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
Abstract 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 d...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-01-01
|
| Series: | BMC Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12916-022-02669-7 |
| _version_ | 1797958672884695040 |
|---|---|
| author | Xuan Wang Zhiguo Luo Jing Chen Yu Chen Dongmei Ji Li Fan Ling Chen Qian Zhao Pei Hu Peng Sun Zhongwei Jia Jun Guo Lu Si |
| author_facet | Xuan Wang Zhiguo Luo Jing Chen Yu Chen Dongmei Ji Li Fan Ling Chen Qian Zhao Pei Hu Peng Sun Zhongwei Jia Jun Guo Lu Si |
| author_sort | Xuan Wang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-11T00:22:19Z |
| format | Article |
| id | doaj.art-c8dabd3a4e3f4c76bee2716e3f966d74 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-04-11T00:22:19Z |
| publishDate | 2023-01-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-c8dabd3a4e3f4c76bee2716e3f966d742023-01-08T12:14:00ZengBMCBMC Medicine1741-70152023-01-0121111210.1186/s12916-022-02669-7First-in-human phase I dose-escalation and dose-expansion trial of the selective MEK inhibitor HL-085 in patients with advanced melanoma harboring NRAS mutationsXuan Wang0Zhiguo Luo1Jing Chen2Yu Chen3Dongmei Ji4Li Fan5Ling Chen6Qian Zhao7Pei Hu8Peng Sun9Zhongwei Jia10Jun Guo11Lu Si12Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Research InstituteFudan University Shanghai Cancer CenterUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyFujian Medical University Cancer HospitalFudan University Shanghai Cancer CenterUnion Hospital, Tongji Medical College, Huazhong University of Science and TechnologyFujian Medical University Cancer HospitalClinical 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 DrugsClinical 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 DrugsDepartment of Clinical Research and Development, Shanghai Kechow Pharma, Inc.Department of Clinical Research and Development, Shanghai Kechow Pharma, Inc.Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Research InstituteKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Renal Cancer and Melanoma, Peking University Cancer Hospital and Research InstituteAbstract 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.https://doi.org/10.1186/s12916-022-02669-7HL-085MEK inhibitorAdvanced melanomaNRAS mutation, Circulating tumor DNA |
| spellingShingle | Xuan Wang Zhiguo Luo Jing Chen Yu Chen Dongmei Ji Li Fan Ling Chen Qian Zhao Pei Hu Peng Sun Zhongwei Jia Jun Guo Lu Si 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 BMC Medicine HL-085 MEK inhibitor Advanced melanoma NRAS mutation, Circulating tumor DNA |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | HL-085 MEK inhibitor Advanced melanoma NRAS mutation, Circulating tumor DNA |
| url | https://doi.org/10.1186/s12916-022-02669-7 |
| work_keys_str_mv | AT xuanwang firstinhumanphaseidoseescalationanddoseexpansiontrialoftheselectivemekinhibitorhl085inpatientswithadvancedmelanomaharboringnrasmutations AT zhiguoluo firstinhumanphaseidoseescalationanddoseexpansiontrialoftheselectivemekinhibitorhl085inpatientswithadvancedmelanomaharboringnrasmutations AT jingchen firstinhumanphaseidoseescalationanddoseexpansiontrialoftheselectivemekinhibitorhl085inpatientswithadvancedmelanomaharboringnrasmutations AT yuchen firstinhumanphaseidoseescalationanddoseexpansiontrialoftheselectivemekinhibitorhl085inpatientswithadvancedmelanomaharboringnrasmutations AT dongmeiji firstinhumanphaseidoseescalationanddoseexpansiontrialoftheselectivemekinhibitorhl085inpatientswithadvancedmelanomaharboringnrasmutations AT lifan firstinhumanphaseidoseescalationanddoseexpansiontrialoftheselectivemekinhibitorhl085inpatientswithadvancedmelanomaharboringnrasmutations AT lingchen firstinhumanphaseidoseescalationanddoseexpansiontrialoftheselectivemekinhibitorhl085inpatientswithadvancedmelanomaharboringnrasmutations AT qianzhao firstinhumanphaseidoseescalationanddoseexpansiontrialoftheselectivemekinhibitorhl085inpatientswithadvancedmelanomaharboringnrasmutations AT peihu firstinhumanphaseidoseescalationanddoseexpansiontrialoftheselectivemekinhibitorhl085inpatientswithadvancedmelanomaharboringnrasmutations AT pengsun firstinhumanphaseidoseescalationanddoseexpansiontrialoftheselectivemekinhibitorhl085inpatientswithadvancedmelanomaharboringnrasmutations AT zhongweijia firstinhumanphaseidoseescalationanddoseexpansiontrialoftheselectivemekinhibitorhl085inpatientswithadvancedmelanomaharboringnrasmutations AT junguo firstinhumanphaseidoseescalationanddoseexpansiontrialoftheselectivemekinhibitorhl085inpatientswithadvancedmelanomaharboringnrasmutations AT lusi firstinhumanphaseidoseescalationanddoseexpansiontrialoftheselectivemekinhibitorhl085inpatientswithadvancedmelanomaharboringnrasmutations |