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

Swiss Group for Clinical Cancer Research

Status and phase: Completed; Phase 2; Phase 1

Conditions: Colorectal Cancer

Treatments: Radiation: radiation therapy; Drug: sorafenib tosylate; Drug: capecitabine

Study type: Interventional

Funder types: Other

Identifiers

NCT00869570

CDR0000634955 (Other Identifier)

SWS-SAKK-41-08

SAKK 41/08

2008-006312-38 (EudraCT Number)

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 54 patients

Sex: All

Ages: 18 to 120 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

---

54 participants in 1 patient group

Arm A: Sorafenib & Capecitabine & RT

Experimental group

Description:

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

Treatment:

Drug: capecitabine

Drug: sorafenib tosylate

Radiation: radiation therapy