S0713: Oxaliplatin, Capecitabine, Cetuximab, and RT Followed By Surgery in Pts W/Stage II or III Rectal Cancer

A Phase II Study of Oxaliplatin, Capecitabine, Cetuximab and Radiation in Pre-Operative Therapy of Rectal Cancer

RATIONALE: Drugs used in chemotherapy, such as oxaliplatin and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, 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. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving chemotherapy and radiation therapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PURPOSE: This phase II trial is studying the side effects and how well giving oxaliplatin, capecitabine, and cetuximab together with radiation therapy followed by surgery works in treating patients with stage II or stage III rectal cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Biological: cetuximab; Drug: capecitabine; Drug: oxaliplatin; Procedure: therapeutic surgical procedure; Radiation: radiation therapy

Detailed Description

OBJECTIVES:

• To assess the pathologic complete response rate for the combination of oxaliplatin, capecitabine, and cetuximab alone and concurrently with external beam radiotherapy for patients with adenocarcinoma of the rectum, stages II and III with wild-type K-ras.
• To estimate the 3-year disease-free survival probability in this patient population when treated with this regimen.
• To assess the frequency and severity of toxicities associated with this regimen in these patients.
• To explore, preliminarily, the association between expression levels of genes involved in the DNA repair, EGFR (epidermal growth factor receptor), angiogenesis, and 5-FU pathway (i.e., k-ras, TS [Thymidylate Synthase], ERCC-1 [excision repair cross complementing-1), TP [Thymidine phosphorylase], DPD [Dihydropyrimidine dehydrogenase], EGFR, VEGF [vascular endothelial growth factor], and IL-8 [interleukin-8]) and pathologic complete response. (Due to advances in methodology, the translational medicine objectives are being reconsidered. Therefore, results for this objective are not reported)
• To explore, preliminarily, the intratumoral gene expression levels of these genes after completion of study treatment.(Due to advances in methodology, the translational medicine objectives are being reconsidered. Therefore, results for this objective are not reported)
• To obtain, preliminarily, data on genomic polymorphisms of these genes for correlation with clinical outcome and toxicity. (Due to advances in methodology, the translational medicine objectives are being reconsidered. Therefore, results for this objective are not reported)

OUTLINE: This is a multicenter study.

• Neoadjuvant therapy (course 1): Patients receive oxaliplatin IV over 2 hours once a week for 5 weeks, oral capecitabine twice daily 5 days a week for 5 weeks, and cetuximab IV over 1-2 hours once a week for 5 weeks.
• Neoadjuvant therapy with concurrent radiotherapy (course 2): Beginning two weeks later, patients receive oxaliplatin IV over 2 hours once a week in weeks 1, 2, 4, and 5. Patients also receive capecitabine and cetuximab as in course 1. Patients also undergo external beam radiotherapy 5 days a week for 5 weeks beginning in week 1.

Treatment continues in the absence of disease progression or unacceptable toxicity. Patients undergo surgery 3-8 weeks after completion of chemoradiotherapy.

Blood samples are collected for germline polymorphism testing and tissue samples are collected and assessed for gene expression analysis.

After completion of study treatment, patients are followed every 6 months for 4 years.

