394P - Phase 1 study of ipatasertib (AKT inhibitor) for investigating safety, tolerability, pharmacokinetics (PK), efficacy, and biomarkers in Japanese pa...

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Anti-Cancer Agents & Biologic Therapy
Drug Development
Pharmacology
Prostate Cancer
Genitourinary Cancers
Presenter Shunji Takahashi
Citation Annals of Oncology (2017) 28 (suppl_5): v122-v141. 10.1093/annonc/mdx367
Authors S. Takahashi1, Y. Fujiwara2, N. Matsubara3, J. Tomomatsu4, S. Iwasa2, A. Yamasaki5, C. Endo6, S. Yokoyama5, T. Doi7
  • 1Department Of Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 135-8550 - Tokyo/JP
  • 2Department Of Experimental Therapeutics, National Cancer Center Hospital, Tokyo/JP
  • 3Division Of Breast And Medical Oncology, National Cancer Center Hospital East, 277-8577 - Kashiwa/JP
  • 4Department Of Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo/JP
  • 5Clinical Development Div., Chugai pharmaceutical co., LTD., 103-8324 - Tokyo/JP
  • 6Translational Clinical Research Div., Chugai pharmaceutical co., LTD., 103-8324 - Tokyo/JP
  • 7Department Of Experimental Therapeutics, National Cancer Center Hospital East, 277-8577 - Kashiwa/JP

Abstract

Background

Ipatasertib is a highly selective small-molecule inhibitor of AKT showing antitumor activity. Clinical efficacy and safety in non-Japanese pts with metastatic CRPC has been reported (ASCO, ESMO 2016). We investigated safety, tolerability, PK, efficacy, and biomarkers in Japanese pts.

Methods

Phase 1, open label, dose-escalation study; 3 + 3 design. Primary endpoints were safety, tolerability, and PK. In Stage 1, pts with solid tumors were administered 200, 400, or 600 mg ipatasertib PO daily for 21 days of a 28-day cycle. In Stage 2, pts with CRPC were administered ipatasertib (200 or 400 mg PO daily) in combination with abiraterone acetate (AA) (1000 mg PO daily) plus prednisolone (5 mg PO twice a day) for the whole 28-day cycle. In an exploratory analysis of biomarkers, we investigated the relationship between PI3K pathway alterations (PIK3CA mutation or amplification and PTEN loss) and clinical efficacy of ipatasertib.

Results

A total of 21 pts were enrolled. Stage 1: 3, 4, and 8 pts were enrolled in the 200, 400, and 600 mg cohorts. One pt in the 600 mg cohort experienced DLT [Gr3 nausea]. The most common AEs of any grade (≥30% of pts) were nausea, diarrhea, decreased appetite, vomiting, and fatigue. Cmax and AUC of ipatasertib were dose-proportional from 200 to 600 mg. Eight pts had stable disease (SD); 2 of those 8 pts continued study treatment beyond 4 months. Stage 2: 3 pts each were enrolled in the 200 and 400 mg cohorts. No DLTs were observed. The most common AEs of any grade were nausea, diarrhea, vomiting, diabetes mellitus, dysgeusia, and dizziness. Ipatasertib Cmax and AUC were similar to those in monotherapy. Of the 6 pts, complete response was observed in 1 pt and SD was observed in 1 pt. Three pts continued study treatment beyond 4 months; 2 of those 3 pts had previously received AA and enzalutamide. Biomarker results will be presented.

Conclusions

Ipatasertib was well tolerable for Japanese pts. Based on our results, the recommended doses of ipatasertib for further development are 600 mg for monotherapy and 400 mg for in combination with AA plus prednisolone.

Clinical trial identification

JapicCTI-152910, 22-May-2015

Legal entity responsible for the study

Chugai Pharmaceutical co., LTD.

Funding

Chugai Pharmaceutical co., LTD.

Disclosure

S. Takahashi: Corporate-sponsored Research: AstraZeneca, MSD, Taiho, Chugai, Novartis, Daiichi-Sankyo, Bayer, Parexel, Ono. Y. Fujiwara: Advisory Board: Bristol-Myers Squibb, Ono. Corporate-sponsored Research: AstraZeneca, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, GlaxoSmithKline (GSK), MerckSerono, MSD. N. Matsubara: Advisory Board: Janssen Pharma, Sanofi. Corporate-sponsored Research: Janssen Pharma, Bayer, MSD, Chugai, Taiho, Sanofi. J. Tomomatsu: Industrial Physician: Eisai. S. Iwasa: Corporate-sponsored Research: Eli Lilly, Daiichi-Sankyo, Novartis, Bristol-Myers Squibb, Chugai, Eisai. A. Yamasaki: Employee of Chugai. C. Endo, S. Yokoyama: Employee and Stock ownership: Chugai. T. Doi: Advisory Board: Eli Lilly, MSD, Amgen, Daiichi-Sankyo. Corporate-sponsored Research: Eli Lilly, Taiho, Novartis, Merck Serono, MSD, Boehringer Ingelheim, Pfizer, Sumitomo Dainippon, Chugai, Kyowa Hakko Kirin, Daiichi-Sankyo, Celgene, Quintiles, Janssen, Astellas.