PMID- 32578154 OWN - NLM STAT- MEDLINE DCOM- 20210910 LR - 20230526 IS - 1573-0646 (Electronic) IS - 0167-6997 (Print) IS - 0167-6997 (Linking) VI - 38 IP - 6 DP - 2020 Dec TI - Phase 1 dose-escalation study of a novel oral PI3K/mTOR dual inhibitor, LY3023414, in patients with cancer. PG - 1836-1845 LID - 10.1007/s10637-020-00968-5 [doi] AB - LY3023414 is an oral, selective adenosine triphosphate-competitive inhibitor of class I phosphatidylinositol 3-kinase isoforms, mammalian target of rapamycin, and DNA-protein kinase in clinical development. We report results of a 3 + 3 dose-escalation Phase 1 study for twice-daily (BID) dosing of LY3023414 monotherapy in Japanese patients with advanced malignancies. The primary objective was to evaluate tolerability and safety of LY3023414. Secondary objectives were to evaluate pharmacokinetics and to explore antitumor activity. A total of 12 patients were enrolled and received 150 mg (n = 3) or 200 mg (n = 9) LY3023414 BID. Dose-limiting toxicities were only reported at 200 mg LY3023414 for 2 patients with Grade 3 stomatitis. Common treatment-related adverse events (AEs) across both the dose levels included stomatitis (75.0%), nausea (66.7%), decreased appetite (58.3%), diarrhea, and decreased platelet count (41.7%), and they were mostly mild or moderate in severity. Related AEs Grade >/= 3 reported for >/=1 patient included anemia, stomatitis, hypophosphatemia, and hyperglycemia (n = 2, 16.7%). Two patients discontinued due to AEs (interstitial lung disease and stomatitis). No fatal events were reported. The pharmacokinetic profile of LY3023414 was characterized by rapid absorption and elimination. Five patients had a best overall response of stable disease (150 mg, n = 3; 200 mg, n = 2) for a 55.6% disease control rate. LY3023414 up to 200 mg BID is tolerable and safe in Japanese patients with advanced malignancies. FAU - Kondo, Shunsuke AU - Kondo S AUID- ORCID: 0000-0001-9565-117X AD - Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan. shkondo@ncc.go.jp. FAU - Tajimi, Masaomi AU - Tajimi M AD - Eli Lilly Japan K.K., Kobe, Japan. FAU - Funai, Tomohiko AU - Funai T AD - Eli Lilly Japan K.K., Kobe, Japan. FAU - Inoue, Koichi AU - Inoue K AD - Eli Lilly Japan K.K., Kobe, Japan. FAU - Asou, Hiroya AU - Asou H AD - Eli Lilly Japan K.K., Kobe, Japan. FAU - Ranka, Vinay Kumar AU - Ranka VK AD - Eli Lilly Services India Private Limited, Bengaluru, India. FAU - Wacheck, Volker AU - Wacheck V AD - Eli Lilly GmbH, Vienna, Austria. FAU - Doi, Toshihiko AU - Doi T AD - Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan. LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200623 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 (Protein 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 EIN - Invest New Drugs. 2020 Sep 7;:. PMID: 32894386 MH - Adult MH - Aged MH - Antineoplastic Agents/*administration & dosage/adverse effects/blood/pharmacokinetics MH - Female MH - Humans MH - Magnetic Resonance Imaging MH - Male MH - Middle Aged MH - Neoplasms/blood/diagnostic imaging/*drug therapy/metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - Phosphoinositide-3 Kinase Inhibitors/*administration & dosage/adverse effects/blood/pharmacokinetics MH - Protein Kinase Inhibitors/*administration & dosage/adverse effects/blood/pharmacokinetics MH - Pyridines/*administration & dosage/adverse effects/blood/pharmacokinetics MH - Quinolones/*administration & dosage/adverse effects/blood/pharmacokinetics MH - Response Evaluation Criteria in Solid Tumors MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism MH - Tomography, X-Ray Computed PMC - PMC7575488 OTO - NOTNLM OT - Advanced malignancies OT - Dose-escalation study OT - Japanese patients OT - LY3023414 OT - Safety COIS- Shunsuke Kondo reports research funding from ASLAN Pharmaceuticals, AstraZeneca, Bayer, Eli Lilly, MSD, and Pfizer; Toshihiko Doi reports grants and personal fees from Eli Lilly Japan, Kyowa Hakko Kirin, MSD, Daiichi Sankyo, Sumitomo Dainippon, Taiho, Novartis, Boehringer Ingelheim, Chugai Pharma, Bristol-Myers Squibb, Abbvie, personal fees from Bayer, Rakuten Medical, Ono Pharmaceutical, Astellas Pharma, Oncolys BioPharma, Amgen, Takeda, grants from Merck Serono, Janssen, Pfizer, Quintiles, and Eisai; Masaomi Tajimi, Tomohiko Funai, Koichi Inoue, Hiroya Asou, Vinay Kumar Ranka, and Volker Wacheck are employees and shareholders of Eli Lilly and Company. The study was designed under the responsibility of Eli Lilly and Company, in conjunction with the steering committee. The study was funded by Eli Lilly and Company. LY3023414 was provided by Eli Lilly and Company. Eli Lilly and Company collected and analyzed the data and contributed to the interpretation of the study. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. EDAT- 2020/06/25 06:00 MHDA- 2021/09/11 06:00 PMCR- 2020/06/23 CRDT- 2020/06/25 06:00 PHST- 2020/02/07 00:00 [received] PHST- 2020/06/18 00:00 [accepted] PHST- 2020/06/25 06:00 [pubmed] PHST- 2021/09/11 06:00 [medline] PHST- 2020/06/25 06:00 [entrez] PHST- 2020/06/23 00:00 [pmc-release] AID - 10.1007/s10637-020-00968-5 [pii] AID - 968 [pii] AID - 10.1007/s10637-020-00968-5 [doi] PST - ppublish SO - Invest New Drugs. 2020 Dec;38(6):1836-1845. doi: 10.1007/s10637-020-00968-5. Epub 2020 Jun 23.