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

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

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: capecitabine; Drug: sorafenib tosylate; Radiation: radiation therapy

Detailed 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.

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Hungary
  • Budapest, Hungary, 1097
    • Szent Laszlo Korhaz
• Switzerland
  • Basel, Switzerland, CH-4016
    • Saint Claraspital AG
  • Basel, Switzerland, CH-4031
    • Universitaetsspital-Basel
  • Bellinzona, Switzerland, 6500
    • Istituto Oncologico della Svizzera Italiana - Ospedale Regionale Bellinzona e Valli
  • Bern, Switzerland, CH-3010
    • Inselspital, Bern
  • Biel, Switzerland, CH-2501
    • Spitalzentrum Biel
  • Bruderholz, Switzerland, CH-4101
    • Kantonsspital Bruderholz
  • Chur, Switzerland, CH-7000
    • Kantonsspital Graubuenden
  • Geneva, Switzerland, CH-1211
    • Hopital Cantonal Universitaire de Geneva HUG
  • Luzern, Switzerland, 6000
    • Kantonsspital Luzern
  • Luzern, Switzerland, 6006
    • OnkoZentrum Luzern at Klinik St. Anna
  • St. Gallen, Switzerland, CH-9007
    • Kantonsspital - St. Gallen
  • Thun, Switzerland, 3600
    • SpitalSTS AG Simmental-Thun-Saanenland
  • Winterthur, Switzerland, CH-8400
    • Kantonsspital Winterthur
  • Zurich, Switzerland, CH-8091
    • Universitaetsspital Zuerich
  • Zurich, Switzerland, 8002
    • Onkozentrum - Klinik im Park
  • Zurich, Switzerland, CH-8008
    • Onkozentrum Hirslanden
  • Zürich, Switzerland, 8063
    • Stadtspital Triemli

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Arm A: Sorafenib & Capecitabine & RT; 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; Phase II: 2 x 825 mg/m2 per day (during 5 weeks); Other Names: XELODA; Drug: sorafenib tosylate; Phase II: 1 x 400 mg per day (during 5 weeks); Other Names: BAY 43-9006; Radiation: radiation therapy; Phase II: 1.8 Gy per day in 25 fractions (during 5 weeks)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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.

Collaborators and Investigators

• Sponsor: Swiss Group for Clinical Cancer Research
• Investigators: Study Chair: Roger von Moos, MD, Kantonsspital Graubuenden

Publications and helpful links

General Publications

• von Moos R, Koeberle D, Schacher S, Hayoz S, Winterhalder RC, Roth A, Bodoky G, Samaras P, Berger MD, Rauch D, Saletti P, Plasswilm L, Zwahlen D, Meier UR, Yan P, Izzo P, Klingbiel D, Bartschi D, Zaugg K; Swiss Group for Clinical Cancer Research (SAKK). Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer: A phase I/II trial (SAKK 41/08). Eur J Cancer. 2018 Jan;89:82-89. doi: 10.1016/j.ejca.2017.11.005. Epub 2017 Dec 11.

Study record dates

Study Major Dates

• Study Start: March 1, 2009
• Primary Completion (ACTUAL): May 1, 2013
• Study Completion (ACTUAL): September 1, 2016

Study Registration Dates

• First Submitted: March 25, 2009
• First Submitted That Met QC Criteria: March 25, 2009
• First Posted (ESTIMATE): March 26, 2009

Study Record Updates

• Last Update Posted (ACTUAL): May 15, 2019
• Last Update Submitted That Met QC Criteria: May 14, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage II rectal cancer; stage III rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Protein Kinase Inhibitors; Sorafenib; Capecitabine
• Other Study ID Numbers: SAKK 41/08; SWS-SAKK-41-08; 2008-006312-38 (EUDRACT_NUMBER); CDR0000634955 (OTHER: www.clinicalcollections.org)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO