Sequential and Concurrent FOLFOXIRI/Bevacizumab Regimens Versus FOLFOX/Bevacizumab in First-Line Metastatic Colorectal Cancer

NCT01765582 | Terminated Phase 2 Results FDA Drug

• 1 other identifier: ML28442
• Study Type: interventional
• Target: 280
• Locations: 1 country
• Sites: 45

Brief Summary

This randomized, open-label, multicenter study will evaluate the efficacy and safety of folinic acid (leucovorin), 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI) / bevacizumab regimens (concurrent and sequential) versus folinic acid (leucovorin), 5-fluorouracil, and oxaliplatin (FOLFOX) / bevacizumab in first-line in participants with metastatic colorectal cancer. Participants will be randomized to receive bevacizumab 5 milligrams per kilogram (mg/kg) intravenously every 2 weeks with either concurrent or sequential FOLFOXIRI or with FOLFOX for 4 to 6 months of induction therapy, followed by maintenance therapy with bevacizumab plus either leucovorin/5-fluorouracil or capecitabine until disease progression occurs. After disease progression, participants will receive treatment with a fluoropyrimidine-based chemotherapy plus bevacizumab.

Conditions

Colorectal Neoplasms

Outcome Measures

Primary Outcomes (2)

• Percentage of Participants With Overall Response During First-Line Therapy (ORR1)

  ORR1 was the percentage of participants with complete response (CR) or partial response (PR) during first-line therapy as assessed by investigator according to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v.1.1). CR was defined as disappearance of all extranodal target lesions and all pathological lymph nodes had to have decreased to \<10 millimeter (mm) in short axis. PR was defined as at least a 30% decrease in the sum of longest diameters of target lesions, taking as reference the baseline sum diameters. ORR1 = CR + PR

  Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years)

• Progression-Free Survival During First-Line Therapy (PFS1)

  PFS1 was defined as time from randomization to the first occurrence of disease progression during first-line therapy, as assessed by the Investigator using RECIST v1.1, or death from any cause, whichever occurs first. Disease progression was defined as sum of longest diameters increased by at least 20% from the smallest value on study. The sum of longest diameters must also demonstrate an absolute increase of at least 5 mm.

  Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years)

Secondary Outcomes (5)

• Time to PFS2

  Randomization up to disease progression during second-line therapy or death, whichever occurs first (up to approximately 3 years)

• Overall Survival (OS)

  Randomization until death due to any cause (up to approximately 3 years)

• Proportion of Participants Who Underwent Liver Metastases Resections

  Randomization up to approximately 3 years

• Proportion of Participants Considered by the Investigator to be Unresectable on Study Enrollment Who Subsequently Underwent Attempted Curative Resections of Metastases

  Randomization up to approximately 3 years

• Percentage of Participants With Adverse Events

  Randomization up to approximately 3 years

Study Arms (3)

Arm A: Concurrent FOLFOXIRI + Bevacizumab

EXPERIMENTAL

Participants will receive concurrent FOLFOXIRI along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4 month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.

Drug: 5-fluorouracil; Drug: bevacizumab; Drug: capecitabine; Drug: irinotecan; Drug: folinic acid; Drug: oxaliplatin

Arm B: Sequential FOLFOXIRI + Bevacizumab

EXPERIMENTAL

Participants will receive alternating 4-week administrations of FOLFOX/bevacizumab and folinic acid (leucovorin), 5-FU, and irinotecan (FOLFIRI) /Bevacizumab with a treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.

Drug: 5-fluorouracil; Drug: bevacizumab; Drug: capecitabine; Drug: irinotecan; Drug: folinic acid; Drug: oxaliplatin

Arm C: FOLFOX + Bevacizumab

EXPERIMENTAL

Participants will receive FOLFOX along with 5 mg/kg of bevacizumab with treatment cycle of 2 weeks during first 4-month induction phase (plus optional 2 months of induction for participants who exhibit good response and tolerate the regimen) followed by administration of 5-FU with bevacizumab or capecitabine with bevacizumab as per investigator's discretion in maintenance phase. Following progression on first-line therapy (PD1), bevacizumab (dose equivalent, 2.5 mg/kg/week) will be administered as second-line therapy in combination with fluoropyrimidine based chemotherapy at the investigator's discretion.

