Trial Outcomes & Findings for Pralatrexate and Fluorouracil in Treating Patients With Recurrent Solid Tumors (NCT NCT01206465)

NCT ID: NCT01206465

Last Updated: 2023-12-26

Results Overview

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

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

29 participants

Primary outcome timeframe

During the initial course (day 1 & 15 of a 4 week schedule)

Results posted on

2023-12-26

Participant Flow

29 signed a consent form. Two patients never received any study drug: one became ineligible due to rise in bilirubin; another decided against participating.

Participant milestones

Participant milestones
Measure	75 mg/m^2 pralatrexate (PDX) dose level	94 mg/m^2 pralatrexate (PDX) dose level	118 mg/m^2 pralatrexate (PDX) dose level	148 mg/m^2 pralatrexate (PDX) dose level	185 mg/m^2 pralatrexate (PDX) dose level
Overall Study STARTED	3	6	6	6	6
Overall Study COMPLETED	3	6	6	6	6
Overall Study NOT COMPLETED	0	0	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Pralatrexate and Fluorouracil in Treating Patients With Recurrent Solid Tumors

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Treatment (Enzyme Inhibitor Therapy) n=27 Participants 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.
Age, Continuous	61 years n=5 Participants
Sex: Female, Male Female	13 Participants n=5 Participants
Sex: Female, Male Male	14 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity · Caucasian	24 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity · Black, not of hispanic origin	1 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity · Hispanic	1 Participants n=5 Participants
Race/Ethnicity, Customized Race/Ethnicity · Asian	1 Participants n=5 Participants
Region of Enrollment United States	27 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Treatment (Enzyme Inhibitor Therapy) n=27 Participants 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.	94 mg/m^2 PDX Dose Level 2	118 mg/m^2 PDX Dose level 3	148 mg/m^2 PDX Dose level 4	185 mg/m^2 PDX Dose level 5
Recommended Dose of PDX Given With a Fixed Dose of 5-FU	148 mg per meter square	—	—	—	—

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Treatment (Enzyme Inhibitor Therapy) n=27 Participants 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.	94 mg/m^2 PDX Dose Level 2	118 mg/m^2 PDX Dose level 3	148 mg/m^2 PDX Dose level 4	185 mg/m^2 PDX Dose level 5
Response to Therapy in Subjects With Measurable Disease complete or partial response	0 Participants	—	—	—	—
Response to Therapy in Subjects With Measurable Disease stable disease	18 Participants	—	—	—	—
Response to Therapy in Subjects With Measurable Disease progressive disease	9 Participants	—	—	—	—

SECONDARY outcome

Timeframe: ., "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)

Outcome measures

Outcome measures
Measure	Treatment (Enzyme Inhibitor Therapy) n=27 Participants 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.	94 mg/m^2 PDX Dose Level 2	118 mg/m^2 PDX Dose level 3	148 mg/m^2 PDX Dose level 4	185 mg/m^2 PDX Dose level 5
Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU gr 3-4 neutropenia	4 participants	—	—	—	—
Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU gr 3-4 thrombocytopenia	0 participants	—	—	—	—
Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU gr 3-4 anemia	4 participants	—	—	—	—
Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU gr 3-4 diarrhea	1 participants	—	—	—	—
Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU gr 3-4 mucositis	5 participants	—	—	—	—
Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU gr 3-4 dehydration	1 participants	—	—	—	—
Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU gr 3-4 fatigue	1 participants	—	—	—	—

SECONDARY outcome

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.

Population: AUClast

Plasma concentrations versus time (at all time points)

Outcome measures

Outcome measures
Measure	Treatment (Enzyme Inhibitor Therapy) n=3 Participants 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.	94 mg/m^2 n=6 Participants PDX Dose Level 2	118 mg/m^2 n=6 Participants PDX Dose level 3	148 mg/m^2 n=6 Participants PDX Dose level 4	185 mg/m^2 n=6 Participants PDX Dose level 5
Pharmacokinetics of PDX- AUClast	12,818 ng/ml *hr Standard Deviation 578	16300 ng/ml *hr Standard Deviation 728	15680 ng/ml *hr Standard Deviation 801	23570 ng/ml *hr Standard Deviation 2411	42121 ng/ml *hr Standard Deviation 1051

SECONDARY outcome

Timeframe: Prior to the first dose of protocol therapy

Number of Participants with Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase

Outcome measures

Outcome measures
Measure	Treatment (Enzyme Inhibitor Therapy) n=27 Participants 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.	94 mg/m^2 n=27 Participants PDX Dose Level 2	118 mg/m^2 n=27 Participants PDX Dose level 3	148 mg/m^2 PDX Dose level 4	185 mg/m^2 PDX Dose level 5
Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase thymidylate synthase 28-bp tandem repeats (2 or 3)	14.8 percentage of patients	48.2 percentage of patients	37.0 percentage of patients	—	—
Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase gamma glutamyl hydrolase (GGH) 401C>T	55.6 percentage of patients	37.0 percentage of patients	7.4 percentage of patients	—	—
Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase gamma glutamyl hydrolase (GGH) 452C>T	88.9 percentage of patients	11.1 percentage of patients	0 percentage of patients	—	—
Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase folyl polyglutamate synthase (FPGS) rs10760502A>G	96.0 percentage of patients	4.0 percentage of patients	0 percentage of patients	—	—
Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase methylene tetrahydrofolate reductase MTHFR 1298A>C	51.9 percentage of patients	33.3 percentage of patients	14.8 percentage of patients	—	—
Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase SLC19A1 80G>A	51.9 percentage of patients	40.7 percentage of patients	7.4 percentage of patients	—	—
Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase folyl polyglutamate synthase (FPGS) rs1544105C>T	25.9 percentage of patients	55.6 percentage of patients	18.5 percentage of patients	—	—
Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase methylene tetrahydrofolate reductase (MTHFR 677C>T	55.6 percentage of patients	25.9 percentage of patients	18.5 percentage of patients	—	—

