/43 (4.7%)		0/41 (0%)
Malnutrition	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		0/43 (0%)		2/41 (4.9%)
Metabolic acidosis	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/6 (0%)		1/6 (16.7%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		1/6 (16.7%)		1/3 (33.3%)		2/18 (11.1%)		3/39 (7.7%)		4/43 (9.3%)		4/41 (9.8%)
Arthritis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Back pain	2/6 (33.3%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		1/4 (25%)		1/6 (16.7%)		3/3 (100%)		4/18 (22.2%)		6/39 (15.4%)		3/43 (7%)		6/41 (14.6%)
Bone pain	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		2/41 (4.9%)
Bursa disorder	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Flank pain	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		2/41 (4.9%)
Muscle spasms	1/6 (16.7%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		1/6 (16.7%)		1/3 (33.3%)		1/18 (5.6%)		1/39 (2.6%)		2/43 (4.7%)		3/41 (7.3%)
Muscular weakness	0/6 (0%)		0/6 (0%)		1/4 (25%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		1/43 (2.3%)		0/41 (0%)
Musculoskeletal chest pain	0/6 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		1/43 (2.3%)		1/41 (2.4%)
Musculoskeletal pain	1/6 (16.7%)		0/6 (0%)		1/4 (25%)		3/8 (37.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		2/18 (11.1%)		6/39 (15.4%)		0/43 (0%)		4/41 (9.8%)
Musculoskeletal stiffness	0/6 (0%)		0/6 (0%)		1/4 (25%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Myalgia	0/6 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		1/3 (33.3%)		2/18 (11.1%)		1/39 (2.6%)		1/43 (2.3%)		1/41 (2.4%)
Neck pain	1/6 (16.7%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/18 (0%)		2/39 (5.1%)		0/43 (0%)		0/41 (0%)
Pain in extremity	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		2/18 (11.1%)		4/39 (10.3%)		4/43 (9.3%)		7/41 (17.1%)
Pain in jaw	2/6 (33.3%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		1/43 (2.3%)		4/41 (9.8%)
Trigger finger	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Nervous system disorders
Ageusia	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Aphasia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Ataxia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Convulsion	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Dizziness	2/6 (33.3%)		1/6 (16.7%)		2/4 (50%)		2/8 (25%)		2/6 (33.3%)		0/4 (0%)		2/6 (33.3%)		2/3 (66.7%)		3/18 (16.7%)		8/39 (20.5%)		6/43 (14%)		7/41 (17.1%)
Dysgeusia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		2/6 (33.3%)		0/3 (0%)		1/18 (5.6%)		3/39 (7.7%)		5/43 (11.6%)		8/41 (19.5%)
Headache	4/6 (66.7%)		1/6 (16.7%)		2/4 (50%)		0/8 (0%)		1/6 (16.7%)		1/4 (25%)		0/6 (0%)		1/3 (33.3%)		5/18 (27.8%)		8/39 (20.5%)		6/43 (14%)		13/41 (31.7%)
Hyperaesthesia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		2/43 (4.7%)		1/41 (2.4%)
Hypoaesthesia	1/6 (16.7%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		3/43 (7%)		1/41 (2.4%)
IIIrd nerve disorder	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Lethargy	2/6 (33.3%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		2/43 (4.7%)		0/41 (0%)
Memory impairment	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Migraine	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Mononeuritis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Neuropathy peripheral	3/6 (50%)		2/6 (33.3%)		4/4 (100%)		0/8 (0%)		2/6 (33.3%)		0/4 (0%)		4/6 (66.7%)		0/3 (0%)		5/18 (27.8%)		12/39 (30.8%)		23/43 (53.5%)		17/41 (41.5%)
Neuralgia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Paraesthesia	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		5/43 (11.6%)		7/41 (17.1%)
Peripheral sensory neuropathy	0/6 (0%)		2/6 (33.3%)		1/4 (25%)		0/8 (0%)		3/6 (50%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		9/39 (23.1%)		6/43 (14%)		8/41 (19.5%)
Peripheral motor neuropathy	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		2/41 (4.9%)
Presyncope	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Restless legs syndrome	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Somnolence	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		3/41 (7.3%)
Syncope	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		1/43 (2.3%)		2/41 (4.9%)
Transient ischaemic attack	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Psychiatric disorders
Anxiety	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		3/18 (16.7%)		1/39 (2.6%)		4/43 (9.3%)		5/41 (12.2%)
