Abstract C195: Phase I study of 2 dosing regimens of AS703569, an oral Aurora kinase inhibitor, in patients with solid tumors
Authors: Mita Monica , Gordon Michael , Gianella-Borradori Athos , Longerey Blandine , Rejeb Narmyn , Mendelson David 
Published: June 2012

Abstract
Background and rationale: AS703569 is a novel, orally administered, potent ATP-competitive, small molecule inhibiting aurora kinase A, B, and C as well as other kinases involved in cell proliferation and survival, including FLT3, ABL1, ABL1 (mut. T315I), JAK-2, and FGFR3. In cell lines and tumor xenograft models AS703569 as single agent and in combination with standard-of-care anticancer agents has demonstrated strong inhibition of proliferation and induction of apoptosis leading to tumor regression and prolongation of animal survival.
Methods: This is an open label, phase I, dose-escalation study with the objective to determine the MTD of 2 regimens (R) of AS703569 in patients (pts) with advanced solid tumors. In R1 AS703569 is given once daily (QD) day 1 and 8 and in R2 QD day 1, 2, 3 every 21 days (q21d). The dose escalation followed a 3+3 design, separate for each R; pts were assigned to either one of the 2 R sequentially. Dose escalation was stopped when at least 2/3 or 6 pts experienced DLT in the first cycle and the MTD was defined as the dose level below.
Results: In each regimen 8 dose levels (DL) were explored: 6, 12, 19.8, 30, 42, 55.8, 74 and 100 (R1) / 99 (R2) mg/m2 (total dose per 21d cycle). In R1 42 pts were treated: 18 M/ 24 F, median age 60 (23–82); most frequent tumor types: 9 pts breast cancer (BC), 9 colorectal cancer (CRC), 4 lung and 4 prostate cancer (PC). Number of cycles per pt ranged between 1–16 (median 2), 90% of pts completed 2 cycles and 21% completed at least 4 cycles. DLTs in 2/6 patients occurred at 50mg/m2/d (total dose per cycle 100 mg/m2), the MTD was established at 37mg/m2/d.
In R2 39 pts were treated: 17 M/22 F, median age 62 (25–79); most frequent tumor types:10 pts had CRC, 7 PC, 3 cervix cancer. Number of cycles per pt ranged between 1–22 (median 2), 79% of pts completed 2 cycles and 23% completed at least 4 cycles. DLTs in 3/6 patients occurred at 33mg/m2/d (total dose per cycle 99mg/m2), the MTD was established at 25mg/m2/d. For both R DLTs consisted of hematological toxicity (grade 4 neutropenia and thrombocytopenia). Non-hematological adverse events (AEs) grade 3 reported in more than 10% of pts overall, in either R, were GI disorders (e.g. diarrhea, nausea, vomiting, intestinal obstruction).
Non compartmental PK data of 81 pts (DL 1–8, both R) showed Cmax between 2–4 h (range 0.5–8 h). Cmax and AUC0-24h increased with dose. Stable disease (SD) for more than 4 cycles occurred in 7 pts at the 3 highest DL. In R1 2 pts with BC (6–8 cycles), in R2 2 CRC / rectal cancer (5–6 cycles), 1 PC (8 cycles), 1 cervical cancer (5 cycles) and 1 neuroendocrine tumor (22 cycles).
Conclusion: The objective of the study was achieved, the MTD for AS703569 day 1 and 8 q21d single agent in patients with solid tumors is 37mg/m2 and for day 1,2,3 q21d it is 25mg/m2 (same total dose per cycle). DLT is myelosuppression. Several pts experienced durable SD with tumor regression.
Current investigations include testing a dose-intensified regimen to further evaluate exposure, safety and anti tumor activity.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C195.