Pralatrexate and Fluorouracil in Treating Patients With Recurrent Solid Tumors

Sponsor
University of Nebraska (Other)
Overall Status
Completed
CT.gov ID
NCT01206465
Collaborator
National Cancer Institute (NCI) (NIH)
29
1
1
81
0.4

Study Details

Study Description

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

Condition or Disease Intervention/Treatment Phase
  • Drug: pralatrexate
  • Drug: fluorouracil
  • Other: laboratory biomarker analysis
  • Genetic: DNA analysis
  • Other: high performance liquid chromatography
  • Genetic: polymerase chain reaction
  • Genetic: nucleic acid sequencing
  • Other: pharmacological study
  • Other: pharmacogenomic studies
  • Genetic: polymorphism analysis
Phase 1

Detailed Description

PRIMARY OBJECTIVES:
  1. 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:
  1. To assess clinical response to therapy in subjects with measurable disease and time to disease progression in all subjects.

  2. 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.

  3. 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 Design

Study Type:
Interventional
Actual Enrollment :
29 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
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 Start Date :
Sep 1, 2010
Actual Primary Completion Date :
Feb 4, 2015
Actual Study Completion Date :
Jun 1, 2017

Arms and Interventions

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.

Drug: pralatrexate
Given IV
Other Names:
  • FOLOTYN
  • PDX
  • Drug: fluorouracil
    Given IV
    Other Names:
  • 5-fluorouracil
  • 5-Fluracil
  • 5-FU
  • Other: laboratory biomarker analysis
    Correlative studies

    Genetic: DNA analysis
    Correlative studies

    Other: high performance liquid chromatography
    Correlative studies
    Other Names:
  • HPLC
  • Genetic: polymerase chain reaction
    Correlative studies
    Other Names:
  • PCR
  • Genetic: nucleic acid sequencing
    Correlative studies
    Other Names:
  • Gene Sequencing
  • Molecular Biology, Nucleic Acid Sequencing
  • Other: pharmacological study
    Correlative studies
    Other Names:
  • pharmacological studies
  • Other: pharmacogenomic studies
    Correlative studies
    Other Names:
  • Pharmacogenomic Study
  • Genetic: polymorphism analysis
    Correlative studies

    Outcome Measures

    Primary Outcome Measures

    1. Recommended Dose of PDX Given in Combination With a Fixed Dose of 5-FU Administered as a 48-hour Infusion Given Every Other Week [During the initial course (day 1 & 15 of a 4 week schedule)]

      Maximum 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 Outcome Measures

    1. 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)]

    2. 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]

      patients remained on study as long as they did not progress, and wished to continue on study (no limit on number of cycles)

    3. 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.]

    4. Number of Participants With Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase [Prior to the first dose of protocol therapy]

    5. Pharmacokinetics of 5-FU - Cmax Plasma Levels [22, 23, 45 & 46 hours during the 48 hour infusion]

      5-FU plasma levels

    6. 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)]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    19 Years and Older
    Sexes Eligible for Study:
    All
    Accepts 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 UNMC Eppley Cancer Center at the University of Nebraska Medical Center Omaha Nebraska United States 68198-6805

    Sponsors and Collaborators

    • University of Nebraska
    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Jean Grem, University of Nebraska

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Jean Grem, MD, Primary Investigator, University of Nebraska
    ClinicalTrials.gov Identifier:
    NCT01206465
    Other Study ID Numbers:
    • 238-10
    • NCI-2010-02014
    First Posted:
    Sep 21, 2010
    Last Update Posted:
    Jul 16, 2018
    Last Verified:
    Jul 1, 2018
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail 29 signed a consent form. Two patients never received any study drug: one became ineligible due to rise in bilirubin; another decided against participating.
    Arm/Group Title 75 mg/m^2 94 mg/m^2 118 mg/m^2 148 mg/m^2 185 mg/m^2
    Arm/Group Description pralatrexate (PDX) dose level pralatrexate (PDX) dose level pralatrexate (PDX) dose level pralatrexate (PDX) dose level pralatrexate (PDX) dose level
    Period Title: Overall Study
    STARTED 3 6 6 6 6
    COMPLETED 3 6 6 6 6
    NOT COMPLETED 0 0 0 0 0

