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A Study of Vismodegib (GDC-0449, Hedgehog Pathway Inhibitor) With Concurrent Chemotherapy and Bevacizumab As First-Line Therapy for Metastatic Colorectal Cancer

Primary Purpose

Metastatic Colorectal Cancer

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Vismodegib 150 mg
Placebo to vismodegib
Bevacizumab
Modified FOLFOX
FOLFIRI
Sponsored by
Genentech, Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metastatic Colorectal Cancer focused on measuring Hedgehog, CRC, Colorectal Cancer, Hedgehog Pathway Inhibitor

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age ≥ 18 years
  • Histologically confirmed metastatic colorectal cancer (CRC)
  • Representative tumor specimens in paraffin blocks (preferred) or at least 15 unstained slides, with an associated pathology report, must be confirmed to be available and requested at any time prior to entry of study
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • Adequate hematopoetic capacity
  • Adequate hepatic function
  • Adequate renal function
  • Use of an effective method of barrier contraception (for women of childbearing potential)
  • Signed informed consent

Exclusion Criteria:

  • Prior chemotherapy for metastatic CRC or adjuvant chemotherapy for CRC within the prior 6 months
  • Clinically suspected or confirmed CNS metastases or carcinomatous meningitis
  • Major surgical procedure within 4 weeks prior to the first day of treatment in this study (Day 1)
  • Pelvic radiation within 2 weeks prior to Day 1
  • Wound dehiscence requiring intervention, gastrointestinal perforation, or bowel obstruction
  • Pregnancy or lactation
  • Uncontrolled medical illnesses including the following: Infection requiring intravenous (IV) antibiotics, congestive heart failure not controlled with medication, hypertension not controlled with medication
  • Thromboembolic disease
  • History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the patient at high risk from treatment complications

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Placebo Comparator

    Arm Label

    Vismodegib 150 mg

    Placebo to vismodegib

    Arm Description

    Patients received vismodegib 150 mg orally once daily starting on Day 3 of each 2-week treatment cycle. In addition, patients received either Modified FOLFOX (FOL=leucovorin calcium [folinic acid], F=fluorouracil, OX=oxaliplatin) + bevacizumab or FOLFIRI (FOL=leucovorin calcium [folinic acid] F=fluorouracil, IRI=irinotecan hydrochloride) + bevacizumab on Days 1-3 of each 2-week treatment cycle. The decision of which regimen (FOLFOX or FOLFIRI) to use was made by the treating physician and patient.

    Patients received placebo to vismodegib orally once daily starting on Day 3 of each 2-week treatment. In addition, patients received either Modified FOLFOX (FOL=leucovorin calcium [folinic acid], F=fluorouracil, OX=oxaliplatin) + bevacizumab or FOLFIRI (FOL=leucovorin calcium [folinic acid] F=fluorouracil, IRI=irinotecan hydrochloride) + bevacizumab on Days 1-3 of each 2-week treatment cycle. The decision of which regimen (FOLFOX or FOLFIRI) to use was made by the treating physician and patient.

    Outcomes

    Primary Outcome Measures

    Progression-free Survival (PFS)
    Progression-free survival (PFS) was defined as the time from randomization to the earlier of documented disease progression (PD) or death from any cause. PD: At least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started, unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions. For patients without measurable disease, PD was defined as an increase in the size of a lesion to one that is measurable or unequivocal progression of a non-target lesion.

    Secondary Outcome Measures

    Progression-free Survival (PFS) in Patients With Various Degrees of Hedgehog Antigen Tumor Expression
    Indian + Sonic Hedgehog antigen expression was measured by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) from archival tumor tissue taken from each patient prior to enrollment in the study. Results are reported in 3 categories; the 33% of patients with the lowest level of expression, the 35% of patients with a middle level of expression, and the 32% of patients with the highest level of expression. PFS was defined as the time between randomization and disease progression, as confirmed by radiography, or death for any reason.

