O3-5-3 - Phase I study of roniciclib (BAY1000394), an oral CDK inhibitor in Japanese patients with advanced solid tumors

Abstract

Background: Roniciclib (BAY1000394) is a novel, potent and orally available small molecule inhibitor targeting cyclin-dependent kinases, critical cell cycle and transcription regulatory proteins implicated in tumorigenesis and tumor maintenance. Treatment of patients (pts) with advanced solid tumors at 5 mg bid in 3 days-on/4 days-off schedule is feasible and showed signs of efficacy (Bahleda et al., AACR 2014). We report the safety, tolerability, PK and antitumor activity of roniciclib in Japanese pts with advanced solid tumors.Methods: Roniciclib was administered orally at 2.5/5 mg bid in 3d on/4d off schedule in 3-week cycles. DLT was evaluated in Cycle 1 and 3 + 3 design was employed for dose escalation. PK was evaluated on Days 1 and 10 of Cycle 1. Tumor assessment based on RECIST 1.1 was conducted every 2 cycles.Results: A total of 12 pts (7 male) were treated (2.5/5 mg:6/6 pts); Median age:65 yrs, primary tumor: NSCLC (7 pts). Mean duration of treatment was 57 days (2.5/5 mg:59/56 days). No G4/5 drug-related TEAE was reported. G3 drug-related TEAEs were reported in 3 pts (2.5/5 mg:1/2 pts). Drug-related SAEs were reported in one patient (2.5 mg); G3 ALT, AST and total bilirubin increased and G2 biliary tract infection. Two DLTs were reported:G3 AST, ALT and bilirubin increased in one patient (2.5 mg) and G3 nausea (5 mg). Commonly observed drug-related TEAEs were anorexia, nausea and vomiting. Maximum plasma roniciclib concentration (mean:2.5/5 mg: 42/76 µg/L) was observed 0.5-2 hrs after administration, and decreased with mean half-life of 10 hrs. Dose-proportional increase in the exposure was observed. One partial response in an adrenocortical carcinoma patient at 2.5 mg (at Cycle 20) and 4 stable diseases with disease control rate of 41.7% (2.5/5mg:33/50%) were observed.Conclusions: Roniciclib, at 2.5 and 5 mg bid in 3d on/4d off schedule, was tolerable and demonstrated potential antitumor activity in Japanese patients with advanced solid tumors. Background: Roniciclib (BAY1000394) is a novel, potent and orally available small molecule inhibitor targeting cyclin-dependent kinases, critical cell cycle and transcription regulatory proteins implicated in tumorigenesis and tumor maintenance. Treatment of patients (pts) with advanced solid tumors at 5 mg bid in 3 days-on/4 days-off schedule is feasible and showed signs of efficacy (Bahleda et al., AACR 2014). We report the safety, tolerability, PK and antitumor activity of roniciclib in Japanese pts with advanced solid tumors. Methods: Roniciclib was administered orally at 2.5/5 mg bid in 3d on/4d off schedule in 3-week cycles. DLT was evaluated in Cycle 1 and 3 + 3 design was employed for dose escalation. PK was evaluated on Days 1 and 10 of Cycle 1. Tumor assessment based on RECIST 1.1 was conducted every 2 cycles. Results: A total of 12 pts (7 male) were treated (2.5/5 mg:6/6 pts); Median age:65 yrs, primary tumor: NSCLC (7 pts). Mean duration of treatment was 57 days (2.5/5 mg:59/56 days). No G4/5 drug-related TEAE was reported. G3 drug-related TEAEs were reported in 3 pts (2.5/5 mg:1/2 pts). Drug-related SAEs were reported in one patient (2.5 mg); G3 ALT, AST and total bilirubin increased and G2 biliary tract infection. Two DLTs were reported:G3 AST, ALT and bilirubin increased in one patient (2.5 mg) and G3 nausea (5 mg). Commonly observed drug-related TEAEs were anorexia, nausea and vomiting. Maximum plasma roniciclib concentration (mean:2.5/5 mg: 42/76 µg/L) was observed 0.5-2 hrs after administration, and decreased with mean half-life of 10 hrs. Dose-proportional increase in the exposure was observed. One partial response in an adrenocortical carcinoma patient at 2.5 mg (at Cycle 20) and 4 stable diseases with disease control rate of 41.7% (2.5/5mg:33/50%) were observed. Conclusions: Roniciclib, at 2.5 and 5 mg bid in 3d on/4d off schedule, was tolerable and demonstrated potential antitumor activity in Japanese patients with advanced solid tumors.