A Dose-Escalation Study for Patients With Advanced Cancer

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01214642
• Collaborator: (none)
• Enrollment: 63
• Locations: 2
• Arms: 4
• Duration (Months): 49
• Patients Per Site: 31.5
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This study is being conducted to determine the safety of LY2523355 for the treatment of advanced and/or metastatic cancer (including Non-Hodgkin's lymphoma).

Condition or Disease	Intervention/Treatment	Phase
Advanced Cancer	Drug: pegfilgrastim; Drug: LY2523355	Phase 1

Detailed Description

This study is a multi-center, non-randomized, open label, dose-escalation, Phase 1 study of intravenous LY2523355 in patients with advanced and/or metastatic cancer (including non-Hodgkin's lymphoma) for whom no treatment of higher priority exists.

Study Design

• Study Type: Interventional
• Actual Enrollment: 63 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1 Dose-Escalation Study of LY2523355 in Patients With Advanced Cancer
• Study Start Date: May 1, 2008
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LY2523355 Days 1, 5, 9 LY2523355 administered intravenously on Days 1, 5 and 9, starting dose is 2 milligrams per meter squared (mg/m^2) for 2 planned 21-day cycles. Participants may continue on study drug until disease progression, unacceptable toxicity or other withdrawal criterion are met.	Drug: LY2523355; Administered intravenously
Experimental: LY2523355 Days 1, 8 LY2523355 administered intravenously on Days 1 and 8, starting dose is 8 mg/m^2 for 2 planned 21-day cycles. Participants may continue on study drug until disease progression, unacceptable toxicity or other withdrawal criterion are met.	Drug: LY2523355; Administered intravenously
Experimental: LY2523355 Days 1, 5 + pegfilgrastim LY2523355 administered intravenously on Days 1 and 5, starting dose is 8 mg/m^2 for 2 planned 21-day cycles and 6 mg pegfilgrastim administered subcutaneously on Day 6 of each 21-day cycle for the 2 planned cycles and for any subsequent cycles of LY2523355 received. Participants may continue on study drug until disease progression, unacceptable toxicity or other withdrawal criterion are met.	Drug: pegfilgrastim; Administered subcutaneously; Drug: LY2523355; Administered intravenously
Experimental: LY2523355 Days 1, 4 + pegfilgrastim LY2523355 administered on Days 1 and 4, starting dose is 12 mg/m^2 for 2 planned 21-day cycles and 6 mg pegfilgrastim administered subcutaneously on Day 5 of each 21-day cycle for the 2 planned cycles and for any subsequent cycles of LY2523355 received. Participants may continue on study drug until disease progression, unacceptable toxicity or other withdrawal criterion are met.	Drug: pegfilgrastim; Administered subcutaneously; Drug: LY2523355; Administered intravenously

Outcome Measures

Primary Outcome Measures

1. Recommended Dose and Schedule for Phase 2 Studies [Cycle 1 (21 days): Day 1, 5 and 9, any AE reported]

   The recommended dose and schedule for Phase 2 studies is defined as the maximum tolerated dose (MTD). MTD is defined as the dose level at which no more than 2 dose limiting toxicities (DLTs), no more than 3 dose reductions (DR) or dose omissions (DO) and no more than 1 DLT plus 2 DR/DO occurred. DLT is defined as an adverse event (AE) occurring in Cycle 1 with the following criteria according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0: Any ≥Grade 3 nonhematological toxicity (except nausea/vomiting or diarrhea controlled with treatment or fatigue); ≥Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding; Grade 4 hematological toxicity of >5 days duration, excluding thrombocytopenia; febrile neutropenia.

Secondary Outcome Measures

1. Number of Participants With Clinically Significant Effects [Baseline to Cycle 38 (21-day cycles): daily for AEs]

   Clinically significant effects were defined as serious and other non-serious adverse events (AEs). A summary of serious and other non-serious AEs is located in the Reported Adverse Events module.

2. Pharmacokinetics Maximum Concentration (Cmax), Single Dose [Cycle 1 Day 1 of 21-day cycle: Predose, 1 hour (hr), 2,4,6,8,24,48 and 72 hr postdose]

   Plasma Cmax following a single dose of LY2523355 at each dose level across all schedules and in the presence or absence of pegfilgrastim (PEG).

3. Pharmacokinetics Maximum Concentration (Cmax), Multiple Dose [Cycle 1 Days 4, 5, 8 or 9 of 21-day cycle:Predose, 1 hour (hr), 2,4,6,8,24,48 and 72 hr postdose]

   Plasma Cmax following multiple doses of LY2523355 at each dose level across all schedules and in the presence or absence of pegfilgrastim (PEG).

4. Pharmacokinetics Area Under the Concentration-time Curve (AUC), Single Dose [Cycle 1 Days 4, 5, 8 or 9 of 21-day cycle:Predose, 1 hour (hr), 2,4,6,8,24,48 and 72 hr postdose]

   Plasma AUC from time zero to infinity [AUC(0-∞)] and AUC from time zero to 24 hours post-dose [AUC(0-24)] following a single dose of LY2523355 at each dose level across all schedules and in the presence or absence of pegfilgrastim (PEG).

5. Pharmacokinetic Areas Under the Concentration Time Curve (AUC), Multiple Dose [Cycle 1 Days 4, 5, 8 or 9 of 21-day cycle:Predose, 1 hour (hr), 2,4,6,8,24,48 and 72 hr postdose]

   Plasma AUC from time zero to infinity (0-∞) and AUC from time zero to 24 hours (0-24) post-dose following multiple doses of LY2523355 at each dose level across all schedules and in the presence or absence of pegfilgrastim (PEG).

