Cetuximab + Best Supportive Care Compared With Best Supportive Care Alone in Metastatic Epidermal Growth Factor Receptor-Positive Colorectal Cancer

A Phase III Randomized Study of Cetuximab (Erbitux™, C225) and Best Supportive Care Versus Best Supportive Care in Patients With Pretreated Metastatic Epidermal Growth Factor Receptor (EGFR)-Positive Colorectal Carcinoma

RATIONALE: Monoclonal antibodies, such as cetuximab, can target tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Best supportive care is the use of drugs and other treatments to improve the quality of life of patients. Combining cetuximab with best supportive care may slow the growth of the tumor and help patients live longer and more comfortably. It is not yet known whether cetuximab combined with best supportive care is more effective than best supportive care alone in treating metastatic epidermal growth factor receptor-positive colorectal cancer.

PURPOSE: This randomized phase III trial is studying cetuximab and best supportive care to see how well they work compared to best supportive care alone in treating patients with metastatic epidermal growth factor receptor-positive colorectal cancer.

OBJECTIVES:

Primary

• Compare survival of patients with metastatic epidermal growth factor receptor-positive colorectal cancer treated with cetuximab and best supportive care vs best supportive care alone.

Secondary

• Compare the time to disease progression in patients treated with these regimens.
• Compare the objective response rate in patients treated with these regimens.
• Compare the quality of life of patients treated with these regimens.
• Compare the health utilities of patients treated with these regimens.
• Conduct a comparative economic evaluation in patients treated with these regimens.
• Determine the safety profile of cetuximab in these patients.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to participating center and ECOG performance status (0 or 1 vs 2). Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive an initial loading dose of cetuximab IV over 120 minutes on day 1. Patients continue to receive maintenance infusions of cetuximab IV over 60 minutes weekly. Patients also receive best supportive care, defined as measures designed to provide palliation of symptoms and improve quality of life as much as possible.
• Arm II: Patients receive best supportive care as in arm I. In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

Quality of life is assessed at baseline, and then at 4, 8, 16, and 24 weeks (or until deterioration to ECOG PS 4 or hospitalization for end-of-life care).

Patients are followed every 4 weeks.

PROJECTED ACCRUAL: A total of 500 patients (250 per treatment arm) will be accrued for this study within 20 months.

DISEASE CHARACTERISTICS:

• Histologically confirmed colorectal cancer

  • Metastatic disease

• Epidermal growth factor receptor (EGFR)-positive by immunochemistry

• Measurable or evaluable disease

• Not amenable to standard curative therapy

  • Best supportive care is the only available option

• Must have received a prior thymidylate synthase inhibitor (e.g., fluorouracil, capecitabine, raltitrexed, or fluorouracil-uracil) in the adjuvant or metastatic setting

  • Combination therapy with oxaliplatin or irinotecan allowed

• Must have failed* a prior regimen containing irinotecan and a prior regimen containing oxaliplatin for metastatic disease OR relapsed within 6 months after an adjuvant regimen containing irinotecan or oxaliplatin OR have documented unsuitability for such regimens

• No symptomatic CNS metastases NOTE: *Failure is defined as either disease progression (clinical or radiological) or intolerance to the regimen

PATIENT CHARACTERISTICS:

Age

• 16 and over

Performance status

• ECOG 0-2

Life expectancy

• Not specified

Hematopoietic

• See Disease Characteristics
• Absolute granulocyte count ≥ 1,500/mm^3
• Platelet count ≥ 75,000/mm^3
• Hemoglobin ≥ 8.0 g/dL

Hepatic

• AST and ALT ≤ 5 times upper limit of normal (ULN)
• Bilirubin ≤ 2.5 times ULN

Renal

• Creatinine ≤ 1.5 times ULN

Cardiovascular

• No uncontrolled angina
• No arrhythmias
• No cardiomyopathy
• No congestive heart failure
• No myocardial infarction* within the past 6 months NOTE: *Pre-treatment ECG as only evidence of infarction is allowed

Pulmonary

• No severe restrictive lung disease
• No interstitial lung disease by chest x-ray

Other

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception for 4 weeks before, during, and for 4 weeks after study treatment
• No active pathological condition that would preclude study participation
• No psychological or geographical condition that would preclude study compliance
• No other malignancy within the past 5 years except adequately treated non-melanoma skin cancer or carcinoma in situ of the cervix

PRIOR CONCURRENT THERAPY:

Biologic therapy

• No prior cetuximab
• No prior murine monoclonal antibody therapy (e.g., edrecolomab)

Chemotherapy

• See Disease Characteristics
• At least 4 weeks since prior chemotherapy and recovered
• No concurrent chemotherapy

Radiotherapy

• See Disease Characteristics
• At least 4 weeks since prior radiotherapy and recovered
• Concurrent palliative radiotherapy allowed except to index lesions

Surgery

• At least 4 weeks since prior major surgery and recovered

Other

• No prior EGFR-targeted therapy (e.g., erlotinib or gefitinib)
• More than 30 days since prior experimental therapeutic agents
• More than 4 weeks since prior investigational agents
• No concurrent enrollment in another clinical study
• No other concurrent EGFR-targeted therapy
• No other concurrent non-cytotoxic experimental agents