Phase I study of the Aurora A kinase (AurA) inhibitor TAS-119 with paclitaxel (P) in advanced solid tumors.

Abstract

3031 Background: AurA is a key regulator of cell division, including mitotic spindle assembly. However, elevated levels of AurA have been reported to abrogate the mitotic spindle checkpoint activated by taxanes leading to treatment resistance. Preclinical studies of TAS-119 + P showed enhanced antitumor activity and suggested an optimal timing window of the combination. Study objective was to assess the safety of TAS-119 + P in adult patients (pts) with advanced solid tumors. Methods: Dose escalation used a 3+3 design to determine the maximum tolerated dose (MTD); 7 dose levels (DLs) were explored, starting with 25 mg TAS-119 BID dosed 4 days/week (d/wk) and weekly 90 mg/m2 P for 3 weeks of a 4 week cycle (DL1). Plasma samples were collected during cycle 1 to evaluate pharmacokinetics. In expansion, pts with advanced breast/ovarian cancers were treated at the MTD. Results: Dose escalation enrolled 26 pts with various cancers, the majority being pancreas, colon, and ovarian; 2 pts were not evaluable for DLT assessment and replaced. A DLT (neutropenia and elevated AST) was observed in 2/3 pts in DL1. Dosing was modified to 25 mg TAS-119 BID 2 d/wk and P 70 mg/m2 (DL2) and no DLTs were observed. Zero DLTs were observed in the next 4 doses: 70 mg/m2 P + TAS-119 2 d/wk at 50 mg BID (DL3) or 75 mg BID (DL4), or 80 mg/m2 P + TAS-119 at 75 mg BID 2 d/wk (DL5) or 75 mg BID 3 d/wk (DL6). TAS-119 was escalated to 100 mg BID 3 d/wk (DL7) and 3 DLTs (n=1, elevated ALT; n=1, diarrhea and mucositis) occurred in 2/3 pts. Three additional pts were then enrolled at DL6 to confirm the MTD. One breast and 2 ovarian pts were enrolled in expansion before the trial was suspended by the company. Toxicities observed in ≥30% of pts were diarrhea, nausea, and fatigue (most ≤Gr2). Plasma TAS-119 exposure increased dose-proportionally in 2 d/wk and 3 d/wk schedules; no impact of TAS-119 on PK of paclitaxel was found. The disease control rate was 59% (17/29); 4 of these pts had a partial response. Conclusions: The combination had a manageable toxicity profile at the MTD of 80 mg/m2 P + TAS-119 at 75 mg BID 3 d/wk. Preliminary clinical activity was seen in 59% of pts, including tumor responses in a majority (4/7) of pts with ovarian/fallopian tube cancers. Clinical trial information: NCT02134067.