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Providence Cancer Center at Providence Hospital
  • Arizona
    • Tucson, Arizona, United States, 85704
      • Arizona Cancer Center at UMC Orange Grove
    • Tucson, Arizona, United States, 85719
      • Arizona Cancer Center at University Medical Center North
    • Tucson, Arizona, United States, 85724-5024
      • Arizona Cancer Center at University of Arizona Health Sciences Center
  • California
    • Berkeley, California, United States, 94704
      • Alta Bates Summit Comprehensive Cancer Center
    • Burlingame, California, United States, 94010
      • Peninsula Medical Center
    • Los Angeles, California, United States, 90089-9181
      • USC/Norris Comprehensive Cancer Center and Hospital
    • Novato, California, United States, 94945
      • Sutter Health - Western Division Cancer Research Group
    • Palm Springs, California, United States, 92262
      • Desert Regional Medical Center Comprehensive Cancer Center
    • Roseville, California, United States, 95661
      • Sutter Cancer Center at Roseville Medical Center
    • Sacramento, California, United States, 95816
      • Sutter Cancer center
    • San Francisco, California, United States, 94118
      • California Pacific Medical Center - California Campus
    • Santa Rosa, California, United States, 95403
      • Sutter Pacific Medical Foundation
    • Vallejo, California, United States, 94589
      • Sutter Solano Medical Center
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • Memorial Hospital Cancer Center - Colorado Springs
    • Fort Collins, Colorado, United States, 80524
      • Poudre Valley Hospital
    • Fort Collins, Colorado, United States, 80528
      • Front Range Cancer Specialists
  • Illinois
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital Cancer Care Institute
    • Maywood, Illinois, United States, 60153
      • Cardinal Bernardin Cancer Center at Loyola University Medical Center
    • Springfield, Illinois, United States, 62781-0001
      • Regional Cancer Center at Memorial Medical Center
  • Indiana
    • Beech Grove, Indiana, United States, 46107
      • St. Francis Hospital and Health Centers - Beech Grove Campus
    • Richmond, Indiana, United States, 47374
      • Reid Hospital & Health Care Services
  • Kansas
    • Chanute, Kansas, United States, 66720
      • Cancer Center of Kansas, PA - Chanute
    • Dodge City, Kansas, United States, 67801
      • Cancer Center of Kansas, PA - Dodge City
    • Fort Scott, Kansas, United States, 66701
      • Cancer Center of Kansas - Fort Scott
    • Hays, Kansas, United States, 67601
      • Hays Medical Center
    • Hutchinson, Kansas, United States, 67502
      • Hutchinson Hospital Corporation
    • Independence, Kansas, United States, 67301
      • Cancer Center of Kansas-Independence
    • Kansas City, Kansas, United States, 66160-7357
      • Kansas Masonic Cancer Research Institute at the University of Kansas Medical Center
    • Kansas City, Kansas, United States, 66112
      • Kansas City Cancer Centers - West
    • Kingman, Kansas, United States, 67068
      • Cancer Center of Kansas, PA - Kingman
    • Lawrence, Kansas, United States, 66044
      • Lawrence Memorial Hospital
    • Liberal, Kansas, United States, 67901
      • Cancer Center of Kansas, PA - Liberal
    • Newton, Kansas, United States, 67114
      • Cancer Center of Kansas, PA - Newton
    • Overland Park, Kansas, United States, 66210
      • Kansas City Cancer Centers - Southwest
    • Parsons, Kansas, United States, 67357
      • Cancer Center of Kansas, PA - Parsons
    • Pittsburg, Kansas, United States, 66762
      • Mount Carmel Regional Cancer Center
    • Pratt, Kansas, United States, 67124
      • Cancer Center of Kansas, PA - Pratt
    • Salina, Kansas, United States, 67401
      • Cancer Center of Kansas, PA - Salina
    • Salina, Kansas, United States, 67401
      • Tammy Walker Cancer Center at Salina Regional Health Center
    • Shawnee Mission, Kansas, United States, 66204
      • Kansas City Cancer Center - Shawnee Mission
    • Topeka, Kansas, United States, 66606
      • St. Francis Comprehensive Cancer Center
    • Wellington, Kansas, United States, 67152
      • Cancer Center of Kansas, PA - Wellington
    • Wichita, Kansas, United States, 67214
      • Wesley Medical Center
    • Wichita, Kansas, United States, 67208
      • Cancer Center of Kansas, PA - Medical Arts Tower
    • Wichita, Kansas, United States, 67214
      • Cancer Center of Kansas, PA - Wichita
    • Wichita, Kansas, United States, 67214
      • CCOP - Wichita
    • Wichita, Kansas, United States, 67214
      • Via Christi Cancer Center at Via Christi Regional Medical Center
    • Wichita, Kansas, United States, 67208
      • Associates in Womens Health, PA - North Review
    • Winfield, Kansas, United States, 67156
      • Cancer Center of Kansas, PA - Winfield
  • Maryland
    • Baltimore, Maryland, United States, 21215
      • Alvin and Lois Lapidus Cancer Institute at Sinai Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-0942
      • University of Michigan Comprehensive Cancer Center
    • Battle Creek, Michigan, United States, 49017
      • Battle Creek Health System Cancer Care Center
    • Big Rapids, Michigan, United States, 49307
      • Mecosta County Medical Center
    • Detroit, Michigan, United States, 48202
      • Josephine Ford Cancer Center at Henry Ford Hospital
    • Detroit, Michigan, United States, 48201-1379
      • Barbara Ann Karmanos Cancer Institute
    • Grand Rapids, Michigan, United States, 49503
      • Butterworth Hospital at Spectrum Health
    • Grand Rapids, Michigan, United States, 49503
      • CCOP - Grand Rapids
    • Grand Rapids, Michigan, United States, 49503
      • Lacks Cancer Center at Saint Mary's Health Care
    • Muskegon, Michigan, United States, 49444
      • Mercy General Health Partners
    • Reed City, Michigan, United States, 49677
      • Spectrum Health Reed City Hospital
    • Traverse City, Michigan, United States, 49684
      • Munson Medical Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Cancer Clinic
    • Pascagoula, Mississippi, United States, 39581
      • Regional Cancer Center at Singing River Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Truman Medical Center - Hospital Hill
