Study of Weekly Paclitaxel With Ramucirumab in Participants With Advanced Gastric Adenocarcinomas

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01253525
• Collaborator: (none)
• Enrollment: 6
• Locations: 3
• Arm: 1
• Duration (Months): 11
• Patients Per Site: 2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

Investigate the safety and tolerability of ramucirumab (IMC-1121B) drug product (DP) in combination with paclitaxel.

Condition or Disease	Intervention/Treatment	Phase
Adenocarcinoma	Biological: Ramucirumab (IMC-1121B ); Drug: Paclitaxel	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 6 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b Study of Weekly Paclitaxel With Ramucirumab (IMC-1121B) Drug Product in Patients With Advanced Gastric Adenocarcinomas
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Oct 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ramucirumab (IMC-1121B ) and Pacitaxel Each treatment cycle is 4 weeks (28 days)	Biological: Ramucirumab (IMC-1121B ); 8 milligrams/kilogram (mg/kg) intravenously on Days 1 and 15 of each 28-ay cycle; Other Names: LY3009806 IMC-1121B ; Drug: Paclitaxel; 80 milligram/square meter (mg/m2) intravenously Days 1, 8, and 15 of each 28 day cycle

Outcome Measures

Primary Outcome Measures

1. Number of Participants With a Dose-Limiting Toxicity (DLT) During Cycle 1 [Cycle 1 of 28-day cycle]

   DLT based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE v4.02) in Cycle (Cy) 1 due to study drug (SD) with (w/): Grade (Gr) ≥3 neutropenia w/fever ≥38.5°C or w/bacteremia or sepsis, thrombocytopenia w/bleeding and platelet substitution, prothrombin and/or partial thromboplastin time w/no anticoagulation, hyperbilirubinemia; Gr 4: neutropenia >5 days, thrombocytopenia, Gr 4 or uncontrollable hypertension QTc>500 milliseconds (ms) or increase ≥100 ms increase in 24 hours after SD or significant arrhythmia in this period; Gr ≥3 nonhematologic toxicity (tox), excluding Gr 3 hypersensitivity, hypertension, injection-site reaction, arthralgia/myalgia, asthenia/fatigue, diarrhea w/out loperamide/nausea/vomiting w/out antiemetic and transient aminotransferase elevation. SD tox=delay >1 week in ramucirumab (RAM) dose or omission of 1 dose of RAM or 2 paclitaxel doses due to tox in Cy 1 or delay >2 weeks between Cy 1 and Cy 2 due to persistent tox.

2. Number of Participants With Adverse Events (AEs) [Up to 47 weeks post baseline]

   The number of participants who experienced AEs of any grade, AEs of Grade ≥3 or AEs resulting in death that were considered to be related to ramucirumab [RAM (IMC-1121B)] or paclitaxel (PAC). A summary of serious adverse events (SAEs) and all other non-SAEs, regardless of causality, is located in the Reported Adverse Events module.

3. Number of Participants With Serious Adverse Events (SAEs) [Up to 47 weeks post baseline]

   The number of participants who experienced SAEs that were considered to be related to ramucirumab [RAM (IMC-1121B)] or paclitaxel (PAC). A summary of SAEs and all other non-SAEs, regardless of causality, is located in the Reported Adverse Events module.

Secondary Outcome Measures

1. Ramucirumab Maximum Serum Concentration (Cmax) for Cycle 1 [Cycle 1 Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle]

   Cmax after a single dose of ramucirumab (IMC-1121B).

2. Serum Anti-Ramucirumab Antibody Assessment (Immunogenicity) [Cycle 1 through Cycle 5 (28-day cycles)]

   The percentage of participants who were treatment-emergent positive for anti-ramucirumab (IMC-1121B) antibodies.

3. Ramucirumab Area Under the Concentration Time Curve (AUC) for Cycle 1 [Cycle 1 Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle]

   AUC from time 0 to infinity (0-∞) after a single dose of ramucirumab (IMC-1121B).

4. Ramucirumab Half-Life (t1/2) for Cycle 1 [Cycle 1: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle]

   Terminal t1/2 (the time it takes for the concentration of ramucirumab (IMC-1121B) in plasma or serum to decline by 50%) after a single dose of ramucirumab (IMC-1121B).