6. Number of Participants With Tumor Response [Baseline to measured disease progression or discontinuation up to Cycle 38 (21-day cycles)]

   Response was assessed using Response Evaluation Criteria In Solid Tumors (RECIST) criteria and the Revised International Working Group (IWG) lymphoma response criteria for lymphoma patients. Complete Response (CR) was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter (mm) and normalization of tumor marker level of non-target lesions; Partial Response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD) was defined as at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase over nadir. Tumor response is CR + PR.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Have a diagnosis of advanced and/or metastatic cancer (solid tumors or Non-Hodgkin's lymphoma) that is refractory to standard therapy or for which no proven effective therapy exists. Participants entering the dose confirmation phase (Part B) of the study must also have a tumor that is safely amenable to serial biopsies

• Have the presence of measurable or nonmeasurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) or Revised International Working Group Lymphoma Response Criteria

• Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale

• Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, cancer-related hormonal therapy, or other investigational therapy for at least 28 days (6 weeks for mitomycin-C or nitrosoureas) prior to study enrollment

• Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the trial and for 3 months following the last dose of study drug

• Females with child bearing potential must have had a negative urine or serum pregnancy test less than or equal to 7 days prior to the first dose of study drug

• Have an estimated life expectancy of greater than or equal to 12 weeks.

Exclusion Criteria:

• Have symptomatic, untreated or uncontrolled central nervous system (CNS) metastases. Participants with treated CNS metastases are eligible provided their disease is radiographically stable, asymptomatic, and they are not currently receiving corticosteroids and/or anticonvulsants. Screening of asymptomatic participants without history of CNS metastases is not required

• Have current acute or chronic leukemia

• Have had an autologous or allogenic bone marrow transplant

• Females who are pregnant or lactating

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	Nashville	Tennessee	United States	37203
2	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.	San Antonio	Texas	United States	78229-3307

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01214642
• Other Study ID Numbers: 11619; I1Y-MC-JFBB
• First Posted: Oct 5, 2010
• Last Update Posted: Aug 6, 2018
• Last Verified: Aug 1, 2018

• Keywords provided by Eli Lilly and Company: Advanced Cancer; Cancer
• Additional relevant MeSH terms: Neoplasms

Study Results

Participant Flow

Pre-assignment Detail	Part A is the LY2523355 dose escalation phase and Part B is the LY2523355 dose confirmation phase. The reasons for discontinuation listed in the participant flow are the reasons the participant discontinued treatment and a participant was considered to have "completed" the trial if they received at 2 cycles of treatment.

Arm/Group Title	Part A - Days 1, 5, 9 - 2 mg/m^2/Day	Part A - Days 1, 5, 9 - 4 mg/m^2/Day	Part A - Days 1, 5, 9 - 8 mg/m^2/Day	Part A - Days 1, 5, 9 - 7 mg/m^2/Day	Part A - Days 1, 5, 9 - 6 mg/m^2/Day	Part A - Days 1, 5, 9 - 5 mg/m^2/Day	Part A - Days 1, 8 - 8 mg/m^2/Day	Part A - Days 1, 5+PEG - 8 mg/m^2/Day	Part A and B- Days 1, 5+PEG - 12 mg/m^2/Day	Part A - Days 1, 5+PEG - 16 mg/m^2/Day	Part A - Days 1, 5+PEG - 14 mg/m^2/Day	Part B - Days 1, 4+PEG - 12 mg/m^2/Day
Arm/Group Description	2 milligrams per meter squared per day (mg/m^2/day) LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	4 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	7 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	6 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	5 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 8 of 21-day cycle.	8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus pegfilgrastim (PEG) administered subcutaneously on Day 6.	12 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.	16 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.	14 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.	12 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 4 of 21-day cycle plus PEG administered subcutaneously on Day 5.
Period Title: Overall Study
STARTED	3	3	6	6	6	3	6	3	13	4	4	6
Received at Least 1 Dose of Study Drug	3	3	6	6	6	3	6	3	13	4	4	6
Complete at Least 2 Cycles of Study Drug	3	1	5	4	6	1	6	3	12	2	2	5
COMPLETED	0	0	0	0	0	0	0	0	0	0	0	0
NOT COMPLETED	3	3	6	6	6	3	6	3	13	4	4	6