    Full Information

    First Posted
    March 5, 2008
    Last Updated
    May 15, 2017
    Sponsor
    Genentech, Inc.
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00636610
    Brief Title
    A Study of Vismodegib (GDC-0449, Hedgehog Pathway Inhibitor) With Concurrent Chemotherapy and Bevacizumab As First-Line Therapy for Metastatic Colorectal Cancer
    Official Title
    A Randomized, Placebo-Controlled Phase II Study of Vismodegib (GDC-0449, Systemic Hedgehog Antagonist) With Concurrent Chemotherapy and Bevacizumab As First-Line Therapy for Metastatic Colorectal Cancer
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    May 2017
    Overall Recruitment Status
    Completed
    Study Start Date
    May 2008 (Actual)
    Primary Completion Date
    December 2010 (Actual)
    Study Completion Date
    December 2010 (Actual)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Genentech, Inc.

    4. Oversight

    5. Study Description

    Brief Summary
    This was a randomized, placebo-controlled, double-blind study of vismodegib (GDC-0449) added to biochemotherapy standard-of-care regimens for metastatic colorectal cancer (CRC), with treatment until disease progression. Patients received either FOLFOX (FOL=leucovorin calcium [folinic acid], F=fluorouracil, OX=oxaliplatin) or FOLFIRI (FOL=leucovorin calcium [folinic acid] F=fluorouracil, IRI=irinotecan hydrochloride) chemotherapy with bevacizumab. The decision of which regimen (FOLFOX or FOLFIRI) to use was made by the treating physician and patient. Patients were randomized to receive vismodegib or placebo and were stratified based on the chemotherapy regimen chosen and whether or not Response Evaluation Criteria in Solid Tumors (RECIST) measurable disease was present at baseline.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Metastatic Colorectal Cancer
    Keywords
    Hedgehog, CRC, Colorectal Cancer, Hedgehog Pathway Inhibitor

