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

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.

Study Overview

• Status: Completed
• Conditions: Mucinous Adenocarcinoma of the Colon; Signet Ring Adenocarcinoma of the Colon; Stage IV Colon Cancer; Stage IV Rectal Cancer; Recurrent Colon Cancer; Recurrent Rectal Cancer; Adenocarcinoma of the Rectum
• Intervention / Treatment: Biological: bevacizumab; Drug: oxaliplatin; Drug: leucovorin calcium; Drug: fluorouracil; Biological: cetuximab

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.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10467-2490
      • Montefiore Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (combination chemotherapy); 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.

Biological: bevacizumab; Given IV; Other Names: Avastin; anti-VEGF humanized monoclonal antibody; anti-VEGF monoclonal antibody; 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-FU; 5-fluorouracil; 5-Fluracil; Biological: cetuximab; Given IV; Other Names: C225; IMC-C225; C225 monoclonal antibody; MOAB C225; monoclonal antibody C225

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severe Adverse Event (SAE) Rate	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	The duration of the study
Progression Free Survival Rate		From randomization to the first documented disease progression

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Allyson Ocean, Montefiore Medical Center

Publications and helpful links

General Publications

• Ocean AJ, Polite B, Christos P, Horvath L, Hamilton A, Matulich D, Chen HX, Sparano JA, Kindler HL. Cetuximab is associated with excessive toxicity when combined with bevacizumab Plus mFOLFOX6 in metastatic colorectal carcinoma. Clin Colorectal Cancer. 2010 Dec;9(5):290-6. doi: 10.3816/CCC.2010.n.042.

Study record dates

Study Major Dates

• Study Start: November 1, 2004
• Primary Completion (Actual): July 1, 2011
• Study Completion (Actual): July 1, 2011

Study Registration Dates

• First Submitted: January 6, 2005
• First Submitted That Met QC Criteria: January 6, 2005
• First Posted (Estimate): January 7, 2005

Study Record Updates

• Last Update Posted (Estimate): July 27, 2015
• Last Update Submitted That Met QC Criteria: June 26, 2015
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Neoplasms, Cystic, Mucinous, and Serous; Recurrence; Adenocarcinoma; Rectal Neoplasms; Cystadenocarcinoma; Colonic Neoplasms; Adenocarcinoma, Mucinous; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Antidotes; Vitamin B Complex; Antibodies; Fluorouracil; Oxaliplatin; Immunoglobulins; Bevacizumab; Leucovorin; Levoleucovorin; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Cetuximab
• Other Study ID Numbers: NCI-2012-03006; N01CM62201 (U.S. NIH Grant/Contract); N01CM62204 (U.S. NIH Grant/Contract); NCI-6490 (Other Identifier: CTEP ID)