Capecitabine and Radiation Therapy With or Without Panitumumab in Treating Patients With Advanced Rectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving radiation therapy that uses a 3-dimensional (3-D) image of the tumor to help focus thin beams of radiation directly on the tumor, and giving radiation therapy in higher doses over a shorter period of time, may kill more tumor cells and have fewer side effects. Monoclonal antibodies, such as panitumumab, 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. It is not yet known whether giving capecitabine together with 3-D conformal radiation therapy is more effective with or without panitumumab in treating patients with advanced rectal cancer. PURPOSE: This randomized phase II trial is studying giving capecitabine together with radiation therapy to see how well it works with or without panitumumab in treating patients with advanced rectal cancer.

Detailed Description
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OBJECTIVES: To assess the efficacy and safety of neoadjuvant capecitabine and concurrent 3-dimensional conformal radiotherapy with vs without panitumumab in patients with advanced K-ras unmutated rectal cancer. OUTLINE: This is a multicenter study. Patients are stratified according to participating center, T stage (T3 vs T4), tumor localization measured from caudal part of the tumor to the anocutaneous line (< 10 cm vs ≥ 10 cm), and number of EGFR gene copies (< 2.9 vs ≥ 2.9). Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive panitumumab IV over 30-90 minutes on days 1, 15, 29, 43, and 57 and oral capecitabine twice daily on days 8-40. Beginning on day 8, patients undergo daily fractions of 3-D conformal radiotherapy 5 days a week for 5 weeks. Beginning approximately 6 weeks after completion of panitumumab and chemoradiotherapy, patients undergo surgery. Arm II: Patients receive oral capecitabine twice daily on days 1-33. Patients undergo concurrent 3-D conformal radiotherapy 5 days a week for 5 weeks. Beginning 6 weeks after completion of chemoradiotherapy, patients undergo surgery. After completion of study therapy, patients are followed periodically for up to 3 years.

Official Title
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Neoadjuvant Radiotherapy and Capecitabine With or Without Panitumumab in Patients With Advanced, K-ras Unmutated Rectal Cancer. A Randomized Multicenter Phase II Trial

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Biological: panitumumab
* Drug: capecitabine
* Procedure: therapeutic conventional surgery
* Radiation: 3-dimensional conformal radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed advanced adenocarcinoma of the rectum with or without nodal involvement Stage mrT3-4 and/or mrN1-2, M0 Tumors must express wild type K-ras gene No distant metastasis PATIENT CHARACTERISTICS: WHO performance status 0-1 Able to undergo surgery ANC ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 100 g/L Creatinine clearance ≥ 50 mL/min AST ≤ 2.5 times upper limit normal (ULN) Total bilirubin ≤ 1.5 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must agree to use effective contraception during and for 12 months after completion of study No malignancy within the past 5 years with the exception of adequately treated cervical carcinoma in situ or localized nonmelanoma skin cancer No psychiatric disorder that would preclude understanding study-related information, giving informed consent, or complying with oral drug intake No prior existing conditions that would preclude radiotherapy No clinically significant (i.e., active) cardiac disease (e.g., congestive heart failure, symptomatic coronary artery disease, and cardiac arrhythmia even if controlled with medication) or myocardial infarction within the past 12 months No lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome No serious underlying medical condition that, in the judgement of the investigator, could impair the ability of the patient to participate in the trial (e.g., active autoimmune disease or uncontrolled diabetes) No known dihydropyrimidine dehydrogenase deficiency No known hypersensitivity to trial drugs or hypersensitivity to any other component of the trial drugs PRIOR CONCURRENT THERAPY: More than 30 days since prior treatment in a clinical trial No other concurrent experimental drugs, anticancer therapy, or investigational treatments No prior treatment for rectal cancer No prior anti-EGFR antibody therapy (e.g., cetuximab) or small-molecule EGFR inhibitors (e.g., erlotinib hydrochloride) No concurrent treatment with brivudine, lamivudine, ribavirin, or any other nucleoside analogues No organ allografts No concurrent drugs contraindicated for use with the trial drugs No other concurrent anti-EGFR-targeting agents No other concurrent radiotherapy

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I<br>Patients receive panitumumab IV over 30-90 minutes on days 1, 15, 29, 43, and 57 and oral capecitabine twice daily on days 8-40. Beginning on day 8, patients undergo daily fractions of 3-D conformal radiotherapy 5 days a week for 5 weeks. Beginning approximately 6 weeks after completion of panitumumab and chemoradiotherapy, patients undergo surgery. | Biological: panitumumab<br>* Given IV<br>* Other names: Vectibix;Drug: capecitabine<br>* Given orally<br>* Other names: Xeloda;Procedure: therapeutic conventional surgery<br>* Patients undergo surgical resection<br>Radiation: 3-dimensional conformal radiation therapy<br>* Patients undergo radiotherapy<br>|
| Active Comparator: Arm II<br>Patients receive oral capecitabine twice daily on days 1-33. Patients undergo concurrent 3-D conformal radiotherapy 5 days a week for 5 weeks. Beginning 6 weeks after completion of chemoradiotherapy, patients undergo surgery. | Drug: capecitabine<br>* Given orally<br>* Other names: Xeloda;Procedure: therapeutic conventional surgery<br>* Patients undergo surgical resection<br>Radiation: 3-dimensional conformal radiation therapy<br>* Patients undergo radiotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological complete or near-complete response (Dworak grade 3 and 4) |  | after 13 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological response |  | after 13 weeks. | 
| R0 or R1 resection |  | after 13 weeks. | 
| Postoperative complications (within 8 weeks after surgery) |  | within 8 weeks after surgery | 
| Time to local relapse |  | calculated from randomization to documented relapse or censored at the last CT and/or endorectal ultrasound without local relapse. | 
| Time to distant failure |  | calculated from randomization to documented distant (metastatic) failure or censored at the last CT without distant (metastatic) failure. | 
| Disease-free survival |  | calculated from randomization to first relapse or death (whichever occurs first). | 
| Adverse events |  | All AEs will be assessed according to NCI CTCAE v3.0. | 

 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