Study of IMC-1121B in Patients With Advanced Solid Tumors

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01005355
• Collaborator: Parexel (Industry)
• Enrollment: 15
• Location: 1
• Arm: 1
• Duration (Months): 17
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This trial is testing the investigational drug IMC-1121B administered to Japanese participants with advanced solid tumors who have not responded to standard therapy or for whom no standard therapy is available. The rationale for performing this trial is to establish the safety profile and the pharmacokinetics of IMC-1121B.

Condition or Disease	Intervention/Treatment	Phase
Advanced Solid Tumors	Biological: IMC-1121B	Phase 1

Detailed Description

This single center, open-label, single-arm, Phase 1 study will enroll approximately 15 to 18 participants. The actual size will vary depending on the dose-limiting toxicities (DLTs) observed and the resultant sizes of the cohorts. Participants will receive IMC-1121B, administered intravenously, once every 2 or 3 weeks for 6 weeks (one cycle). After one cycle of treatment, participants who have an objective response or stable disease may continue to receive IMC-1121B at the same dose and schedule until disease progression or other withdrawal criteria are met. A minimum of three participants will be enrolled in each cohort. Dose escalation in successive cohorts will occur once all participants complete one cycle of therapy.

Participants will be enrolled sequentially into each cohort.

A completed participant will be either a participant who completes the initial 6 week treatment period (Cycle 1) or a participant who discontinues therapy for an IMC-1121B related toxicity during Cycle 1. Participants who do not complete the first 6 weeks of treatment for reasons other than an IMC-1121B -related toxicity will be replaced. Toxicity data for each cohort will be reviewed prior to dose escalation. Upon completion of all required safety evaluations during the initial 6 weeks, the next cohort of new participants will be treated at the next higher dose level using a dose escalation scheme.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1 Study of IMC-1121B in Patients With Advanced Solid Tumors
• Study Start Date: Sep 1, 2009
• Actual Primary Completion Date: Feb 1, 2011
• Actual Study Completion Date: Feb 1, 2011

Arms and Interventions

Arm

Intervention/Treatment

Experimental: IMC-1121B Participants receiving IMC-1121B intravenously

Biological: IMC-1121B; Cycle 1: Upon completion of enrollment criteria confirmed at screening, the first dose of study medication should be administered within 7 days. The infusion will be planned every 2 weeks or every 3 weeks on the same day of the week of the first infusion. Dose escalation to Cohort 2 may occur in the absence of a dose-limiting toxicity (DLT) in the first three participants treated in Cohort 1 during the initial 6-week dosing period (Cycle 1). The same procedure will be followed for dose escalation from Cohort 2 to Cohort 3. If 1 of 3 participants in any cohort experiences a DLT in the first 6 weeks (Cycle 1), 3 additional participants will be enrolled in that cohort. Dose escalation to the next cohort may occur if less that 2 of 6 participants experience a DLT during Cycle 1.; Other Names: RAMUCIRUMAB LY3009806

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Drug-Related Adverse Events [Baseline to study completion up to 48 weeks]

   Data presented are the number of participants who experienced adverse events (AE) of any grade, AE of Grade ≥3 based on National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 (NCI-CTCAE v 3.0), serious adverse events (SAE) and AE resulting in death that was considered to be related to IMC-1121B (ramucirumab). A summary of SAEs and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Event module.

2. IMC-1121B Pharmacokinetics: Maximum Serum Concentration (Cmax) - Cohorts 1 and 2 During Cycles 1 and 2 [Day 1 to Day 15 of Cycles 1 and 2 of a 6-week cycle]

3. IMC-1121B Pharmacokinetics: Maximum Serum Concentration (Cmax) - Cohorts 1 and 2 During Cycles 3 to 5 [Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour postdose]

   Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, Cmax could not be calculated.

4. IMC-1121B Pharmacokinetics: Area Under the Concentration (AUC) Versus Time Curve - Cohorts 1 and 2 During Cycles 1 and 2 [Day 1 to Day 15 of Cycles 1 and 2 of a 6-week cycle]

   AUC for Cycle 1 is AUC from time zero to infinity [AUC(0-∞)] and for Cycle 2 is AUC over a dosing interval (AUCτ).

5. IMC-1121B Pharmacokinetics: Area Under the Concentration (AUC) - Cohorts 1 and 2 During Cycles 3 to 5 [Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour postdose]

   Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, AUC could not be calculated.

