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

• Severe adverse event (SAE) rate [ Time Frame: Up to 8 weeks ] [ Designated as safety issue: Yes ]
• PFS rate [ Time Frame: Up to 6 years ] [ Designated as safety issue: No ]
  This regimen would be considered promising with respect to PFS rate if at least 40/67 patients (> 60%) demonstrated PFS of > 8 months, and it would be considered promising with respect to response rate if at least 32 patients (48%) demonstrated an objective response. This design yields approximately 85% power to detect either a true 65% 8 month PFS rate, or a true 55% response rate, for the two endpoint outcome probabilities calculated separately.

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.

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 Folfox 6/bevacizumab/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.

• Adenocarcinoma of the Rectum
• Mucinous Adenocarcinoma of the Colon
• Recurrent Colon Cancer
• Recurrent Rectal Cancer
• Signet Ring Adenocarcinoma of the Colon
• Stage IVA Colon Cancer
• Stage IVA Rectal Cancer
• Stage IVB Colon Cancer
• Stage IVB Rectal Cancer

• Biological: cetuximab
  Given IV
  Other Names:

  • C225
  • C225 monoclonal antibody
  • IMC-C225
  • MOAB C225
  • monoclonal antibody C225
• Biological: bevacizumab
  Given IV
  Other Names:

  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • Avastin
  • rhuMAb VEGF
• Drug: oxaliplatin
  Given IV
  Other Names:

  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
• Drug: leucovorin calcium
  Given IV
  Other Names:

  • CF
  • CFR
  • LV
• Drug: fluorouracil
  Given IV
  Other Names:

  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU

Inclusion Criteria:

• Patients must have 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")
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral CT scan
• Patients previously treated with one chemotherapy regimen that did not include oxaliplatin, bevacizumab or cetuximab may be enrolled to this trial
• 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 women are excluded from this study because oxaliplatin is a platinating agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with oxaliplatin, breastfeeding should be discontinued if the mother is treated with oxaliplatin; both men and women must agree to use birth control pills or other active abortifacient; furthermore, at least 3 months must have elapsed between the last pill of cetuximab and bevacizumab therapy; patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy; therefore, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with oxaliplatin or other agents administered during the study; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated
• 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