Bevacizumab and Oxaliplatin Combined With Irinotecan or Leucovorin and Fluorouracil in Treating Patients With Metastatic or Recurrent Colorectal Cancer

Phase II Study of Treatment Selection Based Upon Tumor Thymidylate Synthase Expression in Previously Untreated Patients With Metastatic Colorectal Cancer

RATIONALE: Drugs used in chemotherapy, such as oxaliplatin, irinotecan, leucovorin, and fluorouracil, 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 bevacizumab, 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. Bevacizumab may also stop the growth of colorectal cancer by blocking blood flow to the tumor. Giving bevacizumab together with combination chemotherapy may be a better way to block tumor growth. Studying the amount of an enzyme found in the tumor may help doctors plan the best treatment.

PURPOSE: This randomized phase II trial is studying giving bevacizumab, oxaliplatin, and irinotecan or giving bevacizumab, oxaliplatin, leucovorin, and fluorouracil in treating patients with metastatic or recurrent colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Biological: bevacizumab; Drug: leucovorin calcium; Drug: fluorouracil; Drug: Oxaliplatin; Drug: irinotecan hydrochloride

Detailed Description

OBJECTIVES:

• Compare the response rate (complete and partial), progression-free survival, and overall survival of patients with previously untreated metastatic or locally recurrent colorectal adenocarcinoma with high vs low thymidylate synthase (TS) expression treated with fluorouracil, leucovorin calcium, oxaliplatin, and bevacizumab or irinotecan, oxaliplatin, and bevacizumab.
• Compare the toxicity of these regimens in these patients.
• Correlate gene expression with response rates in patients treated with these regimens.
• Correlate gene expression with toxicity of these regimens in these patients.
• Correlate dihydropyrimidine dehydrogenase, thymidine phosphorylase, and mammalian excision repair cross complementary protein expression with antitumor response in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to thymidylate synthase (TS) expression levels (high vs low or indeterminate). Patients with high TS expression are randomized to 1 of 2 treatment arms (Arms A or B). Patients with low or indeterminate TS expression are assigned to Arm C.

• Arm A: Patients receive bevacizumab IV over 30-90 minutes followed by oxaliplatin IV over 2 hours and irinotecan IV over 90 minutes on days 1 and 15.
• Arm B: Patients receive bevacizumab and oxaliplatin as in arm A, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15.
• Arm C: Patients receive bevacizumab, oxaliplatin, leucovorin calcium, and fluorouracil as in arm B.

In all arms, courses repeat every 28 days in the absence of unacceptable toxicity or disease progression.

Patients are followed up every 3 months for 2 years and then every 6 months for 2 years from the date of study registration.

