Pralatrexate and Fluorouracil in Treating Patients With Recurrent Solid Tumors

Unspecified Adult Solid Tumor, Protocol Specific Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01206465
• Other study ID #: 0238-10-FB
• Secondary ID: NCI-14191
• Status: Completed
• Phase: Phase 1
• Start date: September 14, 2010
• Est. completion date: June 1, 2017

Study information

• Verified date: December 2023
• Source: University of Nebraska
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 29
• Est. completion date: June 1, 2017
• Est. primary completion date: February 4, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Neoplasms
• Unspecified Adult Solid Tumor, Protocol Specific

Intervention

Drug:
• pralatrexate
Given IV
• fluorouracil
Given IV

Other:
• laboratory biomarker analysis
Correlative studies

Genetic:
• DNA analysis
Correlative studies

Other:
• high performance liquid chromatography
Correlative studies

Genetic:
• polymerase chain reaction
Correlative studies
• nucleic acid sequencing
Correlative studies

Other:
• pharmacological study
Correlative studies
• pharmacogenomic studies
Correlative studies

Genetic:
• polymorphism analysis
Correlative studies

Locations

Country	Name	City	State
United States	University of Nebraska Medical Center, Eppley Cancer Center	Omaha	Nebraska

Sponsors (2)

Lead Sponsor	Collaborator
University of Nebraska	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

References & Publications (1)

Grem JL, Kos ME, Evande RE, Meza JL, Schwarz JK. A phase 1 clinical trial of sequential pralatrexate followed by a 48-hour infusion of 5-fluorouracil given every other week in adult patients with solid tumors. Cancer. 2015 Nov 1;121(21):3862-8. doi: 10.10 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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
Secondary	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.
Secondary	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
Secondary	5-FU Plasma Levels	Pharmacokinetics of 5-FU - Cmax plasma levels	22, 23, 45 & 46 hours during the 48 hour infusion
Secondary	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)