Pralatrexate and Fluorouracil in Treating Patients With Recurrent Solid Tumors

Phase 1

Completed

• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Interventions: 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

• Registration Number: NCT01206465
• Lead Sponsor: University of Nebraska

Brief Summary

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

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.

Study Timeline

• Study Start: 2010-09-14
• Study First Submitted: 2010-09-17
• Study First Submitted QC: 2010-09-20
• Study First Posted: 2010-09-21
• Primary Completion: 2015-02-04
• Study Completion: 2017-06-01
• Results First Submitted: 2018-02-04
• Results First Submitted QC: 2018-07-13
• Results First Posted: 2018-07-16
• Status Verified: 2023-12
• Last Update Submitted: 2023-12-21
• Last Update Posted: 2023-12-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 29

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (enzyme inhibitor therapy)	DNA analysis	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.
Treatment (enzyme inhibitor therapy)	polymerase chain reaction	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.
Treatment (enzyme inhibitor therapy)	laboratory biomarker analysis	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.
Treatment (enzyme inhibitor therapy)	polymorphism analysis	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.
Treatment (enzyme inhibitor therapy)	nucleic acid sequencing	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.
Treatment (enzyme inhibitor therapy)	pharmacological study	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.
Treatment (enzyme inhibitor therapy)	high performance liquid chromatography	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.
Treatment (enzyme inhibitor therapy)	pharmacogenomic studies	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.
Treatment (enzyme inhibitor therapy)	pralatrexate	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.
Treatment (enzyme inhibitor therapy)	fluorouracil	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.

Primary Outcome Measures

Name	Time	Method
Recommended Dose of PDX Given With a Fixed Dose of 5-FU	During the initial course (day 1 & 15 of a 4 week schedule)	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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

University of Nebraska Medical Center, Eppley Cancer Center; 🇺🇸 Omaha, Nebraska, United States