5. Ramucirumab Clearance (CL) or Cycle 1 [Cycle 1: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle]

   CL [the volume of plasma or serum cleared of ramucirumab (IMC-1121B) per unit time] after a single dose of ramucirumab (IMC-1121B).

6. Ramucirumab Steady State Volume of Distribution (Vss) for Cycle 1 [Cycle 1: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle]

   Vss [distribution of ramucirumab (IMC-1121B) in the body at steady state] after a single dose of ramucirumab (IMC-1121B).

7. Ramucirumab Maximum Serum Concentration (Cmax) for Cycle 2 [Cycle 2: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle]

   Cmax after multiple doses of ramucirumab (IMC-1121B).

8. Ramucirumab Area Under the Concentration Time Curve (AUC) for Cycle 2 [Cycle 2: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle]

   AUC within the dosing interval (0-τ) after multiple doses of ramucirumab (IMC-1121B).

9. Ramucirumab Half-Life (t1/2) for Cycle 2 [Cycle 2: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle]

   Terminal t1/2 [the time it takes for the concentration of ramucirumab (IMC-1121B) in plasma or serum to decline by 50%] after multiple doses of ramucirumab(IMC-1121B).

10. Ramucirumab Clearance (CL) for Cycle 2 [Cycle 2: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle]

    CL [the volume of plasma or serum cleared of ramucirumab (IMC-1121B) per unit time] at steady state after multiple doses of ramucirumab (IMC-1121B).

11. Ramucirumab Steady State Volume of Distribution (Vss) for Cycle 2 [Cycle 2: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle]

    Vss [distribution of ramucirumab (IMC-1121B) in in the body at steady state] is not calculated for multiple doses of ramucirumab (IMC-1121B).

12. Ramucirumab Maximum Serum Concentration (Cmax) for Cycle 3 [Cycle 3: Pre-infusion, Day 1 of 28-day cycle]

    Due to sparse pharmacokinetic sampling ramucirumab (IMC-1121B) Cmax could not be calculated in Cycle 3.

13. Ramucirumab Area Under the Concentration Time Curve (AUC) for Cycle 3 [Cycle 3: Pre-infusion, Day 1 of 28-day cycle]

    Due to the sparse pharmacokinetic sampling ramucirumab (IMC-1121B) AUC within the dosing interval (0-τ) could not be calculated in Cycle 3.

14. Ramucirumab Half-Life (t 1/2) for Cycle 3 [Cycle 3: Pre-infusion, Day 1 of 28-day cycle]

    Due to sparse pharmacokinetic sampling ramucirumab (IMC-1121B) t1/2 could not be calculated in Cycle 3.

15. Ramucirumab Clearance (CL) for Cycle 3 [Cycle 3: Pre-infusion, Day 1 of 28-day cycle]

    Due to sparse pharmacokinetic sampling CL could not be calculated for ramucirumab (IMC-1121B) in Cycle 3.

16. Ramucirumab Steady State Volume of Distribution (Vss) for Cycle 3 [Cycle 3: Pre-infusion, Day 1 of 28-day cycle]

    Due to sparse pharmacokinetic sampling Vss for ramucirumab (IMC-1121B) could not be calculated in Cycle 3.

17. Ramucirumab Maximum Serum Concentration (Cmax) for Cycle 4 [Cycle 4: Pre-infusion, Day 1 of 28-day cycle]

    Due to sparse pharmacokinetic sampling ramucirumab (IMC-1121B) Cmax could not be calculated in Cycle 4.

18. Ramucirumab Area Under the Concentration Time Curve (AUC) for Cycle 4 [Cycle 4: Pre-infusion, Day 1 of 28-day cycle]

    Due to sparse pharmacokinetic sampling AUC within the dosing interval (0-τ) for ramucirumab (IMC-1121B) could not be calculated in Cycle 4.

19. Ramucirumab Half-Life (t 1/2) for Cycle 4 [Cycle 4: Pre-infusion, Day 1 of 28-day cycle]

    Due to sparse pharmacokinetic sampling t1/2 for ramucirumab (IMC-1121B) could not be calculated in Cycle 4.

