S0713: Oxaliplatin, Capecitabine, Cetuximab, and RT Followed By Surgery in Pts W/Stage II or III Rectal Cancer

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 the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This phase II trial is studying the side effects and how well giving oxaliplatin, capecitabine, and cetuximab together with radiation therapy followed by surgery works in treating patients with stage II or stage III rectal cancer.

Detailed Description
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OBJECTIVES: To assess the pathologic complete response rate for the combination of oxaliplatin, capecitabine, and cetuximab alone and concurrently with external beam radiotherapy for patients with adenocarcinoma of the rectum, stages II and III with wild-type K-ras. To estimate the 3-year disease-free survival probability in this patient population when treated with this regimen. To assess the frequency and severity of toxicities associated with this regimen in these patients. To explore, preliminarily, the association between expression levels of genes involved in the DNA repair, EGFR (epidermal growth factor receptor), angiogenesis, and 5-FU pathway (i.e., k-ras, TS [Thymidylate Synthase], ERCC-1 [excision repair cross complementing-1), TP [Thymidine phosphorylase], DPD [Dihydropyrimidine dehydrogenase], EGFR, VEGF [vascular endothelial growth factor], and IL-8 [interleukin-8]) and pathologic complete response. (Due to advances in methodology, the translational medicine objectives are being reconsidered. Therefore, results for this objective are not reported) To explore, preliminarily, the intratumoral gene expression levels of these genes after completion of study treatment.(Due to advances in methodology, the translational medicine objectives are being reconsidered. Therefore, results for this objective are not reported) To obtain, preliminarily, data on genomic polymorphisms of these genes for correlation with clinical outcome and toxicity. (Due to advances in methodology, the translational medicine objectives are being reconsidered. Therefore, results for this objective are not reported) OUTLINE: This is a multicenter study. Neoadjuvant therapy (course 1): Patients receive oxaliplatin IV over 2 hours once a week for 5 weeks, oral capecitabine twice daily 5 days a week for 5 weeks, and cetuximab IV over 1-2 hours once a week for 5 weeks. Neoadjuvant therapy with concurrent radiotherapy (course 2): Beginning two weeks later, patients receive oxaliplatin IV over 2 hours once a week in weeks 1, 2, 4, and 5. Patients also receive capecitabine and cetuximab as in course 1. Patients also undergo external beam radiotherapy 5 days a week for 5 weeks beginning in week 1. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo surgery 3-8 weeks after completion of chemoradiotherapy. Blood samples are collected for germline polymorphism testing and tissue samples are collected and assessed for gene expression analysis. After completion of study treatment, patients are followed every 6 months for 4 years.

Official Title
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A Phase II Study of Oxaliplatin, Capecitabine, Cetuximab and Radiation in Pre-Operative Therapy of Rectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Biological: cetuximab
* Drug: capecitabine
* Drug: oxaliplatin
* Procedure: therapeutic surgical procedure
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Biopsy-proven primary adenocarcinoma of the rectum Stage II or III disease The distal border of the tumor must be at or below the peritoneal reflection, defined as within 12 cm of the anal verge by proctoscopic examination No recurrent disease Must have wild-type k-ras status Measurable and/or nonmeasurable disease PATIENT CHARACTERISTICS: Zubrod performance status 0-2 Leukocyte count ≥ 3,000/mcL Granulocyte count ≥ 1,500/mcL Platelet count ≥ 100,000/mcL Bilirubin ≤ 1.5 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2.5 times ULN SGOT (serum glutamate oxaloacetate transaminase) or SGPT (serum glutamate pyruvate transaminase)≤ 2.5 times ULN Creatinine clearance > 50 mL/min No prior severe reaction to a monoclonal antibody Willing to have specimens submitted No peripheral neuropathy ≥ grade 2 No known existing uncontrolled coagulopathy No evidence of current high-grade obstruction At least 2 weeks since prior diverting procedure No history of allergy to platinum compounds or to antiemetics appropriate for administration in conjunction with protocol treatment No prior unanticipated severe reaction to fluoropyrimidine therapy or known sensitivity to fluorouracil or known DPD deficiency No active inflammatory bowel disease, malabsorption syndrome, or inability to swallow that would impair the ingestion or absorption of capecitabine No uncontrolled intercurrent illness No ongoing or active infection No symptomatic congestive heart failure or unstable angina pectoris No cardiac arrhythmia or myocardial infarction within the past 12 months Not pregnant or nursing Fertile patients must use effective contraception No prior malignancy allowed except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or other cancer from which the patient has been disease-free for 5 years PRIOR CONCURRENT THERAPY: Recovered from any recent major surgeries (e.g., coronary artery bypass graft, transurethral resection of prostate, or abdominal surgery) No prior chemotherapy, radiotherapy, or targeted therapy for this tumor More than 4 weeks since prior investigational agents No concurrent anti-retroviral therapy for HIV

