750 TWT-101: a first-in-clinic, phase 1/2 study of CFI-402411, a hematopoietic progenitor kinase-1 (HPK1) inhibitor, as a single agent and in combination with pembrolizumab in subjects with advanced solid malignancies
Notice bibliographique
Résumé
<h3>Background</h3> CFI-402411 is a potent inhibitor of HPK1 (<b>H</b>ematopoietic <b>p</b>rogenitor <b>k</b>inase 1), a protein serine/threonine kinase that negatively-regulates T-cell activation. Following T-cell receptor engagement, HPK1 phosphorylates SLP-76, to down-regulate signals required for T-cell activation and proliferation<sup>1,2</sup>. CFI-402411 is expected to relieve HPK1-mediated inhibition of T-cell activation, facilitating an anti-tumor immune response. <h3>Methods</h3> In this ongoing phase 1 study, part A evaluates CFI-402411 daily dose in dose escalation cohort (3+3 design) and dose expansion, part B evaluates CFI-402411 in combination with pembrolizumab in dose escalation (BOIN design) and dose expansion in pembrolizumab eligible tumors. Dose limiting toxicity (DLT) is any grade ≥3 toxicity in the first cycle of therapy (21d cycles). Starting dose was 80mg. <h3>Results</h3> As of 14 May 2022 (data cutoff), 25 and 9 patients (pts) enrolled to A and B respectively. Median age was 62 (30-79). Median cycles of treatment were 3 (range: 0-20). Majority of patients were male (A, 60% and B, 78%). Median prior regimens were 2 (range: A, 1-4; B, 1-3). 6pts (A, 24%) and 5pts (B, 56%) received prior anti-PD-1/anti-PD-L1 inhibitor. Diagnoses in ≥2pts for A: colorectal (6pts), pancreatic (5pts); for B: small cell lung cancer (2pts). 8 dose levels (80 to 800 mg) have been studied in A, 2 dose levels (60 and 80 mg) in B. TEAEs occurring in ≥40% of A pts: diarrhea (n=17, 68%), nausea (n=11, 44%), decreased appetite (n=10, 40%); and B: vomiting (n=4, 44%). 19pts (76%) in A and 6pts (67%) in B experienced CFI-402411 related AEs. Immune-related AEs were reported in 1pt (A; 4% [ALT and AST increase]) and 2pts (B; 22% [febrile illness, flu-like symptoms]). Grade ≥3 AEs and serious AEs occurred in 14pts (56%) and 10pts (40%) in A; and 3pts (33%) and 4pts (44%) in B. DLTs occurred in 2pts (A [800mg]: diarrhea, spinal cord compression) and 1pt (B [80mg+pembro]: flu-like symptoms). No novel toxicity signals were seen. Disease control rates were 24% in A (6/25) and 44% in B (4/9). One B patient (11%), squamous head and neck cancer (H&N) previously treated with pembrolizumab, has confirmed partial response (PR) and remains on treatment, 8 cycles. An additional H&N patient treated with monotherapy CFI-402411 achieved unconfirmed PR after data cut. <h3>Conclusions</h3> CFI-402411 is a well-tolerated, potent inhibitor of HPK1 with a manageable AE profile and initial evidence of activity. RP2D and additional safety and efficacy data will be reported at conference presentation. <h3>Acknowledgements</h3> Treadwell Therapeutics would like to thank both the patients and the research staff at enrolling centers who have helped to bring this novel therapy to the clinic. <h3>Trial Registration</h3> NCT04521413 <h3>References</h3> Hu MQ. Human HPK1, a novel human hematopoietic progenitor kinase that actives the JNK/SAPK kinase cascade.<i> Genes & Development.</i> 1996;<b>10</b>:2251–2264. Lasserre RC-G. Release of serine/threonine-phosphorylated adaptors from signaling microclusters down-regulates T cell activation. <i>Immuno Res.</i> 2011;<b>295</b>:839–853. <h3>Ethics Approval</h3> This study obtained ethics approvals at the following ethics/IRB’s; Papadopoulos, KP; Advarra IRB ID: Pro00051609 Fu, S; University of Texas MD Anderson Cancer Center Office of Human Subject Protection IRB ID 2020-0678 Hamilton, E; Advarra IRB ID: Pro00051611 Spira, A; Advarra IRB ID: Pro00043629 Laurie, S; Ontario Cancer Research Ethics Board, CTO Project ID 3320 Wang, J; Advarra IRB ID: Pro00051611 Ma, B; Joint Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee CREC Ref. No .: 2020.367-T Spreafico, A; Ontario Cancer Research Ethics Board, CTO Project ID 3320 Sharma, M; Advarra IRB: ID Pro00051609 Chu, Q; Health Research Ethics Board of Alberta Ethics ID: HREBA.CC-20-0504_REN1 Hamid, O; WCG, IRB: IRB Tracking Number: 2020236 As evidenced by verified clinical database information all subjects gave informed consent before taking part in this clinical trial.
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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) | 0,000 | 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 ».