PMID- 36600247 OWN - NLM STAT- MEDLINE DCOM- 20230124 LR - 20230206 IS - 1741-7015 (Electronic) IS - 1741-7015 (Linking) VI - 21 IP - 1 DP - 2023 Jan 4 TI - First-in-human phase I dose-escalation and dose-expansion trial of the selective MEK inhibitor HL-085 in patients with advanced melanoma harboring NRAS mutations. PG - 2 LID - 10.1186/s12916-022-02669-7 [doi] LID - 2 AB - BACKGROUND: HL-085 is a selective, orally administered MEK1/2 inhibitor. We aimed to evaluate the safety and efficacy of HL-085 in patients with advanced melanoma harboring NRAS mutations. METHODS: This was a multicenter phase 1 study. HL-085 was administered twice daily in a standard 3 + 3 dose-escalation design (10 dose cohorts; 0.5-18 mg twice daily), followed by dose expansion at the recommended phase II dose (RP2D). The primary endpoints included tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and RP2D. RESULTS: Between September 13, 2017, and January 18, 2021, 42 patients were enrolled (dose escalation phase: n = 30; dose expansion phase: n = 12). No DLT was reported during dose escalation and MTD was not reached with HL-085 doses up to 18 mg twice daily. The RP2D was 12 mg twice daily. The most common all-grade drug-related adverse events (AEs) across all dose levels were rash (61.9%), increased creatine phosphokinase (CK, 59.5%), face edema (50.0%), increased aspartate aminotransferase (47.6%), peripheral edema (40.5%), diarrhea (33.3%), alanine aminotransferase (33.3%), and paronychia (19.0%), most of which were grade 1 and 2. Most frequency of grade >/= 3 AEs were CK (14.2%), asthenia (7.1%), peripheral edema (4.8%), and acneiform dermatitis (4.8%). In the cohort of 12 mg twice daily dose (15 patients), confirmed objective response rate was 26.7%; disease control rate was 86.7%; median duration of response was 2.9 months; median progression-free survival was 3.6 months. CONCLUSIONS: The HL-085 showed acceptable tolerability and substantial clinical activity in patients with advanced melanoma harboring NRAS mutations. TRIAL REGISTRATION: Trial registration ClinicalTrials.gov number: NCT03973151. CI - (c) 2022. The Author(s). FAU - Wang, Xuan AU - Wang X AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Research Institute, Beijing, China. FAU - Luo, Zhiguo AU - Luo Z AD - Fudan University Shanghai Cancer Center, Shanghai, China. FAU - Chen, Jing AU - Chen J AD - Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Chen, Yu AU - Chen Y AD - Fujian Medical University Cancer Hospital, Fuzhou, China. FAU - Ji, Dongmei AU - Ji D AD - Fudan University Shanghai Cancer Center, Shanghai, China. FAU - Fan, Li AU - Fan L AD - Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. FAU - Chen, Ling AU - Chen L AD - Fujian Medical University Cancer Hospital, Fuzhou, China. FAU - Zhao, Qian AU - Zhao Q AD - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Beijing, China. FAU - Hu, Pei AU - Hu P AD - Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK and PD Investigation for Innovative Drugs, Beijing, China. FAU - Sun, Peng AU - Sun P AD - Department of Clinical Research and Development, Shanghai Kechow Pharma, Inc., Shanghai, China. FAU - Jia, Zhongwei AU - Jia Z AD - Department of Clinical Research and Development, Shanghai Kechow Pharma, Inc., Shanghai, China. FAU - Guo, Jun AU - Guo J AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Research Institute, Beijing, China. guoj307@126.com. FAU - Si, Lu AU - Si L AD - Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Research Institute, Beijing, China. silu15_silu@126.com. LA - eng SI - ClinicalTrials.gov/NCT03973151 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20230104 PL - England TA - BMC Med JT - BMC medicine JID - 101190723 RN - 0 (Antineoplastic Agents) RN - EC 3.6.1.- (GTP Phosphohydrolases) RN - 0 (Membrane Proteins) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) RN - EC 3.6.1.- (NRAS protein, human) RN - 0 (Protein Kinase Inhibitors) SB - IM MH - Humans MH - Antineoplastic Agents/adverse effects/therapeutic use MH - GTP Phosphohydrolases/genetics/therapeutic use MH - *Melanoma/drug therapy/genetics MH - Membrane Proteins/genetics MH - *Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors MH - Mutation MH - Progression-Free Survival MH - Protein Kinase Inhibitors/adverse effects/therapeutic use PMC - PMC9814429 OTO - NOTNLM OT - Advanced melanoma OT - HL-085 OT - MEK inhibitor OT - NRAS mutation, Circulating tumor DNA COIS- L.S. has received speakers' honoraria from MSD, Roche, Novartis, Shanghai Junshi Biosciences and Oriengene. J.G has served on advisory boards/consulted for MSD, Roche, Pfizer, Bayer, Novartis, Simcere, Shanghai Junshi Bioscience, and Oriengene. All other authors declared no potential competing interests with respect to the research, authorship, and/or publication of this article. EDAT- 2023/01/05 06:00 MHDA- 2023/01/07 06:00 PMCR- 2023/01/04 CRDT- 2023/01/04 23:35 PHST- 2022/04/10 00:00 [received] PHST- 2022/11/18 00:00 [accepted] PHST- 2023/01/04 23:35 [entrez] PHST- 2023/01/05 06:00 [pubmed] PHST- 2023/01/07 06:00 [medline] PHST- 2023/01/04 00:00 [pmc-release] AID - 10.1186/s12916-022-02669-7 [pii] AID - 2669 [pii] AID - 10.1186/s12916-022-02669-7 [doi] PST - epublish SO - BMC Med. 2023 Jan 4;21(1):2. doi: 10.1186/s12916-022-02669-7.