First-In-Human Phase 1 Study Of Tak-931, An Oral Cell Division Cycle 7 (Cdc7) Inhibitor, In Patients (Pts) With Advanced Solid Tumors.

2506 Background: TAK-931 is an oral selective inhibitor of CDC7, a protein kinase with key roles in DNA replication and DNA damage response. TAK-931 has demonstrated potent antitumor activity in various preclinical models. Methods: We evaluated safety, dose limiting toxicity (DLT), maximum tolerated dose (MTD), and preliminary antitumor activity of TAK-931 in pts with advanced solid tumors. Four schedules are being tested, and we report data from Schedule A: TAK-931 QD for 14 days on/7 days off in 21-day cycles. A Bayesian logistic regression model with overdose control was used to guide dose escalation and MTD estimation. Results: As of 14-Nov-2017, 25 Japanese pts (60% male; median age 59 [range 42–75] years) were treated with TAK-931 30 mg (n = 3), 40 mg (n = 3), 60 mg (n = 3), and 50 mg (n = 16: 7 pts in dose escalation, 9 pts in expansion). Pts received a median of 3 cycles (range 1–12). Most common any-grade adverse events (AEs) were nausea (n = 15), neutropenia (n = 12), decreased white blood cells (WBCs) (n = 8), decreased appetite, vomiting, and diarrhea (each n = 7). Most common grade ≥3 AEs were neutropenia (n = 11), decreased WBCs (n = 3), leukopenia, and decreased appetite (each n = 2). DLTs (grade 4 neutropenia) were observed in 2 of 3 pts at 60 mg; 50 mg was considered the MTD. Preliminary pharmacokinetics (PK) showed increased systemic exposure of TAK-931 in a dose proportional manner between 30 and 60 mg, with minimal accumulation and mean terminal elimination half-life of 5.4 hours (15% CV). Dose-dependent inhibition of pMCM2, a direct substrate of CDC7, was observed in skin biopsies from most pts treated with TAK-931, which correlated well with drug exposure (R2= 0.6598). Partial responses were observed in pts with duodenal, esophageal, and cervical cancers (1 pt each) as well as prolonged stable disease of ~6 months in a bladder cancer pt and ~9 months in a pancreatic cancer pt. Conclusions: TAK-931 demonstrated an acceptable safety profile with early signs of clinical antitumor activity. Isolated neutropenia was the DLT with the tested schedule. Strong pharmacodynamic (PD) effects and PK-PD correlation provide clinical evidence of target engagement of TAK-931 in pts. Clinical trial information: NCT02699749.