A first-in-human, phase 1a dose-escalation study of the selective MEK1/2 inhibitor FCN-159 in patients with advanced NRAS-mutant melanoma
A phase 1a first-in-human study evaluated the safety/tolerability, preliminary antitumour activity and pharmacokinetics of the oral MEK1/2 inhibitor FCN-159 in Chinese patients with advanced, NRAS-mutant melanoma. Patients received a single FCN-159 dose at assigned levels, proceeding to continuous d...
Gespeichert in:
| Veröffentlicht in: | European journal of cancer (1990) 2022-11, Vol.175, p.125-135 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 135 |
|---|---|
| container_issue | |
| container_start_page | 125 |
| container_title | European journal of cancer (1990) |
| container_volume | 175 |
| creator | Mao, Lili Guo, Jun Zhu, Lingjun Jiang, Yu Yan, Wangjun Zhang, Jian Hui, Ai-Min Yang, Yuchen Diao, Lei Tan, Yan Zhao, Han Jiang, Yiqian Wu, Zhuli Si, Lu |
| description | A phase 1a first-in-human study evaluated the safety/tolerability, preliminary antitumour activity and pharmacokinetics of the oral MEK1/2 inhibitor FCN-159 in Chinese patients with advanced, NRAS-mutant melanoma.
Patients received a single FCN-159 dose at assigned levels, proceeding to continuous dosing (once daily [QD] for 28-day cycles) if no dose-limiting toxicities (DLTs) occurred within the next 3 days. Dose escalation was initiated after review of data for the previous dose level. The primary end-point was incidence of DLTs after the first dose.
Thirty-three patients were enrolled across nine FCN-159 dose groups (0.2–15 mg QD). One DLT occurred: grade 3 folliculitis in the 15-mg group. There was one grade >3 treatment-emergent adverse event (TEAE), death of unknown aetiology (not FCN-159 related). The most common FCN-159–related TEAE was rash (36.4%), and the incidence of grade ≥3 FCN-159–related TEAEs was 15.2%. Antitumour activity at QD doses |
| doi_str_mv | 10.1016/j.ejca.2022.08.005 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_2715441777</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><els_id>S0959804922004816</els_id><sourcerecordid>2754549911</sourcerecordid><originalsourceid>FETCH-LOGICAL-c405t-efc68196d8db8a7e51ca4121bdc21505e4331cd738b10fe59deb47991d330f3d3</originalsourceid><addsrcrecordid>eNp9kUFv1DAQhSMEEkvpH-BkiQsHnI4Te-NIXFarFhBtkaCcLceeKI6SeLGdrfoT-Nd4tZw49DTS6HtPM-8VxTsGJQO2vRpLHI0uK6iqEmQJIF4UGyabloIU1ctiA61oqQTevi7exDgCQCM5bIo_O9K7EBN1Cx3WWS8fyWHQEQnTxPqIFKPRk07OLySm1T4R35M0IIk4oUnuiOTu-hu7qohbBte55AO52d9TJtq8IYesxCVF8ujSQLQ96sWgJfc_dj_pvCa9JDLjpBc_67fFq15PES__zYvi1831w_4Lvf3--et-d0sNB5Eo9mYrWbu10nZSNyiY0ZxVrLOmYgIE8rpmxja17Bj0KFqLHW_altm6hr629UXx4ex7CP73ijGp2UWDU74C_RpV1TDBOWuaJqPv_0NHv4YlX5cpwQXPtixT1ZkywccYsFeH4GYdnhQDdWpHjerUjjq1o0Cq3E4WfTqLML96dBhUNDmpHI4LOVdlvXtO_hfX2ZcW</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2754549911</pqid></control><display><type>article</type><title>A first-in-human, phase 1a dose-escalation study of the selective MEK1/2 inhibitor FCN-159 in patients with advanced NRAS-mutant melanoma</title><source>Elsevier ScienceDirect Journals</source><creator>Mao, Lili ; Guo, Jun ; Zhu, Lingjun ; Jiang, Yu ; Yan, Wangjun ; Zhang, Jian ; Hui, Ai-Min ; Yang, Yuchen ; Diao, Lei ; Tan, Yan ; Zhao, Han ; Jiang, Yiqian ; Wu, Zhuli ; Si, Lu</creator><creatorcontrib>Mao, Lili ; Guo, Jun ; Zhu, Lingjun ; Jiang, Yu ; Yan, Wangjun ; Zhang, Jian ; Hui, Ai-Min ; Yang, Yuchen ; Diao, Lei ; Tan, Yan ; Zhao, Han ; Jiang, Yiqian ; Wu, Zhuli ; Si, Lu</creatorcontrib><description>A phase 1a first-in-human study evaluated the safety/tolerability, preliminary antitumour activity and pharmacokinetics of the oral MEK1/2 inhibitor FCN-159 in Chinese patients with advanced, NRAS-mutant melanoma.