6. IMC-1121B Pharmacokinetics: Half-Life (t1/2) - Cohorts 1 and 2 During Cycles 1 and 2 [Day 1 to Day 15 of Cycles 1 and 2 of a 6-week cycle]

7. IMC-1121B Pharmacokinetics: Half-Life (t 1/2) - Cohorts 1 and 2 During Cycles 3 to 5 [Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour postdose]

   Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, t1/2 could not be calculated.

8. IMC-1121B Pharmacokinetics: Steady State Volume of Distribution (Vss) - Cohorts 1 and 2 During Cycles 1 and 2 [Day 1 to Day 15 of Cycles 1 and 2 of a 6-week cycle]

9. IMC-1121B Pharmacokinetics: Steady State Volume of Distribution (Vss) - Cohorts 1 and 2 During Cycles 3 to 5 [Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour postdose]

   Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, Vss could not be calculated.

10. IMC-1121B Pharmacokinetics: Maximum Serum Concentration (Cmax) - Cohort 3 During Cycles 1 and 2 [Day 1 to Day 22 of Cycles 1 and 2 of a 6-week cycle]

11. IMC-1121B Pharmacokinetics: Maximum Serum Concentration (Cmax) - Cohort 3 During Cycles 3 to 5 [Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour postdose]

    Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, Cmax could not be calculated.

12. IMC-1121B Pharmacokinetics: Area Under the Concentration (AUC) - Cohort 3 During Cycles 1 and 2 [Day 1 to Day 22 of Cycles 1 and 2 of a 6-week cycle]

    AUC for Cycle 1 is AUC from time zero to infinity [AUC(0-∞)] and for Cycle 2 is AUC over a dosing interval (AUCτ).

13. IMC-1121B Pharmacokinetics - Area Under the Concentration (AUC) - Cohort 3 During Cycles 3 to 5 [Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour postdose]

    Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, AUC could not be calculated.

14. IMC-1121B Pharmacokinetics: Half-Life (t1/2) - Cohort 3 During Cycles 1 and 2 [Day 1 to Day 22 of Cycles 1 and 2 of a 6-week cycle]

15. IMC-1121B Pharmacokinetics: Half-Life (t 1/2) - Cohort 3 During Cycles 3 to 5 [Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour postdose]

    Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, t1/2 could not be calculated.

16. IMC-1121B Pharmacokinetics: Steady State Volume of Distribution (Vss) - Cohort 3 During Cycles 1 and 2 [Day 1 and Day 22 of Cycles 1 and 2 of a 6-week cycle]

17. IMC-1121B Pharmacokinetics: Steady State Volume of Distribution (Vss) - Cohort 3 During Cycles 3 to 5 [Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour post-dose]

    Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, Vss could not be calculated.

Secondary Outcome Measures

1. Screen for the Development of Circulating Antibodies Against IMC-1121B (Immunogenicity) [Baseline to study completion up to 48 weeks]

   Data presented are the number of participants with treatment emergent antibody positive.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Solid tumor participant who was been histopathologically or cytologically documented.

• Advanced primary or recurrent solid tumors participant who has not responded to standard therapy or no standard therapy is available.

• The participant has measurable or nonmeasurable lesions according to Response Evaluation Criteria in Solid Tumors (RECIST).

• The participant has an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1 at study entry.

• The participant is able to provide written informed consent.

• The participant is age 20 years or older.

• The participant has a life expectancy of > 3 months.

• The participant has adequate hematologic function, as defined by:

• An absolute neutrophil count (ANC) > 1500/cubic millimeter (mm³) or /microliter (µL)

• A hemoglobin level > 10 grams/deciliter (g/dL)

• A platelet count > 100,000/mm³ or /µL

• The participant has adequate hepatic function, as defined by:

• A total bilirubin level < 1.8 milligrams/deciliter (mg/dL)

• Aspartate transaminase (AST) levels < 86 International Units/liter (IU/L)

• Alanine transaminase (ALT) levels ≤ 86 IU/L

• The participant has adequate renal function, as defined by:

• Serum creatinine level ≤ 1.5 mg/dL, or

• Calculated serum creatinine clearance (Cockcroft-Gault) ≥ 60 milliliters/minute (mL/min)

• The participant's urinary protein is 0 on dipstick or 1+ but participant does not have edema nor serum albumin < lower level of normal (LLN).

