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
Authors: Hotte Sebastien J. , Hirte Hal W. , Turner Sandra , Jonker Derek , Fortin Catherine , Barrett Emma , Freeman Burgess , Kass Carrie , Zacharias Katherine , Chow Laura QM 
Published: June 2012

Abstract
Background: 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.