Baseline Characteristics

Arm/Group Title	Part A - Days 1, 5, 9 - 2 mg/m^2/Day	Part A - Days 1, 5, 9 - 4 mg/m^2/Day	Part A - Days 1, 5, 9 - 8 mg/m^2/Day	Part A - Days 1, 5, 9 - 7 mg/m^2/Day	Part A - Days 1, 5, 9 - 6 mg/m^2/Day	Part A - Days 1, 5, 9 - 5 mg/m^2/Day	Part A - Days 1, 8 - 8 mg/m^2/Day	Part A - Days 1, 5+PEG - 8 mg/m^2/Day	Part A and B - Days 1, 5+PEG - 12 mg/m^2/Day	Part A - Days 1, 5+PEG - 16 mg/m^2/Day	Part A - Days 1, 5+PEG - 14 mg/m^2/Day	Part B - Days 1, 4+PEG - 12 mg/m^2/Day	Total
Arm/Group Description	2 milligrams per meter squared per day (mg/m^2/day) LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	4 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	7 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	6 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	5 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 8 of 21-day cycle.	8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus pegfilgrastim (PEG) administered subcutaneously on Day 6.	12 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6 in Part A and Part B.	16 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.	14 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.	12 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 4 of 21-day cycle plus PEG administered subcutaneously on Day 5.	Total of all reporting groups
Overall Participants	3	3	6	6	6	3	6	3	13	4	4	6	63
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	66.60 (5.484)	48.07 (19.657)	59.73 (7.541)	61.67 (9.352)	58.45 (12.425)	56.73 (7.267)	59.77 (6.959)	67.10 (1.212)	62.02 (7.598)	57.10 (25.069)	60.18 (10.205)	59.43 (18.595)	60.08 (11.471)
Sex: Female, Male (Count of Participants)
Female	2 66.7%	1 33.3%	4 66.7%	1 16.7%	4 66.7%	3 100%	2 33.3%	2 66.7%	4 30.8%	2 50%	3 75%	2 33.3%	30 47.6%
Male	1 33.3%	2 66.7%	2 33.3%	5 83.3%	2 33.3%	0 0%	4 66.7%	1 33.3%	9 69.2%	2 50%	1 25%	4 66.7%	33 52.4%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	1 33.3%	1 33.3%	4 66.7%	6 100%	4 66.7%	3 100%	6 100%	3 100%	10 76.9%	4 100%	3 75%	6 100%	51 81%
African	1 33.3%	0 0%	1 16.7%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%	0 0%	1 25%	0 0%	4 6.3%
Hispanic	1 33.3%	2 66.7%	1 16.7%	0 0%	1 16.7%	0 0%	0 0%	0 0%	1 7.7%	0 0%	0 0%	0 0%	6 9.5%
East Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 7.7%	0 0%	0 0%	0 0%	1 1.6%
West Asian (Indian sub-continent)	0 0%	0 0%	0 0%	0 0%	1 16.7%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 1.6%
Region of Enrollment (participants) [Number]
United States	3 100%	3 100%	6 100%	6 100%	6 100%	3 100%	6 100%	3 100%	13 100%	4 100%	4 100%	6 100%	63 100%

Outcome Measures

1. Primary Outcome

Title	Recommended Dose and Schedule for Phase 2 Studies
Description	The recommended dose and schedule for Phase 2 studies is defined as the maximum tolerated dose (MTD). MTD is defined as the dose level at which no more than 2 dose limiting toxicities (DLTs), no more than 3 dose reductions (DR) or dose omissions (DO) and no more than 1 DLT plus 2 DR/DO occurred. DLT is defined as an adverse event (AE) occurring in Cycle 1 with the following criteria according to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0: Any ≥Grade 3 nonhematological toxicity (except nausea/vomiting or diarrhea controlled with treatment or fatigue); ≥Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia with bleeding; Grade 4 hematological toxicity of >5 days duration, excluding thrombocytopenia; febrile neutropenia.
Time Frame	Cycle 1 (21 days): Day 1, 5 and 9, any AE reported

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of LY2523355.

Arm/Group Title	LY2523355 / LY2523355 +PEG
Arm/Group Description	Escalating doses starting at 2 milligrams per meter squared per day (mg/m^2/day) LY2523355 administered by intravenous infusion over 1 hour on Days 1, 5, and 9; escalating doses starting at 8 mg/m^2/day LY2523355 administered by intravenous infusion over 1 hour on Days 1 and 8 or Days 1 and 5 plus 6 mg pegfilgrastim (PEG) administered subcutaneously on Day 6; or 12 mg/m^2/day LY2523355 administered by intravenous infusion over 1 hour on Days 1 and 4 plus 6 mg PEG administered subcutaneously on Day 5 of 21-day cycle for 2 planned cycles and any subsequent cycle up to 38 cycles of 21-days. The maximum allowed dose was 30 mg/m^2/day.
Measure Participants	63
Number [mg/m^2/day]	8

2. Secondary Outcome

Title	Number of Participants With Clinically Significant Effects
Description	Clinically significant effects were defined as serious and other non-serious adverse events (AEs). A summary of serious and other non-serious AEs is located in the Reported Adverse Events module.
Time Frame	Baseline to Cycle 38 (21-day cycles): daily for AEs

Outcome Measure Data

Analysis Population Description

All participants who had at least 1 dose of LY2523355.

Arm/Group Title	Part A - Days 1, 5, 9 - 2 mg/m^2/Day	Part A - Days 1, 5, 9 - 4 mg/m^2/Day	Part A - Days 1, 5, 9 - 8 mg/m^2/Day	Part A - Days 1, 5, 9 - 7 mg/m^2/Day	Part A - Days 1, 5, 9 - 6 mg/m^2/Day	Part A - Days 1, 5, 9 - 5 mg/m^2/Day	Part A - Days 1, 8 - 8 mg/m^2/Day	Part A - Days 1, 5+PEG - 8 mg/m2/Day	Part A - Days 1, 5+PEG - 12 mg/m^2/Day	Part A - Days 1, 5+PEG - 16 mg/m^2/Day	Part A - Days 1, 5+PEG - 14 mg/m^2/Day	Part B - Days 1, 5+PEG - 12 mg/m^2/Day	Part B - Days 1, 4+PEG - 12 mg/m^2/d
Arm/Group Description	2 milligrams per meter squared per day (mg/m^2/day) LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	4 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	7 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	6 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	5 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 8 of 21-day cycle.	8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus pegfilgrastim (PEG) administered subcutaneously on Day 6.	12 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.	16 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.	14 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.	12 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.	12 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 4 of 21-day cycle plus PEG administered subcutaneously on Day 5.
Measure Participants	3	3	6	6	6	3	6	3	3	4	4	10	6
Serious AEs	1 33.3%	2 66.7%	2 33.3%	2 33.3%	1 16.7%	0 0%	1 16.7%	0 0%	0 0%	3 75%	2 50%	4 66.7%	4 6.3%
Other Non-Serious AEs	3 100%	2 66.7%	6 100%	6 100%	6 100%	3 100%	6 100%	3 100%	3 23.1%	4 100%	4 100%	10 166.7%	6 9.5%

3. Secondary Outcome

Title	Pharmacokinetics Maximum Concentration (Cmax), Single Dose
Description	Plasma Cmax following a single dose of LY2523355 at each dose level across all schedules and in the presence or absence of pegfilgrastim (PEG).
Time Frame	Cycle 1 Day 1 of 21-day cycle: Predose, 1 hour (hr), 2,4,6,8,24,48 and 72 hr postdose

Outcome Measure Data

Analysis Population Description

All participants who received 1 dose of LY2523355 and had Cmax samples collected on Day 1 of Cycle 1.