• The participant has adequate coagulation function, as defined by international normalized ratio (INR) ≤ 1.5.

• The participant agrees to use adequate contraception during the study period and for 12 weeks after the last dose of study treatment.

Exclusion Criteria:

• The participant has had chemotherapy or therapeutic radiotherapy within 28 days (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or participant has ongoing side effects ≥ Grade 2 due to agents administered more than 28 days earlier.

• The participant has obvious evidence of intratumor cavitation.

• The participant has undergone major surgery (example, laparotomy, thoracotomy, removal of organ[s]) within 28 days prior to study entry, or subcutaneous venous access device placement within 7 days prior to study entry.

• The participant has a history of postoperative bleeding complications or wound complications from a surgical procedure.

• The participant has elective or planned surgery to be conducted during the trial.

• The participant has documented and/or symptomatic brain or leptomeningeal metastases. (Participants who are clinically stable [no symptoms during 4 weeks prior to the enrollment] with an assessment that no further treatment [radiation, surgical excision, and administration of steroids] is required, are permitted to enter the study.)

• The participant has uncontrolled intercurrent illness including, but not limited to:

• Thrombotic or hemorrhagic disorders

• Hemoptysis (approximately one-half of a teaspoon)

• Ongoing or active infection requiring systemic antibiotic treatment

• Congestive heart failure (Class III or IV of the New York Heart Association classification for heart disease)

• Angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months

• Uncontrolled hypertension (systolic blood pressure > 150 millimeters of mercury (mmHg), diastolic blood pressure > 95 mm Hg)

• Cardiac arrhythmia requires treatment [National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 (NCI-CTCAE v 3.0), Grade 3], or asymptomatic sustained ventricular tachycardia)

• Peripheral neuropathy of any etiology ≥ Grade 2 (NCI-CTCAE v 3.0)

• The participant has participated in clinical studies of non-approved experimental agents or procedures within 4 weeks prior to study entry for small molecules, or 8 weeks prior to study entry for non-approved monoclonal antibodies.

• The participant, if female, is pregnant (confirmed by urine or serum pregnancy test) or lactating.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ImClone Investigational Site	Tokyo		Japan	104-0045

Sponsors and Collaborators

• Eli Lilly and Company
• Parexel

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: NCT01005355
• Other Study ID Numbers: 13898; CP12-0816; I4T-IE-JVBI
• First Posted: Oct 30, 2009
• Last Update Posted: Jun 18, 2014
• Last Verified: May 1, 2014

• Keywords provided by Eli Lilly and Company: Solid tumor; recombinant human IgG1; MAB; monoclonal antibody; VEGFR 2; human vascular endothelial growth factor receptor 2
• Additional relevant MeSH terms: Neoplasms; Ramucirumab

Study Results

Participant Flow

Pre-assignment Detail	A participant was considered to have completed the study if he or she completed the initial 6-week treatment period (Cycle 1) or if he or she discontinued therapy because of an IMC-1121B (ramucirumab)-related toxicity during Cycle 1.

Arm/Group Title	IMC-1121B 6 mg/kg (Cohort 1)	IMC-1121B 8 mg/kg (Cohort 2)	IMC-1121B 10 mg/kg (Cohort 3)
Arm/Group Description	6 milligrams/kilogram (mg/kg) IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	8 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	10 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 3 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Period Title: Overall Study
STARTED	3	6	6
Received at Least 1 Dose of Study Drug	3	6	6
COMPLETED	3	6	6
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	IMC-1121B 6 mg/kg (Cohort 1)	IMC-1121B 8 mg/kg (Cohort 2)	IMC-1121B 10 mg/kg (Cohort 3)	Total
Arm/Group Description	6 milligrams/kilogram (mg/kg) IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	8 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	10 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 3 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	Total of all reporting groups
Overall Participants	3	6	6	15
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	3 100%	6 100%	4 66.7%	13 86.7%
>=65 years	0 0%	0 0%	2 33.3%	2 13.3%
Sex: Female, Male (Count of Participants)
Female	1 33.3%	5 83.3%	3 50%	9 60%
Male	2 66.7%	1 16.7%	3 50%	6 40%
Race/Ethnicity, Customized (participants) [Number]
Asian	3 100%	6 100%	6 100%	15 100%
Region of Enrollment (participants) [Number]
Japan	3 100%	6 100%	6 100%	15 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Drug-Related Adverse Events
Description	Data presented are the number of participants who experienced adverse events (AE) of any grade, AE of Grade ≥3 based on National Cancer Institute Common Terminology Criteria for Adverse Events, Version 3.0 (NCI-CTCAE v 3.0), serious adverse events (SAE) and AE resulting in death that was considered to be related to IMC-1121B (ramucirumab). A summary of SAEs and all other non-serious AEs, regardless of causality, is located in the Reported Adverse Event module.
Time Frame	Baseline to study completion up to 48 weeks

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug.

