PMID- 33660194 OWN - NLM STAT- MEDLINE DCOM- 20220202 LR - 20220317 IS - 1573-0646 (Electronic) IS - 0167-6997 (Print) IS - 0167-6997 (Linking) VI - 39 IP - 4 DP - 2021 Aug TI - Phase 1 cohort expansion study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced mesothelioma. PG - 1081-1088 LID - 10.1007/s10637-021-01086-6 [doi] AB - BACKGROUND LY3023414 is a selective, ATP competitive inhibitor of class I PI3K isoforms, mTORC1/2 and DNA-PK. A Phase 1 dose escalation, 200 mg twice daily (BID) of LY3023414 was the determined recommended phase 2 dose (RP2D). We report the antitumor activity and safety of LY3023414 monotherapy in patients with advanced mesothelioma.METHODS Patients enrolled had advanced malignant pleural or peritoneal mesothelioma with measurable disease, ECOG PS 0-1, were refractory or ineligible to receive standard therapies. Patients received LY3023414 200 mg BID. This dose expansion cohort is intended to evaluate preliminary antitumor activity of LY3023414 by overall response rate. Safety, tolerability and pharmacokinetics were assessed. Biomarkers associated with treatment response was an exploratory endpoint. RESULTS Forty-two patients received LY3023414 for a median duration of 11.2 weeks (range: 1.1-53.0). One patient had a confirmed partial response (PR) (ORR 2.4%). Three patients had an unconfirmed PR. Seventeen patients had stable disease (SD) (DCR 43%). Most common adverse events (AEs) included fatigue (43%), nausea (43%), decreased appetite (38%), vomiting (33%), and diarrhea (29%). AEs were mostly mild or moderate. Grade >/= 3 AEs were reported for 21% of patients with fatigue as the most frequent event (10%). Alterations of BAP1 were identified in 11/19 patients as the most common molecular aberration, followed by SETD2 and NF2 alterations. No obvious pattern of genetic changes/mutations in single genes or pathways was associated with anti-tumor activity. CONCLUSION LY3023414 monotherapy (200 mg BID) demonstrated an acceptable and manageable safety profile with limited single-agent activity in patients with advanced mesothelioma. ClinicalTrials.gov identifier: NCT01655225; Date of registration: 19 July 2012. CI - (c) 2021. The Author(s). FAU - Zauderer, Marjorie G AU - Zauderer MG AUID- ORCID: 0000-0001-5426-0885 AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. zauderem@mskcc.org. AD - Taiho Oncology Inc, Princeton, NJ, USA. zauderem@mskcc.org. FAU - Alley, Evan W AU - Alley EW AD - Cleveland Clinic Florida, Weston, FL, USA. FAU - Bendell, Johanna AU - Bendell J AD - Sarah Cannon Research Institute / Tennessee Oncology, Nashville, TN, USA. FAU - Capelletto, Enrica AU - Capelletto E AD - University of Turin, Torino, TO, Italy. FAU - Bauer, Todd M AU - Bauer TM AD - Sarah Cannon Research Institute / Tennessee Oncology, Nashville, TN, USA. FAU - Callies, Sophie AU - Callies S AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Szpurka, Anna M AU - Szpurka AM AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Kang, Suhyun AU - Kang S AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Willard, Melinda D AU - Willard MD AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Wacheck, Volker AU - Wacheck V AD - Taiho Oncology Inc, Princeton, NJ, USA. AD - Eli Lilly and Company, Indianapolis, IN, USA. FAU - Varghese, Anna M AU - Varghese AM AD - Memorial Sloan Kettering Cancer Center, New York, NY, USA. LA - eng SI - ClinicalTrials.gov/NCT01655225 GR - P30 CA008748/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20210304 PL - United States TA - Invest New Drugs JT - Investigational new drugs JID - 8309330 RN - 0 (Antineoplastic Agents) RN - 0 (LY3023414) RN - 0 (Phosphoinositide-3 Kinase Inhibitors) RN - 0 (Pyridines) RN - 0 (Quinolones) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents/*administration & dosage/adverse effects MH - Cohort Studies MH - Dose-Response Relationship, Drug MH - Female MH - Humans MH - Male MH - Mesothelioma/*drug therapy/pathology MH - Middle Aged MH - Phosphoinositide-3 Kinase Inhibitors/administration & dosage/adverse effects MH - Pyridines/*administration & dosage/adverse effects MH - Quinolones/*administration & dosage/adverse effects MH - TOR Serine-Threonine Kinases/antagonists & inhibitors MH - Treatment Outcome PMC - PMC8280020 OTO - NOTNLM OT - LY3023414 OT - Mesothelioma OT - PI3K/mTOR inhibitor OT - Solid tumor COIS- M. Zauderer reports grants to their institution for research from Eli Lilly and Company, Department of Defense, NCI, Atara Biotherapeutics for research, GSK, Epizyme, Polaris, Sellas