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
Overview
- Phase
- Phase 2
- Intervention
- oxaliplatin
- Conditions
- Adenocarcinoma of the Gastroesophageal Junction
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 124
- Locations
- 30
- Primary Endpoint
- Median Progression-free Survival (PFS)
- Status
- Completed
- Last Updated
- 10 years ago
Overview
Brief Summary
This randomized phase II trial studies combination chemotherapy when given together with vismodegib to see how well it works compared with combination chemotherapy without vismodegib 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, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more tumor cells. Vismodegib may stop the growth of stomach or gastroesophageal junction cancer by blocking the growth of new blood vessels necessary for tumor growth. It is not yet known whether combination chemotherapy is more effective when given with or without vismodegib in treating stomach cancer and gastroesophageal junction cancer.
Detailed Description
PRIMARY OBJECTIVES: I. To determine if the addition of GDC-0449 (vismodegib) to FOLFOX (fluorouracil, leucovorin calcium, oxaliplatin) 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 human epidermal growth factor receptor 2 (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: 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 vismodegib 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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have 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
- •No prior chemotherapy for advanced disease; patients may have receive adjuvant chemotherapy or chemoradiation if \> 6 months has elapsed since completion of treatment
- •Life expectancy of greater than 3 months
- •Eastern Cooperative Oncology Group (ECOG) performance status \< 2 (Karnofsky \> 70%)
- •Absolute neutrophil count \>= 1,500/mcL
- •Platelets \>= 100,000/mcL
- •Total bilirubin =\< 1.5 times upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 X institutional upper limit of normal (=\< 5.0 X institutional upper limit of normal with presence of liver metastases)
- •Creatinine =\< 1.5 X institutional upper limit of normal OR creatinine clearance \>= 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal
Exclusion Criteria
- •Patients who have had chemotherapy or radiotherapy within 6 months prior to entering the study
- •Patients may not be receiving any other investigational agents
- •Patients with known brain metastases should be excluded from this clinical trial
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to GDC-0449, 5-fluorouracil or oxaliplatin
- •GDC-0449 inhibits cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8), cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9), and cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) drug metabolism enzymes in vitro at concentrations that may be clinically relevant; therefore, caution should be exercised when dosing GDC-0449 concurrently with medications that are substrates of CYP2C8, CYP2C9, and CYP2C19 and have narrow therapeutic windows
- •Patients with malabsorption syndrome or other condition that would interfere with intestinal absorption
- •Patients unable to swallow whole capsules
- •Patients with clinically active liver disease, including viral or other hepatitis or cirrhosis are ineligible
- •Patients with uncontrolled hypocalcemia, hypomagnesemia, hyponatremia or hypokalemia defined as less than the lower limit of normal for the institution, despite adequate electrolyte supplementation are excluded from this study
- •Pre-existing \> grade 1 peripheral sensory neuropathy
Arms & Interventions
Arm I (FOLFOX regimen and placebo)
Patients receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil bolus and then IV over 46-48 hours on day 1. Patients also receive placebo PO QD on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Intervention: oxaliplatin
Arm I (FOLFOX regimen and placebo)
Patients receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil bolus and then IV over 46-48 hours on day 1. Patients also receive placebo PO QD on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Intervention: leucovorin calcium
Arm I (FOLFOX regimen and placebo)
Patients receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil bolus and then IV over 46-48 hours on day 1. Patients also receive placebo PO QD on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Intervention: fluorouracil
Arm I (FOLFOX regimen and placebo)
Patients receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil bolus and then IV over 46-48 hours on day 1. Patients also receive placebo PO QD on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Intervention: placebo
Arm I (FOLFOX regimen and placebo)
Patients receive FOLFOX chemotherapy comprising oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil bolus and then IV over 46-48 hours on day 1. Patients also receive placebo PO QD on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Intervention: laboratory biomarker analysis
Arm II (FOLFOX regimen and vismodegib)
Patients receive FOLFOX chemotherapy as in arm I. Patients also receive vismodegib PO on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Intervention: oxaliplatin
Arm II (FOLFOX regimen and vismodegib)
Patients receive FOLFOX chemotherapy as in arm I. Patients also receive vismodegib PO on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Intervention: leucovorin calcium
Arm II (FOLFOX regimen and vismodegib)
Patients receive FOLFOX chemotherapy as in arm I. Patients also receive vismodegib PO on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Intervention: fluorouracil
Arm II (FOLFOX regimen and vismodegib)
Patients receive FOLFOX chemotherapy as in arm I. Patients also receive vismodegib PO on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Intervention: vismodegib
Arm II (FOLFOX regimen and vismodegib)
Patients receive FOLFOX chemotherapy as in arm I. Patients also receive vismodegib PO on days 1-14. Courses repeat every 2 weeks in the absence of unacceptable toxicity or disease progression.
Intervention: laboratory biomarker analysis
Outcomes
Primary Outcomes
Median Progression-free Survival (PFS)
Time Frame: up to 4 years
PFS is defined as the time from randomization until objective tumor progression or death from any cause and is evaluated per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
Secondary Outcomes
- Objective Response Rate(Up to 4 years)
- Overall Survival(up to 4 years)
- Incidence of Toxicities (Grade 3 and Higher)(Up to 4 years)
- Incidence of Toxicities (grades1 and 2)(Up to 4 years)