Arm/Group Title	IMC-1121B 6 mg/kg (Cohort 1)	IMC-1121B 8 mg/kg (Cohort 2)	IMC-1121B 10 mg/kg (Cohort 3)
Arm/Group Description	6 milligrams/kilogram (mg/kg) IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	8 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	10 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 3 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	3	6	6
AE of any grade	3 100%	6 100%	6 100%
AE of Grade ≥3	0 0%	0 0%	1 16.7%
SAE	0 0%	0 0%	1 16.7%
AE resulting in death	0 0%	0 0%	0 0%

2. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Maximum Serum Concentration (Cmax) - Cohorts 1 and 2 During Cycles 1 and 2
Time Frame	Day 1 to Day 15 of Cycles 1 and 2 of a 6-week cycle

Outcome Measure Data

Analysis Population Description

All participants in Cohorts 1 and 2 who received study drug and had sufficient pharmacokinetics data to calculate Cmax for Cycles 1 and 2.

Arm/Group Title	IMC-1121B 6 mg/kg (Cohort 1)	IMC-1121B 8 mg/kg (Cohort 2)
Arm/Group Description	6 milligrams/kilogram (mg/kg) IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	8 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	3	6
Cycle 1	284 (63.7)	371 (113)
Cycle 2 (n=1, 2)	352 (NA)	694 (123)

3. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Maximum Serum Concentration (Cmax) - Cohorts 1 and 2 During Cycles 3 to 5
Description	Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, Cmax could not be calculated.
Time Frame	Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour postdose

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5.

Arm/Group Title	IMC-1121B 6 mg/kg (Cohort 1)	IMC-1121B 8 mg/kg (Cohort 2)
Arm/Group Description	6 milligrams/kilogram (mg/kg) IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	8 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	0	0

4. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Area Under the Concentration (AUC) Versus Time Curve - Cohorts 1 and 2 During Cycles 1 and 2
Description	AUC for Cycle 1 is AUC from time zero to infinity [AUC(0-∞)] and for Cycle 2 is AUC over a dosing interval (AUCτ).
Time Frame	Day 1 to Day 15 of Cycles 1 and 2 of a 6-week cycle

Outcome Measure Data

Analysis Population Description

All participants in Cohorts 1 and 2 who received study drug and had sufficient pharmacokinetics data to calculate AUC(0-∞) for Cycle 1 and AUCτ for Cycle 2.

Arm/Group Title	IMC-1121B 6 mg/kg (Cohort 1)	IMC-1121B 8 mg/kg (Cohort 2)
Arm/Group Description	6 milligrams/kilogram (mg/kg) IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	8 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	1	2
Cycle 1 - AUC(0-∞) (n=1, 1)	36900 (NA)	73800 (NA)
Cycle 2 - AUCτ (n=1, 2)	56400 (NA)	102000 (10400)

5. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Area Under the Concentration (AUC) - Cohorts 1 and 2 During Cycles 3 to 5
Description	Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, AUC could not be calculated.
Time Frame	Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour postdose

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5.

Arm/Group Title	IMC-1121B 6 mg/kg (Cohort 1)	IMC-1121B 8 mg/kg (Cohort 2)
Arm/Group Description	6 milligrams/kilogram (mg/kg) IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	8 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	0	0

6. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Half-Life (t1/2) - Cohorts 1 and 2 During Cycles 1 and 2
Time Frame	Day 1 to Day 15 of Cycles 1 and 2 of a 6-week cycle

Outcome Measure Data

Analysis Population Description

All participants in Cohorts 1 and 2 who received study drug and had sufficient pharmacokinetics data to calculate t1/2 for Cycles 1 and 2.