    Baseline Characteristics

    Arm/Group Title Treatment (Enzyme Inhibitor Therapy)
    Arm/Group Description 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.
    Overall Participants 27
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    61
    Sex: Female, Male (Count of Participants)
    Female
    13
    48.1%
    Male
    14
    51.9%
    Race/Ethnicity, Customized (Count of Participants)
    Caucasian
    24
    88.9%
    Black, not of hispanic origin
    1
    3.7%
    Hispanic
    1
    3.7%
    Asian
    1
    3.7%
    Region of Enrollment (participants) [Number]
    United States
    27
    100%

    Outcome Measures

    1. Primary Outcome
    Title Recommended Dose of PDX Given in Combination With a Fixed Dose of 5-FU Administered as a 48-hour Infusion Given Every Other Week
    Description Maximum 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)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Enzyme Inhibitor Therapy)
    Arm/Group Description 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.
    Measure Participants 27
    Number [mg per meter square]
    148
    2. Secondary Outcome
    Title Number of Participants With Response to Therapy in Subjects With Measurable Disease
    Description
    Time Frame restaging imaging done after each two 4-week course until time of progression (the maximum duration of PFS = 588 days)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Enzyme Inhibitor Therapy)
    Arm/Group Description 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.
    Measure Participants 27
    complete or partial response
    0
    0%
    stable disease
    18
    66.7%
    progressive disease
    9
    33.3%
    3. Secondary Outcome
    Title Number of Patients Experiencing Grade 3-4 Toxicity While Receiving the Combination of PDX and 5-FU
    Description patients 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Enzyme Inhibitor Therapy)
    Arm/Group Description 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.
    Measure Participants 27
    gr 3-4 neutropenia
    4
    14.8%
    gr 3-4 thrombocytopenia
    0
    0%
    gr 3-4 anemia
    4
    14.8%
    gr 3-4 diarrhea
    1
    3.7%
    gr 3-4 mucositis
    5
    18.5%
    gr 3-4 dehydration
    1
    3.7%
    gr 3-4 fatigue
    1
    3.7%
    4. Secondary Outcome
    Title Pharmacokinetics of PDX- AUClast
    Description
    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.

    Outcome Measure Data

    Analysis Population Description
    AUClast
    Arm/Group Title 75 mg/m^2 94 mg/m^2 118 mg/m^2 148 mg/m^2 185 mg/m^2
    Arm/Group Description pralatrexate (PDX) Dose level 1 PDX Dose Level 2 PDX Dose level 3 PDX Dose level 4 PDX Dose level 5
    Measure Participants 3 6 6 6 6
    Mean (Standard Deviation) [ng/ml *hr]
    12,818
    (578)
    16300
    (728)
    15680
    (801)
    23570
    (2411)
    42121
    (1051)
    5. Secondary Outcome
    Title Number of Participants With Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase
    Description
    Time Frame Prior to the first dose of protocol therapy

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Wild Type Heterozygous Homozygous Variant
    Arm/Group Description
    Measure Participants 27 27 27
    SLC19A1 80G>A
    51.9
    40.7
    7.4
    gamma glutamyl hydrolase (GGH) 401C>T
    55.6
    37.0
    7.4
    gamma glutamyl hydrolase (GGH) 452C>T
    88.9
    11.1
    0
    folyl polyglutamate synthase (FPGS) rs10760502A>G
    96.0
    4.0
    0
    folyl polyglutamate synthase (FPGS) rs1544105C>T
    25.9
    55.6
    18.5
    methylene tetrahydrofolate reductase (MTHFR 677C>T
    55.6
    25.9
    18.5
    methylene tetrahydrofolate reductase MTHFR 1298A>C
    51.9
    33.3
    14.8
    thymidylate synthase 28-bp tandem repeats (2 or 3)
    14.8
    48.2
    37.0
    6. Secondary Outcome
    Title Pharmacokinetics of 5-FU - Cmax Plasma Levels
    Description 5-FU plasma levels
    Time Frame 22, 23, 45 & 46 hours during the 48 hour infusion

