PMID- 38539472 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240330 IS - 2072-6694 (Print) IS - 2072-6694 (Electronic) IS - 2072-6694 (Linking) VI - 16 IP - 6 DP - 2024 Mar 13 TI - A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors. LID - 10.3390/cancers16061137 [doi] LID - 1137 AB - BACKGROUND: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. RESULTS: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56-62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1(T1997M) mutation. CONCLUSIONS: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations. FAU - Janku, Filip AU - Janku F AUID- ORCID: 0000-0002-8123-4065 AD - The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. FAU - Choong, Grace M AU - Choong GM AD - Mayo Clinic Rochester, Department of Oncology, Rochester, MN 55905, USA. FAU - Opyrchal, Mateusz AU - Opyrchal M AUID- ORCID: 0000-0003-2454-7441 AD - Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA. FAU - Dowlati, Afshin AU - Dowlati A AUID- ORCID: 0000-0003-4535-6839 AD - University Hospitals of Cleveland, Cleveland, OH 44106, USA. FAU - Hierro, Cinta AU - Hierro C AD - Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035 Barcelona, Spain. FAU - Rodon, Jordi AU - Rodon J AD - The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. AD - Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital, 08035 Barcelona, Spain. FAU - Wicki, Andreas AU - Wicki A AUID- ORCID: 0000-0002-2924-8080 AD - University Hospital Basel, 4031 Basel, Switzerland. FAU - Forster, Martin D AU - Forster MD AD - UCL Cancer Institute, University College London Hospitals NHS Trust, London NW1 2PG, UK. FAU - Blagden, Sarah P AU - Blagden SP AD - Early Phase Clinical Trials Unit, Department of Oncology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LJ, UK. FAU - Yin, Jun AU - Yin J AD - Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN 55905, USA. FAU - Reid, Joel M AU - Reid JM AD - Mayo Clinic Rochester, Department of Oncology, Rochester, MN 55905, USA. FAU - Muller, Helene AU - Muller H AD - PIQUR Therapeutics AG, 4051 Basel, Switzerland. FAU - Cmiljanovic, Natasa AU - Cmiljanovic N AD - PIQUR Therapeutics AG, 4051 Basel, Switzerland. FAU - Cmiljanovic, Vladimir AU - Cmiljanovic V AD - PIQUR Therapeutics AG, 4051 Basel, Switzerland. FAU - Adjei, Alex A AU - Adjei AA AD - Mayo Clinic Rochester, Department of Oncology, Rochester, MN 55905, USA. LA - eng PT - Journal Article DEP - 20240313 PL - Switzerland TA - Cancers (Basel) JT - Cancers JID - 101526829 PMC - PMC10969742 OTO - NOTNLM OT - PI3K/mTOR inhibitor OT - clinical trial OT - intermittent dosing schedule OT - safety OT - solid tumor COIS- FJ received research support from Astex, Novartis, BioMed Valley Discoveries, Fore Bio, Deciphera, Bristol-Myers Squibb, Asana, Ideaya Biosciences, Sanofi, Merck, F-star, JSI Innopharm, Bioxcel, Lilly, Bicara, PureTech Health, FujiFilm Pharmaceuticals, Piqur, Sotio, Synlogic, NextCure, and Hutchinson Medipharma; served on the Scientific Advisory Boards of Ideaya Biosciences, Synlogic, Sotio, Puretech Health, Deciphera, Crown Bioscience, Asana, Fore Bio, Novartis, Bicara, and PegaOne; served as a paid consultant for Mersana Therapeutics, Flame Bio, Cardiff Oncology, MedinCell and Immunomet; has ownership interests in Cardiff Oncology and Monte Rosa Therapeutics); and has the leadership position in Monte Rosa Therapeutics. MO received research grants from Pfizer, Eli Lilly, and Alphageneron and serves on the Advisory Boards of AZ, Pfizer, and Novartis. AD reported a consulting or advisory role with Astra Zeneca, Merck, Ipsen, Amgen, Seattle Genetics, Abbvie, and BMS. CH reported personal honoraria (lectures, advisory role) with Lilly and MSD; research funding (institutional) with Merck; and travel fees with Amgen, Roche, and Merck. JR reports receiving non-financial support and reasonable reimbursement for travel from the European Society for Medical Oncology; consulting and travel fees from Ellipses Pharma and IONCTURA (including serving on the scientific advisory board); consulting fees from Aadi Bioscience, Clarion Healthcare, Debiopharm, Monte Rosa Therapeutics, and Cullgen. Pfizer, Merus N.V., Macorgenics, Oncology One, Envision Pharma, Columbus Venture Partners, Sardona Therapeutics, Avoro Capital Advisors, Vall d'Hebron Institute of Oncology/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC, and Incyte; receiving research funding from Blueprint Medicines, Black Diamond Therapeutics, Merck Sharp & Dohme, Hummingbird, Yingli and Vall d'Hebron Institute of Oncology/Cancer Core Europe; and serving as investigator in clinical trials with Novartis, Spectrum Pharmaceuticals, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GalxoSmithKline, Taiho, Roche Pharmaceuticals, Hummingbird, Yingli, Bycicle Therapeutics, Merus, Curis, Bayer, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics, and Cancer Core Europe. MDF acknowledges grant support from CRUK, AstraZeneca, Boehringer Ingelheim, MSD, and Merck; is an advisory board member for Transgene; and has consulted for Achilles, Amgen, AstraZeneca, Bayer, Boxer, Bristol-Myers Squibb, Celgene, EQRx, Guardant Health, Immutep, Ixogen, Janssen, Merck, MSD, Nanobiotix, Novartis, Oxford VacMedix, Pharmamar, Pfizer, Roche, Takeda, and UltraHuman. SPB received research funding to conduct clinical trials from Nucana PLC, Astex, Incyte, Tesaro, Redx, MSD, Roche, UCB, Sarah Cannon Institute, BergenBio, and MiNA therapeutics; performed consulting for Ellipses and Amphista, Oxford Investment Consultants, RApportss, and Theolytics; and was the director of RNA Guardian. JMR serves as a consultant for Elucida Oncology, Inc. The remaining authors declare no potential conflicts. EDAT- 2024/03/28 06:45 MHDA- 2024/03/28 06:46 PMCR- 2024/03/13 CRDT- 2024/03/28 01:02 PHST- 2024/02/16 00:00 [received] PHST- 2024/03/07 00:00 [revised] PHST- 2024/03/08 00:00 [accepted] PHST- 2024/03/28 06:46 [medline] PHST- 2024/03/28 06:45 [pubmed] PHST- 2024/03/28 01:02 [entrez] PHST- 2024/03/13 00:00 [pmc-release] AID - cancers16061137 [pii] AID - cancers-16-01137 [pii] AID - 10.3390/cancers16061137 [doi] PST - epublish SO - Cancers (Basel). 2024 Mar 13;16(6):1137. doi: 10.3390/cancers16061137.