Capecitabine, Oxaliplatin, and Gefitinib in Treating Patients With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as capecitabine and oxaliplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Gefitinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Combining capecitabine and oxaliplatin with gefitinib may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of capecitabine when given together with oxaliplatin and gefitinib and to see how well they work in treating patients with metastatic colorectal cancer.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose of capecitabine when given in combination with oxaliplatin and gefitinib in patients with metastatic colorectal cancer. (phase I) Determine the response rate in patients treated with this regimen. (phase II) Secondary Determine the safety and toxic effects of this regimen in these patients. Determine the 1-year survival of patients treated with this regimen. (phase II) Determine the progression-free and overall survival of patients treated with this regimen. (phase II) OUTLINE: This is an open-label, nonrandomized, phase I, dose-escalation study of capecitabine followed by a phase II study. Phase I: Patients receive oral capecitabine twice daily on days 1-14 and oxaliplatin IV over 2 hours on day 1. Patients also receive oral gefitinib once daily beginning 5 days before the initiation of capecitabine and oxaliplatin and continuing for the duration of study treatment. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of capecitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Phase II: Patients receive oral capecitabine (at the MTD determined in phase I), oxaliplatin IV, and oral gefitinib as in phase I. Patients are followed for survival. PROJECTED ACCRUAL: A total of 3-24 patients will be accrued for the phase I portion of this study within 1-12 months; and a total of 26 patients will be accrued for the phase II portion of this study within 8-13 months.

Official Title
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A Phase I/II Study of Capecitabine (XELODA®, Roche) Plus Oxaliplatin (Eloxatin®, Sanofi) Plus ZD 1893 (IRESSA®) in the Treatment of Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: capecitabine
* Drug: gefitinib
* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed* colorectal cancer Metastatic disease The site of the primary tumor must have been confirmed endoscopically, radiologically, or surgically to be the colon or rectum NOTE: *Confirmation is not required for recurrent metastatic disease unless an interval of > 5 years has elapsed between the initial primary surgery and the development of metastases Measurable disease At least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan No CNS metastases PATIENT CHARACTERISTICS: Age 18 to 80 Performance status ECOG 0-1 Life expectancy More than 3 months Hematopoietic Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 9 g/dL (transfusion allowed) Hepatic AST and ALT ≤ 3 times upper limit of normal (ULN) Bilirubin ≤ ULN No unstable or uncompensated hepatic disease Renal Creatinine < 1.5 times ULN OR Creatinine clearance > 60 mL/min No unstable or uncompensated renal disease Cardiovascular No unstable or uncompensated cardiac disease Pulmonary No evidence of clinically active interstitial lung disease Asymptomatic patients with chronic stable radiographic changes are eligible No unstable or uncompensated respiratory disease Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after study participation No known hypersensitivity to gefitinib or any of its excipients No known hypersensitivity to platinum compounds, fluorouracil, or capecitabine No severe or uncontrolled systemic disease Able to receive oral medication No known dihydropyrimidine dehydrogenase (DPD) deficiency No known peripheral neuropathy ≥ grade 1 Absence of deep tendon reflexes as the sole neurological abnormality allowed No other significant clinical disorder or laboratory finding that would preclude study participation No other malignancy within the past 5 years except basal cell skin cancer or carcinoma in situ of the cervix (phase II only) PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy At least 4 weeks since prior chemotherapy for metastatic colorectal cancer (phase I) No prior chemotherapy for metastatic disease (phase II) Prior fluorouracil and leucovorin calcium in the adjuvant setting allowed provided the last treatment was administered more than 6 months before the development of metastatic disease No prior irinotecan and oxaliplatin (phase II) Endocrine therapy Not specified Radiotherapy No concurrent radiotherapy for colorectal cancer Surgery See Disease Characteristics More than 4 weeks since prior major surgery (e.g., laparotomy) Other Recovered from all prior therapy (no unresolved chronic toxicity > grade 2) More than 4 weeks since prior investigational drugs No prior epidermal growth factor receptor inhibitor therapy (phase II) No concurrent phenytoin, carbamazepine, rifampin, barbiturates, or Hypericum perforatum (St. John's wort) No other concurrent investigational drugs No other concurrent systemic therapy for colorectal cancer

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: capecitabine|nan|
|Drug: gefitinib|nan|
|Drug: oxaliplatin|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose |  |  | 
| Response rate |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity |  |  | 
| 1-year survival (phase II) |  |  | 
| Progression-free survival (phase II) |  |  | 
| Overall survival in (phase II) |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent colon cancer, stage IV colon cancer, recurrent rectal cancer, stage IV rectal cancer