Unspecified Adult Solid Tumor, Protocol Specific
Conditions
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.
Interventions
DRUGpralatrexate
Given IV
DRUGfluorouracil
Given IV
OTHERlaboratory biomarker analysis
Correlative studies
GENETICDNA analysis
Correlative studies
OTHERhigh performance liquid chromatography
Correlative studies
GENETICpolymerase chain reaction
Correlative studies
GENETICnucleic acid sequencing
Correlative studies
OTHERpharmacological study
Correlative studies
OTHERpharmacogenomic studies
Correlative studies
GENETICpolymorphism analysis
Correlative studies
Sponsors
National Cancer Institute (NCI)
University of Nebraska
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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) |
| 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 |
| 5-FU Plasma Levels | 22, 23, 45 & 46 hours during the 48 hour infusion | Pharmacokinetics of 5-FU - Cmax plasma levels |
| 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 |
| 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 |
Countries
United States
Participant flow
Pre-assignment details
29 signed a consent form. Two patients never received any study drug: one became ineligible due to rise in bilirubin; another decided against participating.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 27 |
| Total | 27 |
Baseline characteristics
| Characteristic | Treatment (Enzyme Inhibitor Therapy) |
|---|---|
| Age, Continuous | 61 years |
| Race/Ethnicity, Customized Race/Ethnicity Asian | 1 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Black, not of hispanic origin | 1 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Caucasian | 24 Participants |
| Race/Ethnicity, Customized Race/Ethnicity Hispanic | 1 Participants |
| Region of Enrollment United States | 27 participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 27 |
| other Total, other adverse events | 27 / 27 |
| serious Total, serious adverse events | 10 / 27 |
Outcome results
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
Time frame: During the initial course (day 1 & 15 of a 4 week schedule)
Population: All participants 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Recommended Dose of PDX Given With a Fixed Dose of 5-FU | 148 mg per meter square |
Secondary
5-FU Plasma Levels
Pharmacokinetics of 5-FU - Cmax plasma levels
Time frame: 22, 23, 45 & 46 hours during the 48 hour infusion
Population: All participants 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | 5-FU Plasma Levels | 1147 mg/m^2 | Standard Deviation 133 |
| 94 mg/m^2 | 5-FU Plasma Levels | 1159 mg/m^2 | Standard Deviation 121 |
| 118 mg/m^2 | 5-FU Plasma Levels | 1123 mg/m^2 | Standard Deviation 130 |
| 148 mg/m^2 | 5-FU Plasma Levels | 1113 mg/m^2 | Standard Deviation 135 |
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)
Time frame: ., From the time the subject signs the consent form and ending 4 weeks following the final chemotherapy, an average of 3 years
Population: All participants 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU | gr 3-4 neutropenia | 4 participants |
| Treatment (Enzyme Inhibitor Therapy) | Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU | gr 3-4 thrombocytopenia | 0 participants |
| Treatment (Enzyme Inhibitor Therapy) | Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU | gr 3-4 anemia | 4 participants |
| Treatment (Enzyme Inhibitor Therapy) | Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU | gr 3-4 diarrhea | 1 participants |
| Treatment (Enzyme Inhibitor Therapy) | Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU | gr 3-4 mucositis | 5 participants |
| Treatment (Enzyme Inhibitor Therapy) | Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU | gr 3-4 dehydration | 1 participants |
| Treatment (Enzyme Inhibitor Therapy) | Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU | gr 3-4 fatigue | 1 participants |
Secondary
Pharmacokinetics of PDX- AUClast
Plasma concentrations versus time (at all time points)
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.