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    ParticipantInvestigator
    Allocation
    Randomized
    Enrollment
    199 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Vismodegib 150 mg
    Arm Type
    Experimental
    Arm Description
    Patients received vismodegib 150 mg orally once daily starting on Day 3 of each 2-week treatment cycle. In addition, patients received either Modified FOLFOX (FOL=leucovorin calcium [folinic acid], F=fluorouracil, OX=oxaliplatin) + bevacizumab or FOLFIRI (FOL=leucovorin calcium [folinic acid] F=fluorouracil, IRI=irinotecan hydrochloride) + bevacizumab on Days 1-3 of each 2-week treatment cycle. The decision of which regimen (FOLFOX or FOLFIRI) to use was made by the treating physician and patient.
    Arm Title
    Placebo to vismodegib
    Arm Type
    Placebo Comparator
    Arm Description
    Patients received placebo to vismodegib orally once daily starting on Day 3 of each 2-week treatment. In addition, patients received either Modified FOLFOX (FOL=leucovorin calcium [folinic acid], F=fluorouracil, OX=oxaliplatin) + bevacizumab or FOLFIRI (FOL=leucovorin calcium [folinic acid] F=fluorouracil, IRI=irinotecan hydrochloride) + bevacizumab on Days 1-3 of each 2-week treatment cycle. The decision of which regimen (FOLFOX or FOLFIRI) to use was made by the treating physician and patient.
    Intervention Type
    Drug
    Intervention Name(s)
    Vismodegib 150 mg
    Other Intervention Name(s)
    GDC-0449, Erivedge
    Intervention Description
    Vismodegib 150 mg was provided in hard gelatin capsules in 3 different strengths, 25 mg, 125 mg, and 150 mg.
    Intervention Type
    Drug
    Intervention Name(s)
    Placebo to vismodegib
    Intervention Description
    Placebo to vismodegib consisted of the excipients for vismodegib without the active molecule in hard gelatin capsules matching the active drug product in color and size.
    Intervention Type
    Drug
    Intervention Name(s)
    Bevacizumab
    Intervention Description
    Bevacizumab 5 mg/kg was administered intravenously (IV) over 90 minutes for the first infusion, shortening to 60 and 30 minutes for subsequent infusions.
    Intervention Type
    Drug
    Intervention Name(s)
    Modified FOLFOX
    Intervention Description
    Following administration of bevacizumab, patients received oxaliplatin 85 mg/m^2 IV administered over 90 minutes concurrently with folinic acid 400 mg/m^2 (d,I-racemic form, or 200 mg/m^2 I-isomer form) IV administered over 120 minutes, then fluorouracil 400 mg/m^2 administered as an IV bolus, then 2400 mg/m^2 administered as a continuous IV infusion over 46 hours.
    Intervention Type
    Drug
    Intervention Name(s)
    FOLFIRI
    Intervention Description
    Following administration of bevacizumab, patients received irinotecan 180 mg/m^2 IV administered over 90 minutes concurrently with folinic acid 400 mg/m^2 (d,I-racemic form, or 200 mg/m^2 I-isomer form) administered IV over 120 minutes, then fluorouracil 400 mg/m^2 administered as an IV bolus, then fluorouracil 2400 mg/m^2 administered as a continuous IV infusion over 46 hours.
    Primary Outcome Measure Information:
    Title
    Progression-free Survival (PFS)
    Description
    Progression-free survival (PFS) was defined as the time from randomization to the earlier of documented disease progression (PD) or death from any cause. PD: At least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since treatment started, unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions. For patients without measurable disease, PD was defined as an increase in the size of a lesion to one that is measurable or unequivocal progression of a non-target lesion.
    Time Frame
    From first treatment through the data cut-off date of March 15, 2010, up to 90 weeks
    Secondary Outcome Measure Information:
    Title
    Progression-free Survival (PFS) in Patients With Various Degrees of Hedgehog Antigen Tumor Expression
    Description
    Indian + Sonic Hedgehog antigen expression was measured by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) from archival tumor tissue taken from each patient prior to enrollment in the study. Results are reported in 3 categories; the 33% of patients with the lowest level of expression, the 35% of patients with a middle level of expression, and the 32% of patients with the highest level of expression. PFS was defined as the time between randomization and disease progression, as confirmed by radiography, or death for any reason.
    Time Frame
    From first treatment through the data cut-off date of March 15, 2010, up to 90 weeks

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Age ≥ 18 years Histologically confirmed metastatic colorectal cancer (CRC) Representative tumor specimens in paraffin blocks (preferred) or at least 15 unstained slides, with an associated pathology report, must be confirmed to be available and requested at any time prior to entry of study Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Adequate hematopoetic capacity Adequate hepatic function Adequate renal function Use of an effective method of barrier contraception (for women of childbearing potential) Signed informed consent Exclusion Criteria: Prior chemotherapy for metastatic CRC or adjuvant chemotherapy for CRC within the prior 6 months Clinically suspected or confirmed CNS metastases or carcinomatous meningitis Major surgical procedure within 4 weeks prior to the first day of treatment in this study (Day 1) Pelvic radiation within 2 weeks prior to Day 1 Wound dehiscence requiring intervention, gastrointestinal perforation, or bowel obstruction Pregnancy or lactation Uncontrolled medical illnesses including the following: Infection requiring intravenous (IV) antibiotics, congestive heart failure not controlled with medication, hypertension not controlled with medication Thromboembolic disease History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the patient at high risk from treatment complications
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Jennifer Low, M.D., Ph.D.
    Organizational Affiliation
    Genentech, Inc.
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Learn more about this trial

    A Study of Vismodegib (GDC-0449, Hedgehog Pathway Inhibitor) With Concurrent Chemotherapy and Bevacizumab As First-Line Therapy for Metastatic Colorectal Cancer

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