Combination Chemotherapy With or Without GDC-0449 in Treating Patients With Advanced Stomach Cancer or Gastroesophageal Junction Cancer

• Objective response rate [ Time Frame: Not Provided ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: Not Provided ] [ Designated as safety issue: No ]
• Toxicity as assessed by NCI CTCAE v3.0 [ Time Frame: Not Provided ] [ Designated as safety issue: Yes ]
• Hedgehog-signaling pathway expression [ Time Frame: Not Provided ] [ Designated as safety issue: No ]
• Gene-expression profile and clinical outcome [ Time Frame: Not Provided ] [ Designated as safety issue: No ]
• Shed epitopes as a measure of response in the microenvironment [ Time Frame: Not Provided ] [ Designated as safety issue: No ]
• Circulating endothelial progenitor cells as a marker of response to hedgehog antagonist GDC-0449/placebo treatment [ Time Frame: Not Provided ] [ Designated as safety issue: No ]
• Serum growth-factor levels as a measure of response in the microenvironment [ Time Frame: Not Provided ] [ Designated as safety issue: No ]

• Objective response rate [ Designated as safety issue: No ]
• Overall survival [ Designated as safety issue: No ]
• Toxicity as assessed by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]
• Hedgehog-signaling pathway expression [ Designated as safety issue: No ]
• Gene-expression profile and clinical outcome [ Designated as safety issue: No ]
• Shed epitopes as a measure of response in the microenvironment [ Designated as safety issue: No ]
• Circulating endothelial progenitor cells as a marker of response to hedgehog antagonist GDC-0449/placebo treatment [ Designated as safety issue: No ]
• Serum growth-factor levels as a measure of response in the microenvironment [ Designated as safety issue: No ]

This randomized phase II trial is studying giving combination chemotherapy together with GDC-0449 to see how well it works compared with giving combination chemotherapy without GDC-0449 in treating patients with advanced stomach cancer or gastroesophageal junction cancer. Drugs used in chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. GDC-0449 may block the growth of tumor cells. It is not yet known whether combination chemotherapy is more effective when given with or without GDC-0449 in treating stomach cancer and gastroesophageal junction cancer

PRIMARY OBJECTIVES:

I. To determine if the addition of hedgehog antagonist GDC-0449 (GDC-0449) to FOLFOX chemotherapy improves median progression-free survival (PFS) in the first-line treatment of patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma.

II. To determine the level of baseline hedgehog-pathway activation and correlate with clinical outcome and response to treatment with GDC-0449.

III. To determine a primary gastric cancer gene expression profile that may predict response to GDC-0449.

IV. To determine if serum shed collagen epitopes correlate with clinical outcome and may be used to assess efficacy of GDC-0449 treatment.

V. To determine if circulating endothelial progenitor cells (EPCs) correlate with treatment response and may be used to assess efficacy of GDC-0449 treatment.

VI. To determine if serum expression of VEGF, TGF-β, and IGFBP 3 correlate with clinical outcome and may be used to assess efficacy of GDC-0449 treatment.

SECONDARY OBJECTIVES:

I. To determine if the addition of GDC-0449 to FOLFOX chemotherapy increases overall survival.

II. To determine if the addition of GDC-0449 to FOLFOX chemotherapy increases response rate.

III. To determine if the addition of GDC-0449 to FOLFOX chemotherapy affects toxicity rates.

IV. To assess the hedgehog-pathway expression in those patients who consent to repeat biopsy at week 4-5 and compare to baseline values and clinical outcome.

OUTLINE: This is a multicenter study. Patients are stratified according to institution and disease status (advanced vs metastatic). Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on day 1. Patients also receive oral placebo once daily on days 1-14.

ARM II: Patients receive FOLFOX chemotherapy as in arm I. Patients also receive oral hedgehog antagonist GDC-0449 on days 1-14. In both arms, treatment repeats every 2 weeks in the absence of unacceptable toxicity or disease progression.

Tumor tissue and blood samples are collected and analyzed for gene expression and biomarkers.

After completion of study treatment, patients are followed every 3 months.

• Adenocarcinoma of the Gastroesophageal Junction
• Adenocarcinoma of the Stomach
• Recurrent Gastric Cancer
• Stage III Gastric Cancer
• Stage IV Gastric Cancer

• Drug: FOLFOX regimen
  Given IV
  Other Name: FOLinic acid-Fluororuracil-OXaliplatin regimen
• Drug: vismodegib
  Given orally
  Other Names:

  • Erivedge
  • GDC-0449
  • Hedgehog antagonist GDC-0449
• Other: hydrocortisone/placebo
  Given orally
• Drug: oxaliplatin
  Given IV
  Other Names:

  • 1-OHP
  • Dacotin
  • Dacplat
  • Eloxatin
  • L-OHP
• Drug: leucovorin calcium
  Given IV
  Other Names:

  • CF
  • CFR
  • LV
• Drug: fluorouracil
  Given IV
  Other Names:

  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU

• Experimental: Arm I
  Patients receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on day 1. Patients also receive oral placebo once daily on days 1-14. Treatment repeats every 2 weeks in the absence of unacceptable toxicity or disease progression.
  Interventions:

  • Drug: FOLFOX regimen
  • Other: hydrocortisone/placebo
  • Drug: oxaliplatin
  • Drug: leucovorin calcium
  • Drug: fluorouracil
• Experimental: Arm II
  Patients receive FOLFOX chemotherapy as in arm I. Patients also receive oral hedgehog antagonist GDC-0449 on days 1-14. Treatment repeats every 2 weeks in the absence of unacceptable toxicity or disease progression.
  Interventions:

  • Drug: FOLFOX regimen
  • Drug: vismodegib
  • Drug: oxaliplatin
  • Drug: leucovorin calcium
  • Drug: fluorouracil

Inclusion Criteria:

• Histologically or cytologically confirmed gastric or gastroesophageal junction (GEJ) adenocarcinoma not amenable to surgical resection
• Measurable disease, defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan
• Must be willing to provide blood and tissue samples for research purposes
• No known brain metastases
• ECOG performance status (PS) 0-1 or Karnofsky PS 70-100%
• Life expectancy > 3 months
• Absolute neutrophil count ≥ 1,500/mcL
• Platelets ≥ 100,000/mcL
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT ≤ 2.5 times ULN (≤ 5.0 times ULN in the presence of liver metastases)
• Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use 2 forms of effective contraception (i.e., barrier contraception and one other method of contraception) for ≥ 4 weeks before, during, and ≥ 12 months after completion of study treatment
• Must agree to placement of a central venous catheter for chemotherapy administration
• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to hedgehog antagonist GDC-0449, fluorouracil, or oxaliplatin
• No malabsorption syndrome or other condition that would interfere with intestinal absorption
• Able to swallow whole capsules
• No clinically active liver disease, including viral or other hepatitis or cirrhosis
• No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation
• No pre-existing peripheral sensory neuropathy > grade 1
• No previous or other concurrent malignancy, except treated basal cell or squamous cell skin cancer, in situ cervical cancer, lobular carcinoma in situ in one breast, or other cancer from which the patient has been disease-free ≥ 5 years
• No uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (coumadin) are allowed as long as on a stable therapeutic dose
• More than 6 months since prior adjuvant chemotherapy or chemoradiation
• No prior chemotherapy for advanced disease
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No other concurrent investigational agents