Arm/Group Title	2 mg/m^2/Day LY2523355	4 mg/m^2/Day LY2523355	5 mg/m^2/Day LY2523355	6 mg/m^2/Day LY2523355	7 mg/m^2/Day LY2523355	8 mg/m^2/Day LY2523355	12 mg/m^2/Day LY2523355	14 mg/m^2/Day LY2523355	16 mg/m^2/Day LY2523355
Arm/Group Description	2 milligrams per meter squared per day (mg/m^2/day) LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	4 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	5 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	6 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	7 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion across all schedules and in the presence or absence of PEG administered subcutaneously.	12 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6 and on Days 1 and 4 of 21-day cycle plus PEG administered subcutaneously on Day 5.	14 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.	16 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.
Measure Participants	3	3	3	6	6	15	19	4	4
Geometric Mean (Geometric Coefficient of Variation) [nanograms/milliliter (ng/mL)]	45.2 (25)	126 (31)	137 (81)	196 (40)	218 (26)	192 (32)	379 (10)	598 (32)	463 (43)

4. Secondary Outcome

Title	Pharmacokinetics Maximum Concentration (Cmax), Multiple Dose
Description	Plasma Cmax following multiple doses of LY2523355 at each dose level across all schedules and in the presence or absence of pegfilgrastim (PEG).
Time Frame	Cycle 1 Days 4, 5, 8 or 9 of 21-day cycle:Predose, 1 hour (hr), 2,4,6,8,24,48 and 72 hr postdose

Outcome Measure Data

Analysis Population Description

All participants who received 2 doses of study drug and had a Cmax sample collected on Days 4, 5, 8 or 9 of Cycle 1 (based on schedule of administration) after multiple dose administration of LY2523355.

Arm/Group Title	2 mg/m^2/Day LY2523355	4 mg/m^2/Day LY2523355	5 mg/m^2/Day LY2523355	6 mg/m^2/Day LY2523355	7 mg/m^2/Day LY2523355	8 mg/m^2/Day LY2523355	12 mg/m^2/Day LY2523355	14 mg/m^2/Day LY2523355	16 mg/m^2/Day LY2523355
Arm/Group Description	2 milligrams per meter squared per day (mg/m^2/day) LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	4 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	5 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	6 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	7 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion across all schedules and in the presence or absence of PEG administered subcutaneously.	12 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6 and on Days 1 and 4 of 21-day cycle plus PEG administered subcutaneously on Day 5.	14 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.	16 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.
Measure Participants	3	3	3	6	4	11	19	4	4
Geometric Mean (Geometric Coefficient of Variation) [nanograms/milliliter (ng/mL)]	49.1 (15)	121 (58)	196 (43)	124 (40)	200 (69)	186 (42)	367 (35)	415 (46)	485 (45)

5. Secondary Outcome

Title	Pharmacokinetics Area Under the Concentration-time Curve (AUC), Single Dose
Description	Plasma AUC from time zero to infinity [AUC(0-∞)] and AUC from time zero to 24 hours post-dose [AUC(0-24)] following a single dose of LY2523355 at each dose level across all schedules and in the presence or absence of pegfilgrastim (PEG).
Time Frame	Cycle 1 Days 4, 5, 8 or 9 of 21-day cycle:Predose, 1 hour (hr), 2,4,6,8,24,48 and 72 hr postdose

Outcome Measure Data

Analysis Population Description

All participants who received 1 dose of LY2523355 and had pharmacokinetic samples collected on Day 1 of Cycle 1 to enable calculation of AUC(0-∞) and AUC(0-24).

Arm/Group Title	2 mg/m^2/Day LY2523355	4 mg/m^2/Day LY2523355	5 mg/m^2/Day LY25233552	6 mg/m^2/Day LY2523355	7 mg/m^2/Day LY2523355	8 mg/m^2/Day LY2523355	12 mg/m^2/Day LY2523355	14 mg/m^2/Day LY2523355	16 mg/m^2/Day LY2523355
Arm/Group Description	2 milligrams per meter squared per day (mg/m^2/day) LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	4 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	5 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	6 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	7 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion across all schedules and in the presence or absence of PEG administered subcutaneously.	12 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6 and on Days 1 and 4 of 21-day cycle plus PEG administered subcutaneously on Day 5.	14 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.	16 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.
Measure Participants	3	3	3	6	6	15	19	4	4
AUC(0-∞)	158 (55)	517 (71)	584 (70)	648 (45)	758 (32)	669 (28)	1400 (41)	2050 (23)	1900 (28)
AUC(0-24)	106 (47)	351 (63)	366 (57)	507 (30)	566 (32)	513 (27)	1040 (37)	1620 (24)	1400 (26)

6. Secondary Outcome

Title	Pharmacokinetic Areas Under the Concentration Time Curve (AUC), Multiple Dose
Description	Plasma AUC from time zero to infinity (0-∞) and AUC from time zero to 24 hours (0-24) post-dose following multiple doses of LY2523355 at each dose level across all schedules and in the presence or absence of pegfilgrastim (PEG).
Time Frame	Cycle 1 Days 4, 5, 8 or 9 of 21-day cycle:Predose, 1 hour (hr), 2,4,6,8,24,48 and 72 hr postdose

Outcome Measure Data

Analysis Population Description

All participants who received 2 doses of study drug and had pharmacokinetic samples collected on Day 4, 5, 8, or 9 of Cycle 1 (based on schedule of administration) to enable calculation of AUC(0-∞) and AUC(0-24) after multiple dose administration of LY2523355.

