pifusertib (TAS-117)

Oral doses of TAS-117 once daily up to 16 mg/day and intermittent dosing of 24 mg/day were well tolerated. TAS-117 pharmacokinetics were dose proportional at the doses evaluated. Antitumor activity may occur through AKT inhibition.

P1, N=17, Terminated, Taiho Oncology, Inc. | Phase classification: P2 --> P1 | N=96 --> 17 | Trial completion date: Dec 2024 --> Mar 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jun 2024 --> Feb 2023; The Sponsor had decided to terminate this clinical trial due to an insufficient rate of accrual of patients.

P2, N=96, Active, not recruiting, Taiho Oncology, Inc. | Recruiting --> Active, not recruiting

The mechanism of action, safety and dosing regimen for the novel allosteric AKT inhibitor TAS-117 have been explored in a phase I study in Japan in which activity was observed against certain tumor types. Here we describe the study protocol of an international, two-part Phase II study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations.

Taiho Oncology, Inc. reviewed the abstract for scientific accuracy but had no significant input into the content.

Moreover, UNC1999 and a selective Akt inhibitor TAS-117 synergistically inhibit the growth of MM cells through epigenetic mechanisms...Interestingly, a microtubule polymerization inhibitor PTC596 cooperatively downregulates BMI1 protein with proteasome inhibitors, exhibiting in-vitro and in-vivo cytotoxicity in MM cells. Finally, our mouse model with concurrent loss of the histone demethylase Utx and the activating mutation of Braf V600E in post germinal center B cells demonstrates mature B-cell malignancies including plasma cell neoplasms. Our ongoing analyses will reveal the pathogenesis of MM induced by somatic mutations, and this model is a useful tool for the development of novel molecular-targeted therapies for MM patients.

P2, N=100, Taiho Oncology, Inc.

TAS-117 showed limited antitumor activity and manageable toxicity. Clinical efficacy was observed in patients with ovarian cancer harboring PIK3CA E545K mutations and in patients with breast cancer harboring PIK3CA H1047R and Akt1 mutations.Trial registration: This study was retrospectively registered with ClinicalTrial.gov (NCT03017521 on January 11, 2017).

P2, N=96, Recruiting, Taiho Oncology, Inc. | Not yet recruiting --> Recruiting

P2, N=96, Not yet recruiting, Taiho Oncology, Inc.

Our findings suggest that futibatinib plus TAS-117 has synergistic antitumor effects in FGFR-aberrant tumors. A phase 1/2 study of this combination in advanced solid tumors (JapicCTI-194864) is ongoing.