Study of Bevacizumab + mFOLFOX6 Versus Bevacizumab + FOLFIRI With Biomarker Stratification in Participants With Previously Untreated Metastatic Colorectal Cancer (mCRC)

NCT01374425 | Completed Phase 2 Results

• 2 other identifiers: ML257102011-004755-39
• Study Type: interventional
• Target: 376
• Locations: 7 countries
• Sites: 79

Brief Summary

This will be a randomized, open-label, multicenter, Phase II study with primary objectives to assess whether expression of select chemotherapy markers is associated with progression-free survival (PFS) in participants treated with bevacizumab plus leucovorin, 5-fluorouracil, and oxaliplatin (mFOLFOX6) or bevacizumab plus leucovorin, 5-fluorouracil, and irinotecan (FOLFIRI). The study population will consist of participants with first-line mCRC.

Conditions

Colorectal Cancer

Outcome Measures

Primary Outcomes (5)

• Progression-Free Survival (PFS) According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

  Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as greater than or equal to (≥) 20 percent (%) increase in sum of largest diameters (LD) of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 millimeters (mm). Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% confidence interval (CI) was computed using the method of Brookmeyer and Crowley.

  From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

• PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels

  Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

• PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 Levels

  Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

• PFS According to RECIST Version 1.1 in Participants With High ERCC-1 Levels Versus Participants With Low ERCC-1 Levels

  Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

• PFS According to RECIST Version 1.1 in Participants With High Vascular Endothelial Growth Factor (VEGF)-A Levels Versus Participants With Low VEGF-A Levels

  Tumor assessments were performed according to RECIST Version 1.1. Disease progression was defined as ≥20% increase in sum of LD of target lesions in reference to the smallest sum of LD on study, in addition to an absolute increase ≥5 mm. Disease progression was further defined as the last documented progression determined by the Investigator no later than 1 day before initiation of second-line therapy. Death on study included death from any cause occurring no later than 3 months after the last component of study treatment. PFS was defined as the time from randomization to death or disease progression, whichever occurred first. The median duration of PFS was estimated by Kaplan-Meier analysis and expressed in months. The 95% CI was computed using the method of Brookmeyer and Crowley.

  From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

Secondary Outcomes (32)

• PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and High VEGF-A Levels

  From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

• PFS According to RECIST Version 1.1 in Participants With High ERCC-1 and Low VEGF-A Levels

  From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

• PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and High VEGF-A Levels

  From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

• PFS According to RECIST Version 1.1 in Participants With Low ERCC-1 and Low VEGF-A Levels

  From Baseline until death or disease progression; assessed every 6 weeks (maximum up to 45 months overall)

• Overall Survival (OS)

  From Baseline until death (maximum up to 45 months overall)

Study Arms (2)

Bevacizumab + mFOLFOX6

EXPERIMENTAL

Participants will receive bevacizumab plus mFOLFOX6 by intravenous (IV) infusion on Day 1 of each 2-week cycle until disease progression or unacceptable toxicity. Participants may be transitioned to oral capecitabine in the event of unacceptable toxicity to oxaliplatin, with bevacizumab continued in 3-week cycles.

Drug: 5-Fluorouracil; Drug: Bevacizumab; Drug: Leucovorin; Drug: Oxaliplatin; Drug: Capecitabine

Bevacizumab + FOLFIRI

EXPERIMENTAL

Participants will receive bevacizumab plus FOLFIRI by IV infusion on Day 1 of each 2-week cycle until disease progression or unacceptable toxicity. Participants may be transitioned to oral capecitabine in the event of unacceptable toxicity to irinotecan, with bevacizumab continued in 3-week cycles.

Drug: 5-Fluorouracil; Drug: Bevacizumab; Drug: Irinotecan; Drug: Leucovorin; Drug: Capecitabine

Interventions

5-Fluorouracil DRUG

5-Fluorouracil 400 milligrams per meter-squared (mg/m\^2) by IV bolus and subsequent 2400 mg/m\^2 by IV infusion over 46 hours will be administered every 2 weeks until disease progression or unacceptable toxicity.

Bevacizumab + FOLFIRI; Bevacizumab + mFOLFOX6

Bevacizumab DRUG

Bevacizumab 5 milligrams per kilogram (mg/kg) of body weight via IV infusion will be administered every 2 weeks until disease progression or unacceptable toxicity. If participants are discontinued from oxaliplatin or irinotecan due to unacceptable toxicity, bevacizumab may be given in 3-week cycles with capecitabine.

Also known as: Avastin

Bevacizumab + FOLFIRI; Bevacizumab + mFOLFOX6

Irinotecan DRUG

Irinotecan 180 mg/m\^2 via IV infusion over 2 hours will be administered every 2 weeks until disease progression or unacceptable toxicity.

Bevacizumab + FOLFIRI

Leucovorin DRUG

Leucovorin 400 mg/m\^2 or dose deemed appropriate by Investigator via IV infusion over 2 hours will be administered every 2 weeks until disease progression or unacceptable toxicity.

Bevacizumab + FOLFIRI; Bevacizumab + mFOLFOX6

Oxaliplatin DRUG

Oxaliplatin 85 mg/m\^2 via IV infusion over 2 hours will be administered every 2 weeks until disease progression or unacceptable toxicity.

Bevacizumab + mFOLFOX6

Capecitabine DRUG

Capecitabine 850 or 1000 mg/m\^2 may be offered in the event of unacceptable toxicity to oxaliplatin or irinotecan, to be given orally twice a day on Days 1 to 14 in 3-week cycles.