Patients received a single FCN-159 dose at assigned levels, proceeding to continuous dosing (once daily [QD] for 28-day cycles) if no dose-limiting toxicities (DLTs) occurred within the next 3 days. Dose escalation was initiated after review of data for the previous dose level. The primary end-point was incidence of DLTs after the first dose.
Thirty-three patients were enrolled across nine FCN-159 dose groups (0.2–15 mg QD). One DLT occurred: grade 3 folliculitis in the 15-mg group. There was one grade >3 treatment-emergent adverse event (TEAE), death of unknown aetiology (not FCN-159 related). The most common FCN-159–related TEAE was rash (36.4%), and the incidence of grade ≥3 FCN-159–related TEAEs was 15.2%. Antitumour activity at QD doses <6 mg was limited; therefore, efficacy data are presented only for doses ≥6 mg (n = 21). The objective response and clinical benefit rates were 19.0% (four partial responses) and 52.4%, respectively. Median (95% confidence interval) duration of response and progression-free survival were 4.8 months (2.8–not reached) and 3.8 months (1.8–5.6), respectively. FCN-159 exposure increased dose-proportionately; geometric mean terminal half-life was 29.9–56.9 h.
FCN-159 was well tolerated and demonstrated promising antitumour activity at doses ≥6 mg QD in patients with advanced, NRAS-mutant melanoma. The recommended phase 2 dose was 12 mg QD.
NCT03932253. https://clinicaltrials.gov/ct2/show/NCT03932253.
•There is currently no standard targeted therapy for advanced NRASmut melanoma.•FCN-159, a selective MEK1/2 inhibitor, was evaluated in a first-in-human study.•FCN-159 was well tolerated in Chinese patients with advanced NRASmut melanoma.•Preliminary signs of antitumour activity were observed at FCN-159 doses ≥6 mg QD.•The findings support further study of FCN-159 in patients with NRASmut melanoma.</description><identifier>ISSN: 0959-8049</identifier><identifier>EISSN: 1879-0852</identifier><identifier>DOI: 10.1016/j.ejca.2022.08.005</identifier><language>eng</language><publisher>Oxford: Elsevier Ltd</publisher><subject>Advanced melanoma ; Anticancer properties ; Dosage ; Folliculitis ; Inhibitors ; Maximum tolerated dose ; MEK inhibitor ; Melanoma ; Mutants ; NRAS ; Patients ; Pharmacokinetics ; Phase 1 trial ; Recommended phase 2 dose ; Targeted therapy ; Toxicity</subject><ispartof>European journal of cancer (1990), 2022-11, Vol.175, p.125-135</ispartof><rights>2022 Elsevier Ltd</rights><rights>Copyright Elsevier Science Ltd. Nov 2022</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c405t-efc68196d8db8a7e51ca4121bdc21505e4331cd738b10fe59deb47991d330f3d3</citedby><cites>FETCH-LOGICAL-c405t-efc68196d8db8a7e51ca4121bdc21505e4331cd738b10fe59deb47991d330f3d3</cites><orcidid>0000-0002-2123-9761 ; 0000-0003-0716-4334</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0959804922004816$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27903,27904,65309</link.rule.ids></links><search><creatorcontrib>Mao, Lili</creatorcontrib><creatorcontrib>Guo, Jun</creatorcontrib><creatorcontrib>Zhu, Lingjun</creatorcontrib><creatorcontrib>Jiang, Yu</creatorcontrib><creatorcontrib>Yan, Wangjun</creatorcontrib><creatorcontrib>Zhang, Jian</creatorcontrib><creatorcontrib>Hui, Ai-Min</creatorcontrib><creatorcontrib>Yang, Yuchen</creatorcontrib><creatorcontrib>Diao, Lei</creatorcontrib><creatorcontrib>Tan, Yan</creatorcontrib><creatorcontrib>Zhao, Han</creatorcontrib><creatorcontrib>Jiang, Yiqian</creatorcontrib><creatorcontrib>Wu, Zhuli</creatorcontrib><creatorcontrib>Si, Lu</creatorcontrib><title>A first-in-human, phase 1a dose-escalation study of the selective MEK1/2 inhibitor FCN-159 in patients with advanced NRAS-mutant melanoma</title><title>European journal of cancer (1990)</title><description>A phase 1a first-in-human study evaluated the safety/tolerability, preliminary antitumour activity and pharmacokinetics of the oral MEK1/2 inhibitor FCN-159 in Chinese patients with advanced, NRAS-mutant melanoma.
