Combination Chemotherapy With or Without Cetuximab as First-Line Therapy in Treating Patients With Metastatic Colorectal Cancer

Velindre NHS Trust

Status and phase: Unknown; Phase 3

Conditions: Colorectal Cancer

Treatments: Drug: leucovorin calcium; Drug: capecitabine; Drug: fluorouracil; Drug: oxaliplatin; Biological: cetuximab

Study type: Interventional

Funder types: Other

Identifiers

NCT00182715

CDR0000440085

UKM-MRC-COIN-CR10

ISRCTN27286448

EU-20516

EUDRACT-2004-002951-16

Details and patient eligibility

About

RATIONALE: 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. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Monoclonal antibodies, such as 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. It is not yet known whether combination chemotherapy and cetuximab are more effective than combination chemotherapy alone in treating colorectal cancer.

PURPOSE: This randomized phase III trial is studying combination chemotherapy and cetuximab to see how well they work compared to combination chemotherapy alone as first-line therapy in treating patients with metastatic colorectal cancer.

Full description

OBJECTIVES:

Primary

• Compare the overall survival of patients with metastatic colorectal adenocarcinoma treated with continuous combination chemotherapy comprising oxaliplatin, leucovorin calcium, and fluorouracil (OxMdG) or oxaliplatin and capecitabine (XELOX) with vs without cetuximab vs intermittent combination chemotherapy with OxMdG or XELOX as first-line therapy.

Secondary

• Compare time of disease control and progression- and failure-free survival of patients treated with these regimens.
• Compare response in patients treated with these regimens.
• Compare the toxicity of these regimens in these patients.
• Compare the cost effectiveness of these regimens in these patients.
• Compare the quality of life of patients treated with these regimens.

OUTLINE: This is a multicenter, open label, randomized, controlled study. Patients are randomized to 1 of 3 treatment arms.

• Arm I (continuous chemotherapy): Patients receive 1 of the following combination chemotherapy regimens of their choice (or as per participating center):

  • OxMdG: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV over 46 hours on days 1 and 2. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.
  • XELOX: Patients receive oxaliplatin IV over 2 hours on day 1 and oral capecitabine twice daily on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

• Arm II (continuous chemotherapy and cetuximab): Patients receive OxMdG or XELOX as in arm I. Patients also receive cetuximab IV over 1-2 hours on days 1 and 8 (for patients receiving OxMdG) OR days 1, 8, and 15 (for patients receiving XELOX). Treatment with OxMdG and cetuximab repeats every 14 days in the absence of disease progression or unacceptable toxicity. Treatment with XELOX and cetuximab repeats every 21 days in the absence of disease progression or unacceptable toxicity.

• Arm III (intermittent chemotherapy): Patients receive OxMdG or XELOX as in arm I. Treatment with OxMdG repeats every 14 days for up to 6 courses (12 weeks). Treatment with XELOX repeats every 21 days for up to 4 courses (12 weeks). Patients with disease progression after 12 weeks of therapy are removed from study treatment. Patients with stable or responding disease after 12 weeks of therapy stop treatment and undergo clinical evaluation at least every 6 weeks (treatment break) until disease progression or clinical deterioration. Upon evidence of disease progression or clinical deterioration, patients restart treatment with OxMdG or XELOX as before and continue to alternate 12 weeks of treatment with treatment breaks in the absence of disease progression or unacceptable toxicity Quality of life is assessed at baseline, 6 weeks, 12 weeks, and then every 12 weeks thereafter.

After completion of study treatment, patients are followed every 12 weeks for survival.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: A total of 2,421 patients (807 per treatment arm) will be accrued for this study within 3.5 years.

Enrollment: 2,421 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

DISEASE CHARACTERISTICS:

• Diagnosis of colorectal adenocarcinoma, defined by 1 of the following:

  • Histologically confirmed primary adenocarcinoma of the colon or rectum with clinical or radiological evidence of advanced and/or metastatic disease
  • Histologically or cytologically confirmed metastatic adenocarcinoma with clinical or radiological evidence of primary colorectal tumor

• Unidimensionally measurable disease

• Inoperable metastatic or locoregional disease

  • Ineligible for hepatic resection after first-line combination chemotherapy

• No brain metastases

PATIENT CHARACTERISTICS:

Age

• 18 and over

Performance status

• WHO 0-2

Life expectancy

• Not specified

Hematopoietic

• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

Hepatic

• Bilirubin ≤ 1.25 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 5 times ULN
• AST or ALT ≤ 2.5 times ULN

Renal

• Creatinine clearance or glomerular filtration rate ≥ 50 mL/min

Cardiovascular

• No poorly controlled angina
• No myocardial infarction within the past 3 months

Other

• Not pregnant
• Negative pregnancy test
• Fertile patients must use effective contraception
• Must be considered fit to undergo combination chemotherapy
• No psychiatric or neurological condition that would preclude study compliance or giving informed consent
• No partial or complete bowel obstruction
• No other malignant disease that would preclude study treatment
• No preexisting neuropathy > grade 1
• No known hypersensitivity reaction to any of the components of study drugs
• No known DPD deficiency or personal or family history suggestiv of DPD deficiency
• No other severe uncontrolled medical illness that would preclude study treatment

PRIOR CONCURRENT THERAPY:

Biologic therapy

• Not specified

Chemotherapy

• No prior systemic palliative chemotherapy for metastatic disease
• No prior oxaliplatin
• More than 1 month since prior adjuvant fluorouracil (5-FU) (with or without leucovorin calcium), capecitabine, or irinotecan
• More than 1 month since prior rectal chemoradiotherapy with 5-FU (with or without leucovorin calcium) or capecitabine

Endocrine therapy

• Not specified

Radiotherapy

• See Chemotherapy

Surgery

• Not specified

Other

• No concurrent brivudine or sorivudine (for patients receiving capecitabine on study)