• Study Type: Interventional
• Enrollment (Actual): 247
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Greenbrae, California, United States, 94904
      • California Cancer Care, Incorporated - Greenbrae
  • Colorado
    • Aurora, Colorado, United States, 80012
      • Aurora Presbyterian Hospital
    • Boulder, Colorado, United States, 80301-9019
      • Boulder Community Hospital
    • Colorado Springs, Colorado, United States, 80933
      • Penrose Cancer Center at Penrose Hospital
    • Denver, Colorado, United States, 80210
      • Porter Adventist Hospital
    • Denver, Colorado, United States, 80220
      • Rose Medical Center
    • Denver, Colorado, United States, 80218
      • Presbyterian - St. Luke's Medical Center
    • Denver, Colorado, United States, 80204
      • St. Anthony Central Hospital
    • Denver, Colorado, United States, 80218
      • St. Joseph Hospital
    • Denver, Colorado, United States, 80224-2522
      • CCOP - Colorado Cancer Research Program
    • Englewood, Colorado, United States, 80110
      • Swedish Medical Center
    • Grand Junction, Colorado, United States, 81502
      • St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center
    • Greeley, Colorado, United States, 80631
      • North Colorado Medical Center
    • Littleton, Colorado, United States, 80122
      • Littleton Adventist Hospital
    • Lone Tree, Colorado, United States, 80124
      • Sky Ridge Medical Center
    • Longmont, Colorado, United States, 80501
      • Hope Cancer Care Center at Longmont United Hospital
    • Loveland, Colorado, United States, 80539
      • McKee Medical Center
    • Parker, Colorado, United States, 80138
      • Parker Adventist Hospital
    • Pueblo, Colorado, United States, 81004
      • St. Mary - Corwin Regional Medical Center
    • Thornton, Colorado, United States, 80229
      • North Suburban Medical Center
    • Wheat Ridge, Colorado, United States, 80033
      • Exempla Lutheran Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610-0232
      • University of Florida Shands Cancer Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
    • Decatur, Georgia, United States, 30033
      • Veterans Affairs Medical Center - Atlanta (Decatur)
  • Illinois
    • Chicago, Illinois, United States, 60611-3013
      • Robert H. Lurie Comprehensive Cancer Center at Northwestern University
    • Chicago, Illinois, United States, 60611
      • Hematology and Oncology Associates
    • Chicago, Illinois, United States, 60657
      • Saint Joseph Hospital
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital Cancer Care Institute
    • Kankakee, Illinois, United States, 60901
      • Provena St. Mary's Regional Cancer Center - Kankakee
    • Libertyville, Illinois, United States, 60048
      • North Shore Oncology and Hematology Associates, Limited - Libertyville
    • Niles, Illinois, United States, 60714
      • Cancer Care and Hematology Specialists of Chicagoland - Niles
    • Rockford, Illinois, United States, 61104-2315
      • Swedish-American Regional Cancer Center
    • Skokie, Illinois, United States, 60076
      • Hematology Oncology Associates - Skokie
  • Indiana
    • Elkhart, Indiana, United States, 46515
      • Elkhart General Hospital
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46202
      • William N. Wishard Memorial Hospital
    • Indianapolis, Indiana, United States, 46202
      • Veterans Affairs Medical Center - Indianapolis
    • Kokomo, Indiana, United States, 46904
      • Howard Community Hospital
    • La Porte, Indiana, United States, 46350
      • Center for Cancer Therapy at LaPorte Hospital and Health Services
    • Mishawaka, Indiana, United States, 46545-1470
      • Saint Joseph Regional Medical Center
    • South Bend, Indiana, United States, 46601
      • Memorial Hospital of South Bend
    • South Bend, Indiana, United States, 46601
      • CCOP - Northern Indiana CR Consortium
  • Iowa
    • Ottumwa, Iowa, United States, 52501
      • McCreery Cancer Center at Ottumwa Regional
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology-Oncology Associates, LLP
    • Sioux City, Iowa, United States, 51102
      • Mercy Medical Center - Sioux City
    • Sioux City, Iowa, United States, 51104
      • St. Luke's Regional Medical Center
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49001
      • Borgess Medical Center
    • Kalamazoo, Michigan, United States, 49007-3731
      • West Michigan Cancer Center
    • Saint Joseph, Michigan, United States, 49085
      • Lakeside Cancer Specialists, PLLC
    • Saint Joseph, Michigan, United States, 49085
      • Lakeland Regional Cancer Care Center - St. Joseph
  • Minnesota
    • Bemidji, Minnesota, United States, 56601
      • MeritCare Bemidji
    • Burnsville, Minnesota, United States, 55337
      • Fairview Ridges Hospital
    • Coon Rapids, Minnesota, United States, 55433
      • Mercy and Unity Cancer Center at Mercy Hospital
    • Edina, Minnesota, United States, 55435
      • Fairview Southdale Hospital
    • Fridley, Minnesota, United States, 55432
      • Mercy and Unity Cancer Center at Unity Hospital