Arm/Group Title	2 mg/m^2/Day LY2523355	4 mg/m^2/Day LY2523355	5 mg/m^2/Day LY2523355	6 mg/m^2/Day LY2523355	7 mg/m^2/Day LY2523355	8 mg/m^2/Day LY2523355	12 mg/m^2/Day LY2523355	14 mg/m^2/Day LY2523355	16 mg/m^2/Day LY2523355
Arm/Group Description	2 milligrams per meter squared per day (mg/m^2/day) LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	4 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	5 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	6 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	7 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.	8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion across all schedules and in the presence or absence of PEG administered subcutaneously.	12 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6 and on Days 1 and 4 of 21-day cycle plus PEG administered subcutaneously on Day 5.	14 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.	16 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.
Measure Participants	3	3	3	6	4	11	19	4	4
AUC(0-∞)	172 (34)	377 (73)	718 (52)	356 (43)	717 (66)	575 (38)	1340 (49)	1280 (43)	1510 (36)
AUC(0-24)	130 (27)	308 (77)	508 (34)	298 (37)	562 (66)	452 (37)	956 (40)	1110 (46)	1230 (26)

7. Secondary Outcome

Title	Number of Participants With Tumor Response
Description	Response was assessed using Response Evaluation Criteria In Solid Tumors (RECIST) criteria and the Revised International Working Group (IWG) lymphoma response criteria for lymphoma patients. Complete Response (CR) was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter (mm) and normalization of tumor marker level of non-target lesions; Partial Response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD) was defined as at least 20% increase in sum of longest diameter of target lesions and minimum 5 mm increase over nadir. Tumor response is CR + PR.
Time Frame	Baseline to measured disease progression or discontinuation up to Cycle 38 (21-day cycles)

Outcome Measure Data

Analysis Population Description

All participants who received 1 dose of LY2523355.

Arm/Group Title	LY2523355 Days 1, 5 and 9	LY2523355 Days 1 and 8	LY2523355 Days 1 and 5 + PEG	LY2523355 Days 1 and 4 + PEG
Arm/Group Description	Escalating dose started at 2 milligrams per meter squared (mg/m^2) LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5 and 9, for two planned cycles of 21 days. Dose could be escalated by a maximum increment of the lesser of doubling the current dose or 4 milligrams per meter squared per day (mg/m^2/day), with a maximum allowed dose of 30 mg/m^2/day. Participants continued on study drug until disease progression, unacceptable toxicity or other withdrawal criterion were met up to 38 cycles of 21 days.	Escalating dose started at 8 mg/m^2 of LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 8 for two planned 21-day cycles. Dose could be escalated by a maximum of 4 mg/m^2/day, with a maximum allowed dose of 30 mg/m^2/day. Participants continued on study drug until disease progression, unacceptable toxicity or other withdrawal criterion were met up to 38 cycles of 21-days.	Escalating dose started at 8 mg/m^2 LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5, for two planned cycles of 21-days and 6 mg pegfilgrastim (PEG) administered subcutaneously on Day 6 of each 21-day cycle for the 2 planned cycles and for any subsequent cycles of LY2523355 received. Dose could be escalated by a maximum of 4 mg/m^2/day, with a maximum allowed dose of 30 mg/m^2/day. Participants continued on study drug until disease progression, unacceptable toxicity or other withdrawal criterion were met up to 38 cycles of 21-days.	12 mg/m^2 LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 4, for two planned 21 days cycles, 6 mg PEG administered subcutaneously on Day 5 of each 21-day cycle for the 2 planned cycles and for any subsequent cycles of LY2523355 received. Participants continued on study drug until disease progression, unacceptable toxicity or other withdrawal criterion were met up to 38 cycles of 21-days.
Measure Participants	27	6	24	6
Number (90% Confidence Interval) [participants]	0 0%	0 0%	0 0%	0 0%

