Phase II Trial of FOLFOX6, Bevacizumab and Cetuximab in Patients With Colorectal Cancer

Phase 2

Completed

Conditions: Signet Ring Adenocarcinoma of the Colon
Mucinous Adenocarcinoma of the Colon
Stage IV Rectal Cancer
Recurrent Colon Cancer
Adenocarcinoma of the Rectum
Recurrent Rectal Cancer
Stage IV Colon Cancer

Interventions: Biological: cetuximab
Biological: bevacizumab
Drug: oxaliplatin
Drug: leucovorin calcium
Drug: fluorouracil

Registration Number: NCT00100841

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Drugs used in chemotherapy 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 and cetuximab, 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 combination chemotherapy together with bevacizumab and cetuximab may kill more tumor cells. This phase II trial is studying how well giving combination chemotherapy together with bevacizumab and cetuximab works in treating patients with stage IV colorectal cancer that cannot be removed by surgery.

Detailed Description: PRIMARY OBJECTIVES:

I. To determine the safety, feasibility of administration, response rates and progression free survival among chemotherapy naïve patients with advanced colorectal cancer treated with FOLFOX6 plus bevacizumab and cetuximab (FBC).

II. To determine the survival of patients with advanced colorectal cancer treated with FBC.

III. To determine the safety of the current regimen in selected patients who have had prior MoAb therapy.

OUTLINE: This is a multicenter study.

Patients receive cetuximab IV over 60-120 minutes on day 1 in weeks 1-8. Patients also receive bevacizumab IV over 30-90 minutes, oxaliplatin IV over 2 hours, and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 48 hours on days 1 and 2 of weeks 1, 3, 5, and 7. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.

Patients are followed for survival.

PROJECTED ACCRUAL: A total of 40-67 patients will be accrued for this study.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 66

Inclusion Criteria

Histologically or cytologically confirmed adenocarcinoma of the colon or rectum which is beyond the scope of surgical resection (MEDRA code:"Colorectal neoplasms malignant","Colorectal cancer stage IV","10010035")
Measurable disease,
Life expectancy of greater than 3 months
ECOG performance status =< 1
Leukocytes >= 3,500/uL
Absolute neutrophil count >= 1,500/uL
Platelets >= 150,000/uL
Total bilirubin within normal institutional limits
AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal
Creatinine within normal institutional limits
Patients may not have received prior therapy with bevacizumab or cetuximab
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Patients who have had radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to radiotherapy administered more than 4 weeks earlier
Patients may not be receiving any other investigational agents
Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
History of allergic reactions attributed to compounds of similar chemical or biologic composition to any of the agents used in the study
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
Pregnant or lactating women
Serious or non-healing wound, ulcer or bone fracture
Invasive procedures defined as follows:
- Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to Day 1 therapy
- Anticipation of need for major surgical procedures during the course of the study
- Core biopsy within 7 days prior to D1 therapy
If a patient is on full-dose anticoagulants, the following criteria should be met for enrollment:
- The subject must have an in-range INR (usually between 2 and 3) on a stable dose of warfarin or on stable dose of LMW heparin
- The subject must not have active bleeding or pathological conditions that carry high risk of bleeding (e.g. tumor involving major vessels, known varices)
Active infection requiring parental antibiotics on D1
Proteinuria at baseline; subjects unexpectedly discovered to have >= 1+ proteinuria will undergo a 24-hour urine collection, which will be < 1000 mg protein/ 24 hours to be allowed participation in the study
No currently active second malignancy other than non-melanoma skin cancer or carcinoma in-situ of the cervix; patients are not considered to have a "currently active" malignancy if they have completed therapy and have no evidence of recurrence for at least 5 years
Patients with clinically significant cardiovascular disease:
- Uncontrolled hypertension
- Myocardial infarction or unstable angina < 6 months prior to registration
- New York heart association grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication, unstable angina pectoris
- Grade II or greater peripheral vascular disease
- CVA within 6 months of study entry

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (combination chemotherapy)	cetuximab	Patients receive cetuximab IV over 60-120 minutes on day 1 in weeks 1-8. Patients also receive bevacizumab IV over 30-90 minutes, oxaliplatin IV over 2 hours, and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 48 hours on days 1 and 2 of weeks 1, 3, 5, and 7. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (combination chemotherapy)	bevacizumab	Patients receive cetuximab IV over 60-120 minutes on day 1 in weeks 1-8. Patients also receive bevacizumab IV over 30-90 minutes, oxaliplatin IV over 2 hours, and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 48 hours on days 1 and 2 of weeks 1, 3, 5, and 7. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (combination chemotherapy)	leucovorin calcium	Patients receive cetuximab IV over 60-120 minutes on day 1 in weeks 1-8. Patients also receive bevacizumab IV over 30-90 minutes, oxaliplatin IV over 2 hours, and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 48 hours on days 1 and 2 of weeks 1, 3, 5, and 7. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (combination chemotherapy)	oxaliplatin	Patients receive cetuximab IV over 60-120 minutes on day 1 in weeks 1-8. Patients also receive bevacizumab IV over 30-90 minutes, oxaliplatin IV over 2 hours, and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 48 hours on days 1 and 2 of weeks 1, 3, 5, and 7. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
Treatment (combination chemotherapy)	fluorouracil	Patients receive cetuximab IV over 60-120 minutes on day 1 in weeks 1-8. Patients also receive bevacizumab IV over 30-90 minutes, oxaliplatin IV over 2 hours, and leucovorin calcium IV over 2 hours on day 1, and fluorouracil IV continuously over 48 hours on days 1 and 2 of weeks 1, 3, 5, and 7. Courses repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Severe Adverse Event (SAE) Rate	The duration of the study	The primary objective is to evaluate safety in all treated patients specifically the rate of serious adverse events which were defined as grade 5 events, grade 4 hemorrhage or thrombosis or bowel perforation
Progression Free Survival Rate	From randomization to the first documented disease progression

Secondary Outcome Measures