A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of Capecitabine and Cisplatin With or Without Ramucirumab as First-line Therapy in Patients With Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma (RAINFALL)
Overview
- Phase
- Phase 3
- Intervention
- Ramucirumab
- Conditions
- Metastatic Gastric Adenocarcinoma
- Sponsor
- Eli Lilly and Company
- Enrollment
- 645
- Locations
- 31
- Primary Endpoint
- Progression-free Survival (PFS)
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
The main purpose of this study is to evaluate the efficacy of ramucirumab, which is a targeted antibody, in combination with capecitabine and cisplatin compared to capecitabine and cisplatin alone in participants with stomach cancer.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Have a histopathologically confirmed diagnosis of metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. All histologies of nonsquamous cell origin including undifferentiated gastric carcinoma are eligible.
- •Have not received any prior first-line systemic therapy (prior adjuvant or neo-adjuvant therapy is permitted). Participants whose disease has progressed after \>12 months following the last dose of systemic treatment in the adjuvant/neoadjuvant setting are eligible.
- •Have measurable or nonmeasurable but evaluable disease determined using guidelines in Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v 1.1). Baseline tumor assessment should be performed using a high resolution computed tomography (CT) scan using IV and oral contrast unless clinically contra-indicated. Magnetic resonance imaging (MRI) is acceptable if a CT cannot be performed.
- •Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group scale at baseline.
- •Have adequate organ function.
- •Have baseline clinical and laboratory parameters that are consistent with the requirements prescribed in respective labels and are suitable for consideration of treatment with capecitabine (or 5-FU) and cisplatin (for example, dihydropyrimidine dehydrogenase deficiency).
- •Have an estimated life expectancy of ≥12 weeks in the judgment of the investigator.
Exclusion Criteria
- •Participants with adenocarcinoma of the esophagus are excluded.
- •Participants with human epidermal growth factor receptor 2 (HER2)-positive status.
- •Participants receiving chronic therapy with nonsteroidal anti-inflammatory agents.
- •Have radiation therapy within 14 days prior to randomization.
- •Have documented brain metastases, leptomeningeal disease or uncontrolled spinal cord compression.
- •Have significant bleeding disorders, vasculitis, or had a significant bleeding episode from the gastrointestinal tract within 12 weeks prior to randomization.
- •Have experienced any arterial thromboembolic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to randomization.
- •Have symptomatic congestive heart failure (New York Heart Association II-IV) or symptomatic or poorly controlled cardiac arrhythmia.
- •Have uncontrolled hypertension prior to initiating study treatment, despite antihypertensive intervention.
- •Have undergone major surgery within 28 days prior to randomization, or central venous access device placement within 7 days prior to first dose of study treatment, except if the procedure is minimally invasive (for example, introduction of peripherally inserted central catheter \[PICC\] line) and the investigator does not anticipate any significant bleeding.
Arms & Interventions
Ramucirumab + Cisplatin + Capecitabine
8 milligrams/kilogram (mg/kg) ramucirumab given intravenously (IV) on days 1 and 8 in combination with 80 mg/square meter (m\^2) cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m\^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m\^2/day fluorouracil (5-FU) IV on days 1 to 5 of each 21-day cycle.
Intervention: Ramucirumab
Ramucirumab + Cisplatin + Capecitabine
8 milligrams/kilogram (mg/kg) ramucirumab given intravenously (IV) on days 1 and 8 in combination with 80 mg/square meter (m\^2) cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m\^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m\^2/day fluorouracil (5-FU) IV on days 1 to 5 of each 21-day cycle.
Intervention: Capecitabine
Ramucirumab + Cisplatin + Capecitabine
8 milligrams/kilogram (mg/kg) ramucirumab given intravenously (IV) on days 1 and 8 in combination with 80 mg/square meter (m\^2) cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m\^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m\^2/day fluorouracil (5-FU) IV on days 1 to 5 of each 21-day cycle.
Intervention: Cisplatin
Ramucirumab + Cisplatin + Capecitabine
8 milligrams/kilogram (mg/kg) ramucirumab given intravenously (IV) on days 1 and 8 in combination with 80 mg/square meter (m\^2) cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m\^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m\^2/day fluorouracil (5-FU) IV on days 1 to 5 of each 21-day cycle.
