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

Colorectal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00098787
• Other study ID #: CDR0000398096
• Secondary ID: E4203U10CA021115
• Status: Completed
• Phase: Phase 2
• Start date: September 8, 2005
• Est. completion date: April 2015

Study information

• Verified date: June 2023
• Source: Eastern Cooperative Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 247
• Est. completion date: April 2015
• Est. primary completion date: November 2013
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms

Intervention

Biological:
• bevacizumab
Given IV

Drug:
• fluorouracil
Given IV
• irinotecan hydrochloride
Given IV
• leucovorin calcium
Given IV
• Oxaliplatin
Given IV

Locations

Country	Name	City	State
United States	Morgan Cancer Center at Lehigh Valley Hospital - Cedar Crest	Allentown	Pennsylvania
United States	Winship Cancer Institute of Emory University	Atlanta	Georgia
United States	Aurora Presbyterian Hospital	Aurora	Colorado
United States	MeritCare Bemidji	Bemidji	Minnesota
United States	Boulder Community Hospital	Boulder	Colorado
United States	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania
United States	Fairview Ridges Hospital	Burnsville	Minnesota
United States	Erlanger Cancer Center at Erlanger Hospital - Baroness	Chattanooga	Tennessee
United States	Hematology and Oncology Associates	Chicago	Illinois
United States	Robert H. Lurie Comprehensive Cancer Center at Northwestern University	Chicago	Illinois
United States	Saint Joseph Hospital	Chicago	Illinois
United States	Adena Regional Medical Center	Chillicothe	Ohio
United States	Case Comprehensive Cancer Center	Cleveland	Ohio
United States	MetroHealth Cancer Care Center at MetroHealth Medical Center	Cleveland	Ohio
United States	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado
United States	CCOP - Columbus	Columbus	Ohio
United States	Doctors Hospital at Ohio Health	Columbus	Ohio
United States	Grant Medical Center Cancer Care	Columbus	Ohio
United States	Mount Carmel Health - West Hospital	Columbus	Ohio
United States	Riverside Methodist Hospital Cancer Care	Columbus	Ohio
United States	Mercy and Unity Cancer Center at Mercy Hospital	Coon Rapids	Minnesota
United States	Decatur Memorial Hospital Cancer Care Institute	Decatur	Illinois
United States	Veterans Affairs Medical Center - Atlanta (Decatur)	Decatur	Georgia
United States	Grady Memorial Hospital	Delaware	Ohio
United States	CCOP - Colorado Cancer Research Program	Denver	Colorado
United States	Porter Adventist Hospital	Denver	Colorado
United States	Presbyterian - St. Luke's Medical Center	Denver	Colorado
United States	Rose Medical Center	Denver	Colorado
United States	St. Anthony Central Hospital	Denver	Colorado
United States	St. Joseph Hospital	Denver	Colorado
United States	Fairview Southdale Hospital	Edina	Minnesota
United States	Elkhart General Hospital	Elkhart	Indiana
United States	Swedish Medical Center	Englewood	Colorado
United States	CCOP - MeritCare Hospital	Fargo	North Dakota
United States	Roger Maris Cancer Center at MeritCare Hospital	Fargo	North Dakota
United States	Mercy and Unity Cancer Center at Unity Hospital	Fridley	Minnesota
United States	University of Florida Shands Cancer Center	Gainesville	Florida
United States	St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center	Grand Junction	Colorado
United States	North Colorado Medical Center	Greeley	Colorado
United States	California Cancer Care, Incorporated - Greenbrae	Greenbrae	California
United States	Hutchinson Area Health Care	Hutchinson	Minnesota
United States	Indiana University Melvin and Bren Simon Cancer Center	Indianapolis	Indiana
United States	Veterans Affairs Medical Center - Indianapolis	Indianapolis	Indiana
United States	William N. Wishard Memorial Hospital	Indianapolis	Indiana
United States	Borgess Medical Center	Kalamazoo	Michigan
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	West Michigan Cancer Center	Kalamazoo	Michigan
United States	Provena St. Mary's Regional Cancer Center - Kankakee	Kankakee	Illinois
United States	Howard Community Hospital	Kokomo	Indiana
United States	Center for Cancer Therapy at LaPorte Hospital and Health Services	La Porte	Indiana
United States	Fairfield Medical Center	Lancaster	Ohio
United States	North Shore Oncology and Hematology Associates, Limited - Libertyville	Libertyville	Illinois
