Phase II Study of Treatment Selection Based Upon Tumor Thymidylate Synthase Expression in Previously Untreated Patients With Metastatic Colorectal Cancer
Trial Snapshot
- Phase
- Phase 2
- Status
- Completed
- Enrollment
- 247
- Locations
- 110
- Primary Endpoint
- Objective Response Rate
Study Overview
Brief Summary
RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, irinotecan, leucovorin, and fluorouracil, 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 bevacizumab, 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. Bevacizumab may also stop the growth of colorectal cancer by blocking blood flow to the tumor. Giving bevacizumab together with combination chemotherapy may be a better way to block tumor growth. Studying the amount of an enzyme found in the tumor may help doctors plan the best treatment.
PURPOSE: This randomized phase II trial is studying giving bevacizumab, oxaliplatin, and irinotecan or giving bevacizumab, oxaliplatin, leucovorin, and fluorouracil in treating patients with metastatic or recurrent colorectal cancer.
Detailed Description
OBJECTIVES:
- Compare the response rate (complete and partial), progression-free survival, and overall survival of patients with previously untreated metastatic or locally recurrent colorectal adenocarcinoma with high vs low thymidylate synthase (TS) expression treated with fluorouracil, leucovorin calcium, oxaliplatin, and bevacizumab or irinotecan, oxaliplatin, and bevacizumab.
- Compare the toxicity of these regimens in these patients.
- Correlate gene expression with response rates in patients treated with these regimens.
- Correlate gene expression with toxicity of these regimens in these patients.
- Correlate dihydropyrimidine dehydrogenase, thymidine phosphorylase, and mammalian excision repair cross complementary protein expression with antitumor response in patients treated with these regimens.
OUTLINE: This is a randomized, multicenter study. Patients are stratified according to thymidylate synthase (TS) expression levels (high vs low or indeterminate). Patients with high TS expression are randomized to 1 of 2 treatment arms (Arms A or B). Patients with low or indeterminate TS expression are assigned to Arm C.
- Arm A: Patients receive bevacizumab IV over 30-90 minutes followed by oxaliplatin IV over 2 hours and irinotecan IV over 90 minutes on days 1 and 15.
- Arm B: Patients receive bevacizumab and oxaliplatin as in arm A, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15.
- Arm C: Patients receive bevacizumab, oxaliplatin, leucovorin calcium, and fluorouracil as in arm B.
In all arms, courses repeat every 28 days in the absence of unacceptable toxicity or disease progression.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- Not provided
Exclusion Criteria
- Not provided
Arms & Interventions
Arm A (High TS, IROX/bev)
Patients with high TS who are randomized to Arm A receive irinotecan and oxaliplatin plus bevacizumab (IROX/bev). The combination regimen is administered by giving bevacizumab IV over 30-90 minutes followed by oxaliplatin IV over 2 hours and irinotecan IV over 90 minutes on days 1 and 15 every 28 days until disease progression or until any criterion specified in protocol is met.
Intervention: bevacizumab (Biological)
Arm A (High TS, IROX/bev)
Patients with high TS who are randomized to Arm A receive irinotecan and oxaliplatin plus bevacizumab (IROX/bev). The combination regimen is administered by giving bevacizumab IV over 30-90 minutes followed by oxaliplatin IV over 2 hours and irinotecan IV over 90 minutes on days 1 and 15 every 28 days until disease progression or until any criterion specified in protocol is met.
Intervention: irinotecan hydrochloride (Drug)
Arm A (High TS, IROX/bev)
Patients with high TS who are randomized to Arm A receive irinotecan and oxaliplatin plus bevacizumab (IROX/bev). The combination regimen is administered by giving bevacizumab IV over 30-90 minutes followed by oxaliplatin IV over 2 hours and irinotecan IV over 90 minutes on days 1 and 15 every 28 days until disease progression or until any criterion specified in protocol is met.
Intervention: Oxaliplatin (Drug)
Arm B (High TS, FOLFOX/bev)
Patients with high TS who are randomized to Arm B receive 5-Fluorouracil, leucovorin, oxaliplatin, and bevacizumab (FOLFOX/bev). The combination regimen is administered by giving bevacizumab and oxaliplatin as in Arm A, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15 every 28 days until disease progression or until any criterion specified in protocol is met.
Intervention: bevacizumab (Biological)
Arm B (High TS, FOLFOX/bev)
Patients with high TS who are randomized to Arm B receive 5-Fluorouracil, leucovorin, oxaliplatin, and bevacizumab (FOLFOX/bev). The combination regimen is administered by giving bevacizumab and oxaliplatin as in Arm A, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15 every 28 days until disease progression or until any criterion specified in protocol is met.
Intervention: fluorouracil (Drug)
Arm B (High TS, FOLFOX/bev)
Patients with high TS who are randomized to Arm B receive 5-Fluorouracil, leucovorin, oxaliplatin, and bevacizumab (FOLFOX/bev). The combination regimen is administered by giving bevacizumab and oxaliplatin as in Arm A, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15 every 28 days until disease progression or until any criterion specified in protocol is met.
Intervention: leucovorin calcium (Drug)
Arm B (High TS, FOLFOX/bev)
Patients with high TS who are randomized to Arm B receive 5-Fluorouracil, leucovorin, oxaliplatin, and bevacizumab (FOLFOX/bev). The combination regimen is administered by giving bevacizumab and oxaliplatin as in Arm A, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15 every 28 days until disease progression or until any criterion specified in protocol is met.
Intervention: Oxaliplatin (Drug)
Arm C (Low or intermediate TS, FOLFOX/bev)
Patients with low or intermediate TS receive 5-Fluorouracil, leucovorin, oxaliplatin, and bevacizumab (FOLFOX/bev) as in Arm B.
Intervention: bevacizumab (Biological)
Arm C (Low or intermediate TS, FOLFOX/bev)
Patients with low or intermediate TS receive 5-Fluorouracil, leucovorin, oxaliplatin, and bevacizumab (FOLFOX/bev) as in Arm B.
Intervention: fluorouracil (Drug)
Arm C (Low or intermediate TS, FOLFOX/bev)
Patients with low or intermediate TS receive 5-Fluorouracil, leucovorin, oxaliplatin, and bevacizumab (FOLFOX/bev) as in Arm B.
Intervention: leucovorin calcium (Drug)
Arm C (Low or intermediate TS, FOLFOX/bev)
Patients with low or intermediate TS receive 5-Fluorouracil, leucovorin, oxaliplatin, and bevacizumab (FOLFOX/bev) as in Arm B.
Intervention: Oxaliplatin (Drug)
Outcomes
Primary Outcomes
Objective Response Rate
Time Frame: Assessed every 3 months if the patient is within 2 years of registration and every 6 months up to 4 years post-registration.
Objective response rate is defined as proportion of patients who achieve complete response (CR) or partial response (PR). Response was assessed using Solid Tumor Response Criteria (RECIST). CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter.
Secondary Outcomes
- Overall Survival (OS)(Assessed every 3 months if the patient is within 2 years of registration and every 6 months once the patient is 2-4 years post-registration.)
- Progression-Free Survival (PFS)(Assessed every 3 months if the patient is within 2 years of registration and every 6 months once the patient is 2-4 years post-registration.)