20. Ramucirumab Clearance (CL) for Cycle 4 [Cycle 4: Pre-infusion, Day 1 of 28-day cycle]

    Due to sparse pharmacokinetic sampling CL for ramucirumab (IMC-1121B) could not be calculated in Cycle 4.

21. Ramucirumab Steady State Volume of Distribution (Vss) for Cycle 4 [Cycle 4: Pre-infusion, Day 1 of 28-day cycle]

    Due to sparse pharmacokinetic sampling Vss for ramucirumab (IMC-1121B) could not be calculated in Cycle 4.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Has a histopathologically or cytologically confirmed diagnosis of gastric or gastroesophageal junction (GEJ) adenocarcinoma

• Has an advanced or metastatic solid gastric adenocarcinoma that has failed standard therapy

• Has resolution of all clinically significant toxic effects of prior therapy, surgery, treatment with an investigational agent or device, treatment monoclonal antibody or small molecule, and radiotherapy or chemotherapy.

• Has adequate organ function

• Eligible participants of reproductive potential (both sexes) agree to use adequate contraceptive methods (hormonal or barrier methods) during the study period and for 12 weeks after the last dose of study medication

Exclusion Criteria:

• Has undergone major surgery within 28 days prior to the study, or subcutaneous venous access device placement within 7 days prior to the study registration date

• Has elective or planned surgery to be conducted during the trial

• Has had treatment with an investigational agent or device, an antineoplastic small molecule, or antineoplastic radiotherapy or chemotherapy

• Was previously treated with a chemotherapy regimen containing nitrosoureas or mitomycin C

• Has had treatment with an antineoplastic monoclonal antibody within 8 weeks prior to the study registration date

• Has a history of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism prior to the study registration date

• Has experienced any arterial thrombotic event, including myocardial infarction, cerebrovascular accident, or transient ischemic attack, within 6 months prior to the study date

• Is receiving therapeutic anticoagulation with warfarin, low-molecular weight heparin or similar agents. (Participants receiving prophylactic, low-dose anticoagulation therapy are eligible provided that the coagulation parameters International Normalized Ratio (INR) ≤ 1.5, prothrombin time (PT) and partial thromboplastin time (PTT) or - Is receiving chronic therapy with nonsteroidal anti-inflammatory agents [Aspirin use at doses up to 325 milligrams/day (mg/day) is permitted]

• Has significant bleeding disorders, vasculitis, history of postoperative bleeding complications, hemoptysis or had a significant bleeding episode from the gastrointestinal (GI) tract within 3 months prior to the study date

• Has a history of GI perforation and/or fistulae within 6 months prior to the study date

• Has symptomatic congestive heart failure, unstable angina pectoris, or symptomatic or poorly controlled cardiac arrhythmia

• Has uncontrolled arterial hypertension despite standard medical management.

• Has a serious or nonhealing wound or peptic ulcer or bone fracture within 28 days prior to the study date

• Has a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection, Crohn's disease, ulcerative colitis, or chronic diarrhea

• Has a serious illness or medical condition(s)

• Is pregnant or lactating

• Has received treatment with another investigational drug or participation in another interventional clinical trial within 28 days prior to the study date

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	ImClone Investigational Site	Chiba		Japan	277-8577
2	ImClone Investigational Site	Osaka		Japan	569-8686
3	ImClone Investigational Site	Osaka		Japan	589-5811

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: NCT01253525
• Other Study ID Numbers: 14204; CP12-1026; I4T-IE-JVBW
• First Posted: Dec 3, 2010
• Last Update Posted: Jun 18, 2014
• Last Verified: May 1, 2014

• Keywords provided by Eli Lilly and Company: Adenocarcinoma; Gastroesophageal Junction
• Additional relevant MeSH terms: Adenocarcinoma; Paclitaxel; Ramucirumab