    • Hutchinson, Minnesota, United States, 55350
      • Hutchinson Area Health Care
    • Maplewood, Minnesota, United States, 55109
      • HealthEast Cancer Care at St. John's Hospital
    • Maplewood, Minnesota, United States, 55109
      • Minnesota Oncology - Maplewood
    • Minneapolis, Minnesota, United States, 55407
      • Virginia Piper Cancer Institute at Abbott - Northwestern Hospital
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center - Minneapolis
    • New Ulm, Minnesota, United States, 56073
      • New Ulm Medical Center
    • Robbinsdale, Minnesota, United States, 55422-2900
      • Humphrey Cancer Center at North Memorial Outpatient Center
    • Saint Louis Park, Minnesota, United States, 55416
      • CCOP - Metro-Minnesota
    • Saint Louis Park, Minnesota, United States, 55416
      • Park Nicollet Cancer Center
    • Saint Paul, Minnesota, United States, 55102
      • United Hospital
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital Cancer Care Center
    • Shakopee, Minnesota, United States, 55379
      • St. Francis Cancer Center at St. Francis Medical Center
    • Stillwater, Minnesota, United States, 55082
      • Lakeview Hospital
    • Waconia, Minnesota, United States, 55387
      • Ridgeview Medical Center
    • Willmar, Minnesota, United States, 56201
      • Willmar Cancer Center at Rice Memorial Hospital
    • Woodbury, Minnesota, United States, 55125
      • Minnesota Oncology - Woodbury
  • Nebraska
    • Lincoln, Nebraska, United States, 68510
      • Cancer Resource Center - Lincoln
    • Omaha, Nebraska, United States, 68106
      • CCOP - Missouri Valley Cancer Consortium
    • Omaha, Nebraska, United States, 68122
      • Immanuel Medical Center
    • Omaha, Nebraska, United States, 68124
      • Alegant Health Cancer Center at Bergan Mercy Medical Center
    • Omaha, Nebraska, United States, 68131-2197
      • Creighton University Medical Center
    • Omaha, Nebraska, United States, 68130
      • Lakeside Hospital
  • New Jersey
    • Marlton, New Jersey, United States, 08053
      • Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton
  • North Dakota
    • Fargo, North Dakota, United States, 58122
      • CCOP - MeritCare Hospital
    • Fargo, North Dakota, United States, 58122
      • Roger Maris Cancer Center at MeritCare Hospital
  • Ohio
    • Chillicothe, Ohio, United States, 45601
      • Adena Regional Medical Center
    • Cleveland, Ohio, United States, 44106-5065
      • Case Comprehensive Cancer Center
    • Cleveland, Ohio, United States, 44109
      • MetroHealth Cancer Care Center at MetroHealth Medical Center
    • Columbus, Ohio, United States, 43214-3998
      • Riverside Methodist Hospital Cancer Care
    • Columbus, Ohio, United States, 43222
      • Mount Carmel Health - West Hospital
    • Columbus, Ohio, United States, 43215
      • CCOP - Columbus
    • Columbus, Ohio, United States, 43215
      • Grant Medical Center Cancer Care
    • Columbus, Ohio, United States, 43228
      • Doctors Hospital at Ohio Health
    • Delaware, Ohio, United States, 43015
      • Grady Memorial Hospital
    • Lancaster, Ohio, United States, 43130
      • Fairfield Medical Center
    • Lima, Ohio, United States, 45801
      • St. Rita's Medical Center
    • Marietta, Ohio, United States, 45750
      • Strecker Cancer Center at Marietta Memorial Hospital
    • Mount Vernon, Ohio, United States, 43050
      • Knox Community Hospital
    • Newark, Ohio, United States, 43055
      • Licking Memorial Cancer Care Program at Licking Memorial Hospital
    • Portsmouth, Ohio, United States, 45662
      • Southern Ohio Medical Center Cancer Center
    • Springfield, Ohio, United States, 45505
      • Community Hospital of Springfield and Clark County
    • Zanesville, Ohio, United States, 43701
      • Genesis - Good Samaritan Hospital
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74136
      • Natalie Warren Bryant Cancer Center at St. Francis Hospital
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18105
      • Morgan Cancer Center at Lehigh Valley Hospital - Cedar Crest
    • Bryn Mawr, Pennsylvania, United States, 19010
      • Bryn Mawr Hospital
    • Paoli, Pennsylvania, United States, 19301-1792
      • Cancer Center of Paoli Memorial Hospital
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center - Philadelphia
    • Reading, Pennsylvania, United States, 19612-6052
      • McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center
    • Wynnewood, Pennsylvania, United States, 19096
      • Lankenau Cancer Center at Lankenau Hospital
    • Wynnewood, Pennsylvania, United States, 19096
      • CCOP - Main Line Health
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Avera Cancer Institute
    • Sioux Falls, South Dakota, United States, 57117-5039
      • Sanford Cancer Center at Sanford USD Medical Center
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • Erlanger Cancer Center at Erlanger Hospital - Baroness
  • Texas
    • Temple, Texas, United States, 76508
      • CCOP - Scott and White Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

