A Study of Paclitaxel With or Without Ramucirumab (IMC-1211B) in Metastatic Gastric Adenocarcinoma

Study Overview
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Brief Summary
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This is a Phase III randomized multicenter double-blind, placebo controlled trial evaluating the safety and efficacy of paclitaxel plus ramucirumab (IMC-1211B) drug product (DP) compared to paclitaxel plus placebo.

Detailed Description
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The aim of this study is to determine if paclitaxel given together with ramucirumab (IMC-1211B) as second line therapy will prolong overall survival (OS) compared to paclitaxel alone. Approximately 663 participants (at least 18 years) in approximately 200 study centers and in approximately 30 countries will be randomized with histologically or cytologically confirmed metastatic gastric or gastroesophageal junction adenocarcinoma. Participants must have received at least one cycle of first line therapy with any platinum/fluoropyrimidine doublet with or without anthracycline (epirubicin or doxorubicin) and must have discontinued this therapy prior to study entry due to disease progression. Upon registration and completion of screening procedure and reviewing the Inclusion and Exclusion Criteria eligible participants will be randomized to receive either paclitaxel plus ramucirumab or paclitaxel plus placebo. Ramucirumab (IMC-1211B) DP/placebo will be administered IV on Days 1 and 15, paclitaxel will be administered IV on Days 1, 8 and 15 of a 4 weekly cycle. Participants will be continuously treated and monitored until radiographic or symptomatic progression of disease, toxicity requiring cessation, protocol noncompliance, or withdrawal of consent.

Official Title
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A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase 3 Study of Weekly Paclitaxel With or Without Ramucirumab (IMC-1121B) Drug Product in Patients With Metastatic Gastric Adenocarcinoma, Refractory to or Progressive After First-Line Therapy With Platinum and Fluoropyrimidine

Conditions
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Gastric Cancer

Intervention / Treatment
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* Biological: Ramucirumab (IMC-1211B) DP
* Drug: Placebo
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent histologically or cytologically confirmed gastric or gastroesophageal junction adenocarcinoma Metastatic disease or locally advanced, unresectable disease Disease progression during or within 4 months after the last dose of the first-line therapy (platinum/fluoropyrimidine doublet with or without anthracycline) Organs are functioning well (liver, kidney, blood) Good performance status Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 to 1 Exclusion Criteria: First line chemotherapy for metastatic gastric cancer other than platinum/fluoropyrimidine doublet with or without anthracycline Previous systemic therapy with other anti-angiogenic drugs Uncontrolled high blood pressure Symptomatic or poorly controlled heart disease or had a heart attack or stroke within the last 6 month Evidence of central nervous system (CNS) metastasis at baseline