SECONDARY outcome

Timeframe: 22, 23, 45 & 46 hours during the 48 hour infusion

Pharmacokinetics of 5-FU - Cmax plasma levels

Outcome measures

Outcome measures
Measure	Treatment (Enzyme Inhibitor Therapy) n=27 Participants 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.	94 mg/m^2 n=27 Participants PDX Dose Level 2	118 mg/m^2 n=27 Participants PDX Dose level 3	148 mg/m^2 n=27 Participants PDX Dose level 4	185 mg/m^2 PDX Dose level 5
5-FU Plasma Levels	1147 mg/m^2 Standard Deviation 133	1159 mg/m^2 Standard Deviation 121	1123 mg/m^2 Standard Deviation 130	1113 mg/m^2 Standard Deviation 135	—

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Treatment (Enzyme Inhibitor Therapy) n=27 Participants 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.	94 mg/m^2 PDX Dose Level 2	118 mg/m^2 PDX Dose level 3	148 mg/m^2 PDX Dose level 4	185 mg/m^2 PDX Dose level 5
Time to Disease Progression	112 days Interval 28.0 to 588.0	—	—	—	—

Adverse Events

Treatment (Enzyme Inhibitor Therapy)

Serious events: 10 serious events

Other events: 27 other events

Deaths: 3 deaths

Serious adverse events

Serious adverse events
Measure	Treatment (Enzyme Inhibitor Therapy) n=27 participants at risk 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.
Vascular disorders Thromboembolic Event	14.8% 4/27 • Number of events 4 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
General disorders Pain	7.4% 2/27 • Number of events 2 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Gastrointestinal disorders gastrointestinal disorders - Other	3.7% 1/27 • Number of events 1 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Nervous system disorders Nervous system disorders- Other	3.7% 1/27 • Number of events 1 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Infections and infestations Sepsis	3.7% 1/27 • Number of events 1 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Gastrointestinal disorders Abdominal pain	11.1% 3/27 • Number of events 3 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Injury, poisoning and procedural complications Fracture	3.7% 1/27 • Number of events 1 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Injury, poisoning and procedural complications Wound complication	3.7% 1/27 • Number of events 2 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Vascular disorders hypotension	3.7% 1/27 • Number of events 1 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Infections and infestations Infection and infestations- Other	3.7% 1/27 • Number of events 1 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Infections and infestations Joint infection	3.7% 1/27 • Number of events 1 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Gastrointestinal disorders Diarrhea	7.4% 2/27 • Number of events 2 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Gastrointestinal disorders Nausea	3.7% 1/27 • Number of events 1 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Gastrointestinal disorders Vomiting	3.7% 1/27 • Number of events 1 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Metabolism and nutrition disorders Dehydration	3.7% 1/27 • Number of events 1 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.

Other adverse events

Other adverse events
Measure	Treatment (Enzyme Inhibitor Therapy) n=27 participants at risk 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.
Renal and urinary disorders Hemoglobinuria	18.5% 5/27 • Number of events 10 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Metabolism and nutrition disorders Hypoalbuminemia	7.4% 2/27 • Number of events 2 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Gastrointestinal disorders Mucositis oral	85.2% 23/27 • Number of events 23 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Gastrointestinal disorders Ascites	7.4% 2/27 • Number of events 2 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Investigations white blood cell decreased	7.4% 2/27 • Number of events 3 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
General disorders Localized Edema	7.4% 2/27 • Number of events 2 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Metabolism and nutrition disorders Hypokalemia	7.4% 2/27 • Number of events 2 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Investigations Neutrophil count decreased	48.1% 13/27 • Number of events 13 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Investigations Platelet count decreased	59.3% 16/27 • Number of events 16 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Blood and lymphatic system disorders Anemia	74.1% 20/27 • Number of events 20 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Gastrointestinal disorders Diarrhea	40.7% 11/27 • Number of events 11 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Metabolism and nutrition disorders dehydration	33.3% 9/27 • Number of events 9 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
General disorders Fatigue	55.6% 15/27 • Number of events 15 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Skin and subcutaneous tissue disorders rash, maculo-papular	25.9% 7/27 • Number of events 7 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Gastrointestinal disorders Nausea	29.6% 8/27 • Number of events 8 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
Gastrointestinal disorders constipation	7.4% 2/27 • Number of events 2 • Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.

Additional Information

Jean L Grem

University of Nebraska Medical Center

Phone: 402-559-5166

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place