Patients received a single FCN-159 dose at assigned levels, proceeding to continuous dosing (once daily [QD] for 28-day cycles) if no dose-limiting toxicities (DLTs) occurred within the next 3 days. Dose escalation was initiated after review of data for the previous dose level. The primary end-point was incidence of DLTs after the first dose.
Thirty-three patients were enrolled across nine FCN-159 dose groups (0.2–15 mg QD). One DLT occurred: grade 3 folliculitis in the 15-mg group. There was one grade >3 treatment-emergent adverse event (TEAE), death of unknown aetiology (not FCN-159 related). The most common FCN-159–related TEAE was rash (36.4%), and the incidence of grade ≥3 FCN-159–related TEAEs was 15.2%. Antitumour activity at QD doses <6 mg was limited; therefore, efficacy data are presented only for doses ≥6 mg (n = 21). The objective response and clinical benefit rates were 19.0% (four partial responses) and 52.4%, respectively. Median (95% confidence interval) duration of response and progression-free survival were 4.8 months (2.8–not reached) and 3.8 months (1.8–5.6), respectively. FCN-159 exposure increased dose-proportionately; geometric mean terminal half-life was 29.9–56.9 h.
FCN-159 was well tolerated and demonstrated promising antitumour activity at doses ≥6 mg QD in patients with advanced, NRAS-mutant melanoma. The recommended phase 2 dose was 12 mg QD.
NCT03932253. https://clinicaltrials.gov/ct2/show/NCT03932253.
•There is currently no standard targeted therapy for advanced NRASmut melanoma.•FCN-159, a selective MEK1/2 inhibitor, was evaluated in a first-in-human study.•FCN-159 was well tolerated in Chinese patients with advanced NRASmut melanoma.•Preliminary signs of antitumour activity were observed at FCN-159 doses ≥6 mg QD.•The findings support further study of FCN-159 in patients with NRASmut melanoma.</description><subject>Advanced melanoma</subject><subject>Anticancer properties</subject><subject>Dosage</subject><subject>Folliculitis</subject><subject>Inhibitors</subject><subject>Maximum tolerated dose</subject><subject>MEK inhibitor</subject><subject>Melanoma</subject><subject>Mutants</subject><subject>NRAS</subject><subject>Patients</subject><subject>Pharmacokinetics</subject><subject>Phase 1 trial</subject><subject>Recommended phase 2 dose</subject><subject>Targeted therapy</subject><subject>Toxicity</subject><issn>0959-8049</issn><issn>1879-0852</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><recordid>eNp9kUFv1DAQhSMEEkvpH-BkiQsHnI4Te-NIXFarFhBtkaCcLceeKI6SeLGdrfoT-Nd4tZw49DTS6HtPM-8VxTsGJQO2vRpLHI0uK6iqEmQJIF4UGyabloIU1ctiA61oqQTevi7exDgCQCM5bIo_O9K7EBN1Cx3WWS8fyWHQEQnTxPqIFKPRk07OLySm1T4R35M0IIk4oUnuiOTu-hu7qohbBte55AO52d9TJtq8IYesxCVF8ujSQLQ96sWgJfc_dj_pvCa9JDLjpBc_67fFq15PES__zYvi1831w_4Lvf3--et-d0sNB5Eo9mYrWbu10nZSNyiY0ZxVrLOmYgIE8rpmxja17Bj0KFqLHW_altm6hr629UXx4ex7CP73ijGp2UWDU74C_RpV1TDBOWuaJqPv_0NHv4YlX5cpwQXPtixT1ZkywccYsFeH4GYdnhQDdWpHjerUjjq1o0Cq3E4WfTqLML96dBhUNDmpHI4LOVdlvXtO_hfX2ZcW</recordid><startdate>202211</startdate><enddate>202211</enddate><creator>Mao, Lili</creator><creator>Guo, Jun</creator><creator>Zhu, Lingjun</creator><creator>Jiang, Yu</creator><creator>Yan, Wangjun</creator><creator>Zhang, Jian</creator><creator>Hui, Ai-Min</creator><creator>Yang, Yuchen</creator><creator>Diao, Lei</creator><creator>Tan, Yan</creator><creator>Zhao, Han</creator><creator>Jiang, Yiqian</creator><creator>Wu, Zhuli</creator><creator>Si, Lu</creator><general>Elsevier