    • Kansas City, Missouri, United States, 64154
      • Kansas City Cancer Centers - North
    • Kansas City, Missouri, United States, 64131
      • Kansas City Cancer Centers - South
    • Lee's Summit, Missouri, United States, 64064
      • Kansas City Cancer Centers - East
  • Nebraska
    • Kearney, Nebraska, United States, 68848-1990
      • Good Samaritan Cancer Center at Good Samaritan Hospital
  • New York
    • Rochester, New York, United States, 14642
      • James P. Wilmot Cancer Center at University of Rochester Medical Center
    • Rochester, New York, United States, 14623
      • Interlakes Oncology/Hematology PC
  • North Carolina
    • Charlotte, North Carolina, United States, 28233-3549
      • Presbyterian Cancer Center at Presbyterian Hospital
    • Goldsboro, North Carolina, United States, 27534
      • Wayne Memorial Hospital, Incorporated
    • Statesville, North Carolina, United States, 28677
      • Iredell Memorial Hospital
  • Ohio
    • Akron, Ohio, United States, 44307
      • McDowell Cancer Center at Akron General Medical Center
    • Dayton, Ohio, United States, 45405
      • Grandview Hospital
    • Dayton, Ohio, United States, 45406
      • Good Samaritan Hospital
    • Dayton, Ohio, United States, 45409
      • David L. Rike Cancer Center at Miami Valley Hospital
    • Dayton, Ohio, United States, 45415
      • Samaritan North Cancer Care Center
    • Dayton, Ohio, United States, 45420
      • CCOP - Dayton
    • Findlay, Ohio, United States, 45840
      • Blanchard Valley Medical Associates
    • Franklin, Ohio, United States, 45005-1066
      • Middletown Regional Hospital
    • Greenville, Ohio, United States, 45331
      • Wayne Hospital
    • Kettering, Ohio, United States, 45429
      • Charles F. Kettering Memorial Hospital
    • Troy, Ohio, United States, 45373-1300
      • UVMC Cancer Care Center at Upper Valley Medical Center
    • Xenia, Ohio, United States, 45385
      • Ruth G. McMillan Cancer Center at Greene Memorial Hospital
  • South Carolina
    • Anderson, South Carolina, United States, 29621
      • AnMed Cancer Center
    • Charleston, South Carolina, United States, 29401
      • Roper St. Francis Cancer Center at Roper Hospital
    • Greenville, South Carolina, United States, 29601
      • Bon Secours St. Francis Health System
    • Spartanburg, South Carolina, United States, 29303
      • CCOP - Upstate Carolina
    • Spartanburg, South Carolina, United States, 29303
      • Gibbs Regional Cancer Center at Spartanburg Regional Medical Center
  • Tennessee
    • Knoxville, Tennessee, United States, 37920-6999
      • U.T. Medical Center Cancer Institute
  • Texas
    • Austin, Texas, United States, 78705
      • Southwest Regional Cancer Center - Central
    • Austin, Texas, United States, 78731
      • Texas Oncology, PA at Texas Oncology Cancer Center - Central
    • Austin, Texas, United States, 78745
      • Texas Oncology, PA at South Austin Cancer Center
    • Austin, Texas, United States, 78758
      • Texas Oncology, PA - Austin North
    • Cedar Park, Texas, United States, 78613
      • Texas Oncology, PA - Cedar Park
    • Houston, Texas, United States, 77030
      • Ben Taub General Hospital
    • Houston, Texas, United States, 77030
      • Veterans Affairs Medical Center - Houston
    • Houston, Texas, United States, 77030
      • Baylor University Medical Center - Houston
    • Houston, Texas, United States, 77030
      • St. Luke's Texas Cancer Institute at St. Luke's Episcopal Hospital
    • Round Rock, Texas, United States, 78681
      • Texas Oncology, PA at Texas Cancer Center Round Rock
    • Round Rock, Texas, United States, 78665
      • Texas Oncology, PA - Seton Williamson
    • San Marcos, Texas, United States, 78666
      • Texas Oncology, PA - San Marcos
  • Utah
    • American Fork, Utah, United States, 84003
      • American Fork Hospital
    • Cedar City, Utah, United States, 84720
      • Sandra L. Maxwell Cancer Center
    • Logan, Utah, United States, 84321
      • Logan Regional Hospital
    • Murray, Utah, United States, 84157
      • Jon and Karen Huntsman Cancer Center at Intermountain Medical Center
    • Ogden, Utah, United States, 84403
      • Val and Ann Browning Cancer Center at McKay-Dee Hospital Center
    • Provo, Utah, United States, 84604
      • Utah Valley Regional Medical Center - Provo
    • Saint George, Utah, United States, 84770
      • Dixie Regional Medical Center - East Campus
    • Salt Lake City, Utah, United States, 84143
      • LDS Hospital
  • Washington
    • Anacortes, Washington, United States, 98221
      • Island Hospital Cancer Care Center at Island Hospital
    • Bellingham, Washington, United States, 98225
      • St. Joseph Cancer Center
    • Bremerton, Washington, United States, 98310
      • Olympic Hematology and Oncology
    • Burien, Washington, United States, 98166
      • Highline Medical Center Cancer Center
    • Issaquah, Washington, United States, 98029
      • Swedish Medical Center - Issaquah Campus
    • Kennewick, Washington, United States, 99336
      • Columbia Basin Hematology
    • Mount Vernon, Washington, United States, 98274
      • Skagit Valley Hospital Cancer Care Center
    • Poulsbo, Washington, United States, 98370
      • Harrison Poulsbo Hematology and Onocology
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Research Center
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
    • Seattle, Washington, United States, 98112
      • Group Health Central Hospital
    • Seattle, Washington, United States, 98122-4307
      • Swedish Cancer Institute at Swedish Medical Center - First Hill Campus
    • Seattle, Washington, United States, 98122
      • Polyclinic First Hill
    • Seattle, Washington, United States, 98195
      • University Cancer Center at University of Washington Medical Center
    • Sedro-Woolley, Washington, United States, 98284
      • North Puget Oncology at United General Hospital
    • Spokane, Washington, United States, 99202
      • Cancer Care Northwest - Spokane South
    • Spokane, Washington, United States, 99218
      • Evergreen Hematology and Oncology, PS
    • Wenatchee, Washington, United States, 98801-2028
      • Wenatchee Valley Medical Center

