1775 - First-in-human phase I study of TAS-117, an allosteric AKT inhibitor, in patients with advanced solid tumors

Background

TAS-117 is a novel highly potent and selective oral allosteric AKT inhibitor. This study investigated the safety, efficacy, pharmacokinetics, pharmacodynamics, and pharmacogenomics profiles of TAS-117 in patients (pts) with advanced solid tumors, for whom no standard treatment remains.

Methods

The primary objective was to evaluate the safety profile of TAS-117, including the identification of the maximum tolerated dose (MTD) and the recommended dose (RD) with regimen (RR) in a 21-day cycle. Dose escalation was assessed in a once-daily repeated dosing regimen (QD), starting at 4 mg/day, with an accelerated titration design. Dose-limiting toxicity (DLT) was evaluated in a first cycle. After RD and RR were determined, pts with endometrial cancer (EC) harboring PIK3CA or AKT gene alterations or ovarian clear cell carcinoma (OCC) were enrolled for further safety evaluation.

Results

TAS-117 was administered QD (n = 12) and in a 4 days on/3 days off regimen (4d/3d) (n = 10). The dose was escalated to 24 mg/day in QD dosing and 32 mg/day in 4d/3d; the MTD was not reached. The DLT was a grade 3 rash maculo-papular at 32 mg/day in 4d/3d dosing. The RD and RR were determined as TAS-117 24 mg/day and 4d/3d. As of 24 Apr 2019, 42 pts (15 with PIK3CA-mutated (mt) EC, 7 with AKT-altered EC, and 20 with OCC) were enrolled, and safety profiles were investigated. The common (≥30%) treatment-related adverse events (TRAEs) were rash maculo-papular (grade 3, observed in 42.5% of pts), stomatitis, hyperglycemia, white blood cell decrease, and neutrophil count decreased. Common TRAEs, especially rash maculo-papular, were manageable with dose reduction, dose interruption, or symptomatic therapy. TAS-117 exposure tended to increase in a dose-dependent matter. In efficacy-evaluable pts, objective responses were observed in 1 pt with PIK3CA-mt EC and 5 pts with OCC. The disease control rate was 61.5% in 13 pts with PIK3CA-mt EC, 80.0% in 5 pts with AKT-altered EC, and 37.5% in 16 pts with OCC.

Conclusions

TAS-117 had a manageable safety profile with clinical antitumor activity in pts with advanced solid tumors. Further investigation of the drug in a combination therapy is in preparation.

Clinical trial identification

JapicCTI-152780.

Editorial acknowledgement

Legal entity responsible for the study

Taiho Pharmaceutical Co., Ltd.

Funding

Has not received any funding.

Disclosure

S. Takahashi: Honoraria (self), Research grant / Funding (self): Eisai; Honoraria (self): Bristol-Myers-Squibb; Honoraria (self), Research grant / Funding (self): Taiho; Honoraria (self): Bayer; Research grant / Funding (self): MSD; Research grant / Funding (self): Astrazeneka; Research grant / Funding (self): Quintiles; Research grant / Funding (self): IQVIA; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Ono pharmaceutical. D. Aoki: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical Co., Ltd.; Honoraria (self), Advisory / Consultancy: AstraZeneca K.K.; Honoraria (self), Research grant / Funding (institution): Chugai Pharmaceutical Co., Ltd.; Honoraria (self), Advisory / Consultancy: MSD K.K.. K. Yonemori: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eisai; Honoraria (self), Research grant / Funding (institution): Taiho; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Ono; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Chugai; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): ICON Japan; Research grant / Funding (institution): Kissei; Research grant / Funding (institution): Kyowa Hakko Kirin; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Nippon Kayaku; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): 3D MATRIX. H. Hara: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharma; Honoraria (self), Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Honoraria (self): Yakult Honsha; Honoraria (self), Research grant / Funding (institution): Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Research grant / Funding (institution): Takeda; Honoraria (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): MSD; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Dainippon Sumitomo Pharma; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): LSK BioPharma; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Incyte. K. Hasegawa: Honoraria (self), Research grant / Funding (self): Daiichi-Sankyo; Honoraria (self): Chugai; Honoraria (self): Nippon Kayaku; Honoraria (self): Bayer; Honoraria (self): AstraZeneca; Advisory / Consultancy: MSD; Research grant / Funding (self): OncoTherapy Science; Research grant / Funding (self): Yakult Honsha. K. Takehara: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Kyowa Kirin; Speaker Bureau / Expert testimony: Taiho; Speaker Bureau / Expert testimony: Nippon Kayaku; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Treumo; Speaker Bureau / Expert testimony: Ono; Speaker Bureau / Expert testimony: Daiichi Sankyo; Speaker Bureau / Expert testimony: Chugai Pharma; Speaker Bureau / Expert testimony: Eisai. K. Harano: Honoraria (self): Eisai; Honoraria (self), Advisory / Consultancy: Taiho; Honoraria (self): AstraZeneca; Honoraria (self), Non-remunerated activity/ies: Chugai; Advisory / Consultancy: Takeda. E. Noguchi: Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Nippon Kayaku; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Chugai; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): ICON Japan; Research grant / Funding (institution): Kissei; Research grant / Funding (institution): Kyowa Hakko Kirin; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Ono; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): 3D MATRIX. T. Doi: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai; Advisory / Consultancy, Research grant / Funding (institution): Merck Serono; Advisory / Consultancy: Otsuka; Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Kyowa Hakko Kirin; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): Bayer; Advisory / Consultancy: AstraZeneka; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy, Research grant / Funding (institution): Daiichisankyo; Advisory / Consultancy, Research grant / Funding (institution): Dainippon Sumitomo; Advisory / Consultancy, Research grant / Funding (institution): Takeda; Advisory / Consultancy, Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): Taiho, Zenyaku Kogyo, Astellas; Research grant / Funding (institution): Janssen, Eisai, Sanofi; Research grant / Funding (institution): NanoCarrier, Quintiles, Pfizer; Research grant / Funding (institution): Bristol-myers; Research grant / Funding (institution): Bristol-Myers-Squibb. All other authors have declared no conflicts of interest.