Adverse Events

Arm/Group Title	Part A - Days 1, 5, 9 - 2 mg/m^2/Day		Part A - Days 1, 5, 9 - 4 mg/m^2/Day		Part A - Days 1, 5, 9 - 8 mg/m^2/Day		Part A - Days 1, 5, 9 - 7 mg/m^2/Day		Part A - Days 1, 5, 9 - 6 mg/m^2/Day		Part A - Days 1, 5, 9 - 5 mg/m^2/Day		Part A - Days 1, 8 - 8 mg/m^2/Day		Part A - Days 1, 5+PEG - 8 mg/m^2/Day		Part A - Days 1, 5+PEG - 12 mg/m^2/Day		Part A - Days 1, 5+PEG - 16 mg/m^2/Day		Part A - Days 1, 5+PEG - 14 mg/m^2/Day		Part B - Days 1, 5+PEG - 12 mg/m^2/Day		Part B - Days 1, 4+PEG - 12 mg/m^2/d
Arm/Group Description	Part A (Dose Escalation Phase): 2 milligrams per meter squared per day (mg/m^2/day) LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.		Part A (Dose Escalation Phase): 4 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.		Part A (Dose Escalation Phase): 8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.		Part A (Dose Escalation Phase): 7 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.		Part A (Dose Escalation Phase): 6 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.		Part A (Dose Escalation Phase): 5 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1, 5, and 9 of 21-day cycle.		Part A (Dose Escalation Phase): 8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 8 of 21-day cycle.		Part A (Dose Escalation Phase): 8 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus pegfilgrastim (PEG) administered subcutaneously on Day 6.		Part A (Dose Escalation Phase): 12 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.		Part A (Dose Escalation Phase): 16 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.		Part A (Dose Escalation Phase): 14 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.		Part B (Dose Maintenance Phase): 12 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 5 of 21-day cycle plus PEG administered subcutaneously on Day 6.		Part B (Dose Maintenance Phase): 12 mg/m^2/day LY2523355 administered intravenously as a 1-hour infusion on Days 1 and 4 of 21-day cycle plus PEG administered subcutaneously Day 5.
All Cause Mortality
	Part A - Days 1, 5, 9 - 2 mg/m^2/Day		Part A - Days 1, 5, 9 - 4 mg/m^2/Day		Part A - Days 1, 5, 9 - 8 mg/m^2/Day		Part A - Days 1, 5, 9 - 7 mg/m^2/Day		Part A - Days 1, 5, 9 - 6 mg/m^2/Day		Part A - Days 1, 5, 9 - 5 mg/m^2/Day		Part A - Days 1, 8 - 8 mg/m^2/Day		Part A - Days 1, 5+PEG - 8 mg/m^2/Day		Part A - Days 1, 5+PEG - 12 mg/m^2/Day		Part A - Days 1, 5+PEG - 16 mg/m^2/Day		Part A - Days 1, 5+PEG - 14 mg/m^2/Day		Part B - Days 1, 5+PEG - 12 mg/m^2/Day		Part B - Days 1, 4+PEG - 12 mg/m^2/d
	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	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Part A - Days 1, 5, 9 - 2 mg/m^2/Day		Part A - Days 1, 5, 9 - 4 mg/m^2/Day		Part A - Days 1, 5, 9 - 8 mg/m^2/Day		Part A - Days 1, 5, 9 - 7 mg/m^2/Day		Part A - Days 1, 5, 9 - 6 mg/m^2/Day		Part A - Days 1, 5, 9 - 5 mg/m^2/Day		Part A - Days 1, 8 - 8 mg/m^2/Day		Part A - Days 1, 5+PEG - 8 mg/m^2/Day		Part A - Days 1, 5+PEG - 12 mg/m^2/Day		Part A - Days 1, 5+PEG - 16 mg/m^2/Day		Part A - Days 1, 5+PEG - 14 mg/m^2/Day		Part B - Days 1, 5+PEG - 12 mg/m^2/Day		Part B - Days 1, 4+PEG - 12 mg/m^2/d
	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	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		2/3 (66.7%)		2/6 (33.3%)		2/6 (33.3%)		1/6 (16.7%)		0/3 (0%)		1/6 (16.7%)		0/3 (0%)		0/3 (0%)		3/4 (75%)		2/4 (50%)		4/10 (40%)		4/6 (66.7%)
Blood and lymphatic system disorders
Febrile neutropenia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	1/10 (10%)	1	1/6 (16.7%)	1
Neutropenia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	1/10 (10%)	1	0/6 (0%)	0
Thrombocytopenia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Diarrhoea	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Gastrointestinal haemorrhage	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Nausea	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Pancreatitis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Proctitis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Small intestinal obstruction	0/3 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Vomiting	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
General disorders
Asthenia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Mucosal inflammation	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Oedema	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Pyrexia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Infections and infestations
Neutropenic sepsis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Perirectal abscess	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Pneumonia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	1/6 (16.7%)	1
Sepsis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Metabolism and nutrition disorders
Dehydration	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Nervous system disorders
Cerebrovascular accident	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Psychiatric disorders
Mental status changes	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	2/6 (33.3%)	2	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Pulmonary embolism	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Skin and subcutaneous tissue disorders
Angioedema	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Vascular disorders
Deep vein thrombosis	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Other (Not Including Serious) Adverse Events
	Part A - Days 1, 5, 9 - 2 mg/m^2/Day		Part A - Days 1, 5, 9 - 4 mg/m^2/Day		Part A - Days 1, 5, 9 - 8 mg/m^2/Day		Part A - Days 1, 5, 9 - 7 mg/m^2/Day		Part A - Days 1, 5, 9 - 6 mg/m^2/Day		Part A - Days 1, 5, 9 - 5 mg/m^2/Day		Part A - Days 1, 8 - 8 mg/m^2/Day		Part A - Days 1, 5+PEG - 8 mg/m^2/Day		Part A - Days 1, 5+PEG - 12 mg/m^2/Day		Part A - Days 1, 5+PEG - 16 mg/m^2/Day		Part A - Days 1, 5+PEG - 14 mg/m^2/Day		Part B - Days 1, 5+PEG - 12 mg/m^2/Day		Part B - Days 1, 4+PEG - 12 mg/m^2/d
	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	Affected / at Risk (%)	# Events
Total	3/3 (100%)		2/3 (66.7%)		6/6 (100%)		6/6 (100%)		6/6 (100%)		3/3 (100%)		6/6 (100%)		3/3 (100%)		3/3 (100%)		4/4 (100%)		4/4 (100%)		10/10 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Anaemia	0/3 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	1/6 (16.7%)	1	2/6 (33.3%)	2	0/3 (0%)	0	0/6 (0%)	0	2/3 (66.7%)	2	2/3 (66.7%)	2	1/4 (25%)	1	1/4 (25%)	1	4/10 (40%)	4	3/6 (50%)	3
Febrile neutropenia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Leukopenia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Neutropenia	0/3 (0%)	0	0/3 (0%)	0	3/6 (50%)	3	4/6 (66.7%)	4	5/6 (83.3%)	5	2/3 (66.7%)	2	5/6 (83.3%)	5	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	1/4 (25%)	1	1/10 (10%)	1	3/6 (50%)	3
Thrombocytopenia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/4 (25%)	1	0/10 (0%)	0	2/6 (33.3%)	2
Cardiac disorders
Tachycardia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Ear and labyrinth disorders
Ear pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Tinnitus	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Eye disorders
Blindness	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Dry eye	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Vision blurred	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Visual impairment	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	1/6 (16.7%)	1
