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

Colorectal Neoplasms Clinical Trial

— STEAM  

Official title:

Steam (Sequencing Triplet With Avastin and Maintenance): FOLFOXIRI/Bevacizumab Regimens (Concurrent and Sequential) vs. FOLFOX/Bevacizumab in First-Line Metastatic Colorectal Cancer

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01765582
• Other study ID #: ML28442
• Status: Terminated
• Phase: Phase 2
• First received: January 9, 2013
• Last updated: August 18, 2017
• Start date: January 23, 2013
• Est. completion date: March 14, 2016

Study information

• Verified date: August 2017
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 280
• Est. completion date: March 14, 2016
• Est. primary completion date: March 14, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Colorectal Neoplasms

Intervention

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.
• 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.
• 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.
• 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.
• 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.
• 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 .

Locations

Country	Name	City	State
United States	St. Joseph Mercy Hospital; Cancer Care Center.	Ann Arbor	Michigan
United States	University Cancer & Blood Center, LLC	Athens	Georgia
United States	Emory University Clinic	Atlanta	Georgia
United States	Johns Hopkins Univ; Bunting Blaustein Cancer Center	Baltimore	Maryland
United States	Tufts Medical Center	Boston	Massachusetts
United States	Chattanooga Oncology and Hematology Associates, PC	Chattanooga	Tennessee
United States	Cheyenne Oncology & Hematology Associates	Cheyenne	Wyoming
United States	Oncology Hematology Care Inc	Cincinnati	Ohio
United States	UT Southwestern MC at Dallas	Dallas	Texas
United States	Kaiser Permanente - Franklin	Denver	Colorado
United States	Karmanos Cancer Institute..	Detroit	Michigan
United States	Florida Cancer Specialists - Fort Myers (Colonial Center Dr)	Fort Myers	Florida
United States	Ctr for Cancer and Blood Disorders	Fort Worth	Texas
United States	West Clinic	Germantown	Tennessee
United States	Vince Lombardi Cancer Center	Green Bay	Wisconsin
United States	Ingalls Memorial Hosp	Harvey	Illinois
United States	Milton S. Hershey Medical Center; Penn State Cancer Inst.	Hershey	Pennsylvania
United States	Seattle Cancer Care Alliance - Evergreen Health	Kirkland	Washington
United States	Dartmouth Hitchcock Med Center	Lebanon	New Hampshire
United States	University of Kentucky Medical Center	Lexington	Kentucky
United States	Southeast Nebraska Cancer Center;; Southeast Nebraska Hematology and Oncology	Lincoln	Nebraska
United States	Long Beach Memorial Medical Center; Oncology	Long Beach	California
United States	LAC-USC Medical Center	Los Angeles	California
United States	USC Norris Cancer Center	Los Angeles	California
United States	Central Georgia Cancer Care PC	Macon	Georgia
United States	Medical College of Wisconsin; Dept Froedtert Clin Can Ctr	Milwaukee	Wisconsin
United States	University of South Alabama; Mitchell Cancer Institute	Mobile	Alabama
United States	Pacific Cancer Care - Monterey	Monterey	California
United States	Edward Cancer Center Naperville	Naperville	Illinois
United States	Sarah Cannon Cancer Center and Research Institute	Nashville	Tennessee
United States	Yale Cancer Center	New Haven	Connecticut
United States	University of Oklahoma; Stephenson Oklahoma Canc Ctr	Oklahoma City	Oklahoma
United States	Nebraska Methodist Hospital; Cancer Center	Omaha	Nebraska
United States	Edward Cancer Center Plainfield	Plainfield	Illinois
United States	Virginia Cancer Institute	Richmond	Virginia
United States	Sacramento Center for Hematolo	Sacramento	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Florida Cancer Specialist, North Region	Saint Petersburg	Florida
United States	Pacific Cancer Care	Salinas	California
United States	Summit Cancer Care PC	Savannah	Georgia
United States	Seattle Cancer Care Alliance	Seattle	Washington
United States	Medical Oncology Associates	Spokane	Washington
United States	Scott and White Hospital; Cancer Center	Temple	Texas
United States	Sibley Memorial Hospital	Washington, D.C.	District of Columbia
United States	Aurora Research Institute	Wauwatosa	Wisconsin

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	Time to PFS2	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.	Randomization up to disease progression during second-line therapy or death, whichever occurs first (up to approximately 3 years)
Secondary	Overall Survival (OS)	OS was defined as the time from the date of randomization to the date of death from any cause.	Randomization until death due to any cause (up to approximately 3 years)
Secondary	Proportion of Participants Who Underwent Liver Metastases Resections	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.	Randomization up to approximately 3 years
Secondary	Proportion of Participants Considered by the Investigator to be Unresectable on Study Enrollment Who Subsequently Underwent Attempted Curative Resections of Metastases	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.	Randomization up to approximately 3 years
Secondary	Percentage of Participants With Adverse Events	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.	Randomization up to approximately 3 years