Pralatrexate and Oxaliplatin in Treating Patients With Unresectable or Metastatic Esophageal, Stomach, or Gastroesophageal Junction Cancer

Study Overview
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Brief Summary
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This phase II trial studies how well pralatrexate and oxaliplatin work in treating patients with esophageal, stomach, or gastroesophageal junction cancer that cannot be removed by surgery or has spread from the primary site (place where it started) to other places in the body. Pralatrexate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as oxaliplatin, 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 pralatrexate with oxaliplatin may be an effective treatment for esophageal, stomach, or gastroesophageal junction cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the overall response rate in patients with advanced esophago-gastric cancer (EGC) to combination pralatrexate and oxaliplatin. SECONDARY OBJECTIVES: I. To examine the toxicity and tolerability of this regimen. II. To determine the time-to-progression and overall survival using this regimen. III. To examine whether functionally relevant polymorphisms of genes of the folate metabolism pathway correlate with efficacy and toxicity of pralatrexate. IV. To examine whether response to pralatrexate can be predicted by micro-ribonucleic acid (microRNA) expression profiling of the epithelial component of the tumor. OUTLINE: Patients receive pralatrexate intravenously (IV) over 3-5 minutes and oxaliplatin IV over 2 hours on day 1. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Oxaliplatin will be discontinued after 12 courses. After completion of study treatment, patients are followed up for 30 days and then periodically thereafter for up to 5 years.

Official Title
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Pralatrexate in Combination With Oxaliplatin in Advanced Esophago-gastric Cancer: A Phase II Trial With Predictive Molecular Correlates

Conditions
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Stage IV Gastric Cancer, Adenocarcinoma of the Gastroesophageal Junction, Esophageal Undifferentiated Carcinoma, Gastric Adenocarcinoma, Gastric Squamous Cell Carcinoma, Recurrent Esophageal Adenocarcinoma, Recurrent Esophageal Squamous Cell Carcinoma, Recurrent Gastric Carcinoma, Stage IIIB Esophageal Adenocarcinoma, Stage IIIB Esophageal Squamous Cell Carcinoma, Stage IIIB Gastric Cancer, Stage IIIC Esophageal Adenocarcinoma, Stage IIIC Esophageal Squamous Cell Carcinoma, Stage IIIC Gastric Cancer, Stage IV Esophageal Adenocarcinoma, Stage IV Esophageal Squamous Cell Carcinoma, Undifferentiated Gastric Carcinoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Oxaliplatin
* Drug: Pralatrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed carcinoma of the esophagus, stomach or gastro-esophageal junction that is metastatic, or locally advanced and inoperable for cure; histological sub-types permitted include adenocarcinoma, squamous-cell carcinoma, or undifferentiated carcinoma; small-cell carcinoma variant is not eligible No previous systemic therapy for metastatic or recurrent disease; therapy (chemotherapy, radiotherapy, or both) administered in the neo-adjuvant, adjuvant, or definitive setting for previously localized disease is permitted, provided it was completed more than 6 months prior to enrollment; palliative radiotherapy is permitted provided it is completed >= 3 weeks prior to study therapy initiation Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Life expectancy >= 12 weeks Hemoglobin >= 9 g/dl Absolute neutrophil count >= 1500/mm^3 Platelet count >= 100,000/mm^3 Serum creatinine =< institutional upper limit normal (ULN) Bilirubin =< 1.5 x ULN Transaminases =< 3 x ULN; for documented liver metastases, transaminases up to 5 x ULN is permitted No evidence of >= grade 2 peripheral neuropathy Patients with reproductive potential must be willing to use an adequate contraceptive method (e.g., abstinence, intrauterine device, oral contraceptives, barrier device with spermicide or surgical sterilization) during treatment and for three months after completing treatment; a negative pregnancy test is required for women of child-bearing potential; nursing women are ineligible Written, informed consent Exclusion Criteria: Hypersensitivity to platinum compounds Uncontrolled inter-current illness including but not limited to active infection, symptomatic congestive heart failure, unstable angina, uncontrolled cardiac arrhythmia, or psychiatric illness that would limit compliance with study requirements Presence of brain metastases Patients with third-space (pleural, peritoneal) fluid not controllable with usual drainage methods are not eligible History of second primary malignancy within 3 years prior to enrollment, except for in-situ cervix carcinoma or non-melanoma skin cancer Undergone an allogeneic stem cell transplant

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pralatrexate, oxaliplatin)<br>Patients receive pralatrexate IV over 3-5 minutes and oxaliplatin IV over 2 hours on day 1. Courses repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Oxaliplatin will be discontinued after 12 courses. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Oxaliplatin<br>* Given IV<br>* Other names: SR-96669;Drug: Pralatrexate<br>* Given IV<br>* Other names: PDX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Overall response rate to combination pralatrexate and oxaliplatin as assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Objective responses will be confirmed 4 weeks after first documentation of response. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With an Adverse Event | Number of participants with an adverse event. Please refer to the adverse event reporting for more detail. Incidence of toxicity as assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 | Up to 30 days after the last dose of study drug(s) | 
| Overall Survival (OS) | Estimated using the Kaplan-Meier method and proportional hazards models. | From the date of study enrollment to the time of death from any cause, assessed up to 5 years | 
| Time to Progression (TTP) | Estimated using the Kaplan-Meier method and proportional hazards models. | From the date of study enrollment to the first observation of progressive disease, assessed up to 5 years |