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

• ClinicalTrials.gov Identifier: NCT01170663
• Recruitment Status: Completed
• First Posted: July 27, 2010
• Results First Posted: July 31, 2014
• Last Update Posted: September 18, 2019
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: July 21, 2010
• First Posted Date: July 27, 2010
• Results First Submitted Date: July 1, 2014
• Results First Posted Date: July 31, 2014
• Last Update Posted Date: September 18, 2019
• Study Start Date: December 2010
• Actual Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 1, 2014)

Overall Survival Time (OS) [ Time Frame: Randomization up to 27.5 months ]

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.

Original Primary Outcome Measures (submitted: July 26, 2010)

Overall survival time (OS) [ Time Frame: 32 months ]

Randomization to date of death from any cause

Current Secondary Outcome Measures (submitted: February 17, 2018)

• Progression-Free Survival (PFS) [ Time Frame: Randomization up to 22.2 months ]
  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.
• Time to Progressive Disease (TTP) [ Time Frame: Baseline up to 22.2 months ]
  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.
• Best Overall Response (BOR) of Complete Response (CR), Partial Response (PR), Stable Disease (SD) or PD [ Time Frame: Randomization up to 22.2 months ]
  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.
• Percentage of Participants With CR or PR (Objective Response Rate [ORR]) [ Time Frame: Randomization up to 22.2 months ]
  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.
• Percentage of Participants With Anti-Ramucirumab Antibodies (Serum Anti-Ramucirumab Antibody Assessment )(Immunogenicity) [ Time Frame: 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 ]
  Participants who developed treatment-emergent antibody responses to Ramucirumab (IMC-1121B) after baseline.
• Maximum Concentration (Cmax) After First Ramucirumab (IMC-1211B) Infusion [ Time Frame: Cycle 1, Day 1, 1 hour post end of infusion (28-day cycles) ]
• Cmax After 4th Ramucirumab (IMC-1211B) Infusion [ Time Frame: Cycle 2, Day 15 1 hour post end of infusion (28-day cycles) ]
• Cmax After 7th Ramucirumab (IMC-1211B) Infusion [ Time Frame: Cycle 4, Day 1, 1 hour post end of infusion (28-day cycles) ]
• Minimum Concentration (Cmin) Prior to First Ramucirumab (IMC-1211B) Infusion [ Time Frame: Cycle 1, Day 1 predose (28-day cycles) ]
  This outcome measure was included in error as the time point was before ramucirumab (IMC-1211B) was administered. Cmin was not analyzed.
• Cmin Prior to 4th Ramucirumab (IMC-1211B) Infusion [ Time Frame: Cycle 2, Day 15 (28-day cycle) ]
• Cmin Prior to 7th Ramucirumab (IMC-1211B) Infusion [ Time Frame: 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 [ Time Frame: Baseline, end of therapy (up to 103 weeks) ]
  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.
• Change From Baseline to End of Therapy in European Quality of Life Questionnaire-5 Dimension (EuroQol EQ-5D) Index Score [ Time Frame: Baseline, end of therapy (up to 103 weeks) ]
  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.

Original Secondary Outcome Measures (submitted: July 26, 2010)

