This partially randomized phase I/II trial studies the side effects and best dose of c-Met inhibitor AMG 337 when given together with oxaliplatin, leucovorin calcium, and fluorouracil and to see how well they work in treating patients with stomach or esophageal cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment. C-Met inhibitor AMG 337 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. 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 c-Met inhibitor AMG 337 with oxaliplatin, leucovorin calcium, and fluorouracil may kill more tumor cells.
PRIMARY OBJECTIVES: I. To evaluate the toxicity of combination therapy with AMG 337 (c-Met inhibitor AMG 337) and mFOLFOX6 (oxaliplatin, leucovorin calcium, and fluorouracil) chemotherapy in patients with advanced or metastatic gastrointestinal (GI) cancers. (Phase I) II. To determine the dose of AMG 337 to be used in combination with mFOLFOX6 chemotherapy in the phase II portion of the trial. (Phase I) III. To determine the pharmacokinetics of AMG 337 in combination with mFOLFOX6. (Phase I) IV. To determine if the addition of AMG 337 to mFOLFOX6 chemotherapy improves median progression-free survival (PFS) in the first line treatment of patients with human epidermal growth factor receptor 2 (Her2Neu) negative and high c-met proto-oncogene (MET) expressing advanced esophagogastric and gastroesophageal junction (GEJ) adenocarcinoma. (Phase II) SECONDARY OBJECTIVES: I. To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also to evaluate the placebo/mFOLFOX6 chemotherapy combination in the first line treatment of patients with Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ adenocarcinoma, with regards to overall survival (OS). (Phase II) II. To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also to evaluate the placebo/mFOLFOX6 chemotherapy combination in the first line treatment of patients with Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ adenocarcinoma, with regards to response rate and disease control rate. (Phase II) III. To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also to evaluate the placebo/mFOLFOX6 chemotherapy combination in the first line treatment of patients with Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ adenocarcinoma, with regards to toxicity rates. (Phase II) IV. To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also to evaluate the placebo/mFOLFOX6 chemotherapy combination in the first line treatment of patients with Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ adenocarcinoma, with regards to time to development of new metastasis. (Phase II) V. To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also to evaluate the placebo/mFOLFOX6 chemotherapy combination in the first line treatment of patients with Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ adenocarcinoma, with regards to evaluation of MET amplification. (Phase II) VI. To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also to evaluate the placebo/mFOLFOX6 chemotherapy combination in the first line treatment of patients with Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ adenocarcinoma, with regards to evaluation of MET amplification and MET expression as determined by DAKO immunohistochemistry (IHC) for comparison to Ventana IHC. (Phase II) VII. To evaluate the addition of AMG 337 to mFOLFOX6 chemotherapy and also to evaluate the placebo/mFOLFOX6 chemotherapy combination in the first line treatment of patients with Her2Neu negative and high c-MET expressing advanced esophagogastric and GEJ adenocarcinoma, with regards to a retrospective re-evaluation of the cutpoint used by the computer algorithm for c-MET IHC to assess its ability to distinguish responding versus non-responding patients will be undertaken in this population, so that a potentially more optimal cutpoint to define high c-MET tumors in patients can be identified. (Phase II) OUTLINE: This is a phase I, dose-escalation study of c-Met inhibitor AMG 337 followed by a phase II study. PHASE I: Patients receive c-Met inhibitor AMG 337 orally (PO) once daily (QD) on days 1-28; and oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive c-Met inhibitor AMG 337 PO QD on days 1-28; and oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on days 1 and 15. ARM B: Patients receive placebo PO QD on days 1-28; and oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46-48 hours on days 1 and 15. In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 2 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Given PO
Given PO
Given IV
Given IV
Given IV
Correlative studies
Correlative studies
ECOG-ACRIN Cancer Research Group
Philadelphia, Pennsylvania, United States
Maximum tolerated dose of c-Met inhibitor AMG 337, defined as the highest dose level at which < 33% of 6 patients experience a dose limiting toxicity graded according to CTCAE v.4 (Phase I)
Time frame: 28 days
Progression-free survival (Phase II)
The study will have 90% power to detect the above improvement in PFS using a one-sided 0.10 level log rank test.
Time frame: Up to 2 years
Overall survival (Phase II)
Time frame: Up to 2 years
Response rate (Phase II)
Time frame: Up to 2 years
Disease control rate (Phase II)
Time frame: Up to 2 years
Incidence of toxicity graded according to CTCAE v.4 (Phase II)
The study will have at least 83% power to detect an absolute differences of 26% or more (e.g. 64% versus 38% true toxicity rates) between the two arms for any given adverse event, using a one-sided 5% level Fisher's exact test.
Time frame: Up to 2 years
Time to development of new metastasis (Phase II)
Time frame: Up to 2 years
Evaluation of MET amplification via fluorescence in situ hybridization (FISH) (Phase II)
Time frame: Up to 2 years
Evaluation of MET amplification and MET expression as determined by DAKO IHC (Phase II)
Comparison of DAKO IHC to Ventana IHC and comparison of amplification by FISH to overexpression by Ventana IHC amongst all pre-registered patients.
Time frame: Up to 2 years
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