Ltd</general><general>Elsevier Science Ltd</general><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-2123-9761</orcidid><orcidid>https://orcid.org/0000-0003-0716-4334</orcidid></search><sort><creationdate>202211</creationdate><title>A first-in-human, phase 1a dose-escalation study of the selective MEK1/2 inhibitor FCN-159 in patients with advanced NRAS-mutant melanoma</title><author>Mao, Lili ; Guo, Jun ; Zhu, Lingjun ; Jiang, Yu ; Yan, Wangjun ; Zhang, Jian ; Hui, Ai-Min ; Yang, Yuchen ; Diao, Lei ; Tan, Yan ; Zhao, Han ; Jiang, Yiqian ; Wu, Zhuli ; Si, Lu</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c405t-efc68196d8db8a7e51ca4121bdc21505e4331cd738b10fe59deb47991d330f3d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Advanced melanoma</topic><topic>Anticancer properties</topic><topic>Dosage</topic><topic>Folliculitis</topic><topic>Inhibitors</topic><topic>Maximum tolerated dose</topic><topic>MEK inhibitor</topic><topic>Melanoma</topic><topic>Mutants</topic><topic>NRAS</topic><topic>Patients</topic><topic>Pharmacokinetics</topic><topic>Phase 1 trial</topic><topic>Recommended phase 2 dose</topic><topic>Targeted therapy</topic><topic>Toxicity</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mao, Lili</creatorcontrib><creatorcontrib>Guo, Jun</creatorcontrib><creatorcontrib>Zhu, Lingjun</creatorcontrib><creatorcontrib>Jiang, Yu</creatorcontrib><creatorcontrib>Yan, Wangjun</creatorcontrib><creatorcontrib>Zhang, Jian</creatorcontrib><creatorcontrib>Hui, Ai-Min</creatorcontrib><creatorcontrib>Yang, Yuchen</creatorcontrib><creatorcontrib>Diao, Lei</creatorcontrib><creatorcontrib>Tan, Yan</creatorcontrib><creatorcontrib>Zhao, Han</creatorcontrib><creatorcontrib>Jiang, Yiqian</creatorcontrib><creatorcontrib>Wu, Zhuli</creatorcontrib><creatorcontrib>Si, Lu</creatorcontrib><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of cancer (1990)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mao, Lili</au><au>Guo, Jun</au><au>Zhu, Lingjun</au><au>Jiang, Yu</au><au>Yan, Wangjun</au><au>Zhang, Jian</au><au>Hui, Ai-Min</au><au>Yang, Yuchen</au><au>Diao, Lei</au><au>Tan, Yan</au><au>Zhao, Han</au><au>Jiang, Yiqian</au><au>Wu, Zhuli</au><au>Si, Lu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A first-in-human, phase 1a dose-escalation study of the selective MEK1/2 inhibitor FCN-159 in patients with advanced NRAS-mutant melanoma</atitle><jtitle>European journal of cancer (1990)</jtitle><date>2022-11</date><risdate>2022</risdate><volume>175</volume><spage>125</spage><epage>135</epage><pages>125-135</pages><issn>0959-8049</issn><eissn>1879-0852</eissn><abstract>A phase 1a first-in-human study evaluated the safety/tolerability, preliminary antitumour activity and pharmacokinetics of the oral MEK1/2 inhibitor FCN-159 in Chinese patients with advanced, NRAS-mutant melanoma.
