A Phase I Study To Assess The Safety, Tolerability And Pharmacokinetics Of Arry-380-An Oral Inhibitor Of Her2

Background: ARRY-380 is a potent, orally active small molecule that selectively inhibits HER2 signaling in vitro and in vivo and significantly inhibits tumor growth in a variety of HER2-dependent tumor xenograft models. Based on its preclinical activity, tolerability and pharmacokinetic (PK) profile, a Phase 1 study was initiated to evaluate the safety, tolerability and PK profile of ARRY-380 as a single agent in patients with solid tumors and to establish the maximum tolerated dose (MTD).Methods: Patients with HER2 positive breast cancer or other tumor types for which published evidence of HER2 expression exists were treated with ARRY-380 as a single oral dose on Cycle 1 Day 1, followed by continuous twice-daily (BID) oral dosing starting on Cycle 1 Day 3. ARRY-380 was escalated in cohorts of 3 to 4 patients, using standard dose-limiting toxicity (DLT) criteria during Cycle 1 to determine dose escalation. Serial PK assessments were made during Cycle 1 on Days 1, 2, 3 and at steady-state on Day 15.Preliminary Results: As of June 1, 2009, 15 patients have been treated in 5 dosing cohorts at doses of 25 to 300 mg BID. Patients had a median age of 61 years (range, 37-77 years) and ECOG PS of 0 to 2. Cancer types included HER2+ breast cancer (8), colorectal (6) and salivary gland (1). No DLTs have been observed and drug-related adverse events have included Grade 1 nausea, rash and fatigue and Grade 2 fatigue in 2 patients at the 200 mg BID dose level. Preliminary PK analyses indicate a trend for increasing Cmax and AUC with increasing dose, a median Tmax of 2 hours and a mean t1/2 of 4.6 hours across all cohorts. Two patients with HER2+ breast cancer have had stable disease for ≥ 4 months with no significant toxicity. One of these two patients had a notable reduction in liver metastases (28%) after 2 cycles of ARRY-380 and is currently on study.Conclusions: ARRY-380 has demonstrated an acceptable safety and PK profile and preliminary signs of clinical benefit. Dose escalation continues to determine the MTD. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5111.