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	1/10 (10%)	1	1/6 (16.7%)	1
Anorectal discomfort	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Aphthous stomatitis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Constipation	1/3 (33.3%)	1	0/3 (0%)	0	3/6 (50%)	3	2/6 (33.3%)	2	4/6 (66.7%)	4	1/3 (33.3%)	1	2/6 (33.3%)	2	0/3 (0%)	0	1/3 (33.3%)	1	2/4 (50%)	2	0/4 (0%)	0	1/10 (10%)	1	3/6 (50%)	3
Diarrhoea	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	3/6 (50%)	3	1/3 (33.3%)	1	2/3 (66.7%)	2	1/4 (25%)	1	0/4 (0%)	0	3/10 (30%)	3	2/6 (33.3%)	2
Dry mouth	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Dyspepsia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Dysphagia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/4 (25%)	1	2/10 (20%)	2	0/6 (0%)	0
Haematochezia	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Haemorrhoids	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Lip swelling	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Mucous stools	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Nausea	1/3 (33.3%)	1	1/3 (33.3%)	1	1/6 (16.7%)	1	2/6 (33.3%)	2	2/6 (33.3%)	2	1/3 (33.3%)	1	3/6 (50%)	3	0/3 (0%)	0	2/3 (66.7%)	2	1/4 (25%)	1	1/4 (25%)	1	3/10 (30%)	3	3/6 (50%)	3
Oesophagitis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Oral pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	1/10 (10%)	1	0/6 (0%)	0
Proctalgia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Stomatitis	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	2/10 (20%)	2	0/6 (0%)	0
Swollen tongue	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Vomiting	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	2/6 (33.3%)	2	3/6 (50%)	3	1/3 (33.3%)	1	2/6 (33.3%)	2	1/3 (33.3%)	1	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	3/10 (30%)	3	3/6 (50%)	3
General disorders
Asthenia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/4 (25%)	1	1/4 (25%)	1	2/10 (20%)	2	1/6 (16.7%)	1
Catheter site pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Chest pain	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Chills	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1	0/3 (0%)	0	1/4 (25%)	1	1/4 (25%)	1	0/10 (0%)	0	1/6 (16.7%)	1
Early satiety	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Face oedema	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Facial pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Fatigue	1/3 (33.3%)	1	1/3 (33.3%)	1	4/6 (66.7%)	4	1/6 (16.7%)	1	3/6 (50%)	3	3/3 (100%)	3	5/6 (83.3%)	5	0/3 (0%)	0	2/3 (66.7%)	2	2/4 (50%)	2	1/4 (25%)	1	7/10 (70%)	7	2/6 (33.3%)	2
Feeling cold	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Gait disturbance	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	1/6 (16.7%)	1
Injection site pruritus	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Mucosal inflammation	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	0/3 (0%)	0	1/3 (33.3%)	1	2/4 (50%)	2	0/4 (0%)	0	4/10 (40%)	4	1/6 (16.7%)	1
Oedema	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	1/6 (16.7%)	1
Oedema peripheral	1/3 (33.3%)	1	0/3 (0%)	0	2/6 (33.3%)	2	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/3 (66.7%)	2	0/4 (0%)	0	1/4 (25%)	1	1/10 (10%)	1	0/6 (0%)	0
Pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	3/10 (30%)	3	0/6 (0%)	0
Pyrexia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	2/6 (33.3%)	2	1/6 (16.7%)	1	1/3 (33.3%)	1	1/6 (16.7%)	1	1/3 (33.3%)	1	2/3 (66.7%)	2	1/4 (25%)	1	0/4 (0%)	0	4/10 (40%)	4	2/6 (33.3%)	2
Temperature intolerance	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Ulcer	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Hepatobiliary disorders
Cholelithiasis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Immune system disorders
Hypersensitivity	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Infections and infestations
Bronchitis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Candidiasis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Central line infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Diverticulitis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Fungal infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Fungal skin infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Genital infection fungal	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Onychomycosis	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Pharyngitis streptococcal	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Pneumonia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Post procedural infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Respiratory tract infection	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Rhinitis	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Upper respiratory tract infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Urinary tract infection	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Viral infection	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Injury, poisoning and procedural complications
Fall	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Thermal burn	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Investigations
Blood bilirubin increased	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Blood cortisol increased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Blood creatinine increased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Blood glucose decreased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Blood iron decreased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Blood potassium decreased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Blood potassium increased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Calcium ionised decreased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Electrocardiogram qt prolonged	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Neutrophil count decreased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Prothrombin time ratio increased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Urine output decreased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Weight decreased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	2/10 (20%)	2	0/6 (0%)	0
White blood cell count increased	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Metabolism and nutrition disorders
Anorexia	0/3 (0%)	0	1/3 (33.3%)	1	2/6 (33.3%)	2	1/6 (16.7%)	1	1/6 (16.7%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	2/4 (50%)	2	1/4 (25%)	1	2/10 (20%)	2	0/6 (0%)	0
Decreased appetite	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/6 (33.3%)	2	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	2/10 (20%)	2	0/6 (0%)	0
Dehydration	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/4 (0%)	0	1/10 (10%)	1	3/6 (50%)	3
Gout	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Hyperglycaemia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Hyperkalaemia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Hypokalaemia	0/3 (0%)	0	0/3 (0%)	0	3/6 (50%)	3	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Hypomagnesaemia	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	2/6 (33.3%)	2	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	2/10 (20%)	2	1/6 (16.7%)	1
Back pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	2/4 (50%)	2	1/10 (10%)	1	1/6 (16.7%)	1