Intervention: Fluorouracil
Placebo + Cisplatin + Capecitabine
Placebo for blinding given IV on days 1 and 8 in combination with 80 mg/m\^2 cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m\^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m\^2/day 5-FU IV on days 1 to 5 of each 21-day cycle.
Intervention: Capecitabine
Placebo + Cisplatin + Capecitabine
Placebo for blinding given IV on days 1 and 8 in combination with 80 mg/m\^2 cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m\^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m\^2/day 5-FU IV on days 1 to 5 of each 21-day cycle.
Intervention: Cisplatin
Placebo + Cisplatin + Capecitabine
Placebo for blinding given IV on days 1 and 8 in combination with 80 mg/m\^2 cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m\^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m\^2/day 5-FU IV on days 1 to 5 of each 21-day cycle.
Intervention: Placebo
Placebo + Cisplatin + Capecitabine
Placebo for blinding given IV on days 1 and 8 in combination with 80 mg/m\^2 cisplatin given IV on day 1 of each 21-day cycle (for up to 6 cycles) and 1000 mg/m\^2 capecitabine given orally twice a day on days 1 through 14. Participants that were unable to take capecitabine will be given 800 mg/m\^2/day 5-FU IV on days 1 to 5 of each 21-day cycle.
Intervention: Fluorouracil
Outcomes
Primary Outcomes
Progression-free Survival (PFS)
Time Frame: Randomization to Radiological Disease Progression or Death from Any Cause (Up to 26 Months)
PFS time was measured from the date of randomization to the date of radiographic(rgr) documentation of progression(by RECIST v.1.1) or the date of death due to any cause, whichever was earlier.If a participant did not have a complete baseline tumor assessment,then the PFS time was censored at the randomization date.If a participant was not known to have died or have rgr documented progression as of the data cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. If death or progressive disease(PD) occurred after 2 or more consecutive missing rgr visits,censoring occurred at the date of the last rgr visit prior to the missed visits.If death or PD occurred after postdiscontinuation(pdis) systemic anticancer therapy,censoring occurred at the date of last rgr visit prior to the start of pdis systemic anticancer therapy. PD was defined according to RECIST v.1.1.
Secondary Outcomes
- Overall Survival (OS)(Randomization to Death from Any Cause (Up To 30 Months))
- Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR])(Randomization to Disease Progression (Up To 26 Months))
- Progression- Free Survival 2 (PFS2)(Randomization to Second Radiological or Symptomatic Disease Progression After the Start of Additional Systemic Anticancer Treatment or Death from Any Cause (Up To 26 Months))
- Time to Progression (TTP)(Randomization to Disease Progression (Up To 24 Months))
- Change in Health Status on the EuroQol 5-Dimensions 5-Level Instrument (EQ-5D- 5L)(Randomization, 30 Days After Treatment Discontinuation (Up To 5 Months))
- Percentage of Participants With Complete Response (CR), Partial Response (PR) or Stable Disease (SD) (Disease Control Rate [DCR])(Randomization to Disease Progression (Up To 26 Months))
- Duration of Response (DoR)(Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Up To 26 Months))
- Time to Deterioration in Quality of Life (QoL) on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) - Global Health Status/ QoL Scale(Randomization, First worsening in QoL (Up To 26 Months))
- Time to Deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)(Randomization to ECOG PS ≥2 (Up To 26 Months))
- Number of Participants With Anti-Ramucirumab Antibodies(Predose Cycle 1 through 30 Days After Treatment Discontinuation (Up To 24 Months))
- Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) of Ramucirumab(Cycle 1 Day 1: 1 hour (hr) end of infusion (EOI), Cycle 3 Day 1: 1hr EOI, Cycle 9 Day 1: 1 hr EOI)
- PK: Minimum Concentration (Cmin) of Ramucirumab(Cycle 1 Day 1: 1 hour (hr) end of infusion (EOI), Cycle 3 Day 1: 1hr EOI, Cycle 9 Day 1: 1 hr EOI)