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

This study has been terminated.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01765582
First Posted: January 10, 2013
Last Update Posted: September 18, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Hoffmann-La Roche
  Purpose
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.

Condition Intervention Phase
Colorectal Neoplasms Drug: 5-fluorouracil Drug: bevacizumab Drug: capecitabine Drug: irinotecan Drug: folinic acid Drug: oxaliplatin Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Steam (Sequencing Triplet With Avastin and Maintenance): FOLFOXIRI/Bevacizumab Regimens (Concurrent and Sequential) vs. FOLFOX/Bevacizumab in First-Line Metastatic Colorectal Cancer

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Percentage of Participants With Overall Response During First-Line Therapy (ORR1) [ Time Frame: Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years) ]
    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

  • Progression-Free Survival During First-Line Therapy (PFS1) [ Time Frame: Randomization up to disease progression during first-line therapy or death, whichever occurs first (up to approximately 3 years) ]
    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.


Secondary Outcome Measures:
  • Time to PFS2 [ Time Frame: Randomization up to disease progression during second-line therapy or death, whichever occurs first (up to approximately 3 years) ]
    Time to PFS2 was defined as time from randomization to the first occurrence of disease progression after reinduction of second-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 5mm.

  • Overall Survival (OS) [ Time Frame: Randomization until death due to any cause (up to approximately 3 years) ]
    OS was defined as the time from the date of randomization to the date of death from any cause.

  • Proportion of Participants Who Underwent Liver Metastases Resections [ Time Frame: Randomization up to approximately 3 years ]
    Reported here is the proportion of participants who underwent liver metastases resections calculated as follows: number of participants who underwent liver metastases resections divided by total number of participants in each arm.

  • Proportion of Participants Considered by the Investigator to be Unresectable on Study Enrollment Who Subsequently Underwent Attempted Curative Resections of Metastases [ Time Frame: Randomization up to approximately 3 years ]
    The proportion of participants considered by the investigator to be unresectable at study enrollment who subsequently underwent attempted curative resections of metastases was calculated as follows: number of participants considered by the investigator to be unresectable at study enrollment who subsequently underwent attempted curative resections of metastases divided by total number of participants in each arm. This outcome represents a measure of the rate of conversion from unresectable to resectable disease.

  • Percentage of Participants With Adverse Events [ Time Frame: Randomization up to approximately 3 years ]
    An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.


Enrollment: 280
Actual Study Start Date: January 23, 2013
Study Completion Date: March 14, 2016
Primary Completion Date: March 14, 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A: Concurrent FOLFOXIRI + Bevacizumab
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
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.
Drug: bevacizumab
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.
Other Name: Avastin
Drug: capecitabine
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.
Other Name: Xeloda
Drug: irinotecan
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.
Drug: folinic acid
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.
Other Name: leucovorin
Drug: oxaliplatin
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 .
Experimental: Arm B: Sequential FOLFOXIRI + Bevacizumab
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
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.
Drug: bevacizumab
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.
Other Name: Avastin
Drug: capecitabine
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.
Other Name: Xeloda
Drug: irinotecan
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.
Drug: folinic acid
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.
Other Name: leucovorin
Drug: oxaliplatin
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 .
Experimental: Arm C: FOLFOX + Bevacizumab
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
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.
Drug: bevacizumab
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.
Other Name: Avastin
Drug: capecitabine
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.
Other Name: Xeloda
Drug: folinic acid
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.
Other Name: leucovorin
Drug: oxaliplatin
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 .

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01765582


  Hide Study Locations
Locations
United States, Alabama
University of South Alabama; Mitchell Cancer Institute
Mobile, Alabama, United States, 36604
United States, California
Long Beach Memorial Medical Center; Oncology
Long Beach, California, United States, 90806
LAC-USC Medical Center
Los Angeles, California, United States, 90033
USC Norris Cancer Center
Los Angeles, California, United States, 90033
Pacific Cancer Care - Monterey
Monterey, California, United States, 93940
Sacramento Center for Hematolo
Sacramento, California, United States, 95816
Pacific Cancer Care
Salinas, California, United States, 93901
United States, Colorado
Kaiser Permanente - Franklin
Denver, Colorado, United States, 80205
United States, Connecticut
Yale Cancer Center
New Haven, Connecticut, United States, 06520
United States, District of Columbia
Sibley Memorial Hospital
Washington, D.C., District of Columbia, United States, 20016
United States, Florida
Florida Cancer Specialists - Fort Myers (Colonial Center Dr)
Fort Myers, Florida, United States, 33905
Florida Cancer Specialist, North Region
Saint Petersburg, Florida, United States, 33705
United States, Georgia
University Cancer & Blood Center, LLC
Athens, Georgia, United States, 30607
Emory University Clinic
Atlanta, Georgia, United States, 30322
Central Georgia Cancer Care PC
Macon, Georgia, United States, 31201
Summit Cancer Care PC
Savannah, Georgia, United States, 31405
United States, Illinois
Ingalls Memorial Hosp
Harvey, Illinois, United States, 60426
Edward Cancer Center Naperville
Naperville, Illinois, United States, 60540
Edward Cancer Center Plainfield
Plainfield, Illinois, United States, 60585
United States, Kentucky
University of Kentucky Medical Center
Lexington, Kentucky, United States, 40536
United States, Maryland
Johns Hopkins Univ; Bunting Blaustein Cancer Center
Baltimore, Maryland, United States, 21231
United States, Massachusetts
Tufts Medical Center
Boston, Massachusetts, United States, 02111
United States, Michigan
St. Joseph Mercy Hospital; Cancer Care Center.
Ann Arbor, Michigan, United States, 48106
Karmanos Cancer Institute..
Detroit, Michigan, United States, 48201
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, Nebraska
Southeast Nebraska Cancer Center;; Southeast Nebraska Hematology and Oncology
Lincoln, Nebraska, United States, 68510
Nebraska Methodist Hospital; Cancer Center
Omaha, Nebraska, United States, 68114
United States, New Hampshire
Dartmouth Hitchcock Med Center
Lebanon, New Hampshire, United States, 03756
United States, Ohio
Oncology Hematology Care Inc
Cincinnati, Ohio, United States, 45242
United States, Oklahoma
University of Oklahoma; Stephenson Oklahoma Canc Ctr
Oklahoma City, Oklahoma, United States, 73104
United States, Pennsylvania
Milton S. Hershey Medical Center; Penn State Cancer Inst.
Hershey, Pennsylvania, United States, 17033
United States, Tennessee
Chattanooga Oncology and Hematology Associates, PC
Chattanooga, Tennessee, United States, 37404
West Clinic
Germantown, Tennessee, United States, 38138
Sarah Cannon Cancer Center and Research Institute
Nashville, Tennessee, United States, 37203
United States, Texas
UT Southwestern MC at Dallas
Dallas, Texas, United States, 75390-9063
Ctr for Cancer and Blood Disorders
Fort Worth, Texas, United States, 76104
Scott and White Hospital; Cancer Center
Temple, Texas, United States, 76508
United States, Virginia
Virginia Cancer Institute
Richmond, Virginia, United States, 23226
United States, Washington
Seattle Cancer Care Alliance - Evergreen Health
Kirkland, Washington, United States, 98034
Seattle Cancer Care Alliance
Seattle, Washington, United States, 98109
Medical Oncology Associates
Spokane, Washington, United States, 99208
United States, Wisconsin
Vince Lombardi Cancer Center
Green Bay, Wisconsin, United States, 54311
Medical College of Wisconsin; Dept Froedtert Clin Can Ctr
Milwaukee, Wisconsin, United States, 53226
Aurora Research Institute
Wauwatosa, Wisconsin, United States, 53226
United States, Wyoming
Cheyenne Oncology & Hematology Associates
Cheyenne, Wyoming, United States, 82001
Sponsors and Collaborators
Hoffmann-La Roche
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT01765582     History of Changes
Other Study ID Numbers: ML28442
First Submitted: January 9, 2013
First Posted: January 10, 2013
Results First Submitted: June 2, 2017
Results First Posted: September 18, 2017
Last Update Posted: September 18, 2017
Last Verified: August 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Bevacizumab
Oxaliplatin
Irinotecan
Capecitabine
Fluorouracil
Leucovorin
Folic Acid
Levoleucovorin
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Topoisomerase I Inhibitors