Arm/Group Title	IMC-1121B 6 mg/kg (Cohort 1)	IMC-1121B 8 mg/kg (Cohort 2)
Arm/Group Description	6 milligrams/kilogram (mg/kg) IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	8 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	3	2
Cycle 1	158 (NA)	165 (NA)
Cycle 2 (n=0, 0)	NA (NA)	NA (NA)

7. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Half-Life (t 1/2) - Cohorts 1 and 2 During Cycles 3 to 5
Description	Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, t1/2 could not be calculated.
Time Frame	Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour postdose

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5.

Arm/Group Title	IMC-1121B 6 mg/kg (Cohort 1)	IMC-1121B 8 mg/kg (Cohort 2)
Arm/Group Description	6 milligrams/kilogram (mg/kg) IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	8 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	0	0

8. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Steady State Volume of Distribution (Vss) - Cohorts 1 and 2 During Cycles 1 and 2
Time Frame	Day 1 to Day 15 of Cycles 1 and 2 of a 6-week cycle

Outcome Measure Data

Analysis Population Description

All participants in Cohorts 1 and 2 who received study drug and had sufficient pharmacokinetics data to calculate Vss for Cycle 1. Vss is not calculated for multiple doses, therefore zero participants were analyzed for Cycle 2.

Arm/Group Title	IMC-1121B 6 mg/kg (Cohort 1)	IMC-1121B 8 mg/kg (Cohort 2)
Arm/Group Description	6 milligrams/kilogram (mg/kg) IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	8 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	1	1
Cycle 1	25.0 (NA)	21.4 (NA)
Cycle 2 (n=0, 0)	NA (NA)	NA (NA)

9. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Steady State Volume of Distribution (Vss) - Cohorts 1 and 2 During Cycles 3 to 5
Description	Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, Vss could not be calculated.
Time Frame	Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour postdose

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5.

Arm/Group Title	IMC-1121B 6 mg/kg (Cohort 1)	IMC-1121B 8 mg/kg (Cohort 2)
Arm/Group Description	6 milligrams/kilogram (mg/kg) IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	8 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	0	0

10. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Maximum Serum Concentration (Cmax) - Cohort 3 During Cycles 1 and 2
Time Frame	Day 1 to Day 22 of Cycles 1 and 2 of a 6-week cycle

Outcome Measure Data

Analysis Population Description

All participants in Cohort 3 who received study drug and had sufficient pharmacokinetics data to calculate Cmax for Cycles 1 and 2.

Arm/Group Title	IMC-1121B 10 mg/kg (Cohort 3)
Arm/Group Description	10 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 3 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	6
Cycle 1	493 (122)
Cycle 2 (n=2)	793 (367)

11. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Maximum Serum Concentration (Cmax) - Cohort 3 During Cycles 3 to 5
Description	Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, Cmax could not be calculated.
Time Frame	Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour postdose

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5.

Arm/Group Title	IMC-1121B 10 mg/kg (Cohort 3)
Arm/Group Description	10 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 3 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	0

12. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Area Under the Concentration (AUC) - Cohort 3 During Cycles 1 and 2
Description	AUC for Cycle 1 is AUC from time zero to infinity [AUC(0-∞)] and for Cycle 2 is AUC over a dosing interval (AUCτ).
Time Frame	Day 1 to Day 22 of Cycles 1 and 2 of a 6-week cycle

Outcome Measure Data

Analysis Population Description

All participants in Cohort 3 who received study drug and had sufficient pharmacokinetics data to calculate AUC(0-∞) for Cycle 1 and AUCτ for Cycle 2.

Arm/Group Title	IMC-1121B 10 mg/kg (Cohort 3)
Arm/Group Description	10 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 3 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	2
Cycle 1 - AUC(0-∞)	61600 (17100)
Cycle 2 - AUCτ	103000 (26200)

13. Primary Outcome

Title	IMC-1121B Pharmacokinetics - Area Under the Concentration (AUC) - Cohort 3 During Cycles 3 to 5
Description	Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, AUC could not be calculated.
Time Frame	Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour postdose

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5.

Arm/Group Title	IMC-1121B 10 mg/kg (Cohort 3)
Arm/Group Description	10 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 3 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	0

14. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Half-Life (t1/2) - Cohort 3 During Cycles 1 and 2
Time Frame	Day 1 to Day 22 of Cycles 1 and 2 of a 6-week cycle

Outcome Measure Data

Analysis Population Description

All participants in Cohort 3 who received study drug and had sufficient pharmacokinetics data to calculate t1/2 for Cycles 1 and 2.