Drug: 5-fluorouracil; Drug: bevacizumab; Drug: capecitabine; Drug: folinic acid; Drug: oxaliplatin

Interventions

5-fluorouracil DRUG

Participants in Arm A will receive 3200 milligrams per square meter (mg/m\^2) by 48-hour continuous intravenous (IV) infusion every 2 weeks, during the 4-6 months' induction followed by maintenance therapy including bolus dose of 400 mg/m\^2, followed by a 46-hour continuous infusion (2400 mg/m\^2) every 2 weeks per investigator's discretion. Participants in Arm B and C will receive a bolus dose of 400 mg/m\^2, followed by a 46-hour continuous infusion (2400 mg/m\^2) every 2 weeks during the 4-6 months of induction and maintenance per investigator's discretion.

Arm A: Concurrent FOLFOXIRI + Bevacizumab; Arm B: Sequential FOLFOXIRI + Bevacizumab; Arm C: FOLFOX + Bevacizumab

bevacizumab DRUG

Participants will receive 5 mg/kg IV every 2 weeks during the first 4-6 months induction phase, followed by 5 mg/kg IV every 2 weeks or 7.5 mg/kg IV every 3 weeks during maintenance therapy, and 2.5 mg/kg per week reinduction after disease progression.

Also known as: Avastin

Arm A: Concurrent FOLFOXIRI + Bevacizumab; Arm B: Sequential FOLFOXIRI + Bevacizumab; Arm C: FOLFOX + Bevacizumab

capecitabine DRUG

Participants will receive 1000 or 850 mg/kg orally twice daily as per investigator's discretion on Day 1 to 14, repeated every 3 weeks in maintenance phase.

Also known as: Xeloda

Arm A: Concurrent FOLFOXIRI + Bevacizumab; Arm B: Sequential FOLFOXIRI + Bevacizumab; Arm C: FOLFOX + Bevacizumab

irinotecan DRUG

Participants will receive IV infusion of 165 mg/m\^2 over 1 hour every 2 weeks (Arm A) or IV infusion of 180 mg/m\^2 over 1 hour in 2 x 2 weeks cycles alternating months (in Arm B), during 4-6 months induction phase.

Arm A: Concurrent FOLFOXIRI + Bevacizumab; Arm B: Sequential FOLFOXIRI + Bevacizumab

folinic acid DRUG

Participants will receive IV infusion of 200 mg/m\^² (Arm A) or 400 mg/m\^2 (Arm B or C) over 2 hours every 2 weeks, during 4-6 months induction phase followed by IV infusion of 400 mg/m\^2 in the maintenance therapy.

Also known as: leucovorin

Arm A: Concurrent FOLFOXIRI + Bevacizumab; Arm B: Sequential FOLFOXIRI + Bevacizumab; Arm C: FOLFOX + Bevacizumab

oxaliplatin DRUG

Participants will receive 85 mg/m\^2 over 2 hours as IV infusion every 2 weeks (Arm A, C ) or 2 x 2 week cycles alternating months (Arm B), during 4-6 months induction phase .

Arm A: Concurrent FOLFOXIRI + Bevacizumab; Arm B: Sequential FOLFOXIRI + Bevacizumab; Arm C: FOLFOX + Bevacizumab

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed colorectal cancer with at least one measurable metastatic lesion by RECIST v 1.1, that is considered unresectable at baseline
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 if age less than (\<) 71 years; ECOG status of 0 if age 71 to 75 years
• Adequate hematological, renal and liver function
• Participants with treated brain metastases are eligible for study participation; participants may not receive ongoing treatment with steroids at screening, anticonvulsants (at stable dose) are allowed
• Females of childbearing potential and males must agree to use effective contraception as defined by protocol during the treatment period and for at least 6 months after the last dose of study drug

