First-in-Human Phase I Clinical Trial of SLC-391, a Novel and Selective AXL Inhibitor, in Patients with Advanced Solid Tumours
Notice bibliographique
Résumé
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).
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».