Patients received a single FCN-159 dose at assigned levels, proceeding to continuous dosing (once daily [QD] for 28-day cycles) if no dose-limiting toxicities (DLTs) occurred within the next 3 days. Dose escalation was initiated after review of data for the previous dose level. The primary end-point was incidence of DLTs after the first dose.
Thirty-three patients were enrolled across nine FCN-159 dose groups (0.2–15 mg QD). One DLT occurred: grade 3 folliculitis in the 15-mg group. There was one grade >3 treatment-emergent adverse event (TEAE), death of unknown aetiology (not FCN-159 related). The most common FCN-159–related TEAE was rash (36.4%), and the incidence of grade ≥3 FCN-159–related TEAEs was 15.2%. Antitumour activity at QD doses <6 mg was limited; therefore, efficacy data are presented only for doses ≥6 mg (n = 21). The objective response and clinical benefit rates were 19.0% (four partial responses) and 52.4%, respectively. Median (95% confidence interval) duration of response and progression-free survival were 4.8 months (2.8–not reached) and 3.8 months (1.8–5.6), respectively. FCN-159 exposure increased dose-proportionately; geometric mean terminal half-life was 29.9–56.9 h.
FCN-159 was well tolerated and demonstrated promising antitumour activity at doses ≥6 mg QD in patients with advanced, NRAS-mutant melanoma. The recommended phase 2 dose was 12 mg QD.
NCT03932253. https://clinicaltrials.gov/ct2/show/NCT03932253.
•There is currently no standard targeted therapy for advanced NRASmut melanoma.•FCN-159, a selective MEK1/2 inhibitor, was evaluated in a first-in-human study.•FCN-159 was well tolerated in Chinese patients with advanced NRASmut melanoma.•Preliminary signs of antitumour activity were observed at FCN-159 doses ≥6 mg QD.•The findings support further study of FCN-159 in patients with NRASmut melanoma.</abstract><cop>Oxford</cop><pub>Elsevier Ltd</pub><doi>10.1016/j.ejca.2022.08.005</doi><tpages>11</tpages><orcidid>https://orcid.org/0000-0002-2123-9761</orcidid><orcidid>https://orcid.org/0000-0003-0716-4334</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0959-8049 |
| ispartof | European journal of cancer (1990), 2022-11, Vol.175, p.125-135 |
| issn | 0959-8049 1879-0852 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2715441777 |
| source | Elsevier ScienceDirect Journals |
| subjects | Advanced melanoma Anticancer properties Dosage Folliculitis Inhibitors Maximum tolerated dose MEK inhibitor Melanoma Mutants NRAS Patients Pharmacokinetics Phase 1 trial Recommended phase 2 dose Targeted therapy Toxicity |
| title | A first-in-human, phase 1a dose-escalation study of the selective MEK1/2 inhibitor FCN-159 in patients with advanced NRAS-mutant melanoma |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-28T02%3A13%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20first-in-human,%20phase%201a%20dose-escalation%20study%20of%20the%20selective%20MEK1/2%20inhibitor%20FCN-159%20in%20patients%20with%20advanced%20NRAS-mutant%20melanoma&rft.jtitle=European%20journal%20of%20cancer%20(1990)&rft.au=Mao,%20Lili&rft.date=2022-11&rft.volume=175&rft.spage=125&rft.epage=135&rft.pages=125-135&rft.issn=0959-8049&rft.eissn=1879-0852&rft_id=info:doi/10.1016/j.ejca.2022.08.005&rft_dat=%3Cproquest_cross%3E2754549911%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2754549911&rft_id=info:pmid/&rft_els_id=S0959804922004816&rfr_iscdi=true |