External-Beam Radiation Therapy, Capecitabine, and Sorafenib in Treating Patients With Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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RATIONALE: Radiation therapy uses high-energy x-rays to kill tumor cells. 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. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving radiation therapy together with capecitabine and sorafenib before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. PURPOSE: This phase I/II trial is studying the side effects and best dose of capecitabine when given together with sorafenib and external-beam radiation therapy and to see how well it works in treating patients with locally advanced rectal cancer.

Detailed Description
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OBJECTIVES: Determine the recommended dose of neoadjuvant capecitabine when given together with sorafenib tosylate and external-beam radiotherapy in patients with K-ras mutated, locally advanced rectal cancer. (Phase I) Assess the efficacy and safety of this regimen in these patients. (Phase II) OUTLINE: This is a multicenter, phase I, dose-escalation study of capecitabine followed by a phase II study. Patients receive oral capecitabine twice daily and oral sorafenib tosylate once daily on days 1-33. Patients also undergo external-beam radiotherapy once daily on days 1-5, 8-12, 15-19, 22-26, and 29-33. Approximately 6 weeks after completion of neoadjuvant therapy, patients undergo surgery. After completion of study therapy, patients are followed at 8 weeks and then periodically for up to 3 years.

Official Title
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Neoadjuvant Radiotherapy Combined With Capecitabine and Sorafenib in Patients With Advanced, K-ras Mutated Rectal Cancer. A Multicenter Phase I/IIa Trial.

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: capecitabine
* Drug: sorafenib tosylate
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed locally advanced adenocarcinoma of the rectum (with or without nodal involvement) requiring surgery Stage mrT3-4, and/or mrN1-2, M0 disease Tumor with K-ras gene mutation as assessed locally No distant metastases PATIENT CHARACTERISTICS: WHO performance status 0-1 Neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hemoglobin ≥ 10.0 g/dL Creatinine clearance ≥ 50mL/min AST ≤ 2.5 times upper limit of normal (ULN) Total bilirubin ≤ 1.5 times ULN PT/INR or PTT ≤ 1.5 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective barrier contraception during and for 12 months after completion of study therapy Is compliant and geographic proximity allows for proper staging and follow-up No other malignancy within the past 5 years except 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 clinically significant (i.e., active) cardiac disease (e.g., congestive heart failure, symptomatic coronary artery disease, or cardiac arrhythmia [even if controlled with medication]) or myocardial infarction within the past 12 months No uncontrolled hypertension No evidence or history of bleeding diathesis No lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome No serious or underlying condition (e.g., active autoimmune disease, uncontrolled diabetes, or uncontrolled infection) that, in the judgement of the investigator, could preclude the ability of the patient to participate in the study No known hypersensitivity to study drugs or to any other component of the study drugs PRIOR CONCURRENT THERAPY: No prior treatment for rectal cancer No prior organ allografts More than 4 weeks since prior major surgery other than colostomy More than 30 days since prior treatment in a clinical trial No other concurrent experimental drugs or anticancer therapy No concurrent brivudine, lamivudine, ribavirin, or any other nucleoside analogue No concurrent drugs contraindicated for use with the study drugs No other concurrent radiotherapy No concurrent anticoagulation therapy other than low molecular weight heparin

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Arm A: Sorafenib & Capecitabine & RT<br>Sorafenib: day 1 to 33 (5 weeks, including Saturday and Sunday) every 24 hours, immediately or within two hours after RT according to the dose escalation table during phase I, and the recommended dose during phase IIa. The intake stops at the last day of RT. On nonradiotherapy days (e.g. Saturday, Sunday), the tablets have to be taken at the same time as during the week. Capecitabine: day 1 to 33 (5 weeks, including Saturday and Sunday) according to dose escalation table during phase I, and at the recommended dose during phase IIa. The intake stops in the evening of the last day of RT. External beam RT: Monday through Friday for 5 weeks starting on day 1 (daily fraction 1.8 Gy, final dose 45 Gy) each day at the same time (e.g. 11:00 a.m. daily). Surgery: 6 weeks (± 1 week) after radiochemotherapy (RCT) has been completed | Drug: capecitabine<br>* Phase II: 2 x 825 mg/m2 per day (during 5 weeks)<br>* Other names: XELODA;Drug: sorafenib tosylate<br>* Phase II: 1 x 400 mg per day (during 5 weeks)<br>* Other names: BAY 43-9006;Radiation: radiation therapy<br>* Phase II: 1.8 Gy per day in 25 fractions (during 5 weeks)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-limiting toxicity of the treatment combination (Phase I) |  | during trial treatment (12 weeks) | 
| Pathological near complete or complete tumor response (Dworak grade 3 and 4) (Phase II) |  | after trial treatment (approx. 12 weeks). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| R0 and R1 resection |  | after trial treatment (approx. 12 weeks) | 
| Postoperative complications |  | within 8 weeks after surgery | 
| Time to distant failure |  | during 3 years follow-up. | 
| Disease-free survival |  | during 3 years follow-up. | 
| Adverse events as assessed by NCI CTCAE v3.0 |  | during trial treatment. | 

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