{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:49:28Z","timestamp":1790401768263,"version":"4.1.0"},"reference-count":22,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: AXL, a receptor tyrosine kinase of the TAM family, has emerged as a key target in cancer therapy due to its role in tumour growth, metastasis, immune evasion, and therapy resistance. SLC-391, a novel, orally bioavailable and selective AXL inhibitor, has demonstrated potent anti-tumour effects in preclinical studies. This first-in-human, open-label, multi-centre Phase I clinical trial (NCT03990454) was conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of SLC-391 in patients with advanced solid tumours. Methods: Using a 3 + 3 design, SLC-391 was administered orally, either once daily (from 25 mg up to 175 mg QD) or twice daily (from 75 mg to 200 mg BID) in 21-day cycles. Results: Following single and repeated dosing, SLC-391 was generally well tolerated by subjects. The maximum tolerated dose (MTD) was not reached in this study. A total of 34\/35 subjects experienced at least one TEAE. Three (8.6%) subjects experienced Grade 3 TRAEs that were considered related to SLC-391. Eight SAEs were reported in five (14.3%) subjects (seven Grade 3 SAEs and one Grade 2 SAE), in 150 mg QD (3\/6, 50%), 175 mg QD (1\/2, 50%), and 110 mg BID (1\/3, 33.3%) cohorts. Four SAEs in three (8.6%) subjects led to dose interruption, drug withdrawal, or study discontinuation. Three DLTs were reported in two subjects: one subject experienced Grade 3 hematochezia (SUSAR\/DLT) at 175 mg QD, and another subject experienced Grade 3 thrombocytopenia associated with Grade 1 hematuria at 200 mg BID. The median Tmax was 2.0 h. Plasma concentrations following multiple doses generally increased with higher doses and appeared to reach steady state by Day 21 and were generally dose-proportional. Twelve (12) out of 35 subjects with solid tumours achieved stable disease according to RECIST or mRECIST (mesothelioma), with durations of stable disease lasting up to 318 days on SLC-391 monotherapy. The clinical benefit rate was 34.3%. Conclusions: This first study of SLC-391 in adult subjects with advanced solid tumours demonstrated that a total daily dose of 300 mg (150 mg BID) of SLC-391 monotherapy was generally well tolerated, with no DLTs or SAEs observed at this dose. The drug\u2019s promising safety profile, along with stable disease reported for several subjects with advanced solid tumours, provides a strong rationale for the phase 1b\/2a clinical investigation of SLC-391 in combination with pembrolizumab in subjects with advanced or metastatic non-small cell lung cancer (NSCLC) (NCT05860296).<\/jats:p>","DOI":"10.3390\/ph18121898","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T09:43:46Z","timestamp":1765964626000},"page":"1898","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["First-in-Human Phase I Clinical Trial of SLC-391, a Novel and Selective AXL Inhibitor, in Patients with Advanced Solid Tumours"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8652-761X","authenticated-orcid":false,"given":"Zaihui","family":"Zhang","sequence":"first","affiliation":[{"name":"SignalChem Lifesciences Corp., Richmond, BC V6V 2J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Morrison","sequence":"additional","affiliation":[{"name":"SignalChem Lifesciences Corp., Richmond, BC V6V 2J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Lu","sequence":"additional","affiliation":[{"name":"SignalChem Lifesciences Corp., Richmond, BC V6V 2J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhu","family":"Singh","sequence":"additional","affiliation":[{"name":"SignalChem Lifesciences Corp., Richmond, BC V6V 2J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yan","sequence":"additional","affiliation":[{"name":"SignalChem Lifesciences Corp., Richmond, BC V6V 2J1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natasha","family":"Leighl","sequence":"additional","affiliation":[{"name":"Princess Margaret Cancer Centre, Toronto, ON M5G 2C4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott A.","family":"Laurie","sequence":"additional","affiliation":[{"name":"The Ottawa Hospital Cancer Centre, Ottawa, ON K1H 8L6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9286-1972","authenticated-orcid":false,"given":"Sebastien","family":"Hotte","sequence":"additional","affiliation":[{"name":"Juravinski Cancer Centre, Hamilton, ON L8V 5C2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Goyette, M.-A., and Cote, J.