Life Sciences, BMS, Millennium/Takeda, Atara, and Curis; advisory role from Takeda, Aldeyra Therapeutics, Atara Biotherapeutics, GSK, Novocure, Aldeyra, Epizyme; personal fees from Research to Practice, Medical Learning Institute and OncLive, and non-financial support from Roche outside the submitted work. E.W. Alley reports no conflict of interest or financial support. J. Bendell reports research grants from Gilead, Genentech/Roche, BMS, Five Prime, Eli Lilly and Company, Merck, MedImmune, Celgene, EMD Serono, Taiho, Macrogenics, GSK, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, BI, Daiichi Sankyo, Bayer, Incyte, Apexigen, Koltan, SynDevRex, Forty Seven, Abbvie, Array, Onyx, Sanofi, Takeda, Eisai, Celldex, Agios, Cytomx, Nektar, ARMO, Boston Biomedical, Ipsen, Merrimack, Tarveda, Tyrogenex, Oncogenex, Marshall Edwards, Pieris, Mersana, Calithera, Blueprint, Evelo, FORMA, Merus, Jacobio, Effector, Novocare, Arrys, Tracon, Sierra, Innate, Arch Oncology, Prelude Therapeutics, Unum Therapeutics, Vyriad, Harpoon, ADC, Amgen, Pfizer, Millennium, Imclome, Acerta Pharma, Rgenix, Bellicum, Gossamer Bio, Arcus Bio, Seattle Genetics, Tepest Tx, Shattuck Labs, Synthorx, Inc., Revolution Medicines, Inc., Bicycle Therapeutics, Zymeworks, Relay Therapeutics, Atlas Medx, Scholar Rock and NGM Biopharma, other payment to institution for consulting services from BMS, Five Prime, Eli Lilly and Company, Merck, Medimmune, Celgene, Taiho, Macrogenics, GSK, Novartis, OncoMed, LEAP, TG Therapeutics, AstraZeneca, BI, Daiichi Sankyo, Bayer, Incyte, Apexigen, Array, Sanofi, Agios, ARMO, Ipsen, Merrimack, Oncogenex, Evelo, FORMA, Innate, Arch Oncology, Prelude Therapeutics, Amgen, Pfizer, Seattle Genetics, Bicycle Therapeutics, Relay Therapeutis, Phoenix Bio, Cyteir, Molecular Partners, Torque, Tizona, Janssen, Tolero, TD2, Moderna Therapeutics, Tanabe Research Laboratories, Beigene, Continuum Clinical, Evelo, Piper Biotech, Samsung Bioepios, outside the submitted work. E. Capelleto reports other payment for consulting services from Boehringer Ingelheim and Astrazeneca; other payments for an advisory role at MSD, outside the submitted work. T. Bauer reports grants from Eli Lilly and Company, during the conduct of the study; grants from Daiichi Sankyo, grants from Medpacto, grants from Incyte, grants from Mirati Therapeutics, grants from MedImmune, grants from Abbvie, grants from AstraZeneca, grants from MabVax, grants from Stemline Therapeutics, grants from Merck, grants from Lilly, grants from GlaxoSmithKline, grants from Novartis, grants from Genentech, grants from Deciphera, grants from Merrimack, grants from Immunogen, grants from Millennium, grants from Phosplatin Therapeutics, grants from Calithera Biosciences, grants from Kolltan Pharmaceuticals, grants from Principa Biopharma, grants from Peleton, grants from Immunocore, grants from Roche, grants from Aileron Therapeutics, grants from Bristol-Myers Squibb, grants from Amgen, grants from Onyx, grants from Sanofi, grants from Boehringer-Ingelheim, grants from Astellas Pharma, grants from Five Prime Therapeutics, grants from Jacobio, grants from Top Alliance BioScience, grants from Janssen, grants from Clovis Oncology, grants from Takeda, grants from Karyopharm Therapeutics, grants from Foundation Medicine, grants from ARMO Biosciences, grants and other from Leap Therapeutics, grants, non-financial support and other from Ignyta, grants, non-financial support and other from Moderna Therapeutics, grants, personal fees and other from Pfizer, grants, personal fees and non-financial support from Loxo, grants, personal fees and non-financial support from Bayer, personal fees and non-financial support from Guardant Health, personal fees from Exelesis, outside the submitted work. S. Callies, A.M. Szpurka, S. Kang, M.D. Willard are employees of Eli Lilly and Company; M.D. Willard report other payments as a stockholder for Eli Lilly and Company. V. Wacheck reports payment as a former employee and shareholder for Eli Lilly and Company during the conduct of this study. EDAT- 2021/03/05 06:00 MHDA- 2022/02/03 06:00 PMCR- 2021/03/04 CRDT- 2021/03/04 06:00 PHST- 2021/01/15 00:00 [received] PHST- 2021/02/11 00:00 [accepted] PHST- 2021/03/05 06:00 [pubmed] PHST- 2022/02/03 06:00 [medline] PHST- 2021/03/04 06:00 [entrez] PHST- 2021/03/04 00:00 [pmc-release] AID - 10.1007/s10637-021-01086-6 [pii] AID - 1086 [pii] AID - 10.1007/s10637-021-01086-6 [doi] PST - ppublish SO - Invest New Drugs. 2021 Aug;39(4):1081-1088. doi: 10.1007/s10637-021-01086-6. Epub 2021 Mar 4.