Oxaliplatin, Fluorouracil, and External-Beam Radiation Therapy Followed by Surgery in Treating Patients With Locally Advanced Cancer of the Rectum

Study Overview
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Brief Summary
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Drugs used in chemotherapy use 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. Combining chemotherapy, radiation therapy, and surgery may be a more effective treatment for cancer of the rectum. Phase II trial to study the effectiveness of combining oxaliplatin, fluorouracil, and external-beam radiation therapy followed by surgery in treating patients who have locally advanced cancer of the rectum

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of oxaliplatin when combined with fluorouracil and external beam radiotherapy in patients with locally advanced adenocarcinoma of the rectum. (Phase I closed to accrual effective 03/27/2003). II. Determine the pathological response rate in patients treated with this preoperative regimen and surgical resection. III.Determine the late toxicity of this preoperative regimen in these patients. IV. Determine, in a preliminary manner, the progression-free survival, local control, and overall survival in patients treated with this regimen. OUTLINE: This is a dose-escalation, multicenter study of oxaliplatin. Patients receive oxaliplatin IV over 1 hour on day 1, fluorouracil IV continuously on days 1-7, and radiotherapy on days 1-5. Treatment repeats weekly for a maximum of 6 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of oxaliplatin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, additional patients are treated at that dose level in the phase II portion of the study. (Phase I closed to accrual effective 03/27/2003). Patients may undergo radical resection of rectal tumor within 4-6 weeks after completion of chemoradiotherapy. Patients are followed every 3 months for 2 years and then every 6 months for 3 years. PROJECTED ACCRUAL: A total of 9-24 patients will be accrued for phase I of the study (phase I closed to accrual effective 03/27/2003) and a total of 19 patients will be accrued for phase II of the study within 12-18 months.

Official Title
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A Phase I/II Study of Preoperative Oxaliplatin (NSC# 266046), 5-Fluorouracil, and External Beam Radiation Therapy in Locally Advanced Rectal Cancer

Conditions
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Adenocarcinoma of the Rectum, Stage II Rectal Cancer, Stage III Rectal Cancer

Intervention / Treatment
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* Drug: oxaliplatin
* Drug: fluorouracil
* Radiation: external beam radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven previously untreated adenocarcinoma of the rectum thatbegins within 12 cm of the anal verge by sigmoidoscopy and/or colonoscopy Locally advanced disease defined as any of the following: Fixed or immovable tumor on physical exam T4 disease with invasion of adjacent structures (e.g., pelvic sidewall, sacral pelvis, bladder, or prostate) by CT scan, rectal ultrasound, or MRI T3 disease with invasion through the wall of the muscularis propria by transrectal ultrasound, CT scan, or MRI No distant metastatic disease Performance status - ECOG 0-2 Granulocyte count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Bilirubin no greater than upper limit of normal (ULN) SGOT/SGPT no greater than 2.5 times ULN Creatinine no greater than 1.5 mg/dL Creatinine clearance at least 60 mL/min No active second malignancy except nonmelanomatous skin cancer or carcinoma in situ of the cervix Patients are not considered to have an active second malignancy if they have completed therapy and are at less than 30% risk of relapse No prior or concurrent evidence of neuropathy No history of allergy to platinum compounds or antiemetics Not pregnant or nursing Fertile patients must use effective contraception No prior fluorouracil or platinum-based therapy for any malignancy No other concurrent chemotherapy Hormonal therapy allowed only for non-disease related conditions (e.g., insulin for diabetes) OR intermittently as an antiemetic (e.g., dexamethasone) No prior pelvic irradiation No concurrent antiretroviral therapy (HAART) for HIV positive patients

Ages Eligible for Study
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Minimum Age: 18 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

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (oxaliplatin, fluorouracil, EBRT)<br>Patients receive oxaliplatin IV over 1 hour on day 1, fluorouracil IV continuously on days 1-7, and radiotherapy on days 1-5. Treatment repeats weekly for a maximum of 6 courses in the absence of disease progression or unacceptable toxicity. | Drug: oxaliplatin<br>* Given IV<br>* Other names: L-OHP;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;Radiation: external beam radiation therapy<br>* Undergo external beam radiation therapy<br>* Other names: EBRT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The maximum tolerated dose of oxaliplatin when delivered concurrently with 5-FU and external beam radiation in patients with locally advanced rectal adenocarcinomas |  | 7 days | 
| Progression-free survival | Will be estimated using the Kaplan-Meier method. | From protocol entry until documented progression of disease or death from any cause, assessed up to 5 years | 
| Pathological complete response rate | The new regimen will be considered worthy of further investigation if 5 or greater CR's are observed among the 25 patients treated at the MTD. Assuming the new regimen will result in a 30% CR rate, the probability of observing 5 or greater CR's in 25 patients studied is 0.91. For an underlying CR rate of 0.25 this probability is 0.79. The probability of observing 5 or greater CR's if the underlying CR rate is 0.10 is 0.10. | Up to 5 years | 
| Latent toxicities graded using the Common Toxicity Criteria (CTC) version 2.0 |  | Up to 5 years |