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A Randomized, Double Blind Placebo Controlled Phase 2 Study of FOLFOX Plus or Minus GDC-0449 in Patients With Advanced Gastric and Gastroesophageal Junction (GEJ) Carcinoma

Phase 2
18 Years
Open (Enrolling)
Adenocarcinoma of the Gastroesophageal Junction, Adenocarcinoma of the Stomach, Recurrent Gastric Cancer, Stage III Gastric Cancer, Stage IV Gastric Cancer

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Trial Information

A Randomized, Double Blind Placebo Controlled Phase 2 Study of FOLFOX Plus or Minus GDC-0449 in Patients With Advanced Gastric and Gastroesophageal Junction (GEJ) Carcinoma


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.


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

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

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

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

- 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

- 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

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Median progression-free survival

Outcome Time Frame:

Not Provided

Safety Issue:


Principal Investigator

Deirdre Cohen

Investigator Role:

Principal Investigator

Investigator Affiliation:

New York Cancer Consortium


United States: Food and Drug Administration

Study ID:




Start Date:

September 2009

Completion Date:

Related Keywords:

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



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Memorial Sloan Kettering Cancer CenterNew York, New York  10021
Loyola University Medical CenterMaywood, Illinois  60153
Ingalls Memorial HospitalHarvey, Illinois  60426
Beth Israel Medical CenterNew York, New York  10003
Weill Medical College of Cornell UniversityNew York, New York  10021
Montefiore Medical CenterBronx, New York  10467-2490
Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical CenterColumbus, Ohio  43210-1240
Crossroads Cancer CenterEffingham, Illinois  62401
Memorial Medical CenterSpringfield, Illinois  62781
University of PittsburghPittsburgh, Pennsylvania  15261
Vanderbilt UniversityNashville, Tennessee  37232-6305
Indiana University Medical CenterIndianapolis, Indiana  46202
UC Davis Comprehensive Cancer CenterSacramento, California  95817
Decatur Memorial HospitalDecatur, Illinois  62526
Virginia Commonwealth UniversityRichmond, Virginia  
University of Chicago Comprehensive Cancer CenterChicago, Illinois  60637-1470
Evanston CCOP-NorthShore University HealthSystemEvanston, Illinois  60201
Illinois Oncology Research Association CCOPPeoria, Illinois  61615
Illinois CancerCare-PeoriaPeoria, Illinois  61615
Fort Wayne Medical Oncology and Hematology Inc - State BoulevardFort Wayne, Indiana  46845
Saint John's Mercy Medical CenterSaint Louis, Missouri  63141
New York University Langone Medical CenterNew York, New York  10016
Saint Luke's Roosevelt Hospital Center - Saint Luke's DivisionNew York, New York  10025
Columbia University Medical CenterNew York, New York  10032
University of Michigan University HospitalAnn Arbor, Michigan  48109
Cancer Care Center of DecaturDecatur, Illinois  62526
New York Cancer ConsortiumNew York, New York  10016