Arm/Group Title	IMC-1121B 10 mg/kg (Cohort 3)
Arm/Group Description	10 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	3
Cycle 1	234 (NA)
Cycle 2 (n=1)	329 (NA)

15. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Half-Life (t 1/2) - Cohort 3 During Cycles 3 to 5
Description	Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, t1/2 could not be calculated.
Time Frame	Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour postdose

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5.

Arm/Group Title	IMC-1121B 10 mg/kg (Cohort 3)
Arm/Group Description	10 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 3 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	0

16. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Steady State Volume of Distribution (Vss) - Cohort 3 During Cycles 1 and 2
Time Frame	Day 1 and Day 22 of Cycles 1 and 2 of a 6-week cycle

Outcome Measure Data

Analysis Population Description

All participants in Cohort 3 who received study drug and had sufficient pharmacokinetics data to calculate Vss for Cycle 1. Vss is not calculated for multiple doses, therefore zero participants were analyzed for Cycle 2.

Arm/Group Title	IMC-1121B 10 mg/kg (Cohort 3)
Arm/Group Description	10 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	2
Cycle 1	40.7 (1.22)
Cycle 2 (n=0)	NA (NA)

17. Primary Outcome

Title	IMC-1121B Pharmacokinetics: Steady State Volume of Distribution (Vss) - Cohort 3 During Cycles 3 to 5
Description	Due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5, Vss could not be calculated.
Time Frame	Cycles 3, 4 and 5 of a 6-week cycle: predose and 1 hour post-dose

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed due to the sparse pharmacokinetic sampling employed in Cycles 3 to 5.

Arm/Group Title	IMC-1121B 10 mg/kg
Arm/Group Description	10 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 3 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	0

18. Secondary Outcome

Title	Screen for the Development of Circulating Antibodies Against IMC-1121B (Immunogenicity)
Description	Data presented are the number of participants with treatment emergent antibody positive.
Time Frame	Baseline to study completion up to 48 weeks

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug.

Arm/Group Title	IMC-1121B 6 mg/kg (Cohort 1)	IMC-1121B 8 mg/kg (Cohort 2)	IMC-1121B 10 mg/kg (Cohort 3)
Arm/Group Description	6 milligrams/kilogram (mg/kg) IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	8 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.	10 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 3 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
Measure Participants	3	6	6
Number [participants]	0 0%	0 0%	0 0%

