Oxaliplatin, Capecitabine, and Radiation Therapy in Treating Patients With Locally Advanced Cancer of the Rectum

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as oxaliplatin and capecitabine, work in different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Oxaliplatin and capecitabine may make tumor cells more sensitive to radiation therapy and may kill more tumor cells. Giving chemotherapy with radiation therapy before surgery may shrink the tumor so that it can be removed. PURPOSE: This phase I/II trial is studying the side effects and best dose of oxaliplatin and capecitabine when given together with radiation therapy and to see how well they work in treating patients who are undergoing surgery for locally advanced cancer of the rectum. NOTE: *The phase I portion of this trial closed 06/2005. The best dose of oxaliplatin and capecitabine has been determined.

Detailed Description
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OBJECTIVES: Primary Determine the maximum tolerated dose of neoadjuvant oxaliplatin and capecitabine when combined with radiotherapy in patients with locally advanced adenocarcinoma of the rectum. (Phase I closed to accrual as of 06/2005.) Determine the rate of complete pathological response in patients treated with this regimen. Secondary Determine the overall survival of patients treated with this regimen. Determine the rate of local and overall failure in patients treated with this regimen. Determine the utility of TS, TP, DPD, ERCC-1, and apoptosis to predict response in patients treated with this regimen. Determine the rate of pathologic down-staging in patients treated with this regimen. Determine the safety and toxicity of this regimen in these patients. Determine the rate of sphincter-saving rectal surgery in patients treated with this regimen who had been deemed candidates for abdominoperineal resection at diagnosis. OUTLINE: This is a multicenter, phase I (phase I closed to accrual as of 06/2005), dose-escalation study of oxaliplatin and capecitabine followed by a phase II study. Phase I (closed to accrual as of 06/2005): Patients undergo radiotherapy once daily 5 days a week for 5.5 weeks and receive oral capecitabine twice daily on days radiotherapy is administered. Beginning on day 1 of radiotherapy, patients also receive oxaliplatin IV over 2 hours on days 1, 8, 15, 22, and 29. Cohorts of 3-6 patients receive escalating doses of oxaliplatin and 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 undergo radiotherapy and receive capecitabine and oxaliplatin as in phase I at the MTD. All patients undergo curative-intent surgery 6-8 weeks after the completion of chemoradiotherapy. Patients are followed every 3 months for 3 years and then every 6 months for 2 years. PROJECTED ACCRUAL: A total of 31-40 patients (6-15 for phase I [phase I closed to accrual as of 06/2005] and 25 for phase II) will be accrued for this study within 2 years.

Official Title
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A Phase I/II Study of Weekly Intravenous Oxaliplatin in Combination With Oral Daily Capecitabine and Radiation Therapy in the Neoadjuvant Treatment of Rectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: capecitabine
* Drug: oxaliplatin
* Procedure: conventional surgery
* Procedure: neoadjuvant therapy
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed adenocarcinoma of the rectum Tumor involving the distal 12 cm of the rectum (above the anal verge) Clinically staged by endoscopic ultrasound with one of the following criteria: T3-T4 disease Evidence of lymph node involvement, defined by the presence of ≥ 1 enlarged peri-rectal lymph node (≥ 1 cm in size) No known distant metastases PATIENT CHARACTERISTICS: Age 18 to 75 Performance status ECOG 0-1 OR Karnofsky 70-100% Life expectancy More than 1 year Hematopoietic WBC ≥ 3,000/mm^3 Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hepatic Bilirubin normal AST and ALT ≤ 2.5 times upper limit of normal Renal Creatinine normal OR Creatinine clearance ≥ 60 mL/min Cardiovascular No symptomatic congestive heart failure No unstable angina pectoris No cardiac arrhythmia Other Able to receive oral medication No other malignancy within the past 5 years except nonmelanoma skin cancer No prior or concurrent significant neuropathy No prior allergic reaction attributed to compounds of similar chemical or biological composition to study drugs No ongoing or active infection No other concurrent uncontrolled illness No psychiatric illness or social situation that would preclude study compliance Not pregnant or nursing Negative pregnancy test Fertile patients must use effective double-method contraception during and for 3 months after study participation PRIOR CONCURRENT THERAPY: Biologic therapy No concurrent granulocyte-stimulating factors Chemotherapy No prior chemotherapy Endocrine therapy Not specified Radiotherapy No prior pelvic radiotherapy Surgery Not specified Other No other concurrent investigational agents No other concurrent anticancer agents or therapies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: capecitabine|oral dose escalating, twice daily.|
|Drug: oxaliplatin|IV over 2 hours on days 1, 8, 15, 22, and 29.|
|Procedure: conventional surgery|curative-intent surgery 6-8 weeks after the completion of chemoradiotherapy|
|Procedure: neoadjuvant therapy|chemotherapy and radiation prior to surgery|
|Radiation: radiation therapy|once daily 5 days a week for 5.5 weeks|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete pathological response rate at time of surgery |  | Time of surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival, safety, and overall survival at 5 years |  | Continuous | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the rectum, stage III rectal cancer, stage II rectal cancer