You may not qualify if:

• Any prior treatment for metastatic colorectal cancer, except for use of palliative radiosensitizers
• Adjuvant chemotherapy for colorectal cancer completed \< 12 months prior to study consent
• Sensory peripheral neuropathy greater than or equal to (\>/=) Grade 2
• Evidence of Gilbert's Syndrome or homozygosity for the Uridine 5-diphospho-glucuronosyltransferase (UGT) 1A1\*28 allele
• Positive for human immunodeficiency virus (HIV) infection
• Malignancies other than metastatic colorectal cancer within 5 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, and ductal carcinoma in situ treated surgically with curative intent
• Radiotherapy to any site for any reason within 28 days prior to randomization, except for palliative radiotherapy to bone lesions within 14 days prior to randomization
• Clinically significant third-space fluid collections (e.g. ascites or pleural effusion) that cannot be controlled by drainage or other procedures prior to study entry
• Treatment with any other investigational agent, or participation in another investigational drug trial within 28 days prior to randomization
• Any disease or condition or laboratory finding giving reasonable suspicion of disease or condition that contraindicates the use of bevacizumab or puts the participant at high risk for treatment-related complications
• Inadequately controlled hypertension
• Clinically significant (that is \[i.e.\] active) cardiovascular disease (For example \[e.g.\] cerebrovascular accident or myocardial infarction within 6 months prior to randomization), unstable angina, congestive heart failure (New York Heart Association Class \>/= II) or serious cardiac arrhythmia that is uncontrolled by medication or may interfere with the administration of the study treatment
• Known hypersensitivity to bevacizumab or any of its excipients or any other study drug

Sponsors & Collaborators

• Hoffmann-La Roche: lead

Study Sites (45)

University of South Alabama; Mitchell Cancer Institute

Mobile, Alabama, 36604, United States

Location

Long Beach Memorial Medical Center; Oncology

Long Beach, California, 90806, United States

Location

LAC-USC Medical Center

Los Angeles, California, 90033, United States

Location

USC Norris Cancer Center

Los Angeles, California, 90033, United States

Location

Pacific Cancer Care - Monterey

Monterey, California, 93940, United States

Location

Sacramento Center for Hematolo

Sacramento, California, 95816, United States

Location

Pacific Cancer Care

Salinas, California, 93901, United States

Location

Kaiser Permanente - Franklin

Denver, Colorado, 80205, United States

Location

Yale Cancer Center

New Haven, Connecticut, 06520, United States

Location

Sibley Memorial Hospital

Washington D.C., District of Columbia, 20016, United States

Location

Florida Cancer Specialists - Fort Myers (Colonial Center Dr)

Fort Myers, Florida, 33905, United States

Location

Florida Cancer Specialist, North Region

St. Petersburg, Florida, 33705, United States

Location

University Cancer & Blood Center, LLC

Athens, Georgia, 30607, United States

Location

Emory University Clinic

Atlanta, Georgia, 30322, United States

Location

Central Georgia Cancer Care PC

Macon, Georgia, 31201, United States

Location

Summit Cancer Care PC

Savannah, Georgia, 31405, United States

Location

Ingalls Memorial Hosp

Harvey, Illinois, 60426, United States

Location

Edward Cancer Center Naperville

Naperville, Illinois, 60540, United States

Location

Edward Cancer Center Plainfield

Plainfield, Illinois, 60585, United States

Location

University of Kentucky Medical Center

Lexington, Kentucky, 40536, United States

Location

Johns Hopkins Univ; Bunting Blaustein Cancer Center

Baltimore, Maryland, 21231, United States

Location

Tufts Medical Center

Boston, Massachusetts, 02111, United States

Location

St. Joseph Mercy Hospital; Cancer Care Center.

Ann Arbor, Michigan, 48106, United States

Location

Karmanos Cancer Institute..

