Abstract 559TiP
Background
Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene and PTEN inactivating mutations lead to activation of the AKT pathway. Germline PTEN dysfunction can cause a spectrum of phenotypes including benign overgrowths, metabolic and neurodevelopmental disorders (such as Cowden syndrome), and is associated with an elevated lifetime risk of cancers such as breast, thyroid, and endometrial cancers. The prognosis of these cancers is poor and unmet medical need is high. TAS-117 is a highly potent and selective oral allosteric AKT1-3 inhibitor that effectively blocks AKT signaling and inhibits phosphorylation of downstream substrates. TAS-117 is currently being studied in multiple clinical trials in Japan and its safety profile is generally acceptable and manageable. Clinical activity has been observed in patients (pts) with endometrial carcinoma and ovarian clear cell carcinoma. This phase 2 study (NCT04770246) is designed as a tumor-agnostic trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of TAS-117 in pts with advanced solid tumors harboring germline PTEN inactivating mutations.
Trial design
The study is conducted in two parts. Part A: safety lead-in and Part B: single-arm phase 2. Dose escalation in the safety lead-in will enrol ∼36 adult pts (age ≥18 years) with advanced solid tumors, irrespective of gene alterations (all-comers) to identify an optimal dose and regimen for Part B. Phase 2 will enrol 60 adolescent or adult pts (age ≥12 years) with advanced solid tumors harboring germline PTEN inactivating mutations. Key exclusion criteria are pts with primary brain tumor, diabetes mellitus requiring insulin, and prior therapy with PI3K/AKT/mTOR pathway inhibitors. The primary endpoint for phase 2 is objective response rate assessed by independent central review. Secondary endpoints are disease control rate, duration of response, progression-free survival, overall survival, and safety. The study was initiated in April 2021.
Clinical trial identification
NCT04770246.
Editorial acknowledgement
The authors thank Dr Mark Loughlin (NexGen Healthcare Communications) for writing and editorial assistance, funded by Taiho Oncology, Inc. Taiho Oncology, Inc. reviewed the abstract for scientific accuracy but had no significant input into the content.
Legal entity responsible for the study
Taiho Oncology, Inc.
Funding
Taiho Oncology, Inc.
Disclosure
J. Rodon: Non-Financial Interests, Personal, Advisory Board: Novartis, Eli Lilly, Orion Pharmaceuticals; Non-Financial Interests, Personal, Advisory Board: Servier Pharmaceuticals, Peptomyc; Non-Financial Interests, Personal, Advisory Board: Merkck Sharp & Dohme; Non-Financial Interests, Personal, Advisory Board: Kelun Pharmaceuticals/Klus Pharma; Non-Financial Interests, Personal, Advisory Board: Spectrum Pharmaceuticals, Inc., Pfizer; Non-Financial Interests, Personal, Advisory Board: Roche Pharmaceuticals; Non-Financial Interests, Personal, Advisory Board: Ellipses Pharma, Certera; Non-Financial Interests, Personal, Advisory Board: Bayer, Molecular Partners, NovellusDX, IONCTURA SA; Non-Financial Interests, Institutional, Research Grant, Research Funding; Clincal Research: Bayer, Novartis, Blueprint Medicines; Non-Financial Interests, Personal, Other, Travel Reimbursement: ESMO, Department of Defense, Merck Sharp & Dohme, Louisiana State University, Kelun Pharmaceuticals/Klus Pharma, Huntsman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute, King Abdullah International Medical Research Center, Bayer, WIN Co; Non-Financial Interests, Personal, Other: European Journal of Cancer, VHIO/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline. P. Funchain: Financial Interests, Institutional, Research Grant: Pfizer; Financial Interests, Institutional, Principal Investigator: BMS. T.W. Laetsch: Financial Interests, Personal and Institutional, Advisory Board, Research funding: Bayer; Financial Interests, Personal, Advisory Board: Cellectis; Financial Interests, Personal and Institutional, Advisory Board, Research funding: Novartis; Financial Interests, Personal, Advisory Board: Deciphera; Financial Interests, Personal, Advisory Board: Y-mAbs Therapeutics; Financial Interests, Personal, Advisory Board: Jumo Health; Financial Interests, Institutional, Research Grant: Pfizer. H. Arkenau: Financial Interests, Personal, Full or part-time Employment: HCA Healthcare UK/ Sarah Cannon; Financial Interests, Personal and Institutional, Advisory Role: Bicycle; Financial Interests, Personal and Institutional, Advisory Role: Biontech; Financial Interests, Personal and Institutional, Advisory Role: Bayer; Financial Interests, Personal and Institutional, Advisory Role: Servier; Financial Interests, Personal and Institutional, Advisory Role: Guardant; Financial Interests, Personal and Institutional, Advisory Role: Roche; Financial Interests, Personal and Institutional, Advisory Role: Engitix; Financial Interests, Personal and Institutional, Advisory Role: iOnctura; Financial Interests, Personal and Institutional, Advisory Role: Beigene. S.P. Chawla: Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Amgen; Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Roche; Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: GlaxoSmithKline; Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Threshold Pharmaceuticals; Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: CytRx Corporation; Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Ignyta,; Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: TRACON Pharma; Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Karyopharm Therapeutics; Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: SARC: Sarcoma Alliance for Research though Collaboration; Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Janssen; Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Advenchen Laboratories; Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Bayer; Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: NKMax; Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: InhibRx; Financial Interests, Personal and Institutional, Funding, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Tyme; Financial Interests, Personal, Stocks/Shares: AADi; Financial Interests, Personal, Stocks/Shares: Cellestia Biotech; Financial Interests, Personal, Stocks/Shares: Immix BioPharma; Financial Interests, Personal and Institutional, Funding, Grants or contracts from any entity, Consulting fees, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Immune Design. K.A. Benhadji: Financial Interests, Personal, Full or part-time Employment: Taiho Oncology; Financial Interests, Personal, Stocks/Shares: Lilly. O. Takahashi: Financial Interests, Personal, Full or part-time Employment: Taiho Oncology Inc. S. Delaloge: Financial Interests, Institutional, Invited Speaker, and Advisory Board, Steering Committee Member: AstraZeneca; Financial Interests, Institutional, Advisory Board: Cellectis; Financial Interests, Institutional, Invited Speaker: Exact Sciences; Financial Interests, Institutional, Advisory Board: Isis/servier; Financial Interests, Institutional, Invited Speaker: Lilly; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Advisory Board: Novartis; Financial Interests, Institutional, Advisory Board: Orion; Financial Interests, Institutional, Invited Speaker, and Steering Committee Member: Pfizer; Financial Interests, Institutional, Advisory Board: Pierre fabre; Financial Interests, Institutional, Advisory Board: Rappta; Financial Interests, Institutional, Advisory Board, and Steering Committee Member: Sanofi; Financial Interests, Institutional, Invited Speaker: Seagen; Financial Interests, Institutional, Other, Steering Committee Member: BMS; Financial Interests, Institutional, Funding: GE; Financial Interests, Institutional, Other, Local PI: Orion; Financial Interests, Institutional, Other, Steering Committee Member: Puma; Financial Interests, Institutional, Other, Steering Committee Member: Roche Genentech; Financial Interests, Institutional, Funding, clinical research funding to my institution, Coordinating PI: Taiho; Non-Financial Interests, Personal, Member of the Board of Directors, Société Française de Sénologie et Pathologie Mammaire: SFSPM. All other authors have declared no conflicts of interest.