United States	St. Rita's Medical Center	Lima	Ohio
United States	Cancer Resource Center - Lincoln	Lincoln	Nebraska
United States	Littleton Adventist Hospital	Littleton	Colorado
United States	Sky Ridge Medical Center	Lone Tree	Colorado
United States	Hope Cancer Care Center at Longmont United Hospital	Longmont	Colorado
United States	McKee Medical Center	Loveland	Colorado
United States	HealthEast Cancer Care at St. John's Hospital	Maplewood	Minnesota
United States	Minnesota Oncology - Maplewood	Maplewood	Minnesota
United States	Strecker Cancer Center at Marietta Memorial Hospital	Marietta	Ohio
United States	Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton	Marlton	New Jersey
United States	Hennepin County Medical Center - Minneapolis	Minneapolis	Minnesota
United States	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota
United States	Saint Joseph Regional Medical Center	Mishawaka	Indiana
United States	Knox Community Hospital	Mount Vernon	Ohio
United States	New Ulm Medical Center	New Ulm	Minnesota
United States	Licking Memorial Cancer Care Program at Licking Memorial Hospital	Newark	Ohio
United States	Cancer Care and Hematology Specialists of Chicagoland - Niles	Niles	Illinois
United States	Alegant Health Cancer Center at Bergan Mercy Medical Center	Omaha	Nebraska
United States	CCOP - Missouri Valley Cancer Consortium	Omaha	Nebraska
United States	Creighton University Medical Center	Omaha	Nebraska
United States	Immanuel Medical Center	Omaha	Nebraska
United States	Lakeside Hospital	Omaha	Nebraska
United States	McCreery Cancer Center at Ottumwa Regional	Ottumwa	Iowa
United States	Cancer Center of Paoli Memorial Hospital	Paoli	Pennsylvania
United States	Parker Adventist Hospital	Parker	Colorado
United States	Fox Chase Cancer Center - Philadelphia	Philadelphia	Pennsylvania
United States	Southern Ohio Medical Center Cancer Center	Portsmouth	Ohio
United States	St. Mary - Corwin Regional Medical Center	Pueblo	Colorado
United States	McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center	Reading	Pennsylvania
United States	Humphrey Cancer Center at North Memorial Outpatient Center	Robbinsdale	Minnesota
United States	Swedish-American Regional Cancer Center	Rockford	Illinois
United States	Lakeland Regional Cancer Care Center - St. Joseph	Saint Joseph	Michigan
United States	Lakeside Cancer Specialists, PLLC	Saint Joseph	Michigan
United States	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota
United States	Park Nicollet Cancer Center	Saint Louis Park	Minnesota
United States	Regions Hospital Cancer Care Center	Saint Paul	Minnesota
United States	United Hospital	Saint Paul	Minnesota
United States	St. Francis Cancer Center at St. Francis Medical Center	Shakopee	Minnesota
United States	Mercy Medical Center - Sioux City	Sioux City	Iowa
United States	Siouxland Hematology-Oncology Associates, LLP	Sioux City	Iowa
United States	St. Luke's Regional Medical Center	Sioux City	Iowa
United States	Avera Cancer Institute	Sioux Falls	South Dakota
United States	Sanford Cancer Center at Sanford USD Medical Center	Sioux Falls	South Dakota
United States	Hematology Oncology Associates - Skokie	Skokie	Illinois
United States	CCOP - Northern Indiana CR Consortium	South Bend	Indiana
United States	Memorial Hospital of South Bend	South Bend	Indiana
United States	Community Hospital of Springfield and Clark County	Springfield	Ohio
United States	Lakeview Hospital	Stillwater	Minnesota
United States	CCOP - Scott and White Hospital	Temple	Texas
United States	North Suburban Medical Center	Thornton	Colorado
United States	Natalie Warren Bryant Cancer Center at St. Francis Hospital	Tulsa	Oklahoma
United States	Ridgeview Medical Center	Waconia	Minnesota
United States	Exempla Lutheran Medical Center	Wheat Ridge	Colorado
United States	Willmar Cancer Center at Rice Memorial Hospital	Willmar	Minnesota
United States	Minnesota Oncology - Woodbury	Woodbury	Minnesota
United States	CCOP - Main Line Health	Wynnewood	Pennsylvania
United States	Lankenau Cancer Center at Lankenau Hospital	Wynnewood	Pennsylvania
United States	Genesis - Good Samaritan Hospital	Zanesville	Ohio

Sponsors (2)

Lead Sponsor	Collaborator
Eastern Cooperative Oncology Group	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.
Secondary	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.