-F. (2022). AXL receptor tyrosine kinase as a promising therapeutic target directing multiple aspects of cancer progression and metastasis. Cancers, 14.","DOI":"10.3390\/cancers14030466"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tanaka, M., and Siemann, D.W. (2020). Gas6\/Axl signaling pathway in the tumor immune microenvironment. Cancers, 12.","DOI":"10.3390\/cancers12071850"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Wium, M., Ajayi-Smith, A.F., Paccez, J.D., and Zerbini, L.F. (2021). The role of the receptor tyrosine kinase Axl in carcinogenesis and development of therapeutic resistance: An overview of molecular mechanisms and future applications. Cancers, 13.","DOI":"10.3390\/cancers13071521"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Auyez, A., Sayan, A.E., Kriajevska, M., and Tulchinsky, E. (2021). AXL receptor in cancer metastasis and drug resistance: When normal functions go askew. Cancers, 13.","DOI":"10.3390\/cancers13194864"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"67","DOI":"10.2147\/LCTT.S305484","article-title":"Targeting AXL in NSCLC","volume":"12","author":"Zaman","year":"2021","journal-title":"Lung Cancer Targets Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1186\/s12943-019-1090-3","article-title":"AXL receptor tyrosine kinase as a promising anti-cancer approach: Functions, molecular mechanisms and clinical applications","volume":"18","author":"Zhu","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Son, H.Y., and Jeong, H.K. (2021). Immune evasion mechanism and AXL. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.756225"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.2217\/fon-2020-0967","article-title":"Addressing resistance to immune checkpoint inhibitor therapy: An urgent unmet need","volume":"17","author":"Malouf","year":"2021","journal-title":"Future Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Engelsen, A.S.T., Lotsberg, M.L., Khouzam, R.A., Thiery, J.-P., Lorens, J.B., Chouaib, S., and Terry, S. (2022). Dissecting the Role of AXL in Cancer Immune Escape and Resistance to Immune Checkpoint Inhibition. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.869676"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Sang, Y.B., Kin, J.H., Kim, C.G., Hong, M.H., Kim, H.R., Cho, B.C., and Lim, S.M. (2022). The development of AXL inhibitors in lung cancer: Recent progress and challenges. Front. Oncol., 12.","DOI":"10.3389\/fonc.2022.811247"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3641","DOI":"10.1182\/blood.2020007651","article-title":"Targeting AXL kinase sensitizes leukemic stem and progenitor cells to venetoclax treatment in acute myeloid leukemia","volume":"137","author":"Niu","year":"2021","journal-title":"Blood"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2716","DOI":"10.1158\/1538-7445.AM2014-2716","article-title":"Discovery of novel TAM family kinase inhibitors","volume":"74","author":"Zhang","year":"2014","journal-title":"Cancer Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1746","DOI":"10.1158\/1538-7445.AM2014-1746","article-title":"Novel and Selective Axl Inhibitors","volume":"74","author":"Zhang","year":"2014","journal-title":"Cancer Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5393","DOI":"10.1158\/1538-7445.AM2015-5393","article-title":"Evaluation of Compounds Developed against AXL Kinase","volume":"75","author":"Zhang","year":"2015","journal-title":"Cancer Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4196","DOI":"10.1158\/1538-7445.AM2017-4196","article-title":"Anti-Tumor Activity of a TAM Kinase-targeting Compound in CT-26 Syngeneic Mouse Model","volume":"77","author":"Lai","year":"2017","journal-title":"Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"B148","DOI":"10.1158\/1535-7163.TARG-17-B148","article-title":"Activity of the TAM kinase-targeting compound, SLC-391, is mediated by the engagement of the immune system in CT-26 syngeneic mouse model","volume":"17","author":"Lai","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3853","DOI":"10.1158\/1538-7445.AM2018-3853","article-title":"AXL inhibitor promotes anti-tumor immunity through modulation of macrophage polarization","volume":"78","author":"Lai","year":"2018","journal-title":"Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1007\/s11912-023-01392-7","article-title":"AXL Inhibitors: Status of Clinical Development","volume":"25","author":"Bhalla","year":"2023","journal-title":"Curr. Oncol. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1080\/13543784.2025.2511178","article-title":"Prospects of current AXL-targeting therapies in early phase cancer trials","volume":"34","author":"Yim","year":"2025","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.ejca.2008.10.026","article-title":"New Response Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (Version 1.1)","volume":"45","author":"Eisenhauer","year":"2009","journal-title":"Eur. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1093\/jnci\/92.3.205","article-title":"New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada","volume":"92","author":"Therasse","year":"2000","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1093\/jnci\/89.15.1138","article-title":"Accelerated Titration Designs for Phase I Clinical Trials in Oncology","volume":"89","author":"Simon","year":"1997","journal-title":"J. Natl. Cancer Inst."}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/12\/1898\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T09:50:21Z","timestamp":1765965021000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/18\/12\/1898"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,17]]},"references-count":22,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ph18121898"],"URL":"https:\/\/doi.org\/10.3390\/ph18121898","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,17]]}}}