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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00982592
First received: September 22, 2009
Last updated: August 26, 2013
Last verified: August 2013

September 22, 2009
August 26, 2013
September 2009
April 2012   (final data collection date for primary outcome measure)
Median progression-free survival [ Time Frame: Time from randomization day until objective or symptomatic progression or death from any cause, assessed up to 2 years ] [ Designated as safety issue: No ]
The PFS distributions of the two treatment arms will be estimated by Kaplan-Meier survival analysis and the PFS distributions will be compared by an unstratified log-rank test. Ninety-five percent confidence intervals for the Kaplan-Meier PFS estimates will be calculated using Greenwood's formulae.
Median progression-free survival [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00982592 on ClinicalTrials.gov Archive Site
  • Objective response rate (CR+PR) [ Time Frame: Up to 2 years ] [ Designated as safety issue: No ]
    Estimated via binomial proportions. Ninety-five percent confidence intervals will be calculated for the objective response proportion in each group via binomial proportions. Comparison of the objective response rate between the treatment groups will be performed by the chi-square test or Fisher's exact test, as appropriate. Response will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1).
  • Overall survival [ Time Frame: Time from randomization day until death from any cause, assessed up to 2 years ] [ Designated as safety issue: No ]
    Estimated by Kaplan-Meier. The comparison of the overall survival distributions between the treatment groups will be performed by the log-rank test.
  • Toxicity as assessed by NCI CTCAE v4.0 [ Time Frame: Up to 2 years ] [ Designated as safety issue: Yes ]
    The frequency of subjects experiencing toxicities will be tabulated. Exact 95% confidence intervals around the toxicity proportions will be calculated to assess the precision of the obtained estimates.
  • 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 ]
Not Provided
Not Provided
 
Combination Chemotherapy With or Without GDC-0449 in Treating Patients With Advanced Stomach Cancer or Gastroesophageal Junction Cancer
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

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 GDC-0449 to FOLFOX chemotherapy improves median progression free survival (PFS) in the first line treatment of patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma.

SECONDARY OBJECTIVES:

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

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

III. To determine if the addition of GDC-0449 to FOLFOX chemotherapy affects toxicity rates in the first line treatment of patients with advanced gastric and GEJ adenocarcinoma.

TERTIARY OBJECTIVES:

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

II. In those patients who consent to repeat biopsy at week 4-5, hedgehog pathway expression will again be assessed (every attempt will be made to obtain repeat biopsy from the same site as the initial biopsy) and compared to baseline values and clinical outcome.

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 (EPC)'s correlate with treatment response and may be used to assess efficacy of GDC-0449 treatment.

VI. To determine if hedgehog pathway expression is downregulated in EPC's following treatment with GDC-0449.

VII. To determine if serum expression of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-beta, and insulin-like growth factor binding protein (IGFBP) 3 correlate with clinical outcome and may be used to assess efficacy of GDC-0449 treatment.

VIII. To determine if Her2 expression is predictive in assessing the efficacy of GDC-0449 treatment. Of note, Her2 status will be collected retrospectively for those patients who were tested as part of standard of care established in October 2010.

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 intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on day 1. Patients also receive placebo orally (PO) once daily (QD) on days 1-14.

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

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

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
  • 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 PO
    Other Names:
    • Erivedge
    • GDC-0449
    • Hedgehog antagonist GDC-0449
  • Other: hydrocortisone/placebo
    Given PO
  • 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
  • Other: flow cytometry
    Correlative studies
  • Other: enzyme-linked immunosorbent assay
    Correlative studies
    Other Name: ELISA
  • Genetic: reverse transcriptase-polymerase chain reaction
    Correlative studies
    Other Name: RT-PCR
  • Other: laboratory biomarker analysis
    Correlative studies
  • Experimental: Arm I (FOLFOX regimen and placebo)
    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 placebo PO QD 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
    • Other: flow cytometry
    • Other: enzyme-linked immunosorbent assay
    • Genetic: reverse transcriptase-polymerase chain reaction
  • Experimental: Arm II (FOLFOX regimen and vismodegib)
    Patients receive FOLFOX chemotherapy as in arm I. Patients also receive hedgehog antagonist GDC-0449 PO 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
    • Other: flow cytometry
    • Other: enzyme-linked immunosorbent assay
    • Genetic: reverse transcriptase-polymerase chain reaction
    • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
116
Not Provided
April 2012   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Histologically or cytologically confirmed gastric or gastroesophageal junction (GEJ) adenocarcinoma not amenable to surgical resection
  • Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan
  • Must be willing to provide blood and tissue samples for research purposes
  • No known brain metastases
  • Eastern Cooperative Oncology Group (ECOG) performance status < 2 (Karnofsky > 70%)
  • Life expectancy > 3 months
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< 1.5 times upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 times ULN (=< 5.0 times ULN in the presence of liver metastases)
  • Creatinine =< 1.5X institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • 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 human immunodeficiency virus (HIV)-positive patients
  • No other concurrent investigational agents
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00982592
NCI-2011-01425, NCI-2011-01425, 09-0356, CDR0000655339, NYU 09-0356, 8376, N01CM00070, N01CM00071, N01CM00038, P30CA016087
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Deirdre Cohen New York University Langone Medical Center
National Cancer Institute (NCI)
August 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP