First-in-Human Phase I Clinical Trial of SLC-391, a Novel and Selective AXL Inhibitor, in Patients with Advanced Solid Tumours

Our plain-English summary of First-in-Human Phase I Clinical Trial of SLC-391, a Novel and Selective AXL Inhibitor, in Patients with Advanced Solid Tumours, by Z. Zhang, D. Morrison, L. Lu, et al (Pharmaceuticals, 2025).

The study

• Authors: Z. Zhang, D. Morrison, L. Lu, M. Singh, J. Yan, N. Leighl, S.A. Laurie, S. Hotte
• Journal: Pharmaceuticals
• Published: 2025;18(12)
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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's 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).

In plain English

This was a first-in-human, open-label, multi-centre phase I trial of SLC-391, an experimental oral drug that blocks a protein called AXL. It enrolled 35 adults in Canada with advanced solid tumours. Using a 3 + 3 dose-escalation design, 20 patients took the drug once daily (25 mg to 175 mg) and 15 took it twice daily (75 mg to 200 mg), in 21-day cycles. Non-small cell lung cancer was the most common tumour. Four patients had mesothelioma, including one peritoneal and one pleural epithelioid case. Adverse events during treatment, whatever their cause, occurred in 34 of 35 patients, most often nausea, fatigue, diarrhoea and vomiting. Investigators judged at least one event related to the drug in 31 patients. Three (8.6%) had severe (Grade 3) drug-related adverse events. Dose-limiting toxicities occurred at 175 mg once daily (Grade 3 haematochezia, meaning bloody stools) and at 200 mg twice daily (Grade 3 low platelets with Grade 1 blood in the urine). The maximum tolerated dose was not reached. Twelve of 35 patients had stable disease, including all four with mesothelioma, lasting 44 to 318 days. The authors concluded that 150 mg twice daily was generally well tolerated.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: First-in-human, open-label, multi-centre phase I dose-escalation trial using a standard 3 + 3 design (NCT03990454)
• Who was studied: 35 adults in Canada with previously treated advanced, metastatic or unresectable solid tumours (first patient dosed 7 November 2019). Non-small cell lung cancer was the most common tumour type (16 of 35). Four patients had mesothelioma: 2 listed as mesothelioma, 1 peritoneal mesothelioma and 1 pleural epithelioid mesothelioma.
• Exposure: The experimental AXL inhibitor SLC-391 taken by mouth in 21-day cycles, either once daily (25, 50, 100, 125, 150 or 175 mg; 20 patients) or twice daily (75, 110, 150 or 200 mg; 15 patients). The study did not examine or report asbestos exposure.
• Main results:
  • 34 of 35 patients (97.1%) had at least one treatment-emergent adverse event, regardless of its relationship to the drug
  • 31 of 35 patients (88.6%) had at least one adverse event that the investigator considered related to SLC-391
  • The most common treatment-emergent adverse events, regardless of severity or relationship to the drug, were nausea, fatigue, diarrhoea and vomiting, in both the once-daily and twice-daily groups
  • 3 of 35 patients (8.6%) had Grade 3 treatment-related adverse events considered related to SLC-391
  • Eight serious adverse events occurred in five patients (14.3%): seven Grade 3 and one Grade 2
  • Dose-limiting toxicities: Grade 3 haematochezia in one of the two patients at 175 mg once daily, and Grade 3 thrombocytopenia with Grade 1 haematuria in one patient at 200 mg twice daily
  • The maximum tolerated dose was not reached. The 150 mg twice-daily dose (6 patients) had no dose-limiting toxicities and no serious adverse events.
  • 12 of 35 patients had stable disease as their best response (RECIST 1.1, or modified RECIST for mesothelioma)
  • Stable disease occurred in all 4 mesothelioma patients and in 4 of 16 NSCLC patients, among others, and lasted 44 to 318 days
  • Among the twice-daily cohorts, the stable disease rate was 50.0% (3 of 6) at 150 mg twice daily
  • The clinical benefit rate was 34.3%
• The authors' conclusion: The authors concluded that a total daily dose of 300 mg (150 mg twice daily) of SLC-391 alone was generally well tolerated, with no dose-limiting toxicities or serious adverse events at that dose, and that the drug warrants future clinical investigations.
• Limitations the authors state:
  • The authors state that the drug's efficacy was not definitively established at this phase of development
  • The drug's half-life is long compared with the dosing interval, so some pharmacokinetic measures, such as plasma half-life, could not be calculated

Topics

Medical terms in this study, explained in our Lexicon: Clinical Trial, Metastasis, Mesothelioma, Pembrolizumab (Keytruda), Non-Small Cell Lung Cancer.

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