Pralatrexate and Fluorouracil in Treating Patients With Recurrent Solid Tumors
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 |
---|---|---|
|
Phase 1 |
Detailed Description
PRIMARY OBJECTIVES:
- 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:
-
To assess clinical response to therapy in subjects with measurable disease and time to disease progression in all subjects.
-
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.
-
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
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:
Drug: fluorouracil
Given IV
Other Names:
Other: laboratory biomarker analysis
Correlative studies
Genetic: DNA analysis
Correlative studies
Other: high performance liquid chromatography
Correlative studies
Other Names:
Genetic: polymerase chain reaction
Correlative studies
Other Names:
Genetic: nucleic acid sequencing
Correlative studies
Other Names:
Other: pharmacological study
Correlative studies
Other Names:
Other: pharmacogenomic studies
Correlative studies
Other Names:
Genetic: polymorphism analysis
Correlative studies
|
Outcome Measures
Primary Outcome Measures
- 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
- 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 [., "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)
- 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.]
- Number of Participants With Polymorphisms in Methylenetetrahydrofolate Reductase and Thymidylate Synthase [Prior to the first dose of protocol therapy]
- Pharmacokinetics of 5-FU - Cmax Plasma Levels [22, 23, 45 & 46 hours during the 48 hour infusion]
5-FU plasma levels
- 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
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.- 238-10
- NCI-2010-02014
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
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
|
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%
|
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%
|
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)
|
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
|
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)
|
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
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 |
jgrem@unmc.edu |
- 238-10
- NCI-2010-02014