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

• Toxicity as assessed by NCI CTCAE version 4.0 [ Time Frame: 3 months ] [ Designated as safety issue: Yes ]
• Time to progression [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• To examine whether functionally relevant polymorphisms of genes of the folate metabolism pathway correlate with efficacy and toxicity of pralatrexate. [ Time Frame: 1 year ] [ Designated as safety issue: No ]
• To examine whether response to pralatrexate can be predicted by microRNA expression profiling of the epithelial component of the tumor. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

RATIONALE: 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 or by stopping them from dividing. Giving pralatrexate and oxaliplatin together may kill more tumor cells. PURPOSE: This phase II trial is studying how well pralatrexate and oxaliplatin work in treating patients with unresectable or metastatic esophageal, stomach, or gastroesophageal junction cancer.

PRIMARY OBJECTIVES: I. To determine the overall response rate in patients with advanced esophago-gastric cancer 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 microRNA expression profiling of the epithelial component of the tumor. OUTLINE: Patients receive pralatrexate IV over 3-5 minutes and oxaliplatin IV over 2 hours on day 1. Treatment repeats every 2 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days and then periodically thereafter for up to 5 years.

• Adenocarcinoma of the Esophagus
• Adenocarcinoma of the Gastroesophageal Junction
• Diffuse Adenocarcinoma of the Stomach
• Intestinal Adenocarcinoma of the Stomach
• Mixed Adenocarcinoma of the Stomach
• Recurrent Esophageal Cancer
• Recurrent Gastric Cancer
• Squamous Cell Carcinoma of the Esophagus
• Stage III Esophageal Cancer
• Stage III Gastric Cancer
• Stage IV Esophageal Cancer
• Stage IV Gastric Cancer

• Drug: pralatrexate
  Given IV
  Other Names:

  • FOLOTYN
  • PDX
• Drug: oxaliplatin
  Given IV
  Other Names:

  • 1-OHP
  • Dacotin
  • Dacplat
  • diaminocyclohexane oxalatoplatinum
  • Eloxatin
  • L-OHP
• Other: pharmacogenomic studies
  Correlative studies
  Other Name: Pharmacogenomic Study
• Genetic: RNA analysis
  Correlative studies
• Genetic: polymorphism analysis
  Correlative studies
• Genetic: polymerase chain reaction
  Correlative studies
  Other Name: PCR
• Genetic: microarray analysis
  Correlative studies
  Other Name: gene expression profiling
• Procedure: esophagogastroduodenoscopy
  Correlative studies
  Other Name: EGD
• Procedure: biopsy
  Correlative studies
  Other Name: biopsies
• Other: laboratory biomarker analysis
  Correlative studies

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 included 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
• 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
• 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
• Nursing women are ineligible