Claustrophobia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Confusional state	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		3/39 (7.7%)		1/43 (2.3%)		1/41 (2.4%)
Delirium	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Depression	2/6 (33.3%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		5/43 (11.6%)		9/41 (22%)
Disorientation	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Insomnia	0/6 (0%)		2/6 (33.3%)		2/4 (50%)		2/8 (25%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		1/18 (5.6%)		11/39 (28.2%)		7/43 (16.3%)		10/41 (24.4%)
Mood altered	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Paranoia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Sleep disorder	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		2/43 (4.7%)		0/41 (0%)
Renal and urinary disorders
Chromaturia	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Dysuria	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		2/18 (11.1%)		3/39 (7.7%)		3/43 (7%)		3/41 (7.3%)
Glycosuria	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Haematuria	0/6 (0%)		0/6 (0%)		0/4 (0%)		2/8 (25%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		3/39 (7.7%)		3/43 (7%)		1/41 (2.4%)
Nephrolithiasis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Pollakiuria	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/18 (0%)		0/39 (0%)		2/43 (4.7%)		0/41 (0%)
Proteinuria	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		1/4 (25%)		2/6 (33.3%)		0/3 (0%)		3/18 (16.7%)		5/39 (12.8%)		5/43 (11.6%)		12/41 (29.3%)
Renal failure	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Urethral haemorrhage	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Urge incontinence	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Urinary hesitation	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		2/43 (4.7%)		0/41 (0%)
Urinary incontinence	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Urinary retention	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		2/39 (5.1%)		1/43 (2.3%)		0/41 (0%)
Reproductive system and breast disorders
Amenorrhoea	0/6 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Genital rash	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Respiratory, thoracic and mediastinal disorders
Apnoea	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Cough	4/6 (66.7%)		1/6 (16.7%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		1/4 (25%)		0/6 (0%)		1/3 (33.3%)		3/18 (16.7%)		6/39 (15.4%)		7/43 (16.3%)		8/41 (19.5%)
Dysphonia	2/6 (33.3%)		2/6 (33.3%)		2/4 (50%)		2/8 (25%)		2/6 (33.3%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		2/18 (11.1%)		8/39 (20.5%)		1/43 (2.3%)		8/41 (19.5%)
Dyspnoea	2/6 (33.3%)		1/6 (16.7%)		1/4 (25%)		2/8 (25%)		1/6 (16.7%)		1/4 (25%)		0/6 (0%)		2/3 (66.7%)		6/18 (33.3%)		5/39 (12.8%)		8/43 (18.6%)		10/41 (24.4%)
Dyspnoea exertional	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		2/43 (4.7%)		2/41 (4.9%)
Epistaxis	1/6 (16.7%)		2/6 (33.3%)		1/4 (25%)		4/8 (50%)		3/6 (50%)		0/4 (0%)		2/6 (33.3%)		1/3 (33.3%)		1/18 (5.6%)		10/39 (25.6%)		13/43 (30.2%)		12/41 (29.3%)
Hiccups	0/6 (0%)		2/6 (33.3%)		1/4 (25%)		0/8 (0%)		2/6 (33.3%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		1/18 (5.6%)		3/39 (7.7%)		2/43 (4.7%)		4/41 (9.8%)
Hypoxia	1/6 (16.7%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		1/43 (2.3%)		0/41 (0%)
Nasal congestion	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		2/39 (5.1%)		1/43 (2.3%)		0/41 (0%)
Nasal discomfort	0/6 (0%)		1/6 (16.7%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		1/41 (2.4%)
Nasal disorder	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Nasal dryness	0/6 (0%)		1/6 (16.7%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Oropharyngeal pain	1/6 (16.7%)		2/6 (33.3%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		4/39 (10.3%)		2/43 (4.7%)		6/41 (14.6%)
Paranasal sinus hypersecretion	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		2/6 (33.3%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		2/43 (4.7%)		0/41 (0%)
Pleural effusion	2/6 (33.3%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		1/43 (2.3%)		1/41 (2.4%)
Pleurisy	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Productive cough	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		4/43 (9.3%)		2/41 (4.9%)
Pulmonary embolism	0/6 (0%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		2/41 (4.9%)
Pulmonary haemorrhage	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Rhinitis allergic	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		2/43 (4.7%)		0/41 (0%)
