Pralatrexate and Fluorouracil in Treating Patients With Recurrent Solid Tumors

Study Overview
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Brief Summary
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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 fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving pralatrexate together with fluorouracil may kill more tumor cells. PURPOSE: This phase I trial is studying the side effects and best dose of pralatrexate when given together with fluorouracil in treating patients with recurrent solid tumors

Detailed Description
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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.

Official Title
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A Phase I Clinical Trial of Sequential Pralatrexate Followed by a 48-hour Infusion of 5- Fluorouracil Given Every Other Week in Adult Patients With Solid Tumors

Conditions
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Unspecified Adult Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: pralatrexate
* Drug: fluorouracil
* Other: laboratory biomarker analysis
* Genetic: DNA analysis
* Other: high performance liquid chromatography
* Genetic: polymerase chain reaction
* Genetic: nucleic acid sequencing
* Other: pharmacological study
* Other: pharmacogenomic studies
* Genetic: polymorphism analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 19 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 (enzyme inhibitor therapy)<br>Patients receive pralatrexate 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. | Drug: pralatrexate<br>* Given IV<br>* Other names: PDX;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;Other: laboratory biomarker analysis<br>* Correlative studies<br>Genetic: DNA analysis<br>* Correlative studies<br>Other: high performance liquid chromatography<br>* Correlative studies<br>* Other names: HPLC;Genetic: polymerase chain reaction<br>* Correlative studies<br>* Other names: PCR;Genetic: nucleic acid sequencing<br>* Correlative studies<br>* Other names: Molecular Biology, Nucleic Acid Sequencing;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;Other: pharmacogenomic studies<br>* Correlative studies<br>* Other names: Pharmacogenomic Study;Genetic: polymorphism analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Dose of PDX Given With a Fixed Dose of 5-FU | Recommended dose of PDX given in combination with a fixed dose of 5-FU administered as a 48-hour infusion given every other weekMaximum tolerated dose will have been exceeded when 2 patients entered at a given dose level experience specified dose-limiting toxicities in the initial cycle | During the initial course (day 1 & 15 of a 4 week schedule) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to Therapy in Subjects With Measurable Disease | Number of Participants With Response to Therapy in Subjects With Measurable Disease | restaging imaging done after each two 4-week course until time of progression (the maximum duration of PFS = 588 days) | 
| Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU | Participants remained on study as long as they did not progress, and wished to continue on study (no limit on number of cycles) | ., From the time the subject signs the consent form and ending 4 weeks following the final chemotherapy, an average of 3 years | 
| Pharmacokinetics of PDX- AUClast | Plasma concentrations versus time (at all time points) | Pre-treatment, end of infusion, at 15, 30, and 60 min, and then at 2, 4, 6, 8, 12, 22, 23, 24, 45, and 46 hours for PDX. | 
| Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | Number of Participants with Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | Prior to the first dose of protocol therapy | 
| 5-FU Plasma Levels | Pharmacokinetics of 5-FU - Cmax plasma levels | 22, 23, 45 & 46 hours during the 48 hour infusion | 
| Time to Disease Progression | Time to disease progression in all Participants | restaging imaging done after each two 4-week course until time of progression (longest time to progression = 588 days) |