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: Chemo + Chemo and radiation + Surgery<br>Chemotherapy Cycle 1 (1 cycle is 35 days): Oxaliplatin, 50 mg/m^2, IV, Days 1,8,15,22,29 Cetuximab, 400 mg/m^2, IV, Day 1 Cetuximab, 250 mg/m^2, IV, Days 8,15,22,29 Capecitabine, 1650 mg/m^2/day, PO, Monday-Friday (Day 1-35) Chemotherapy+ Radiation Cycle 2: Oxaliplatin, 50 mg/m^2, IV, Days 50,57,71,78 Cetuximab, 250 mg/m^2, IV, Days 50,57,64,71,78 Capecitabine, 1650 mg/m^1, PO, Monday-Friday (Day 50-84) Radiation therapy: Planning target value 1: 4500 cGy (centigray) in 25 fractions; Planning target value 2 (stage T3 patients): Boost of 540 cGy in 3 fractions; Planning target value 2 (stage T4 patients): Boost of 900 cGy in 5 fractions. Therapeutic Surgical procedure: Resection | Biological: cetuximab<br>* Chemotherapy cycle 1: Cetuximab, 400 mg/m^2, IV, Day 1; Cetuximab, 250 mg/m^2, IV, Days 8,15,22,29 Chemotherapy+ Radiation Cycle 2: Cetuximab, 250 mg/m^2, IV, Days 50,57,64,71,78<br>* Other names: NSC-714692;Drug: capecitabine<br>* Chemotherapy Cycle 1: Capecitabine, 1650 mg/m^2/day, PO, Monday-Friday (Day 1-35) Chemotherapy+ Radiation Cycle 2: Capecitabine, 1650 mg/m^1, PO, Monday-Friday (Day 50-84)<br>* Other names: NSC-712807;Drug: oxaliplatin<br>* Chemotherapy Cycle 1: Oxaliplatin, 50 mg/m^2, IV, Days 1,8,15,22,29 Chemotherapy+ Radiation Cycle 2: Oxaliplatin, 50 mg/m^2, IV, Days 50,57,71,78<br>* Other names: NSC-266046;Procedure: therapeutic surgical procedure<br>* Surgical resection<br>* Other names: Resection;Radiation: radiation therapy<br>* IMRT (intensity-modulated radiation therapy)<br>* Other names: RT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response Rate | Pathologic response is evaluated after the patient has had surgery, and is based on local pathology review of the resected surgical specimen, according to the following: a) Pathologic complete response (pCR): on review of the resected rectal specimen and accompanying lymph nodes, no cancer is recognized by the pathologist; b) Microscopic cancer: gross tumor is not seen by the pathologist but tumor remains in the microscopic analysis of any part of the entire specimen; c) no response: gross cancer is found on pathologic examination of the resected rectal cancer and draining lymph nodes. | 15-20 weeks from registration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-year Disease-free Survival | From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact. | 3 years | 
| Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to This Regimen. | Only adverse events that are possibly, probably or definitely related to study regimen are reported. | Up to 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the rectum, stage IIA rectal cancer, stage IIB rectal cancer, stage IIC rectal cancer, stage IIIA rectal cancer, stage IIIB rectal cancer, stage IIIC rectal cancer