Study Results

Participant Flow

Pre-assignment Detail	Participants were considered completed if they either completed Cycle 1 of study drug or discontinued study drug due to a dose limiting toxicity (DLT) during Cycle 1.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Period Title: Overall Study
STARTED	6
Received Any Quantity of Study Drug	6
COMPLETED	6
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Overall Participants	6
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.6 (15.50)
Sex: Female, Male (Count of Participants)
Female	1 16.7%
Male	5 83.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	6 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	6 100%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
Japan	6 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With a Dose-Limiting Toxicity (DLT) During Cycle 1
Description	DLT based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE v4.02) in Cycle (Cy) 1 due to study drug (SD) with (w/): Grade (Gr) ≥3 neutropenia w/fever ≥38.5°C or w/bacteremia or sepsis, thrombocytopenia w/bleeding and platelet substitution, prothrombin and/or partial thromboplastin time w/no anticoagulation, hyperbilirubinemia; Gr 4: neutropenia >5 days, thrombocytopenia, Gr 4 or uncontrollable hypertension QTc>500 milliseconds (ms) or increase ≥100 ms increase in 24 hours after SD or significant arrhythmia in this period; Gr ≥3 nonhematologic toxicity (tox), excluding Gr 3 hypersensitivity, hypertension, injection-site reaction, arthralgia/myalgia, asthenia/fatigue, diarrhea w/out loperamide/nausea/vomiting w/out antiemetic and transient aminotransferase elevation. SD tox=delay >1 week in ramucirumab (RAM) dose or omission of 1 dose of RAM or 2 paclitaxel doses due to tox in Cy 1 or delay >2 weeks between Cy 1 and Cy 2 due to persistent tox.
Time Frame	Cycle 1 of 28-day cycle

Outcome Measure Data

Analysis Population Description

All enrolled participants who complete the first cycle of study drug or discontinued study drug due to a DLT during Cycle 1.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	6
Number [participants]	0 0%

2. Primary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	The number of participants who experienced AEs of any grade, AEs of Grade ≥3 or AEs resulting in death that were considered to be related to ramucirumab [RAM (IMC-1121B)] or paclitaxel (PAC). A summary of serious adverse events (SAEs) and all other non-SAEs, regardless of causality, is located in the Reported Adverse Events module.
Time Frame	Up to 47 weeks post baseline

Outcome Measure Data

Analysis Population Description

All enrolled participants who received any quantity of study drug.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	6
RAM-Related AEs Any Grade	6 100%
PAC-Related AEs Any Grade	6 100%
RAM-Related AEs Any Grade ≥3	2 33.3%
PAC-Related AEs Any Grade ≥3	4 66.7%
RAM-Related AEs Resulting in Death	0 0%
PAC-Related AEs Resulting in Death	0 0%

3. Primary Outcome

Title	Number of Participants With Serious Adverse Events (SAEs)
Description	The number of participants who experienced SAEs that were considered to be related to ramucirumab [RAM (IMC-1121B)] or paclitaxel (PAC). A summary of SAEs and all other non-SAEs, regardless of causality, is located in the Reported Adverse Events module.
Time Frame	Up to 47 weeks post baseline

Outcome Measure Data

Analysis Population Description

All enrolled participants who received any quantity of study drug.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	6
RAM-Related SAEs	2 33.3%
PAC-Related SAEs	2 33.3%

4. Secondary Outcome

Title	Ramucirumab Maximum Serum Concentration (Cmax) for Cycle 1
Description	Cmax after a single dose of ramucirumab (IMC-1121B).
Time Frame	Cycle 1 Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle

Outcome Measure Data

Analysis Population Description

All enrolled participants who received any quantity of study drug and had evaluable Cmax values.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	6
Mean (Standard Deviation) [micrograms/milliliter (µg/mL)]	176 (46.6)

5. Secondary Outcome

Title	Serum Anti-Ramucirumab Antibody Assessment (Immunogenicity)
Description	The percentage of participants who were treatment-emergent positive for anti-ramucirumab (IMC-1121B) antibodies.
Time Frame	Cycle 1 through Cycle 5 (28-day cycles)

Outcome Measure Data

Analysis Population Description

All enrolled participants who received at least 1 dose of study drug and were analyzed for anti-ramucirumab (IMC-1121B) antibodies.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	6
Number [percentage of participants]	0 0%

6. Secondary Outcome

Title	Ramucirumab Area Under the Concentration Time Curve (AUC) for Cycle 1
Description	AUC from time 0 to infinity (0-∞) after a single dose of ramucirumab (IMC-1121B).
Time Frame	Cycle 1 Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle