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:

• Biopsy-proven primary adenocarcinoma of the rectum

  • Stage II or III disease
  • The distal border of the tumor must be at or below the peritoneal reflection, defined as within 12 cm of the anal verge by proctoscopic examination
  • No recurrent disease
• Must have wild-type k-ras status
• Measurable and/or nonmeasurable disease

PATIENT CHARACTERISTICS:

• Zubrod performance status 0-2
• Leukocyte count ≥ 3,000/mcL
• Granulocyte count ≥ 1,500/mcL
• Platelet count ≥ 100,000/mcL
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 2.5 times ULN
• SGOT (serum glutamate oxaloacetate transaminase) or SGPT (serum glutamate pyruvate transaminase)≤ 2.5 times ULN
• Creatinine clearance > 50 mL/min
• No prior severe reaction to a monoclonal antibody
• Willing to have specimens submitted
• No peripheral neuropathy ≥ grade 2
• No known existing uncontrolled coagulopathy

• No evidence of current high-grade obstruction

  • At least 2 weeks since prior diverting procedure
• No history of allergy to platinum compounds or to antiemetics appropriate for administration in conjunction with protocol treatment
• No prior unanticipated severe reaction to fluoropyrimidine therapy or known sensitivity to fluorouracil or known DPD deficiency
• No active inflammatory bowel disease, malabsorption syndrome, or inability to swallow that would impair the ingestion or absorption of capecitabine
• No uncontrolled intercurrent illness
• No ongoing or active infection
• No symptomatic congestive heart failure or unstable angina pectoris
• No cardiac arrhythmia or myocardial infarction within the past 12 months
• Not pregnant or nursing
• Fertile patients must use effective contraception
• No prior malignancy allowed except for adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or other cancer from which the patient has been disease-free for 5 years

