Pralatrexate and Oxaliplatin 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
(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.

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