Ro 31-7453 in Treating Patients With Recurrent or Refractory Metastatic Colorectal Cancer

OBJECTIVES:

• Compare the objective disease rate of patients with recurrent or refractory metastatic colorectal cancer treated with two dose schedules of Ro 31-7453.
• Compare the safety and tolerability of these regimens in these patients.
• Compare the response duration in patients treated with these regimens.
• Compare the time to progression and time to treatment failure in patients treated with these regimens.
• Determine the pharmacokinetic profiles of Ro 31-7453 and its major metabolites in these patients.
• Compare the overall survival of patients treated with these regimens.

OUTLINE: This is a randomized, open label, multicenter study. Patients are randomized to one of two treatment arms.

• Arm I: Patients receive oral Ro 31-7453 twice daily on days 1-4. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
• Arm II: Patients receive oral Ro 31-7453 twice daily on days 1-14. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Patients are followed at 28 days and then every 3 months.

PROJECTED ACCRUAL: Approximately 160 patients (49 per treatment arm plus 61 additional patients in the arm determined to be most effective) will be accrued for this study within 1 year.

DISEASE CHARACTERISTICS:

• Histologically confirmed metastatic adenocarcinoma of the colon or rectum
• Bidimensionally measurable disease

• At least 2.0 x 2.0 cm
• Failed prior fluoropyrimidine and irinotecan chemotherapy in adjuvant or metastatic setting

• Must have had disease progression while receiving chemotherapy OR
• If received fluorouracil with or without irinotecan in adjuvant setting, must also have failed therapy with these agents in metastatic setting (unless manifesting metastatic disease during adjuvant therapy)
• No known CNS metastases

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 70-100%

Life expectancy:

• Not specified

Hematopoietic:

• Hemoglobin at least 9 g/dL
• Absolute neutrophil count at least 1,500/mm^3
• WBC at least 3,000/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• AST/ALT no greater than 2.5 times ULN (5 times ULN if liver metastases present)
• Alkaline phosphatase no greater than 2.5 ULN (5 times ULN if bone or liver metastases present)

Renal:

• Creatinine no greater than 1.5 times ULN

Cardiovascular:

• No New York Heart Association class III or IV congestive heart failure
• No myocardial infarction within the past 6 months

Gastrointestinal:

• No bowel obstruction
• No active uncontrolled malabsorption syndrome

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No active infection
• No other prior malignancy within the past 5 years except carcinoma in situ of the cervix or non-melanoma skin cancer
• No other active cancers, including stable disease on adjuvant therapy
• No other medical condition that would preclude study

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• See Chemotherapy
• At least 2 weeks since prior biologic therapy and recovered

Chemotherapy:

• See Disease Characteristics
• No more than 2 prior cytotoxic chemotherapy regimens for metastatic disease
• Monoclonal antibody (MOAB) therapy and antiangiogenic agents not included as prior cytotoxic chemotherapy
• At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin) and recovered

Endocrine therapy:

• Not specified

Radiotherapy:

• At least 3 weeks since prior radiotherapy and recovered

Surgery:

• No prior total gastrectomy

Other:

• No other concurrent investigational agents