Abstract 2754: Phase I and pharmacokinetic (PK) study of two regimens combining the aurora kinase inhibitor AS703569 and gemcitabine in patients with advanced solid tumors

Background: AS703569 is an orally available, ATP-competitive, small-molecule inhibitor of aurora kinases A, B, and C and other cancer-relevant kinases. AS703569 has shown in vitro and in vivo antitumor activity as a single agent and in combinations, including with gemcitabine (Gem). Phase I monotherapy studies in patients (pts) with solid tumors and hematologic malignancies are ongoing. Objective: To define the maximum tolerated dose (MTD) of 2 regimens (Rs) of sequential-combination AS703569 and Gem (fixed dose 1000 mg/m2/day [d]). Methods: This multicenter, dose-escalation study with a 3+3 design was performed in pts with advanced solid tumors. R1: AS703569 d2 and 9, Gem d1 and 8; R2: AS703569 d1 and 8, Gem d2 and 9 of 21-d cycles. MTD definition: dose level (DL) below that at which >1/3 or >1/6 pts experienced a dose-limiting toxicity (DLT) in cycle 1. Secondary objectives included PK evaluations and antitumor activity. AS703569 starting dose (DL1) was 10 mg/m2/d; other DLs assessed were 15, 21, 28, and 37 mg/m2/d (ongoing). Results: To date, 45 pts have been treated. R1 (19 pts): median (range) age 62 (31-75) years (y); 13 (68%) men; most common tumors: pancreatic (n=5), and lung, colorectal, and stomach (n=2 each); 1-16 cycles completed per pt. R2 (26 pts): median age 58 (20-80) y; 19 (73%) men; most common tumors: colorectal (n=5), liver (n=3), and lung, bladder, and pancreas (n=2 each); 1-10 cycles completed per pt. DLTs reported over the DLs studied to date: in R1, CTCAE Grade (Gr) 4 neutropenia ≥7 d and Gr 4 thrombocytopenia (37 mg/m2/d); in R2, Gr 4 neutropenia and septic shock (10 mg/m2/d), general status deterioration and asthenia (15 mg/m2/d), and Gr 4 neutropenia ≥7 d (28 and 37 mg/m2/d). Related treatment-emergent adverse events (TEAEs) ≥Gr 3 occurred in 13 pts (68%) in R1 and 19 pts (73%) in R2, most commonly neutropenia (R1 n=8; R2 n=13), lymphopenia (R1 n=11; R2 n=9), anemia (R1 n=4; R2 n=5), and thrombocytopenia (R1 n=2; R2 n=3). Other TEAEs ≥Gr 3 included nausea (R1 n=1), asthenia (R1 n=4; R2 n=2), and fatigue (R1 and R2 n=1). Two TEAEs led to deaths in R2 (10 mg/m2/d): 1 pt with Gr 4 neutropenia and septic shock; 1 pt with digestive hemorrhage. Preliminary PK data (n=34): peak AS703569 plasma concentrations (DL 10-37 mg/m2/d) were mostly reached between 2-4 (range 1-8) h. Cmax and AUClast increased with dose. PK data are comparable to those from monotherapy Phase I studies. Stable disease (SD; >4 cycles) was seen in 11/33 pts; 1 pt with non-small-cell lung cancer had a partial response lasting 6 months. Conclusion: AS703569 can be safely combined with standard-dose Gem. Most toxicities were hematologic and reversible. The MTD is being defined for both Rs and AS703569 exposure seems unaltered by Gem coadministration. Some pretreated pts experienced tumor responses and long-lasting SD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2754.