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

Abstract

BACKGROUND: Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5-FU). METHODS: Twenty-seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m 2 on day 1 followed 24 hours later by 5-FU at a dose of 3000 mg/m 2 /48 hours every 2 weeks with folic acid and vitamin B12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase. RESULTS: Mucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6%), dehydration (33.3%), fatigue (25.9%), and diarrhea (22.2%). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities The median progression-free survival (PFS) was 112 days (range, 28-588 days). Seven patients (26%) had a PFS of >180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non-small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity. CONCLUSIONS: The recommended dose of PDX was 148 mg/m 2 . A subset of heavily pretreated patients had PFS durations of 6 months with this regimen. Cancer 2015;121:3862-8. INTRODUCTION 5-fluorouracil (5-FU) and folate inhibitors of dihydrofolate reductase (DHFR), including methotrexate (MTX), are active in a variety of malignancies. There is strong preclinical evidence that the optimal sequence for combining DHFR inhibitors with 5-FU involves pretreatment with the DHFR inhibitor followed by 5-FU. 1-4 Administration of 5-FU followed by MTX is antagonistic in both in vitro and in vivo studies. The antipurine action of MTX is believed to result from 2 factors: 1) partial depletion of 10-formyl-tetrahydrofolate, which is required for purine synthesis; and 2) buildup of dihydrofolate, which is an inhibitor of de novo purine synthesis. Ongoing thymidylate synthesis is required to deplete the cellular reduced-folate pool. Pretreatment with 5-FU inhibits thymidylate synthase (TS) thereby blocking the conversion of reduced folates to dihydrofolate. The reduced-folate pool is thus spared for purine synthesis, and the dihydrofolate pool does not expand. When MTX precedes 5-FU, ongoing thymidylate synthesis depletes reduced folates and dihydrofolate pools accumulate, thus allowing blockade of purine biosynthesis. Inhibition of de novo purine synthesis expands the intracellular pool of phosphoribosyl pyrophosphate, which is then available for the anabolism of 5-FU to fluorouridine monophosphate by orotate phosphoribosyl transferase. Enhancement o...

Pharmacogenomics Testing in Phase I Oncology Clinical Trials: Constructive Criticism Is Warranted

“…Most genotype-directed dosing studies have tested differential dosing of irinotecan or other SN-38-related medications in patients carrying UGT1A1 variants [ 19 , 20 , 21 , 22 , 23 ]. Differential dosing for SN-38 was recommended in all studies.…”

“…Others have evaluated variants in ABCB1 , CYP3A4 , CYP3A5 , UGT1A6 , UGT1A7 , and UGT1A9 ; however, only one study found UGT1A6 phenotype status was related to toxicity [ 37 ]. As stated previously, some Phase I studies have studied differential dosing in patients with different UGT1A1 allelic variants [ 19 , 20 , 21 , 22 , 23 ]. Eight studies provided no formal statistical analysis for an association between UGT1A1 genotypes and clinical data derived from phase I studies [ 19 , 44 , 45 , 46 , 47 , 48 ].…”