Outcome Measure Data

Analysis Population Description

All enrolled participants who received any quantity of study drug and had evaluable AUC0-∞ values.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	1
Mean (Standard Deviation) [micrograms*hour/milliliter (µg*h/mL)]	34100 (NA)

7. Secondary Outcome

Title	Ramucirumab Half-Life (t1/2) for Cycle 1
Description	Terminal t1/2 (the time it takes for the concentration of ramucirumab (IMC-1121B) in plasma or serum to decline by 50%) after a single dose of ramucirumab (IMC-1121B).
Time Frame	Cycle 1: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle

Outcome Measure Data

Analysis Population Description

All enrolled participants who received any quantity of study drug and had evaluable t1/2 values.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	4
Median (Full Range) [hours (h)]	190

8. Secondary Outcome

Title	Ramucirumab Clearance (CL) or Cycle 1
Description	CL [the volume of plasma or serum cleared of ramucirumab (IMC-1121B) per unit time] after a single dose of ramucirumab (IMC-1121B).
Time Frame	Cycle 1: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle

Outcome Measure Data

Analysis Population Description

All enrolled participants who received any quantity of study drug and had evaluable CL values.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	1
Mean (Standard Deviation) [liters/hour (L/h)]	0.0166 (NA)

9. Secondary Outcome

Title	Ramucirumab Steady State Volume of Distribution (Vss) for Cycle 1
Description	Vss [distribution of ramucirumab (IMC-1121B) in the body at steady state] after a single dose of ramucirumab (IMC-1121B).
Time Frame	Cycle 1: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle

Outcome Measure Data

Analysis Population Description

All enrolled participants who received any quantity of study drug and had evaluable Vss values.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	1
Mean (Standard Error) [liters (L)]	3.27 (NA)

10. Secondary Outcome

Title	Ramucirumab Maximum Serum Concentration (Cmax) for Cycle 2
Description	Cmax after multiple doses of ramucirumab (IMC-1121B).
Time Frame	Cycle 2: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle

Outcome Measure Data

Analysis Population Description

All enrolled participants who received any quantity of study drug and had evaluable Cmax values.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	4
Mean (Standard Deviation) [micrograms/milliliter (µg/mL)]	284 (39.7)

11. Secondary Outcome

Title	Ramucirumab Area Under the Concentration Time Curve (AUC) for Cycle 2
Description	AUC within the dosing interval (0-τ) after multiple doses of ramucirumab (IMC-1121B).
Time Frame	Cycle 2: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle

Outcome Measure Data

Analysis Population Description

All enrolled participants who received any quantity of study drug and had evaluable AUC 0-τ values.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	2
Mean (Standard Deviation) [micrograms*hour/milliliter (µg*h/mL)]	41900 (951)

12. Secondary Outcome

Title	Ramucirumab Half-Life (t1/2) for Cycle 2
Description	Terminal t1/2 [the time it takes for the concentration of ramucirumab (IMC-1121B) in plasma or serum to decline by 50%] after multiple doses of ramucirumab(IMC-1121B).
Time Frame	Cycle 2: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle

Outcome Measure Data

Analysis Population Description

All enrolled participants who received any quantity of study drug and had evaluable t1/2 values.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	1
Median (Full Range) [hours (h)]	218

13. Secondary Outcome

Title	Ramucirumab Clearance (CL) for Cycle 2
Description	CL [the volume of plasma or serum cleared of ramucirumab (IMC-1121B) per unit time] at steady state after multiple doses of ramucirumab (IMC-1121B).
Time Frame	Cycle 2: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle

Outcome Measure Data

Analysis Population Description

All enrolled participants who received any quantity of study drug and had evaluable CL values.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	2
Mean (Standard Deviation) [liters/hour (L/h)]	0.0136 (0.000342)

14. Secondary Outcome

Title	Ramucirumab Steady State Volume of Distribution (Vss) for Cycle 2
Description	Vss [distribution of ramucirumab (IMC-1121B) in in the body at steady state] is not calculated for multiple doses of ramucirumab (IMC-1121B).
Time Frame	Cycle 2: Pre-infusion, Days 1, 2, 3, 5, 8, 12, and 15 of 28-day cycle

