Pralatrexate and Fluorouracil in Treating Patients With Recurrent Solid Tumors

PRIMARY OBJECTIVES:

I. To determine the recommended dose of PDX (pralatrexate) given in combination with a fixed dose of 5-FU (fluorouracil) administered as a 48-hour infusion given every other week.

SECONDARY OBJECTIVES:

I. To assess clinical response to therapy in subjects with measurable disease and time to disease progression in all subjects.

II. To assess the toxicity profile of the combination of PDX and 5-FU. III. To determine the pharmacokinetics of PDX and 5-FU and correlate with clinical toxicity.

IV. To analyze polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase (TS) and correlate with clinical toxicity.

OUTLINE: This is a dose-escalation study of pralatrexate.

Patients receive pralatrexate intravenously (IV) over 5 minutes on day 1 and fluorouracil IV continuously over 48 hours on days 2 and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion criteria

• Cancer patients who have failed standard therapy for their disease or for whom no such therapy is available are eligible, for which 5-fluoropyrimdines, including 5-FU, or inhibitors of DHFR (dihydrofolate reductase), including pralatrexate, have the potential for therapeutic benefit
• Objectively measurable disease is preferred, but not required
• Performance status of 0-2 (Eastern Cooperative Oncology Group [ECOG])
• Prior treatment:
• The patient should have recovered from the toxicities associated with prior chemotherapy (at least 3 weeks from prior therapy)
• At least two or more weeks should have elapsed since any radiotherapy, and the patient should have recovered from the toxicity associated with such therapy
• If a recent surgical procedure has been performed, the patient should have recovered from the surgery prior to entering this trial
• Absolute granulocyte count of 1500 per mcL or greater
• Platelet count of 100,000 per mcL or greater
• Serum bilirubin less than 1.5 times the upper limits of the institutional normal
• Serum creatinine less than the upper limits of normal
• The patient must willingly give signed informed consent

Exclusion criteria

• Pregnant women and nursing mothers are ineligible; eligible patients of reproductive potential should use adequate contraception if sexually active
• Serious concurrent medical illness which would jeopardize the ability of the patient to receive the chemotherapy program outlined in this protocol with reasonable safety
• Patients with active infections requiring intravenous antibiotic therapy are not eligible until the infection has resolved
• Patients who are human immunodeficiency virus (HIV) antibody positive and are receiving highly active antiretroviral therapy (HAART) are ineligible
• Concomitant administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and trimethoprim/sulfamethoxazole will not be allowed