Rhinorrhoea	1/6 (16.7%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		2/6 (33.3%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		0/18 (0%)		2/39 (5.1%)		2/43 (4.7%)		5/41 (12.2%)
Sinus congestion	2/6 (33.3%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		3/43 (7%)		1/41 (2.4%)
Tachypnoea	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Upper-airway cough syndrome	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		1/43 (2.3%)		0/41 (0%)
Skin and subcutaneous tissue disorders
Alopecia	0/6 (0%)		0/6 (0%)		0/4 (0%)		2/8 (25%)		1/6 (16.7%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		2/18 (11.1%)		4/39 (10.3%)		4/43 (9.3%)		1/41 (2.4%)
Blister	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		2/41 (4.9%)
Decubitus ulcer	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Dermatitis	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Dry skin	0/6 (0%)		2/6 (33.3%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		2/39 (5.1%)		4/43 (9.3%)		3/41 (7.3%)
Ecchymosis	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Erythema	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		2/41 (4.9%)
Facial wasting	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Hyperhidrosis	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		2/41 (4.9%)
Nail disorder	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		3/41 (7.3%)
Night sweats	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		3/43 (7%)		5/41 (12.2%)
Palmar-plantar erythrodysaesthesia syndrome	3/6 (50%)		2/6 (33.3%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/4 (0%)		1/6 (16.7%)		1/3 (33.3%)		0/18 (0%)		5/39 (12.8%)		1/43 (2.3%)		7/41 (17.1%)
Palmar erythema	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Plantar erythema	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Pruritus	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		0/43 (0%)		3/41 (7.3%)
Rash	2/6 (33.3%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		3/6 (50%)		1/4 (25%)		1/6 (16.7%)		0/3 (0%)		3/18 (16.7%)		7/39 (17.9%)		3/43 (7%)		8/41 (19.5%)
Rash erythematous	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Rash generalised	0/6 (0%)		0/6 (0%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		1/41 (2.4%)
Rash macular	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Rash maculo-papular	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		0/43 (0%)		0/41 (0%)
Skin burning sensation	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Skin discolouration	0/6 (0%)		1/6 (16.7%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		1/39 (2.6%)		0/43 (0%)		1/41 (2.4%)
Skin exfoliation	0/6 (0%)		0/6 (0%)		0/4 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		2/39 (5.1%)		0/43 (0%)		0/41 (0%)
Skin irritation	1/6 (16.7%)		1/6 (16.7%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Skin hyperpigmentation	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		2/39 (5.1%)		3/43 (7%)		0/41 (0%)
Urticaria	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Vascular disorders
Deep vein thrombosis	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		1/4 (25%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		3/43 (7%)		3/41 (7.3%)
Embolism	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Flushing	1/6 (16.7%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)
Haemorrhage	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		1/6 (16.7%)		0/3 (0%)		0/18 (0%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Hypertension	6/6 (100%)		3/6 (50%)		4/4 (100%)		2/8 (25%)		2/6 (33.3%)		2/4 (50%)		2/6 (33.3%)		2/3 (66.7%)		8/18 (44.4%)		16/39 (41%)		8/43 (18.6%)		26/41 (63.4%)
Hypotension	1/6 (16.7%)		1/6 (16.7%)		0/4 (0%)		5/8 (62.5%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		1/3 (33.3%)		6/18 (33.3%)		1/39 (2.6%)		5/43 (11.6%)		7/41 (17.1%)
Intermittent claudication	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		0/43 (0%)		0/41 (0%)
Orthostatic hypotension	0/6 (0%)		1/6 (16.7%)		1/4 (25%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		0/18 (0%)		1/39 (2.6%)		0/43 (0%)		2/41 (4.9%)
Pallor	0/6 (0%)		0/6 (0%)		0/4 (0%)		0/8 (0%)		0/6 (0%)		0/4 (0%)		0/6 (0%)		0/3 (0%)		1/18 (5.6%)		0/39 (0%)		1/43 (2.3%)		0/41 (0%)

Limitations/Caveats

Time to Treatment Failure (TTF) was included as a secondary endpoint of the study after change in analysis plan.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.