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	0

15. Secondary Outcome

Title	Ramucirumab Maximum Serum Concentration (Cmax) for Cycle 3
Description	Due to sparse pharmacokinetic sampling ramucirumab (IMC-1121B) Cmax could not be calculated in Cycle 3.
Time Frame	Cycle 3: Pre-infusion, Day 1 of 28-day cycle

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	0

16. Secondary Outcome

Title	Ramucirumab Area Under the Concentration Time Curve (AUC) for Cycle 3
Description	Due to the sparse pharmacokinetic sampling ramucirumab (IMC-1121B) AUC within the dosing interval (0-τ) could not be calculated in Cycle 3.
Time Frame	Cycle 3: Pre-infusion, Day 1 of 28-day cycle

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	0

17. Secondary Outcome

Title	Ramucirumab Half-Life (t 1/2) for Cycle 3
Description	Due to sparse pharmacokinetic sampling ramucirumab (IMC-1121B) t1/2 could not be calculated in Cycle 3.
Time Frame	Cycle 3: Pre-infusion, Day 1 of 28-day cycle

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	0

18. Secondary Outcome

Title	Ramucirumab Clearance (CL) for Cycle 3
Description	Due to sparse pharmacokinetic sampling CL could not be calculated for ramucirumab (IMC-1121B) in Cycle 3.
Time Frame	Cycle 3: Pre-infusion, Day 1 of 28-day cycle

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	0

19. Secondary Outcome

Title	Ramucirumab Steady State Volume of Distribution (Vss) for Cycle 3
Description	Due to sparse pharmacokinetic sampling Vss for ramucirumab (IMC-1121B) could not be calculated in Cycle 3.
Time Frame	Cycle 3: Pre-infusion, Day 1 of 28-day cycle

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	0

20. Secondary Outcome

Title	Ramucirumab Maximum Serum Concentration (Cmax) for Cycle 4
Description	Due to sparse pharmacokinetic sampling ramucirumab (IMC-1121B) Cmax could not be calculated in Cycle 4.
Time Frame	Cycle 4: Pre-infusion, Day 1 of 28-day cycle

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	0

21. Secondary Outcome

Title	Ramucirumab Area Under the Concentration Time Curve (AUC) for Cycle 4
Description	Due to sparse pharmacokinetic sampling AUC within the dosing interval (0-τ) for ramucirumab (IMC-1121B) could not be calculated in Cycle 4.
Time Frame	Cycle 4: Pre-infusion, Day 1 of 28-day cycle

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	0

22. Secondary Outcome

Title	Ramucirumab Half-Life (t 1/2) for Cycle 4
Description	Due to sparse pharmacokinetic sampling t1/2 for ramucirumab (IMC-1121B) could not be calculated in Cycle 4.
Time Frame	Cycle 4: Pre-infusion, Day 1 of 28-day cycle

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	0

23. Secondary Outcome

Title	Ramucirumab Clearance (CL) for Cycle 4
Description	Due to sparse pharmacokinetic sampling CL for ramucirumab (IMC-1121B) could not be calculated in Cycle 4.
Time Frame	Cycle 4: Pre-infusion, Day 1 of 28-day cycle

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	0

24. Secondary Outcome

Title	Ramucirumab Steady State Volume of Distribution (Vss) for Cycle 4
Description	Due to sparse pharmacokinetic sampling Vss for ramucirumab (IMC-1121B) could not be calculated in Cycle 4.
Time Frame	Cycle 4: Pre-infusion, Day 1 of 28-day cycle

Outcome Measure Data

Analysis Population Description

Zero participants were analyzed.

