741 TWT-101: a first-in-clinic study of CFI-402411, a hematopoietic progenitor Kinase-1 (HPK1) inhibitor, as single agent or combined with pembrolizumab in subjects with advanced solid malignancies
Notice bibliographique
Résumé
Background CFI-402411, a potent HPK1 inhibitor, may promote T-cell response to tumors through a variety of mechanisms that enhance T-cell function in the cancer immunity cycle, and potentially in settings where antigens are expressed poorly and heterogeneously.1 Preliminary results demonstrated tolerable safety profile with efficacy signals in select tumor types.2 Methods In this ongoing phase 1/2 study, part A evaluates CFI-402411 daily dose (3+3 design) and dose expansion; part B evaluates CFI-402411 in combination with pembrolizumab (200mg) as BOIN design and dose expansion in pembrolizumab eligible tumors. Dose limiting toxicity (DLT) is any grade ≥3 toxicity in cycle 1. Starting dose was 80mg. Results At 02-May-2023 the study enrolled 59 patients (pts; A, 40pts; B, 19pts). In US, checkpoint inhibitor (CPI) pretreated patients were eligible. Diagnoses in ≥2pts for A: colorectal (11pts), melanoma (6pts), pancreatic (5pts) and non-small cell lung and prostate (2pts each) cancers; for B: head and neck squamous cell (HNSCC; 3pts) and esophageal, non-small cell lung and small cell lung cancers (2pts, each). Part A tested 9 dose levels (80 - 800mg). B tested 5 dose levels (60 - 400mg) to date. Immune-related AEs (irAE) were reported in 7 pts (A; 18%) and 5 pts (B; 26%). Grade ≥3 AEs occurred in 25 pts (A: 63%) and 10pts (B: 53%). SAE’s occurred in 21 pts (A: 53%) and 11 pts (B: 58%). Diarrhea was the most common TEAE (A: 73%; B: 47%), related AE (A: 63%; B: 42%), irAE (A: 15%; B: 11%), and grade ≥3 AE in A (18%). Most common grade ≥3 AE in B was pulmonary embolism (PE) and AST increase (11% both). The most common SAE was sepsis (A: 15%) and PE (B: 11%). Diarrhea was the most common DLT occurring at 400mg+pembro; 800mg, 720mg, 640mg monotherapy doses. Disease control rates (CR, PR, or SD ≥ 6 weeks from baseline) at 3 months were 18% (A) and 29% (B). Two HNSCC pts achieved a PR (A: 400mg) and confirmed CR (B: 60mg+pembro). A third HNSCC pt’s (B: 400mg+pembro) tumor lesion size reduced 16% at week 5 and pt remains on study. One RCC pt achieved long term SD, 2 years. All 4 pts had prior CPI exposure. Conclusions CFI-402411 is well-tolerated with a manageable AE profile. Responses as monotherapy and in combination with CPI in CPI exposed patients were seen. Monotherapy part A expansion at 560 mg is underway in HNSCC and RCC. Acknowledgements 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. Trial Registration NCT04521413 References You D, Hillerman S, Locke G, et al. Enhanced antitumor immunity by a novel small molecule HPK1 inhibitor. J Immunother Cancer 2021;9(1):e001402 Papadopoulos K, Fu S, Hamilton E, et al. 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. Journal for ImmunoTherapy of Cancer 2022;10:doi: 10.1136/jitc-2022-SITC2022.0750 Ethics Approval This study obtained ethics approvals; Papadopoulos; ID: Pro00051609 Fu; ID2020–0678 Hamilton; ID: Pro00051611 Spira; ID: Pro00043629 Laurie; CTO Project ID 3320 Wang; ID: Pro00051611 Ma; CREC Ref: 2020.367-T Spreafico; CTO Project ID 3320 Sharma; ID Pro00051609 Chu; ID: HREBA.CC-20–0504_REN1 Hamid; IRB: 2020236 Consent As evidenced by verified clinical database information all subjects gave informed consent before taking part in this clinical trial.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,002 | 0,001 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,001 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,002 | 0,004 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,007 | 0,002 |
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 source (Gemma direct ou Codex distillé), 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 ».