Demonstration of gender-specific variability in a pharmacokinetic (PK) analysis of the PERSIST-5 trial of adjuvant imatinib (IM) for patients with primary gastrointestinal stromal tumor (GIST) at significant risk of recurrence.

Abstract

10538 Background: ThePERSIST-5 phase II trial is evaluating 5 years of adjuvant IM therapy in patients with resected GIST at significant risk of recurrence. This analysis studied the effect of chronic therapy on steady-state trough levels in patients who received IM for up to 24 months to evaluate potential PK variations. Methods: Eligible patients were adults with KIT+ primary GIST who were considered to be at significant risk for recurrence (primary tumor any site ≥2 cm andmitotic rate ≥5/50 high-power fields, or non-gastric primary GIST ≥5 cm) without metastases. R0 resection of primary GIST was performed ≤12 weeks prior to the first IM dose. Patients are to receive oral IM 400 mg/day for up to 5 years or until progression, relapse, or intolerance. Plasma samples for PK analysis were collected at 1, 4, 12, and 24 months. IM plasma concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. Results: In-study assay performance (%CV) was ≤9.6% and bias was -1.3% to 5.2%. IM concentrations ranged from below quantifiable limits to 4798 ng/mL. After daily IM doses for up to 12 months (or 24 months in 3 patients), IM trough levels remained constant over time. The range of IM trough levels (mean ± SD) was 957 ± 750 ng/mL to 1219 ± 822 ng/mL at month 1, and 727 ± 430 ng/mL to 996 ± 405 ng/mL at month 12. Inter-patient variability was 40.7-78.4%. There was no significant difference in IM trough levels between months 1 and 4, 1 and 12, or 4 and 12. Trough levels did not significantly differ by location of GIST. Most notably, mean IM trough concentrations were on average ~33% higher in females vs males. Conclusions: In this study,IM trough levels remained relatively unaltered in patients with high-risk GIST who received adjuvant IM for 1 year. The 33% higher mean trough levels in females warrants further study for clinical decision making. Clinical trial information: NCT00867113. [Table: see text]