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
Measure Participants	0

Adverse Events

Arm/Group Title	Ramucirumab + Paclitaxel
Arm/Group Description	Ramucirumab (IMC-1121B): 8 milligrams/kilogram (mg/kg) administered intravenously on Days 1 and 15 of each 28-day cycle. Paclitaxel: 80 milligrams/square meter (mg/m2) administered intravenously on Days 1, 8, and 15 of each 28-day cycle.
All Cause Mortality
	Ramucirumab + Paclitaxel
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Ramucirumab + Paclitaxel
	Affected / at Risk (%)	# Events
Total	4/6 (66.7%)
Gastrointestinal disorders
Gastrointestinal haemorrhage	1/6 (16.7%)	1
Intestinal obstruction	1/6 (16.7%)	1
Infections and infestations
Pneumonia	2/6 (33.3%)	2
Metabolism and nutrition disorders
Decreased appetite	1/6 (16.7%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lymphangiosis carcinomatosa	1/6 (16.7%)	1
Nervous system disorders
Meningism	1/6 (16.7%)	7
Other (Not Including Serious) Adverse Events
	Ramucirumab + Paclitaxel
	Affected / at Risk (%)	# Events
Total	6/6 (100%)
Blood and lymphatic system disorders
Anaemia	2/6 (33.3%)	5
Leukopenia	1/6 (16.7%)	3
Lymphopenia	1/6 (16.7%)	1
Neutropenia	4/6 (66.7%)	7
Ear and labyrinth disorders
Hearing impaired	1/6 (16.7%)	1
Eye disorders
Retinal haemorrhage	1/6 (16.7%)	1
Gastrointestinal disorders
Constipation	1/6 (16.7%)	1
Diarrhoea	2/6 (33.3%)	4
Haemorrhoidal haemorrhage	2/6 (33.3%)	2
Nausea	3/6 (50%)	5
Vomiting	2/6 (33.3%)	5
General disorders
Face oedema	1/6 (16.7%)	1
Fatigue	2/6 (33.3%)	4
Oedema peripheral	1/6 (16.7%)	2
Pyrexia	3/6 (50%)	6
Immune system disorders
Hypersensitivity	1/6 (16.7%)	1
Infections and infestations
Lung infection	1/6 (16.7%)	1
Onychomycosis	1/6 (16.7%)	1
Injury, poisoning and procedural complications
Skin laceration	1/6 (16.7%)	1
Investigations
Alanine aminotransferase increased	2/6 (33.3%)	2
Aspartate aminotransferase increased	2/6 (33.3%)	2
Blood alkaline phosphatase increased	1/6 (16.7%)	1
Blood lactate dehydrogenase increased	1/6 (16.7%)	1
Blood urine present	1/6 (16.7%)	1
Neutrophil count decreased	1/6 (16.7%)	2
Platelet count decreased	2/6 (33.3%)	3
Weight decreased	1/6 (16.7%)	1
White blood cell count decreased	2/6 (33.3%)	6
Metabolism and nutrition disorders
Decreased appetite	3/6 (50%)	4
Hyperglycaemia	2/6 (33.3%)	2
Hyperuricaemia	1/6 (16.7%)	1
Hypoalbuminaemia	1/6 (16.7%)	1
Hyponatraemia	2/6 (33.3%)	2
Hypophosphataemia	1/6 (16.7%)	1
Musculoskeletal and connective tissue disorders
Back pain	2/6 (33.3%)	2
Muscular weakness	1/6 (16.7%)	1
Nervous system disorders
Headache	2/6 (33.3%)	2
Neuropathy peripheral	1/6 (16.7%)	1
Peripheral sensory neuropathy	2/6 (33.3%)	2
Psychiatric disorders
Insomnia	1/6 (16.7%)	1
Renal and urinary disorders
Haematuria	1/6 (16.7%)	1
Proteinuria	3/6 (50%)	4
Respiratory, thoracic and mediastinal disorders
Dysphonia	1/6 (16.7%)	1
Epistaxis	5/6 (83.3%)	8
Hiccups	1/6 (16.7%)	1
Nasal congestion	1/6 (16.7%)	1
Skin and subcutaneous tissue disorders
Alopecia	3/6 (50%)	3
Onychoclasis	1/6 (16.7%)	1
Rash	4/6 (66.7%)	6
Rash maculo-papular	1/6 (16.7%)	1
Vascular disorders
Hot flush	1/6 (16.7%)	3
Hypertension	2/6 (33.3%)	3

Limitations/Caveats

Cycle 3 and beyond pharmacokinetic sampling was collected per the protocol-defined limited sampling schedule.

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.