INCLUSION:

• Metastatic or locally recurrent colorectal adenocarcinoma
• Measurable disease
• At least 2 formalin-fixed paraffin embedded core needle biopsies OR fine needle aspirate containing a minimum of 3 clusters of malignant cells and fixed tissue from the previous biopsy
• If no tissue samples are available the patient must be willing to undergo biopsy of a metastatic site
• Age 18 and over
• Eastern Cooperative Oncology Group (ECOG) Performance status 0-2
• Absolute neutrophil count ≥ 1,500/mm^3
• Platelet count ≥ 100,000/mm^3

• Prothrombin time (PT)/international normalized ratio (INR) ≤ 1.5 unless patient is receiving full-dose anticoagulants AND the following criteria are met:

  • In-range INR (usually between 2 and 3) AND on a stable dose of warfarin or low molecular weight heparin
  • No active bleeding or pathological condition that is associated with a high risk of bleeding
• Partial thromboplastin time (PTT) < 1.5 times upper limit of normal (ULN)
• Alanine transaminase (ALT) and aspartate aminotransferase (AST) < 3 times ULN
• Bilirubin ≤ 1.5 times ULN
• Creatinine ≤ 1.8 mg/dL

• Meets 1 of the following criteria:

  • Protein negative on urine dipstick
  • Urine protein/creatinine ratio < 1.0
  • Less than 2 g protein on 24-hour urine collection

• Patients with a history of hypertension must meet the following criteria:

  • Blood pressure < 150/90 mm Hg
  • Stable regimen of anti-hypertensive therapy
• More than 28 days since prior major or open surgery
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 3 months after study participation

• Prior non-colorectal malignancies are allowed provided the following criteria are met:

  • No current clinical evidence of persistent or recurrent disease
  • No active therapy for non-colorectal malignancy, including hormonal therapy

EXCLUSION:

• Pregnant or nursing

• Arterial thromboembolic events within the past 6 months, including the following:

  • Transient ischemic attack
  • Cerebrovascular accident
  • Unstable angina pectoris
  • Myocardial infarction
• Symptomatic arrhythmia
• Symptomatic congestive heart failure
• Clinically significant peripheral artery disease
• New York Heart Association class III or IV heart disease
• Serious nonhealing wound, ulcer, or bone fracture within the past 28 days
• Significant traumatic injury within the past 28 days
• Neuropathy ≥ grade 2
• Ongoing or active infection
• Concurrent prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF)
• Prior chemotherapy for metastatic disease. Adjuvant therapy completed at least 12 months before first evidence of metastasis allowed
• Cardiovascular, renal, hepatic, or other nonmalignant systemic disease that would preclude study therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A (High TS, IROX/bev); Patients with high TS who are randomized to Arm A receive irinotecan and oxaliplatin plus bevacizumab (IROX/bev). The combination regimen is administered by giving bevacizumab IV over 30-90 minutes followed by oxaliplatin IV over 2 hours and irinotecan IV over 90 minutes on days 1 and 15 every 28 days until disease progression or until any criterion specified in protocol is met.	Biological: bevacizumab; Given IV; Other Names: NSC 704865, RhuMAb VEGF, Recombinant Humanized Monoclonal Anti-VEGF Antibody; Drug: Oxaliplatin; Given IV; Other Names: Eloxatin, trans-l-diaminocyclohexane oxalatoplatinum, cis-[oxalato(trans-l-1,2-diaminocyclohexane)platinum(II)].; Drug: irinotecan hydrochloride; Given IV; Other Names: Camptothecin-11, CPT-11, Camptosar
Experimental: Arm B (High TS, FOLFOX/bev); Patients with high TS who are randomized to Arm B receive 5-Fluorouracil, leucovorin, oxaliplatin, and bevacizumab (FOLFOX/bev). The combination regimen is administered by giving bevacizumab and oxaliplatin as in Arm A, leucovorin calcium IV over 2 hours, and fluorouracil IV over 5 minutes and then continuously over 46 hours on days 1 and 15 every 28 days until disease progression or until any criterion specified in protocol is met.	Biological: bevacizumab; Given IV; Other Names: NSC 704865, RhuMAb VEGF, Recombinant Humanized Monoclonal Anti-VEGF Antibody; Drug: leucovorin calcium; Given IV; Other Names: Leucovorin, Wellcovorin' citrovorum factor, folinic acid, 5-formyl tetrahydrofolate, LV, LCV.; Drug: fluorouracil; Given IV; Other Names: 5-Fluorouracil, 5-FU, Adrucil, Efudex; Drug: Oxaliplatin; Given IV; Other Names: Eloxatin, trans-l-diaminocyclohexane oxalatoplatinum, cis-[oxalato(trans-l-1,2-diaminocyclohexane)platinum(II)].
Experimental: Arm C (Low or intermediate TS, FOLFOX/bev); Patients with low or intermediate TS receive 5-Fluorouracil, leucovorin, oxaliplatin, and bevacizumab (FOLFOX/bev) as in Arm B.	Biological: bevacizumab; Given IV; Other Names: NSC 704865, RhuMAb VEGF, Recombinant Humanized Monoclonal Anti-VEGF Antibody; Drug: leucovorin calcium; Given IV; Other Names: Leucovorin, Wellcovorin' citrovorum factor, folinic acid, 5-formyl tetrahydrofolate, LV, LCV.; Drug: fluorouracil; Given IV; Other Names: 5-Fluorouracil, 5-FU, Adrucil, Efudex; Drug: Oxaliplatin; Given IV; Other Names: Eloxatin, trans-l-diaminocyclohexane oxalatoplatinum, cis-[oxalato(trans-l-1,2-diaminocyclohexane)platinum(II)].

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate	Objective response rate is defined as proportion of patients who achieve complete response (CR) or partial response (PR). Response was assessed using Solid Tumor Response Criteria (RECIST). CR is defined as the disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter.	Assessed every 3 months if the patient is within 2 years of registration and every 6 months up to 4 years post-registration.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-Free Survival (PFS)	Progression-free survival is defined as time from randomization (to Arm A or Arm B) or registration (to Arm C) to the earlier of disease progression or death. Patients alive and progression-free at last follow-up were censored.	Assessed every 3 months if the patient is within 2 years of registration and every 6 months once the patient is 2-4 years post-registration.
Overall Survival (OS)	Overall survival is defined as time from randomization (to Arm A or Arm B) or registration (to Arm C) to death. Patients alive at last follow-up were censored.	Assessed every 3 months if the patient is within 2 years of registration and every 6 months once the patient is 2-4 years post-registration.

Collaborators and Investigators

• Sponsor: Eastern Cooperative Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Neal J. Meropol, MD, Fox Chase Cancer Center; Study Chair: Jean L. Grem, MD, University of Nebraska

Study record dates

Study Major Dates

• Study Start (Actual): September 8, 2005
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: December 8, 2004
• First Submitted That Met QC Criteria: December 8, 2004
• First Posted (Estimated): December 9, 2004

Study Record Updates

• Last Update Posted (Actual): July 5, 2023
• Last Update Submitted That Met QC Criteria: June 20, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage IV rectal cancer; stage IV colon cancer; adenocarcinoma of the colon; recurrent colon cancer; recurrent rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Antineoplastic Agents, Phytogenic; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Vitamins; Topoisomerase I Inhibitors; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Bevacizumab; Leucovorin; Irinotecan; Levoleucovorin; Camptothecin; Tetrahydrofolates; Formyltetrahydrofolates
• Other Study ID Numbers: CDR0000398096; U10CA021115 (U.S. NIH Grant/Contract); E4203 (Other Identifier: Eastern Cooperative Oncology Group (ECOG))