Population: AUClast
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Pharmacokinetics of PDX- AUClast | 12,818 ng/ml *hr | Standard Deviation 578 |
| 94 mg/m^2 | Pharmacokinetics of PDX- AUClast | 16300 ng/ml *hr | Standard Deviation 728 |
| 118 mg/m^2 | Pharmacokinetics of PDX- AUClast | 15680 ng/ml *hr | Standard Deviation 801 |
| 148 mg/m^2 | Pharmacokinetics of PDX- AUClast | 23570 ng/ml *hr | Standard Deviation 2411 |
| 185 mg/m^2 | Pharmacokinetics of PDX- AUClast | 42121 ng/ml *hr | Standard Deviation 1051 |
Secondary
Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase
Number of Participants with Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase
Time frame: Prior to the first dose of protocol therapy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | SLC19A1 80G>A | 51.9 percentage of patients |
| Treatment (Enzyme Inhibitor Therapy) | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | gamma glutamyl hydrolase (GGH) 401C>T | 55.6 percentage of patients |
| Treatment (Enzyme Inhibitor Therapy) | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | gamma glutamyl hydrolase (GGH) 452C>T | 88.9 percentage of patients |
| Treatment (Enzyme Inhibitor Therapy) | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | folyl polyglutamate synthase (FPGS) rs10760502A>G | 96.0 percentage of patients |
| Treatment (Enzyme Inhibitor Therapy) | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | folyl polyglutamate synthase (FPGS) rs1544105C>T | 25.9 percentage of patients |
| Treatment (Enzyme Inhibitor Therapy) | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | methylene tetrahydrofolate reductase (MTHFR 677C>T | 55.6 percentage of patients |
| Treatment (Enzyme Inhibitor Therapy) | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | methylene tetrahydrofolate reductase MTHFR 1298A>C | 51.9 percentage of patients |
| Treatment (Enzyme Inhibitor Therapy) | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | thymidylate synthase 28-bp tandem repeats (2 or 3) | 14.8 percentage of patients |
| 94 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | gamma glutamyl hydrolase (GGH) 452C>T | 11.1 percentage of patients |
| 94 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | methylene tetrahydrofolate reductase MTHFR 1298A>C | 33.3 percentage of patients |
| 94 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | folyl polyglutamate synthase (FPGS) rs10760502A>G | 4.0 percentage of patients |
| 94 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | folyl polyglutamate synthase (FPGS) rs1544105C>T | 55.6 percentage of patients |
| 94 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | methylene tetrahydrofolate reductase (MTHFR 677C>T | 25.9 percentage of patients |
| 94 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | SLC19A1 80G>A | 40.7 percentage of patients |
| 94 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | gamma glutamyl hydrolase (GGH) 401C>T | 37.0 percentage of patients |
| 94 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | thymidylate synthase 28-bp tandem repeats (2 or 3) | 48.2 percentage of patients |
| 118 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | gamma glutamyl hydrolase (GGH) 452C>T | 0 percentage of patients |
| 118 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | gamma glutamyl hydrolase (GGH) 401C>T | 7.4 percentage of patients |
| 118 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | SLC19A1 80G>A | 7.4 percentage of patients |
| 118 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | folyl polyglutamate synthase (FPGS) rs10760502A>G | 0 percentage of patients |
| 118 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | methylene tetrahydrofolate reductase MTHFR 1298A>C | 14.8 percentage of patients |
| 118 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | methylene tetrahydrofolate reductase (MTHFR 677C>T | 18.5 percentage of patients |
| 118 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | folyl polyglutamate synthase (FPGS) rs1544105C>T | 18.5 percentage of patients |
| 118 mg/m^2 | Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase | thymidylate synthase 28-bp tandem repeats (2 or 3) | 37.0 percentage of patients |
Secondary
Response to Therapy in Subjects With Measurable Disease
Number of Participants With 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)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Response to Therapy in Subjects With Measurable Disease | complete or partial response | 0 Participants |
| Treatment (Enzyme Inhibitor Therapy) | Response to Therapy in Subjects With Measurable Disease | stable disease | 18 Participants |
| Treatment (Enzyme Inhibitor Therapy) | Response to Therapy in Subjects With Measurable Disease | progressive disease | 9 Participants |
Secondary
Time to Disease Progression
Time to disease progression in all Participants
Time frame: restaging imaging done after each two 4-week course until time of progression (longest time to progression = 588 days)
Population: All participants 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment (Enzyme Inhibitor Therapy) | Time to Disease Progression | 112 days |