Phase I Study of OSI-7904L, a Novel Liposomal Thymidylate Synthase Inhibitor in Patients with Refractory Solid Tumors

Abstract

Purpose: OSI-7904L is a liposomal formulation of a potent noncompetitive thymidylate synthase inhibitor (TSI) that does not require polyglutamation for activity. This phase I study was done to establish the safety, tolerability, maximum tolerated dose, recommended dose, and pharmacokinetics of OSI-7904L in patients with advanced solid tumors refractory to standard therapy. Design: OSI-7904L was given as a 30-minute i.v. infusion every 21 days to 31patients at eight dose levels from 0.4 to 15.0 mg/m 2 , using three patients per dose level, up to 10 patients at the recommended dose. Baseline plasma homocysteine and 2V -deoxyuridine and genotype polymorphism were measured as potential predictors of biological activity. Results: Minimal toxicity was reported up to 9.6 mg/m 2 , but dose-limiting toxicity was seen in both patients at 15 mg/m 2 including stomatitis, fatigue, tachyarrhythmia, rash and hand-foot syndrome, diarrhea, and fatal neutropenic sepsis. Other toxicity such as nausea and vomiting was mild or moderate.This resulted in the investigation of an intermediate dose level of 12 mg/m 2 , identified as the recommended dose for phase II studies. Prolonged disease stabilization was reported in 11of 31heavily pretreated patients. Pharmacokinetic data indicate that this liposomal formulation alters the disposition properties of the parent drug resulting in a prolonged plasma residence time. Conclusions: OSI-7904L given as a 30-minute i.v. infusion every 21 days is feasible and well tolerated at the recommended phase II dose of 12 mg/m 2 . The main toxicities are rash, pruritis, lethargy, stomatitis, and myelosuppression. Observed toxicities were predictable and characteristic forTSIs.Thymidylate synthase is the rate-limiting enzyme in the biosynthesis of DNA catalyzing the methylation of dUMP to TMP, an essential precursor for DNA synthesis (1). Because thymidine nucleotides are used exclusively for synthesis of DNA, thymidylate synthase is an important target for anticancer therapy. Thymidylate synthase inhibitors (TSI) such as members of the fluoropyrimidine family [5-fluorouracil (5-FU), capecitabine, UFT, and S-1 or newer antifolates such as raltitrexed and pemetrexed] have shown efficacy in colon, breast, mesothelioma, and non -small cell lung carcinomas (2 -10). Resistance to available TSIs occurs via several mechanisms, including (i) increased gene expression resulting in elevated enzyme levels, (ii) reduced polyglutamation due to decreased activity or lower levels of folypolyglutamate synthase, or (iii) reduction of fluoropyrimidine drug levels by increased metabolism by dihydropyrimidine dehydrogenase. There is therefore a strong rationale to develop new potent TSIs that circumvent those mechanisms of resistance.OSIis a potent TSI with an inhibition constant (K i ) of 90 pmol/L. Although structurally related to the folate cofactor, OSI-7904 is a noncompetitive inhibitor and its binding to thymidylate synthase in the ternary complex with dUMP is unaffected by 5,10-methylenetetrahydrofolate (11,...

Multicentre phase II pharmacokinetic and pharmacodynamic study of OSI-7904L in previously untreated patients with advanced gastric or gastroesophageal junction adenocarcinoma

“…The high level of interpatient variability in OSI-7904L clearance seen in the phase I trial of OSI-7904L was again evident (Beutel et al, 2005). Those patients with higher AUC were more likely to experience a CTC grade 3/4 toxicity (Figure 2).…”

“…Blood samples were collected in EDTA tubes and then processed and analysed for OSI-7904 concentration as previously reported (Beutel et al, 2005). Plasma concentrations vs time data for OSI-7904 were analysed by a noncompartmental method using WinNonlin version 4.1.b (Pharsight Corporation, Mountain View, CA, USA).…”

“…Samples were collected into tubes containing sodium fluoride ethylenediamine tetra-acetic acid (NaF EDTA) and processed and analysed for relative 2 0 -dU concentration as previously reported (Beutel et al, 2005).…”

“…This formulation increases plasma residence, tissue distribution and offers superior preclinical antitumour activity compared to parent drug or 5-FU (Desjardins et al, 2004). A phase I study with OSI-7904L utilising a day 1 every 21 days schedule determined 12 mg m À2 as the recommended phase II dose (Beutel et al, 2005). The toxicity profile was manageable and characteristic of other TS inhibitors (TSIs), including skin-related, gastrointestinal, fatigue and myelosuppression.…”

“…Pharmacokinetic data from this trial demonstrated that in comparison to the nonliposomal drug, the liposomal formulation OSI-7904L had altered disposition properties and exhibited a longer plasma circulation time. Plasma levels of 2 0 -deoxyuridine (2 0 -dU) were found to be elevated two-to four-fold for 4 -7 days, indicating that the target enzyme was inhibited following administration of OSI-7904L (Beutel et al, 2005).…”