Pralatrexate and Fluorouracil in Treating Patients With Recurrent Solid Tumors

December 21, 2023 updated by: University of Nebraska

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

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

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

29

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Nebraska
      • Omaha, Nebraska, United States, 68198-6805
        • University of Nebraska Medical Center, Eppley Cancer Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

19 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Treatment (enzyme inhibitor therapy)
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.
Other: laboratory biomarker analysis
Correlative studies
Genetic: polymerase chain reaction
Correlative studies
Other Names:
  • PCR
Drug: fluorouracil
Given IV
Other Names:
  • 5-FU
  • 5-fluorouracil
  • 5-Fluracil
Other: pharmacological study
Correlative studies
Other Names:
  • pharmacological studies
Genetic: DNA analysis
Correlative studies
Other: pharmacogenomic studies
Correlative studies
Other Names:
  • Pharmacogenomic Study
Genetic: polymorphism analysis
Correlative studies
Other: high performance liquid chromatography
Correlative studies
Other Names:
  • HPLC
Drug: pralatrexate
Given IV
Other Names:
  • FOLOTYN
  • PDX
Genetic: nucleic acid sequencing
Correlative studies
Other Names:
  • Gene Sequencing
  • Molecular Biology, Nucleic Acid Sequencing

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Recommended Dose of PDX Given With a Fixed Dose of 5-FU
Time Frame: 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
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
Time Frame: 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
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
Time Frame: ., "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)
., "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
Time Frame: 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)
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
Time Frame: Prior to the first dose of protocol therapy
Number of Participants with Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase
Prior to the first dose of protocol therapy
5-FU Plasma Levels
Time Frame: 22, 23, 45 & 46 hours during the 48 hour infusion
Pharmacokinetics of 5-FU - Cmax plasma levels
22, 23, 45 & 46 hours during the 48 hour infusion
Time to Disease Progression
Time Frame: 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
restaging imaging done after each two 4-week course until time of progression (longest time to progression = 588 days)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Nebraska

Collaborators

National Cancer Institute (NCI)

Investigators

  • Principal Investigator: Jean Grem, University of Nebraska

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 14, 2010

Primary Completion (Actual)

February 4, 2015

Study Completion (Actual)

June 1, 2017

Study Registration Dates

First Submitted

September 17, 2010

First Submitted That Met QC Criteria

September 20, 2010

First Posted (Estimated)

September 21, 2010

Study Record Updates

Last Update Posted (Actual)

December 26, 2023

Last Update Submitted That Met QC Criteria

December 21, 2023

Last Verified

December 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 0238-10-FB
  • NCI-14191 (Other Grant/Funding Number: National Cancer Institute)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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