Bone pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Flank pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Limb discomfort	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Muscle spasms	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Muscular weakness	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Musculoskeletal pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Musculoskeletal stiffness	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Myalgia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	1/10 (10%)	1	0/6 (0%)	0
Neck pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Pain in extremity	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Pathological fracture	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Tumour pain	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	1/6 (16.7%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	2/4 (50%)	2	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Nervous system disorders
Ataxia	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Dizziness	1/3 (33.3%)	1	0/3 (0%)	0	2/6 (33.3%)	2	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	2/10 (20%)	2	0/6 (0%)	0
Drooling	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Dysarthria	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Dysgeusia	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Headache	2/3 (66.7%)	2	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	3/10 (30%)	3	1/6 (16.7%)	1
Hyperaesthesia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Hypoaesthesia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Lethargy	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Neuralgia	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Neuropathy peripheral	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Syncope	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Psychiatric disorders
Anxiety	0/3 (0%)	0	0/3 (0%)	0	2/6 (33.3%)	2	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	2/10 (20%)	2	0/6 (0%)	0
Confusional state	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/3 (66.7%)	2	0/6 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Depression	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Hallucination	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Insomnia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1	1/3 (33.3%)	1	0/6 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/4 (25%)	1	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Mental status changes	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Sleep talking	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Renal and urinary disorders
Dysuria	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Micturition urgency	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Renal failure chronic	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Urinary hesitation	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Urine odour abnormal	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Reproductive system and breast disorders
Pelvic pain	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Penile oedema	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/0 (NaN)	0	1/4 (25%)	1	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/1 (0%)	0	0/7 (0%)	0	0/4 (0%)	0
Scrotal oedema	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/0 (NaN)	0	1/4 (25%)	1	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/1 (0%)	0	0/7 (0%)	0	0/4 (0%)	0
Testicular swelling	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/5 (0%)	0	0/2 (0%)	0	0/0 (NaN)	0	0/4 (0%)	0	0/1 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/1 (0%)	0	1/7 (14.3%)	1	0/4 (0%)	0
Vulval disorder	0/2 (0%)	0	0/1 (0%)	0	0/4 (0%)	0	0/1 (0%)	0	1/4 (25%)	1	0/3 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/1 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0
Vulvovaginal pruritus	0/2 (0%)	0	0/1 (0%)	0	1/4 (25%)	1	0/1 (0%)	0	0/4 (0%)	0	0/3 (0%)	0	0/2 (0%)	0	0/2 (0%)	0	0/1 (0%)	0	0/2 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/2 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	2/3 (66.7%)	2	0/3 (0%)	0	1/6 (16.7%)	1	2/6 (33.3%)	2	1/6 (16.7%)	1	0/3 (0%)	0	1/6 (16.7%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	0/4 (0%)	0	1/4 (25%)	1	1/10 (10%)	1	1/6 (16.7%)	1
Dysphonia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Dyspnoea	1/3 (33.3%)	1	1/3 (33.3%)	1	2/6 (33.3%)	2	1/6 (16.7%)	1	1/6 (16.7%)	1	1/3 (33.3%)	1	1/6 (16.7%)	1	1/3 (33.3%)	1	1/3 (33.3%)	1	1/4 (25%)	1	1/4 (25%)	1	0/10 (0%)	0	1/6 (16.7%)	1
Dyspnoea exertional	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Haemoptysis	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Hypoxia	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Oropharyngeal pain	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Paranasal sinus hypersecretion	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Pharyngeal oedema	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Pleural effusion	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	1/6 (16.7%)	1
Productive cough	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Pulmonary embolism	0/3 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Respiratory distress	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Respiratory tract congestion	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Rhinorrhoea	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Sinus congestion	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	1/6 (16.7%)	1
Throat irritation	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Dry skin	0/3 (0%)	0	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Erythema	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Nail disorder	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	0/6 (0%)	0
Night sweats	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/4 (0%)	0	2/10 (20%)	2	1/6 (16.7%)	1
Pain of skin	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Palmar-plantar erythrodysaesthesia syndrome	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Periorbital oedema	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Pruritus	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	2/3 (66.7%)	2	1/4 (25%)	1	1/4 (25%)	1	2/10 (20%)	2	0/6 (0%)	0
Rash	2/3 (66.7%)	2	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	2/3 (66.7%)	2	2/4 (50%)	2	1/4 (25%)	1	2/10 (20%)	2	0/6 (0%)	0
Rash erythematous	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Rash maculo-papular	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Rash pruritic	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	0/6 (0%)	0
Skin exfoliation	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	1/10 (10%)	1	1/6 (16.7%)	1
Skin hyperpigmentation	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Skin irritation	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Urticaria	1/3 (33.3%)	1	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Vascular disorders
Hypertension	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	1/6 (16.7%)	1	0/3 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/4 (0%)	0	0/10 (0%)	0	0/6 (0%)	0
Hypotension	0/3 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/6 (0%)	0	0/3 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/4 (25%)	1	0/10 (0%)	0	1/6 (16.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.