Adverse Events

Arm/Group Title	IMC-1121B 6 mg/kg (Cohort 1)		IMC-1121B 8 mg/kg (Cohort 2)		IMC-1121B 10 mg/kg (Cohort 3)
Arm/Group Description	6 milligrams/kilogram (mg/kg) IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.		8 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 2 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.		10 mg/kg IMC-1121B (ramucirumab) based on participant's body weight administered intravenously over 1 hour on Day 1 every 3 weeks for 6 weeks (1 cycle). After 1 cycle of treatment, participants who had an objective response or stable disease were permitted to receive IMC-1121B (ramucirumab) at the same dose and schedule until disease progression or unacceptable toxicity occurred, or another withdrawal criterion was met.
All Cause Mortality
	IMC-1121B 6 mg/kg (Cohort 1)		IMC-1121B 8 mg/kg (Cohort 2)		IMC-1121B 10 mg/kg (Cohort 3)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	IMC-1121B 6 mg/kg (Cohort 1)		IMC-1121B 8 mg/kg (Cohort 2)		IMC-1121B 10 mg/kg (Cohort 3)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		2/6 (33.3%)		2/6 (33.3%)
Nervous system disorders
Syncope	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Surgical and medical procedures
Hospitalisation	1/3 (33.3%)	1	2/6 (33.3%)	2	1/6 (16.7%)	1
Other (Not Including Serious) Adverse Events
	IMC-1121B 6 mg/kg (Cohort 1)		IMC-1121B 8 mg/kg (Cohort 2)		IMC-1121B 10 mg/kg (Cohort 3)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		6/6 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Leukopenia	1/3 (33.3%)	1	1/6 (16.7%)	1	1/6 (16.7%)	1
Neutropenia	0/3 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1
Cardiac disorders
Pericardial effusion	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Eye disorders
Conjunctival haemorrhage	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Eyelid oedema	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Myodesopsia	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Gastrointestinal disorders
Abdominal pain upper	2/3 (66.7%)	2	0/6 (0%)	0	0/6 (0%)	0
Anal haemorrhage	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0
Constipation	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0
Diarrhoea	2/3 (66.7%)	4	2/6 (33.3%)	2	1/6 (16.7%)	1
Gastritis	1/3 (33.3%)	1	0/6 (0%)	0	1/6 (16.7%)	1
Gingival bleeding	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Gingivitis	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Nausea	0/3 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1
Stomatitis	1/3 (33.3%)	1	0/6 (0%)	0	1/6 (16.7%)	2
Vomiting	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
General disorders
Chills	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Face oedema	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Fatigue	1/3 (33.3%)	1	1/6 (16.7%)	1	3/6 (50%)	5
Injection site pain	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Injection site rash	1/3 (33.3%)	5	1/6 (16.7%)	1	3/6 (50%)	3
Oedema peripheral	0/3 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1
Pyrexia	1/3 (33.3%)	1	2/6 (33.3%)	2	4/6 (66.7%)	4
Infections and infestations
Abscess oral	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Nasopharyngitis	0/3 (0%)	0	3/6 (50%)	3	0/6 (0%)	0
Oral herpes	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Pharyngitis	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Fall	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Investigations
Alanine aminotransferase increased	1/3 (33.3%)	1	2/6 (33.3%)	2	2/6 (33.3%)	2
Aspartate aminotransferase increased	2/3 (66.7%)	2	2/6 (33.3%)	2	2/6 (33.3%)	2
Blood albumin decreased	0/3 (0%)	0	2/6 (33.3%)	2	0/6 (0%)	0
Blood alkaline phosphatase increased	0/3 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1
Blood amylase increased	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Blood urine present	0/3 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1
Electrocardiogram T wave amplitude decreased	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Weight decreased	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Weight increased	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Metabolism and nutrition disorders
Anorexia	1/3 (33.3%)	1	0/6 (0%)	0	2/6 (33.3%)	3
Dehydration	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Hyperkalaemia	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Hypoalbuminaemia	0/3 (0%)	0	1/6 (16.7%)	1	2/6 (33.3%)	3
Hyponatraemia	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Hypovolaemia	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Back pain	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0
Musculoskeletal pain	1/3 (33.3%)	1	1/6 (16.7%)	1	0/6 (0%)	0
Neck pain	1/3 (33.3%)	1	0/6 (0%)	0	1/6 (16.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphangiosis carcinomatosa	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Nervous system disorders
Dizziness	2/3 (66.7%)	2	1/6 (16.7%)	2	0/6 (0%)	0
Headache	1/3 (33.3%)	1	4/6 (66.7%)	5	5/6 (83.3%)	10
Peripheral sensory neuropathy	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Psychiatric disorders
Insomnia	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Renal and urinary disorders
Proteinuria	0/3 (0%)	0	3/6 (50%)	4	0/6 (0%)	0
Reproductive system and breast disorders
Breast haemorrhage	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Vaginal haemorrhage	1/1 (100%)	3	0/5 (0%)	0	0/3 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dysphonia	0/3 (0%)	0	0/6 (0%)	0	2/6 (33.3%)	2
Epistaxis	0/3 (0%)	0	2/6 (33.3%)	2	1/6 (16.7%)	1
Oropharyngeal discomfort	0/3 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Oropharyngeal pain	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Skin and subcutaneous tissue disorders
Acne	2/3 (66.7%)	3	1/6 (16.7%)	1	1/6 (16.7%)	2
Dry skin	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Haemorrhage subcutaneous	1/3 (33.3%)	1	0/6 (0%)	0	0/6 (0%)	0
Palmar-plantar erythrodysaesthesia syndrome	2/3 (66.7%)	2	1/6 (16.7%)	1	0/6 (0%)	0
Pruritus	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	2
Purpura	0/3 (0%)	0	1/6 (16.7%)	1	1/6 (16.7%)	1
Rash	1/3 (33.3%)	1	0/6 (0%)	0	2/6 (33.3%)	3
Skin exfoliation	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Urticaria	0/3 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Vascular disorders
Hypertension	1/3 (33.3%)	1	3/6 (50%)	9	2/6 (33.3%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Investigators agreed to delay independently publishing or disclosing data, findings or conclusions from the study except as part of a multi-center publication. Upon study publication or if the draft publication is not produced within approximately 6 months of the final report of the study results, investigators may independently publish, subject to confidential information review/redaction by sponsor. The sponsor may request publication delay up to 90 days to seek patent protection.