A Study of Vismodegib (GDC-0449, Hedgehog Pathway Inhibitor) With Concurrent Chemotherapy and Bevacizumab As First-Line Therapy for Metastatic Colorectal Cancer
Condition: Metastatic Colorectal Cancer
MeSH terms: Colorectal Neoplasms
Intervention: Vismodegib 150 mg; Placebo to vismodegib; Bevacizumab; Modified FOLFOX; FOLFIRI
Intervention description: Vismodegib 150 mg was provided in hard gelatin capsules in 3 different strengths, 25 mg, 125 mg, and 150 mg.; 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.; Bevacizumab 5 mg/kg was administered intravenously (IV) over 90 minutes for the first infusion, shortening to 60 and 30 minutes for subsequent infusions.; 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.; 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.
Intervention MeSH terms: Bevacizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 199.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Hedgehog; CRC; Colorectal Cancer; Hedgehog Pathway Inhibitor

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.
    

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