Abstract 4433: A Phase I study of two dosing regimens of oral AS703569, an inhibitor of aurora kinase and other kinases, in patients with hematologic malignancies

Background: AS703569 is a novel, orally available, ATP-competitive, small-molecule inhibitor of aurora kinases A, B, and C and several other kinases relevant in hematologic malignancies (HM), including FLT3, ABL1, ABL1 (mutation T315I), JAK-2, and FGFR3. AS703569 has shown potent antitumor activity in preclinical in vitro and in vivo studies as monotherapy and in combination. Objectives: To determine the maximum tolerated dose (MTD) and evaluate safety, pharmacokinetics, and antitumor activity of 2 regimens (Rs) in patients (pts) with advanced HM. Methods: Phase I, 2-arm, dose-escalation study. Pts were sequentially assigned to either AS703569 on days (d) 1-3 and 8-10 (R1) or d 1-6 (R2) of a 21-d cycle. Starting dose: 3mg/m2/d (18mg/m2/cycle); dose escalation followed a 3+3 design with 12 pts at the MTD, defined as dose level (DL) below that at which >1/3 or >1/6 pts had a dose-limiting toxicity (DLT) in cycle 1. Results: DLs assessed in both Rs: 3, 6, 10, 15, 21, 28, 37, and 47mg/m2/d. R1 (36 pts): median age 67 (35-83) years (y); 22 (61%) men; diagnosis: acute myeloid leukemia (AML n=24; 67%); myeloproliferative disorder (MPD n=4), myelodysplastic syndrome (MDS n=3), chronic myeloid leukemia (CML n=3), Ph+ acute lymphocytic leukemia (ALL n=1), and non-Hodgkin's lymphoma (n=1); 0-9 cycles were completed. MTD was 37mg/m2/d; DLTs occurred in 2/3 pts at 47mg/m2/d (diarrhea, hyponatremia, sepsis). R2 (39 pts): median age 70 (22-82) y; 25 (64%) men; diagnosis: AML (n=30; 77%), MPD (n=3), MDS (n=2), CML (n=2), and ALL (n=2); 0-6 cycles were completed. MTD was 28mg/m2/d; DLTs occurred in 3/6 pts at 37mg/m2/d (mucositis, neutropenic infection, diarrhea). AS703569-related adverse events ≥Grade 3 occurred in 26 pts (72%) in R1 and 24 pts (62%) in R2; mainly diarrhea (R1 [n=5] 37 and 47 mg/m2/d; R2 [n=4] 28-47 mg/m2/d), stomatitis/mucositis (R1 [n=1] 37 mg/m2/d; R2 [n=8] 28-47 mg/m2/d), and sepsis (R1 [n=3] 21 and 37 mg/m2/d; R2 [n=1] 28 mg/m2/d). Peak drug plasma concentrations (n=74) were mostly reached between 1-4 (range 0.5-8) hours across all DLs in both Rs; Cmax and AUC0-24 increased with dose (3-47mg/m2/d). Best response was complete remission (CR) in 2/54 pts with AML (R2: 37 and 47mg/m2/d), and in 1 pt with Ph+ ALL (R1: 37mg/m2/d). Evidence of activity also included blasts reduction to