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

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

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: capecitabine; Radiation: 3-dimensional conformal radiation therapy; Biological: panitumumab; Procedure: therapeutic conventional surgery

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 2

Contacts and Locations

Study Locations

• Hungary
  • Budapest, Hungary, 1097
    • Szent Laszlo Korhaz
• Switzerland
  • Aarau, Switzerland, CH-5001
    • Hirslanden Klinik Aarau
  • Aarau, Switzerland, CH-5001
    • Kantonspital Aarau
  • Baden, Switzerland, CH-5404
    • Kantonsspital Baden
  • Basel, Switzerland, CH-4016
    • Saint Claraspital AG
  • Basel, Switzerland, CH-4031
    • Universitaetsspital-Basel
  • Bellinzona, Switzerland, 6500
    • Istituto Oncologico della Svizzera Italiana
  • 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
    • Hôpital Cantonal Universitaire de Genève
  • Lausanne, Switzerland, CH-1011
    • Centre Hospitalier Universitaire Vaudois
  • Luzern, Switzerland, 6006
    • OnkoZentrum Luzern at Klinik St. Anna
  • Luzerne, Switzerland, CH-6000
    • Kantonsspital, Luzerne
  • Olten, Switzerland, CH-4600
    • Kantonsspital Olten
  • Sion, Switzerland, CH -1951
    • Hopital Regional de Sion-Herens-Conthey
  • St. Gallen, Switzerland, CH-9007
    • Kantonsspital - St. Gallen
  • Thun, Switzerland, 3600
    • Regionalspital
  • Winterthur, Switzerland, CH-8400
    • Kantonsspital Winterthur
  • Zurich, Switzerland, 8038
    • Onkozentrum
  • Zurich, Switzerland, CH-8063
    • City Hospital Triemli
  • Zurich, Switzerland, CH-8091
    • Universitaetsspital Zuerich
  • Zurich, Switzerland, CH-8032
    • Klinik Hirslanden

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Drug: capecitabine; Given orally; Other Names: Xeloda; Radiation: 3-dimensional conformal radiation therapy; Patients undergo radiotherapy; Biological: panitumumab; Given IV; Other Names: Vectibix; Procedure: therapeutic conventional surgery; Patients undergo surgical resection
ACTIVE_COMPARATOR: 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.	Drug: capecitabine; Given orally; Other Names: Xeloda; Radiation: 3-dimensional conformal radiation therapy; Patients undergo radiotherapy; Procedure: therapeutic conventional surgery; Patients undergo surgical resection

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Time Frame
Adverse events	All AEs will be assessed according to NCI CTCAE v3.0.
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).

Collaborators and Investigators

• Sponsor: Swiss Group for Clinical Cancer Research
• Investigators: Study Chair: Daniel Helbling, MD, Onkozentrum Zürich

Publications and helpful links

General Publications

• Helbling D, Bodoky G, Gautschi O, Sun H, Bosman F, Gloor B, Burkhard R, Winterhalder R, Madlung A, Rauch D, Saletti P, Widmer L, Borner M, Baertschi D, Yan P, Benhattar J, Leibundgut EO, Bougel S, Koeberle D. Neoadjuvant chemoradiotherapy with or without panitumumab in patients with wild-type KRAS, locally advanced rectal cancer (LARC): a randomized, multicenter, phase II trial SAKK 41/07. Ann Oncol. 2013 Mar;24(3):718-25. doi: 10.1093/annonc/mds519. Epub 2012 Nov 8.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (ACTUAL): May 1, 2010
• Study Completion (ACTUAL): January 1, 2014

Study Registration Dates

• First Submitted: December 24, 2008
• First Submitted That Met QC Criteria: December 24, 2008
• First Posted (ESTIMATE): December 25, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): April 30, 2014
• Last Update Submitted That Met QC Criteria: April 29, 2014
• Last Verified: April 1, 2014

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; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antineoplastic Agents, Immunological; Capecitabine; Panitumumab
• Other Study ID Numbers: SAKK 41/07; SWS-SAKK-41-07; EudraCT-2008-006012-38; EU-20894; CDR0000629101