Bevacizumab + FOLFIRI; Bevacizumab + mFOLFOX6

Eligibility Criteria

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

You may qualify if:

• Histologically or cytologically confirmed colorectal cancer (CRC) with at least one measurable metastatic lesion by RECIST Version 1.1
• Archival tumor tissue sample must be requested and available prior to study entry. If no archival tumor tissue sample is available, a fresh biopsy tissue sample must be obtained but should be discussed first with the medical monitor. A copy of the local pathology report must be submitted along with the specimens.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• 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. Treatment for brain metastases may be whole-brain radiotherapy, radiosurgery, neurosurgery, or a combination as deemed appropriate by the treating physician. Radiotherapy and stereotactic radiosurgery must be completed at least 28 days prior to randomization.
• Female participants should not be pregnant or breastfeeding. Female participants with childbearing potential should agree to use effective, non-hormonal means of contraception during the study and for a period of at least 6 months following the last administration of study drugs. Female participants with an intact uterus (unless amenorrheic for the last 24 months) must have a negative serum pregnancy test within 7 days prior to randomization into the study.
• Male participants must agree to use effective contraception during the study and for a period of at least 6 months following the last administration of study drugs, even if they have been surgically sterilized.

You may not qualify if:

• Any prior systemic treatment for mCRC
• Adjuvant chemotherapy for CRC completed \<12 months
• Evidence of Gilbert's syndrome or of homozygosity for the UGT1A1\*28 allele
• Known positivity for human immunodeficiency virus (HIV)
• Malignancies other than mCRC 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 detectable third-space fluid collections 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

Sponsors & Collaborators

• Genentech, Inc.: lead

Study Sites (79)

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Birmingham, Alabama, 35294, United States

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Little Rock, Arkansas, 72205-7199, United States

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Bellflower, California, 90706, United States

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Duarte, California, 91010, United States

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Fountain Valley, California, 92708, United States

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Fresno, California, 93720, United States

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Hayward, California, 94545, United States

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Los Angeles, California, 90033, United States

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Oakland, California, 94611, United States

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Pleasant Hill, California, 94523, United States

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Roseville, California, 95661, United States

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Sacramento, California, 95817, United States

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Sacramento, California, 95825, United States

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San Francisco, California, 94115, United States

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San Jose, California, 95119, United States

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Santa Clara, California, 95051, United States

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South San Francisco, California, 94080, United States

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Vallejo, California, 94589, United States

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Walnut Creek, California, 94596, United States

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Denver, Colorado, 80218, United States

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Stamford, Connecticut, 06902, United States

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Trumbull, Connecticut, 06611, United States

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Hollywood, Florida, 33021, United States

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Jacksonville, Florida, 32256, United States

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Miami, Florida, 33136, United States

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Port Saint Lucie, Florida, 34952, United States

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Boise, Idaho, 83712, United States

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Joliet, Illinois, 60435, United States

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Maywood, Illinois, 60153, United States

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Peoria, Illinois, 61615, United States

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Goshen, Indiana, 46526, United States

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Indianapolis, Indiana, 46237, United States

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Terre Haute, Indiana, 47802, United States

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Fairway, Kansas, 66205, United States

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Elizabethtown, Kentucky, 42791, United States

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Scarborough, Maine, 04074, United States

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Burlington, Massachusetts, 01805, United States

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Billings, Montana, 59102, United States

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Lincoln, Nebraska, 68506, United States

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Cherry Hill, New Jersey, 08003, United States

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Manasquan, New Jersey, 08736, United States

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Albuquerque, New Mexico, 87106, United States

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Albuquerque, New Mexico, 87110, United States

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Albuquerque, New Mexico, 87131-5636, United States

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Farmington, New Mexico, 87401, United States

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Las Cruces, New Mexico, 88011, United States

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Santa Fe, New Mexico, 87505, United States

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Rochester, New York, 14642, United States

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Durham, North Carolina, 27710, United States

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Greensboro, North Carolina, 27403, United States

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High Point, North Carolina, 27262, United States

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Washington, North Carolina, 27889, United States

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Winston-Salem, North Carolina, 27103, United States

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Columbus, Ohio, 43219, United States

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Toledo, Ohio, 43623, United States

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Oklahoma City, Oklahoma, 73142, United States

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Dunmore, Pennsylvania, 18512, United States

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Media, Pennsylvania, 19063, United States

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Philadelphia, Pennsylvania, 19107, United States

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Pittsburgh, Pennsylvania, 15212, United States

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Charleston, South Carolina, 29414, United States

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Corpus Christi, Texas, 78404, United States

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Houston, Texas, 77090, United States

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Madison, Wisconsin, 53792, United States

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Wauwatosa, Wisconsin, 53226, United States

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Edmonton, Alberta, T6G 1Z2, Canada

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Tallinn, 13419, Estonia

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Tartu, 51014, Estonia

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Cork, Ireland

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Dublin, 24, Ireland

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Galway, Ireland

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Oslo, 0407, Norway

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Coimbra, 3000-075, Portugal

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Lisbon, 1649-035, Portugal

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Porto, 4200-072, Portugal

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Aarau, 5000, Switzerland

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Basel, 4031, Switzerland

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Lucerne, 6004, Switzerland

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Zurich, 8063, Switzerland

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MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Fluorouracil; Bevacizumab; Irinotecan; Leucovorin; Oxaliplatin; Capecitabine

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; Camptothecin; Alkaloids; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Coordination Complexes; Organic Chemicals; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

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

genentech@druginfo.com

800-821-8590

Study Officials

• Christiane Langer, M.D.

  Genentech, Inc.

  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: June 14, 2011
• First Posted: June 16, 2011
• Study Start: August 1, 2011
• Primary Completion: May 1, 2015
• Study Completion: July 1, 2015
• Last Updated: August 11, 2016
• Results First Posted: August 11, 2016

Record last verified: 2016-06

Locations

CH (4); CA (1); NO (1); ES (2); PT (3); IE (3); US (65)