Clinical trial NCT01206465: Pralatrexate and Fluorouracil in Treating Patients With Recurrent Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Unspecified Adult Solid Tumor, Protocol Specific
Lead sponsor: University of Nebraska
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2010-09-21
Enrollment: 29
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Recommended Dose of PDX Given With a Fixed Dose of 5-FU
timeFrame: During the initial course (day 1 & 15 of a 4 week schedule)
Secondary outcomes:
measure: Response to Therapy in Subjects With Measurable Disease
timeFrame: restaging imaging done after each two 4-week course until time of progression (the maximum duration of PFS = 588 days)
measure: Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU
timeFrame: ., "From the time the subject signs the consent form and ending 4 weeks following the final chemotherapy, an average of 3 years
measure: Pharmacokinetics of PDX- AUClast
timeFrame: 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.
measure: Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase
timeFrame: Prior to the first dose of protocol therapy
measure: 5-FU Plasma Levels
timeFrame: 22, 23, 45 & 46 hours during the 48 hour infusion
measure: Time to Disease Progression
timeFrame: restaging imaging done after each two 4-week course until time of progression (longest time to progression = 588 days)
Other outcomes:
Locations:
city: Omaha
country: United States
facility: University of Nebraska Medical Center, Eppley Cancer Center
state: Nebraska
Study officials:
affiliation: University of Nebraska
name: Jean Grem
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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: 10.1002/cncr.29504. Epub 2015 Aug 4.