• Progression-free survival (PFS) [ Time Frame: 32 months ]
  Radiographic assessment: Time from randomization to the first radiographic documented PD or death
• Time to progressive disease (TTP) [ Time Frame: 32 months ]
  Time from Pretreatment, every 6 weeks after first infusion until first radiographic progressive disease (PD)
• Best overall response (BOR) [ Time Frame: 32 months ]
  Pretreatment, every 6 weeks after first infusion until progressive disease (PD) will be determined using the RECIST (version1.1) guidelines
• Objective response rate (ORR) [ Time Frame: 32 months ]
  Pretreatment, every 6 weeks after first infusion until progressive disease (PD); calculated as the number of patients who achieved a BOR of complete response (CR) or partial response (PR), divided by the total number of patients randomized
• Serum Anti-Ramucirumab Antibody Assessment [ Time Frame: 32 months ]
  Prior to (within Pretreatment period) 1st ramucirumab infusion, prior to 4th ramucirumab infusion ( ~ week 6 after 1st dose), prior to 7th ramucirumab infusion (~ week 12 after first dose) and 30 - 37 days after last dose of therapy
• Maximum concentration (Cmax) (ramucirumab + placebo) [ Time Frame: Cycle 1, Day 1 ]
  Prior to (within Pretreatment period) 1st ramucirumab infusion, prior to 4th ramucirumab infusion ( ~ week 6 after 1st dose), prior to 7th ramucirumab infusion (~ week 12 after first dose) and 30 - 37 days after last dose of therapy
• Maximum concentration (Cmax) (ramucirumab + placebo) [ Time Frame: Cycle 2, Day 1 ]
  Prior to (within Pretreatment period) 1st ramucirumab infusion, prior to 4th ramucirumab infusion ( ~ week 6 after 1st dose), prior to 7th ramucirumab infusion (~ week 12 after first dose) and 30 - 37 days after last dose of therapy
• Maximum concentration (Cmax) (ramucirumab + placebo) [ Time Frame: Cycle 4, Day 1 ]
  Prior to (within Pretreatment period) 1st ramucirumab infusion, prior to 4th ramucirumab infusion ( ~ week 6 after 1st dose), prior to 7th ramucirumab infusion (~ week 12 after first dose) and 30 - 37 days after last dose of therapy
• Maximum concentration (Cmin) (ramucirumab + placebo) [ Time Frame: Cycle 1, Day 1 ]
  Prior to (within Pretreatment period) 1st ramucirumab infusion, prior to 4th ramucirumab infusion ( ~ week 6 after 1st dose), prior to 7th ramucirumab infusion (~ week 12 after first dose) and 30 - 37 days after last dose of therapy
• Maximum concentration (Cmin) (ramucirumab + placebo) [ Time Frame: Cycle 2, Day 1 ]
  Prior to (within Pretreatment period) 1st ramucirumab infusion, prior to 4th ramucirumab infusion ( ~ week 6 after 1st dose), prior to 7th ramucirumab infusion (~ week 12 after first dose) and 30 - 37 days after last dose of therapy
• Maximum concentration (Cmin) (ramucirumab + placebo) [ Time Frame: Cycle 4, Day 1 ]
  Prior to (within Pretreatment period) 1st ramucirumab infusion, prior to 4th ramucirumab infusion ( ~ week 6 after 1st dose), prior to 7th ramucirumab infusion (~ week 12 after first dose) and 30 - 37 days after last dose of therapy

Current Other Pre-specified Outcome Measures (submitted: July 1, 2014)

Number of Participants With Serious and Other Non-serious Adverse Events (AE) and Who Died [ Time Frame: Baseline up to 103 weeks and within 30 days of last dose of study drug ]

Participants who died or who had clinically significant events defined as serious AEs (SAEs) and other non-serious AEs (regardless of causality). A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Paclitaxel With or Without Ramucirumab (IMC-1211B) in Metastatic Gastric Adenocarcinoma
• Official Title: 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
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Gastric Cancer

Intervention

• Biological: Ramucirumab (IMC-1211B) DP
  8 milligrams/kilogram (mg/kg) intravenous (IV) infusion on Days 1 and 15 of every 4-week cycle
  Other Names:

  • LY3009806
  • IMC-1211B
• Drug: Placebo
  Ramucirumab placebo IV infusion on Days 1 and 15 of every 4-week cycle
• Drug: Paclitaxel
  Paclitaxel 80 milligrams per square meter (mg/m²) IV infusion on Days 1, 8, and 15 of every 4-week cycle

Study Arms

• Experimental: Ramucirumab (IMC-1211B) Drug Product (DP) and Paclitaxel
  Ramucirumab (IMC-1211B) DP and Paclitaxel
  Interventions:

  • Biological: Ramucirumab (IMC-1211B) DP
  • Drug: Paclitaxel
• Placebo Comparator: Placebo and Paclitaxel
  Placebo and Paclitaxel
  Interventions:

  • Drug: Placebo
  • Drug: Paclitaxel

Publications *

• Mitani S, Chen Y, Inoue K, Mori J, Gao L, Long A, Wakabayashi S. Clinical Impact of a Shortened Infusion Duration of Ramucirumab in Japanese Patients -A Model-Based Approach. Gan To Kagaku Ryoho. 2021 Nov;48(11):1381-1387.
• Yamaguchi K, Shimada Y, Hironaka S, Sugimoto N, Komatsu Y, Nishina T, Omuro Y, Tamura T, Piao Y, Homma G, Jen MH, Liepa AM, Muro K. Quality of Life Associated with Ramucirumab Treatment in Patients with Advanced Gastric Cancer in Japan: Exploratory Analysis from the Phase III RAINBOW Trial. Clin Drug Investig. 2021 Jan;41(1):53-64. doi: 10.1007/s40261-020-00979-3. Epub 2020 Dec 23.
• Cascinu S, Bodoky G, Muro K, Van Cutsem E, Oh SC, Folprecht G, Ananda S, Girotto G, Wainberg ZA, Miron MLL, Ajani J, Wei R, Liepa AM, Carlesi R, Emig M, Ohtsu A. Tumor Response and Symptom Palliation from RAINBOW, a Phase III Trial of Ramucirumab Plus Paclitaxel in Previously Treated Advanced Gastric Cancer. Oncologist. 2021 Mar;26(3):e414-e424. doi: 10.1002/onco.13623. Epub 2020 Dec 23.
• De Vita F, Borg C, Farina G, Geva R, Carton I, Cuku H, Wei R, Muro K. Ramucirumab and paclitaxel in patients with gastric cancer and prior trastuzumab: subgroup analysis from RAINBOW study. Future Oncol. 2019 Aug;15(23):2723-2731. doi: 10.2217/fon-2019-0243. Epub 2019 Jun 25. Erratum In: Future Oncol. 2021 Sep;17(25):3409.
• Chau I, Fuchs CS, Ohtsu A, Barzi A, Liepa AM, Cui ZL, Hsu Y, Al-Batran SE. Association of quality of life with disease characteristics and treatment outcomes in patients with advanced gastric cancer: Exploratory analysis of RAINBOW and REGARD phase III trials. Eur J Cancer. 2019 Jan;107:115-123. doi: 10.1016/j.ejca.2018.11.013. Epub 2018 Dec 14.
• Tabernero J, Ohtsu A, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Ajani JA, Tomasek J, Safran H, Chandrawansa K, Hsu Y, Heathman M, Khan A, Ni L, Melemed AS, Gao L, Ferry D, Fuchs CS. Exposure-Response Analyses of Ramucirumab from Two Randomized, Phase III Trials of Second-line Treatment for Advanced Gastric or Gastroesophageal Junction Cancer. Mol Cancer Ther. 2017 Oct;16(10):2215-2222. doi: 10.1158/1535-7163.MCT-16-0895. Epub 2017 Jul 17.
• Al-Batran SE, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov ON, Kim TY, Cunningham D, Rougier P, Muro K, Liepa AM, Chandrawansa K, Emig M, Ohtsu A, Wilke H. Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma. Ann Oncol. 2016 Apr;27(4):673-9. doi: 10.1093/annonc/mdv625. Epub 2016 Jan 7.
• Shitara K, Muro K, Shimada Y, Hironaka S, Sugimoto N, Komatsu Y, Nishina T, Yamaguchi K, Segawa Y, Omuro Y, Tamura T, Doi T, Yukisawa S, Yasui H, Nagashima F, Gotoh M, Esaki T, Emig M, Chandrawansa K, Liepa AM, Wilke H, Ichimiya Y, Ohtsu A. Subgroup analyses of the safety and efficacy of ramucirumab in Japanese and Western patients in RAINBOW: a randomized clinical trial in second-line treatment of gastric cancer. Gastric Cancer. 2016 Jul;19(3):927-38. doi: 10.1007/s10120-015-0559-z. Epub 2015 Oct 28.
• Wilke H, Muro K, Van Cutsem E, Oh SC, Bodoky G, Shimada Y, Hironaka S, Sugimoto N, Lipatov O, Kim TY, Cunningham D, Rougier P, Komatsu Y, Ajani J, Emig M, Carlesi R, Ferry D, Chandrawansa K, Schwartz JD, Ohtsu A; RAINBOW Study Group. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1224-35. doi: 10.1016/S1470-2045(14)70420-6. Epub 2014 Sep 17.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 1, 2012): 665
• Original Estimated Enrollment (submitted: July 26, 2010): 663
• Actual Study Completion Date: February 2017
• Actual Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Chile, Estonia, France, Germany, Hungary, Israel, Italy, Japan, Korea, Republic of, Lithuania, Mexico, Poland, Portugal, Romania, Russian Federation, Singapore, Spain, Taiwan, United Kingdom, United States
• Removed Location Countries: Hong Kong

Administrative Information

• NCT Number: NCT01170663
• Other Study ID Numbers: 13894; I4T-IE-JVBE ( Other Identifier: Eli Lilly and Company ); CP12-0922 ( Other Identifier: ImClone Systems ); 2010-020426-18 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: https://vivli.org/

• Current Responsible Party: Eli Lilly and Company
• Original Responsible Party: Chief Medical Officer, ImClone LLC
• Current Study Sponsor: Eli Lilly and Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

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

• PRS Account: Eli Lilly and Company
• Verification Date: September 2019