PRIOR CONCURRENT THERAPY:

• Recovered from any recent major surgeries (e.g., coronary artery bypass graft, transurethral resection of prostate, or abdominal surgery)
• No prior chemotherapy, radiotherapy, or targeted therapy for this tumor
• More than 4 weeks since prior investigational agents
• No concurrent anti-retroviral therapy for HIV

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Chemo + Chemo and radiation + Surgery; Chemotherapy Cycle 1 (1 cycle is 35 days): Oxaliplatin, 50 mg/m^2, IV, Days 1,8,15,22,29; Cetuximab, 400 mg/m^2, IV, Day 1; Cetuximab, 250 mg/m^2, IV, Days 8,15,22,29; Capecitabine, 1650 mg/m^2/day, PO, Monday-Friday (Day 1-35) Chemotherapy+ Radiation Cycle 2: Oxaliplatin, 50 mg/m^2, IV, Days 50,57,71,78; Cetuximab, 250 mg/m^2, IV, Days 50,57,64,71,78; Capecitabine, 1650 mg/m^1, PO, Monday-Friday (Day 50-84); Radiation therapy: Planning target value 1: 4500 cGy (centigray) in 25 fractions; Planning target value 2 (stage T3 patients): Boost of 540 cGy in 3 fractions; Planning target value 2 (stage T4 patients): Boost of 900 cGy in 5 fractions. Therapeutic Surgical procedure: Resection

Biological: cetuximab; Chemotherapy cycle 1: Cetuximab, 400 mg/m^2, IV, Day 1; Cetuximab, 250 mg/m^2, IV, Days 8,15,22,29 Chemotherapy+ Radiation Cycle 2: Cetuximab, 250 mg/m^2, IV, Days 50,57,64,71,78; Other Names: Erbitux; NSC-714692; IMG-C225; Drug: capecitabine; Chemotherapy Cycle 1: Capecitabine, 1650 mg/m^2/day, PO, Monday-Friday (Day 1-35) Chemotherapy+ Radiation Cycle 2: Capecitabine, 1650 mg/m^1, PO, Monday-Friday (Day 50-84); Other Names: Xeloda; NSC-712807; Drug: oxaliplatin; Chemotherapy Cycle 1: Oxaliplatin, 50 mg/m^2, IV, Days 1,8,15,22,29 Chemotherapy+ Radiation Cycle 2: Oxaliplatin, 50 mg/m^2, IV, Days 50,57,71,78; Other Names: Eloxatin; NSC-266046; Procedure: therapeutic surgical procedure; Surgical resection; Other Names: Resection; Radiation: radiation therapy; IMRT (intensity-modulated radiation therapy); Other Names: RT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathologic Complete Response Rate	Pathologic response is evaluated after the patient has had surgery, and is based on local pathology review of the resected surgical specimen, according to the following: a) Pathologic complete response (pCR): on review of the resected rectal specimen and accompanying lymph nodes, no cancer is recognized by the pathologist; b) Microscopic cancer: gross tumor is not seen by the pathologist but tumor remains in the microscopic analysis of any part of the entire specimen; c) no response: gross cancer is found on pathologic examination of the resected rectal cancer and draining lymph nodes.	15-20 weeks from registration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-year Disease-free Survival	From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact.	3 years
Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to This Regimen.	Only adverse events that are possibly, probably or definitely related to study regimen are reported.	Up to 4 years

Collaborators and Investigators

• Sponsor: Southwest Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Cynthia G. Leichman, MD, BreastLink

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (Actual): July 1, 2014
• Study Completion (Actual): March 1, 2018

Study Registration Dates

• First Submitted: May 28, 2008
• First Submitted That Met QC Criteria: May 28, 2008
• First Posted (Estimate): May 29, 2008

Study Record Updates

• Last Update Posted (Actual): May 18, 2018
• Last Update Submitted That Met QC Criteria: April 18, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage IIIB rectal cancer; stage IIIC rectal cancer; stage IIA rectal cancer; stage IIB rectal cancer; stage IIC rectal cancer; stage IIIA 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; Oxaliplatin; Cetuximab
• Other Study ID Numbers: S0713 (Other Identifier: SWOG); U10CA032102 (U.S. NIH Grant/Contract)