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