Detroit, Michigan, 48201, United States

Location

Washington University School of Medicine

St Louis, Missouri, 63110, United States

Location

Southeast Nebraska Cancer Center;; Southeast Nebraska Hematology and Oncology

Lincoln, Nebraska, 68510, United States

Location

Nebraska Methodist Hospital; Cancer Center

Omaha, Nebraska, 68114, United States

Location

Dartmouth Hitchcock Med Center

Lebanon, New Hampshire, 03756, United States

Location

Oncology Hematology Care Inc

Cincinnati, Ohio, 45242, United States

Location

University of Oklahoma; Stephenson Oklahoma Canc Ctr

Oklahoma City, Oklahoma, 73104, United States

Location

Milton S. Hershey Medical Center; Penn State Cancer Inst.

Hershey, Pennsylvania, 17033, United States

Location

Chattanooga Oncology and Hematology Associates, PC

Chattanooga, Tennessee, 37404, United States

Location

West Clinic

Germantown, Tennessee, 38138, United States

Location

Sarah Cannon Cancer Center and Research Institute

Nashville, Tennessee, 37203, United States

Location

UT Southwestern MC at Dallas

Dallas, Texas, 75390-9063, United States

Location

Ctr for Cancer and Blood Disorders

Fort Worth, Texas, 76104, United States

Location

Scott and White Hospital; Cancer Center

Temple, Texas, 76508, United States

Location

Virginia Cancer Institute

Richmond, Virginia, 23226, United States

Location

Seattle Cancer Care Alliance - Evergreen Health

Kirkland, Washington, 98034, United States

Location

Seattle Cancer Care Alliance

Seattle, Washington, 98109, United States

Location

Medical Oncology Associates

Spokane, Washington, 99208, United States

Location

Vince Lombardi Cancer Center

Green Bay, Wisconsin, 54311, United States

Location

Medical College of Wisconsin; Dept Froedtert Clin Can Ctr

Milwaukee, Wisconsin, 53226, United States

Location

Aurora Research Institute

Wauwatosa, Wisconsin, 53226, United States

Location

Cheyenne Oncology & Hematology Associates

Cheyenne, Wyoming, 82001, United States

Location

Related Publications (2)

• Cremolini C, Antoniotti C, Stein A, Bendell J, Gruenberger T, Rossini D, Masi G, Ongaro E, Hurwitz H, Falcone A, Schmoll HJ, Di Maio M. Individual Patient Data Meta-Analysis of FOLFOXIRI Plus Bevacizumab Versus Doublets Plus Bevacizumab as Initial Therapy of Unresectable Metastatic Colorectal Cancer. J Clin Oncol. 2020 Aug 20:JCO2001225. doi: 10.1200/JCO.20.01225. Online ahead of print.

  PMID: 32816630 DERIVED

• Hurwitz HI, Tan BR, Reeves JA, Xiong H, Somer B, Lenz HJ, Hochster HS, Scappaticci F, Palma JF, Price R, Lee JJ, Nicholas A, Sommer N, Bendell J. Phase II Randomized Trial of Sequential or Concurrent FOLFOXIRI-Bevacizumab Versus FOLFOX-Bevacizumab for Metastatic Colorectal Cancer (STEAM). Oncologist. 2019 Jul;24(7):921-932. doi: 10.1634/theoncologist.2018-0344. Epub 2018 Dec 14.

  PMID: 30552157 DERIVED

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Fluorouracil; Bevacizumab; Capecitabine; Irinotecan; Leucovorin; Oxaliplatin

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Camptothecin; Alkaloids; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Coordination Complexes; Organic Chemicals

Limitations and Caveats

This trial was terminated on 12 November 2015, because the primary objective was not met.

Results Point of Contact

• Title: Medical Communications
• Organization: Hoffmann-La Roche

genentech@druginfo.com

800-821-8590

Study Officials

• Clinical Trials

  Hoffmann-La Roche

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 9, 2013
• First Posted: January 10, 2013
• Study Start: January 23, 2013
• Primary Completion: March 14, 2016
• Study Completion: March 14, 2016
• Last Updated: September 18, 2017
• Results First Posted: September 18, 2017

Record last verified: 2017-08

Locations

US (45)