Abstract B54: A phase 1 study to assess the safety, tolerability and pharmacokinetics of the ErbB-family inhibitor ARRY-334543 in patients with advanced solid tumors
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AbstractBackground: ARRY-334543 is an oral, potent, ATP-competitive, selective, reversible ErbB family inhibitor. ARRY-334543 has evolved from a ditosylate salt in capsule to a smaller freebase tablet which eases swallowing. This study (ARRAY-543-103) was initiated to assess the safety and maximum tolerated dose (MTD) of the ARRY-334543 tablet. Effect of food on plasma pharmacokinetics (PK) of ARRY-334543 and intrapatient exposure with the capsule and tablet also were assessed.Methods: Sequential cohorts of patients with advanced solid tumors were enrolled. Doses were escalated with a 3+3 design. For Cycle 1 only: to evaluate potential food effects, patients received single doses of the tablet on Day 1 (fasting) and Day 8 (with high-fat meal); to explore intrapatient exposure between capsule and tablet formulations, 6 additional patients were enrolled at the 300 mg dose only and received a single dose of the capsule on Day 1 and a single dose of the tablet on Day 8 after high-fat meals. In both scenarios, PK was assessed on Days 1 and 8 and starting on Day 10, all patients began twice-daily (BID) dosing regardless of food. All subsequent cycles were BID dosing for 28 days regardless of food. Additional PK assessments were performed on Day 24 at steady state.Preliminary Results: To date, 29 patients (16 females/13 males) have been treated at 4 dose levels ranging from 300 to 600 mg BID. Dose-limiting toxicities (DLTs) occurred in 3 of 10 patients in the 300 mg cohort (1 patient had a Grade 4 AST/Grade 3 ALT increase, 2 patients had Grade 3 fatigue). No DLTs were observed in the 400 mg cohort. Two of 4 patients in the 600 mg cohort had DLTs (1 patient: Grade 3 thrombosis and a Grade 3 AST/ALT increase; 1 patient: Grade 3 anorexia) so a 500 mg cohort was opened. One DLT has been observed at 500 mg BID (1 patient had Grade 3 weakness and Grade 4 ALT/Grade 3 AST) and expansion at this dose level is ongoing. Frequent drug-related adverse events (AEs) were fatigue (65%), diarrhea (35%), rash (35%) and anorexia (31%) with most AEs being Grade 1 or 2. Three patients at doses = 300 mg BID have had stable disease for ≥ 6 cycles. One patient with cervical cancer and 1 patient with squamous cell carcinoma of the skin remain on study after 11+ and 6.8 months, respectively.Mean Cmax and AUC estimates were 1.5 and 2-fold higher, respectively, when tablets were administered with a high-fat meal. In the fed state, mean Cmax and AUC values associated with capsules were 2.6-fold higher than tablets. Steady state mean AUC values for tablets at 300 mg BID were similar to capsules at 400 mg BID in a previous Phase 1 study.Conclusions: ARRY-334543 tablets demonstrated acceptable safety; determination of the MTD is ongoing. Preliminary PK data for tablets indicate a modest food effect and a steady state exposure similar to that obtained with capsules. Based on these results, future studies of ARRY-334543 will be conducted with tablets.Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B54.
