A Randomized Phase II Study of Irinotecan and Cetuximab With or Without the Anti-Angiogenic Antibody, Ramucirumab (IMC-1121B), in Advanced, K-ras Wild-Type Colorectal Cancer Following Progression on Bevacizumab-Containing Chemotherapy
Overview
- Phase
- Phase 2
- Intervention
- cetuximab
- Conditions
- Colorectal Cancer
- Sponsor
- Eastern Cooperative Oncology Group
- Enrollment
- 136
- Locations
- 254
- Primary Endpoint
- Progression-free Survival
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
RATIONALE: Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab and ramucirumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab and ramucirumab may also stop the growth of colorectal cancer by blocking blood flow to the tumor. It is not yet know whether giving cetuximab and irinotecan hydrochloride together is more effective with or without ramucirumab in treating colorectal cancer.
PURPOSE: This randomized phase II trial is studying the side effects and how well giving cetuximab and irinotecan hydrochloride with or without ramucirumab work in treating patients with advanced colorectal cancer with progressive disease after treatment with bevacizumab-containing chemotherapy.
Detailed Description
OBJECTIVES: * To evaluate the progression-free survival of patients with advanced K-ras wild-type colorectal cancer, following progression on bevacizumab-contained chemotherapy, treated with irinotecan hydrochloride and cetuximab with versus without ramucirumab as second-line therapy. * To evaluate the response rate in patients treated with these regimens. * To evaluate the grade 3-4 toxicity rates of these regimens in these patients. * To evaluate the overall survival of patients treated with these regimens. OUTLINE: This is a multicenter, randomized study. Patients are stratified according to performance status (0 vs 1), discontinuation of oxaliplatin before disease progression (yes vs no), and time to disease progression since last treatment (≤ 6 months vs \> 6 months). Patients are randomized to 1 of 2 treatment arms. * Arm A: Patients receive cetuximab IV over 60-120 minutes and irinotecan hydrochloride over 60-90 minutes on day 1. * Arm B: Patients receive ramucirumab IV over 60 minutes on day 1 and cetuximab and irinotecan hydrochloride as in arm A. Arm B was closed early due to excessive toxicities and Arm C was then added to the study with reduced dose of protocol drugs. * Arm C: Patients receive reduced dose of ramucirumab, cetuximab and irinotecan hydrochloride as in arm B. In all arms, courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed up periodically for 5 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Measurable disease
- •Histologically confirmed adenocarcinoma of the colon or rectum
- •K-ras wild type based on either primary or metastatic tumor
- •Must have received prior first-line therapy comprising oxaliplatin-based fluoropyrimidine-containing chemotherapy and bevacizumab for metastatic colorectal cancer
- •Registration within 42 days since confirmed disease progression
- •Performance status 0-1
- •ANC ≥ 1,500/μL
- •Platelet count ≥ 75,000/μL
- •Hemoglobin ≥ 9 g/dL
- •Serum creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 40 mL/min
Exclusion Criteria
- •Brain or CNS metastases
- •Pregnant or nursing
- •Prior therapy with drugs other than oxaliplatin and a fluoropyrimidine plus bevacizumab for colorectal cancer
- •Clinically significant (equivalent to NCI CTCAE grade 3-4) bleeding episodes within the past 3 months
- •Active infection
- •Symptomatic congestive heart failure
- •Unstable angina pectoris
- •Symptomatic or poorly controlled cardiac arrhythmia
- •Uncontrolled thrombotic or hemorrhagic disorder
- •Uncontrolled or poorly controlled hypertension despite standard medical management (e.g., consistently systolic BP \> 160 mm Hg and diastolic BP \> 90 mm Hg)
Arms & Interventions
Arm A (IC)
Patients receive cetuximab (500 mg/m2) intravenously (IV) over 60-120 minutes and irinotecan hydrochloride (180 mg/m2) over 60-90 minutes on day 1. Treatment repeats every 2 weeks until disease progression or unacceptable toxicities.
Intervention: cetuximab
Arm A (IC)
Patients receive cetuximab (500 mg/m2) intravenously (IV) over 60-120 minutes and irinotecan hydrochloride (180 mg/m2) over 60-90 minutes on day 1. Treatment repeats every 2 weeks until disease progression or unacceptable toxicities.
Intervention: irinotecan hydrochloride
Arm B (ICR)
Patients receive ramucirumab (8 mg/kg) IV over 60 minutes on day 1 and cetuximab and irinotecan hydrochloride as in arm A. Treatment repeats every 2 weeks until disease progression or unacceptable toxicities.
Intervention: cetuximab
Arm B (ICR)
Patients receive ramucirumab (8 mg/kg) IV over 60 minutes on day 1 and cetuximab and irinotecan hydrochloride as in arm A. Treatment repeats every 2 weeks until disease progression or unacceptable toxicities.
Intervention: ramucirumab
Arm B (ICR)
Patients receive ramucirumab (8 mg/kg) IV over 60 minutes on day 1 and cetuximab and irinotecan hydrochloride as in arm A. Treatment repeats every 2 weeks until disease progression or unacceptable toxicities.
Intervention: irinotecan hydrochloride
Arm C (mICR)
Patients receive reduced dose of ramucirumab (6 mg/kg) IV over 60 minutes on day 1 and cetuximab (150 mg/m2) and irinotecan hydrochloride (400 mg/m2) as in arm B. Treatment repeats every 2 weeks until disease progression or unacceptable toxicities.
Intervention: cetuximab
Arm C (mICR)
Patients receive reduced dose of ramucirumab (6 mg/kg) IV over 60 minutes on day 1 and cetuximab (150 mg/m2) and irinotecan hydrochloride (400 mg/m2) as in arm B. Treatment repeats every 2 weeks until disease progression or unacceptable toxicities.
Intervention: ramucirumab
Arm C (mICR)
Patients receive reduced dose of ramucirumab (6 mg/kg) IV over 60 minutes on day 1 and cetuximab (150 mg/m2) and irinotecan hydrochloride (400 mg/m2) as in arm B. Treatment repeats every 2 weeks until disease progression or unacceptable toxicities.
Intervention: irinotecan hydrochloride
Outcomes
Primary Outcomes
Progression-free Survival
Time Frame: Assessed every 3 months for 2 years, every 6 months for the 3rd year, then annually up to 5 years
Progression-fee survival is defined as the time from randomization to disease progression or death without documentation of progression. Censoring occurred at the date of last disease assessment without progression for cases without documentation of progression, except for cases where death occurred within a short period of time (4 months) following the date last known progression-free, in which case the death was considered an event. Progression is defined as appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions or at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Secondary Outcomes
- Proportion of Participants With an Objective Response Rate (CR or PR)(Assessed every 3 months for 2 years, every 6 months for the 3rd year, then annually up to 5 years)
- Proportion of Patients With Grade 3 or Higher Treatment-related Adverse Events(Assessed every 2 weeks while on treatment and for 30 days after the end of treatment)
- Overall Survival(Assessed every 3 months for 2 years, every 6 months for the 3rd year, then annually up to 5 years)