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ramucirumab (IMC-1211B) Drug Product (DP) and Paclitaxel<br>Ramucirumab (IMC-1211B) DP and Paclitaxel | Biological: Ramucirumab (IMC-1211B) DP<br>* 8 milligrams/kilogram (mg/kg) intravenous (IV) infusion on Days 1 and 15 of every 4-week cycle<br>* Other names: IMC-1211B;Drug: Paclitaxel<br>* Paclitaxel 80 milligrams per square meter (mg/m²) IV infusion on Days 1, 8, and 15 of every 4-week cycle<br>|
| Placebo Comparator: Placebo and Paclitaxel<br>Placebo and Paclitaxel | Drug: Placebo<br>* Ramucirumab placebo IV infusion on Days 1 and 15 of every 4-week cycle<br>Drug: Paclitaxel<br>* Paclitaxel 80 milligrams per square meter (mg/m²) IV infusion on Days 1, 8, and 15 of every 4-week cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Time (OS) | OS time was measured from date of randomization to date of death from any cause. Participants who were not known to have died on or before the date of data cut-off, OS data was censored on the last date (on or before the cut-off date) the participant was known to be alive. | Randomization up to 27.5 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | PFS was measured from date of randomization to first radiographically documented progressive disease (PD) or death due to any cause. PD defined using Response Evaluation Criteria in Solid Tumors v1.1 (RECIST v1.1) as ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this included the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of at least 5 mm. Participants who had no baseline or post baseline radiological tumor assessment were censored at date of randomization. Participants who had no tumor progression or death within 2 scan intervals following the last assessment were censored at the date of last radiographic tumor assessment. Participants who began new anticancer treatment and had no tumor progression were censored at date of assessment prior to initiation of new therapy. Participants lost to follow-up or withdrew consent were censored at the date of their last assessment. | Randomization up to 22.2 months | 
| Time to Progressive Disease (TTP) | TTP was defined as the time from randomization until date of radiographic progression using RECIST v1.1 criteria. PD was defined as having a ≥20% increase in sum of longest diameter (LD) of target lesions and at minimum 5 millimeters (mm) increase above nadir. Participants who did not progress or were lost to follow-up were censored at the date of last tumor assessment. Participants who had no baseline tumor assessment or no post baseline assessment and no death reported with 2 scan intervals post randomization were censored at date of randomization. Participants with no progression and not died within 2 scan intervals after last assessment were censored at date of last tumor assessment. Participants with no post baseline assessment or tumor progression but death reported within 2 scan intervals after randomization were censored at date of death. | Baseline up to 22.2 months | 
| Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or PD | BOR was defined as the best response across all time points from randomization until radiologically confirmed PD using RECIST, v1.1 criteria. 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 mm and normalization of tumor marker level of non-target lesions. PR was defined as having a ≥30% decrease in sum of LD of target lesions. PD was defined as having a ≥20% increase in sum of LD of target lesions and ≥5 mm increase above nadir. SD was defined as small changes that did not meet above criteria. | Randomization up to 22.2 months | 
| Percentage of Participants With CR or PR (Objective Response Rate [ORR]) | ORR was the percentage of participants who had CR or PR defined using RECIST v1.1 criteria. 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 mm and normalization of tumor marker level of non-target lesions. PR was defined as having a ≥30% decrease in sum of LD of target lesions. Percentage of participants calculated as: (number of participants with CR + PR)/(total number of participants)*100. | Randomization up to 22.2 months | 
| Percentage of Participants With Anti-Ramucirumab Antibodies (Serum Anti-Ramucirumab Antibody Assessment )(Immunogenicity) | Participants who developed treatment-emergent antibody responses to Ramucirumab (IMC-1121B) after baseline. | Prior to and after ramucirumab (IMC-1121B) infusion: Day 1 Cycles 1, 2 and 3 (28-day cycles) Doses 1, 4, 7 and 30-37 days after last dose of study therapy up to 103 weeks | 
| Maximum Concentration (Cmax) After First Ramucirumab (IMC-1211B) Infusion |  | Cycle 1, Day 1, 1 hour post end of infusion (28-day cycles) | 
| Cmax After 4th Ramucirumab (IMC-1211B) Infusion |  | Cycle 2, Day 15 1 hour post end of infusion (28-day cycles) | 
| Cmax After 7th Ramucirumab (IMC-1211B) Infusion |  | Cycle 4, Day 1, 1 hour post end of infusion (28-day cycles) | 
| Minimum Concentration (Cmin) Prior to First Ramucirumab (IMC-1211B) Infusion | This outcome measure was included in error as the time point was before ramucirumab (IMC-1211B) was administered. Cmin was not analyzed. | Cycle 1, Day 1 predose (28-day cycles) | 
| Cmin Prior to 4th Ramucirumab (IMC-1211B) Infusion |  | Cycle 2, Day 15 (28-day cycle) | 
| Cmin Prior to 7th Ramucirumab (IMC-1211B) Infusion |  | Cycle 4, Day 1 (28-day cycles) | 
| Change From Baseline to End of Therapy in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life: Questionnaire (QLQ-C30) in Global Health Status | EORTC QLQ-C30 v3.0 is a 30-item, self-administered questionnaire with multidimensional scales assessing 15 domains (5 functional domains [physical, role, cognitive, emotional, and social], 9 symptom scales [fatigue, pain, nausea and vomiting, dyspnea, loss of appetite, insomnia, constipation and diarrhea, and financial difficulties] and global health status scale). 28 questions assessed on a 1 (not at all) to 4 (very much) scale and the remaining 2 questions used a 1 (poor) to 7 (excellent) scale. A linear transformation was applied to standardize the raw scores to range between 0 and 100 per developer guidelines. For the functional domains and global health status scale, higher scores represent a better level of functioning. For symptoms scales, higher scores represented a greater degree of symptoms. | Baseline, end of therapy (up to 103 weeks) | 
| Change From Baseline to End of Therapy in European Quality of Life Questionnaire-5 Dimension (EuroQol EQ-5D) Index Score | The EQ-5D is a generic, multidimensional, health status instrument. The profile allowed participants to rate their health state in 5 health domains: mobility, self-care, usual activities, pain/discomfort, and mood using a 3-level scale [1 (no problem), 2 (some problems), and 3 (major problems)]. These combinations of responses were converted into a weighted health-state Index Score according to the United Kingdom (UK) population-based algorithm. The possible values for the Index Score ranged from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension). A negative change indicated a worsening of the participant's health status. | Baseline, end of therapy (up to 103 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic Adenocarcinoma, Gastric Adenocarcinoma, Gastroesophageal Junction Adenocarcinoma