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title 22 Hours 23 Hours 45 Hours 46 Hours
    Arm/Group Description 5 FU plasma levels 5 FU plasma levels 5 FU plasma levels 5 FU plasma levels
    Measure Participants 27 27 27 27
    Mean (Standard Deviation) [mg/m^2]
    1147
    (133)
    1159
    (121)
    1123
    (130)
    1113
    (135)
    7. Secondary Outcome
    Title Time to Disease Progression in All Participants
    Description
    Time Frame restaging imaging done after each two 4-week course until time of progression (longest time to progression = 588 days)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Enzyme Inhibitor Therapy)
    Arm/Group Description 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.
    Measure Participants 27
    Median (Full Range) [days]
    112

    Adverse Events

    Time Frame Adverse event data is collected on participants from the time of consent until 30 days after the participant is off study drug.
    Adverse Event Reporting Description
    Arm/Group Title Treatment (Enzyme Inhibitor Therapy)
    Arm/Group Description 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.
    All Cause Mortality
    Treatment (Enzyme Inhibitor Therapy)
    Affected / at Risk (%) # Events
    Total 3/27 (11.1%)
    Serious Adverse Events
    Treatment (Enzyme Inhibitor Therapy)
    Affected / at Risk (%) # Events
    Total 10/27 (37%)
    Gastrointestinal disorders
    gastrointestinal disorders - Other 1/27 (3.7%) 1
    Abdominal pain 3/27 (11.1%) 3
    Diarrhea 2/27 (7.4%) 2
    Nausea 1/27 (3.7%) 1
    Vomiting 1/27 (3.7%) 1
    General disorders
    Pain 2/27 (7.4%) 2
    Infections and infestations
    Sepsis 1/27 (3.7%) 1
    Infection and infestations- Other 1/27 (3.7%) 1
    Joint infection 1/27 (3.7%) 1
    Injury, poisoning and procedural complications
    Fracture 1/27 (3.7%) 1
    Wound complication 1/27 (3.7%) 2
    Metabolism and nutrition disorders
    Dehydration 1/27 (3.7%) 1
    Nervous system disorders
    Nervous system disorders- Other 1/27 (3.7%) 1
    Vascular disorders
    Thromboembolic Event 4/27 (14.8%) 4
    hypotension 1/27 (3.7%) 1
    Other (Not Including Serious) Adverse Events
    Treatment (Enzyme Inhibitor Therapy)
    Affected / at Risk (%) # Events
    Total 27/27 (100%)
    Blood and lymphatic system disorders
    Anemia 20/27 (74.1%) 20
    Gastrointestinal disorders
    Mucositis oral 23/27 (85.2%) 23
    Ascites 2/27 (7.4%) 2
    Diarrhea 11/27 (40.7%) 11
    Nausea 8/27 (29.6%) 8
    constipation 2/27 (7.4%) 2
    General disorders
    Localized Edema 2/27 (7.4%) 2
    Fatigue 15/27 (55.6%) 15
    Investigations
    white blood cell decreased 2/27 (7.4%) 3
    Neutrophil count decreased 13/27 (48.1%) 13
    Platelet count decreased 16/27 (59.3%) 16
    Metabolism and nutrition disorders
    Hypoalbuminemia 2/27 (7.4%) 2
    Hypokalemia 2/27 (7.4%) 2
    dehydration 9/27 (33.3%) 9
    Renal and urinary disorders
    Hemoglobinuria 5/27 (18.5%) 10
    Skin and subcutaneous tissue disorders
    rash, maculo-papular 7/27 (25.9%) 7

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Jean L. Grem,MD
    Organization University of Nebraska Medical Center
    Phone 402-559-5166
    Email jgrem@unmc.edu
    Responsible Party:
    Jean Grem, MD, Primary Investigator, University of Nebraska
    ClinicalTrials.gov Identifier:
    NCT01206465
    Other Study ID Numbers:
    • 238-10
    • NCI-2010-02014
    First Posted:
    Sep 21, 2010
    Last Update Posted:
    Jul 16, 2018
    Last Verified:
    Jul 1, 2018