INCB057643, a bromodomain and extra-terminal protein inhibitor, in combination with ruxolitinib in patients with myelofibrosis: A phase 1 study of safety and efficacy
Notice bibliographique
Résumé
Abstract Background: The pathophysiology of myelofibrosis (MF) and other hematologic malignancies is modulated by the epigenetic reader bromodomain and extra-terminal (BET) protein. Combination therapy with the BET inhibitor INCB057643 and the Janus kinase (JAK) inhibitor ruxolitinib (RUX) has been shown to synergistically reduce levels of various pro-inflammatory cytokines, reduce disease burden, and reverse bone marrow fibrosis in myeloproliferative neoplasm models. Methods:This analysis of an ongoing phase 1, open-label, 3+3 dose-escalation/expansion study (NCT04279847) is evaluating INCB057643 combination therapy (during dose escalation: starting dose 4 mg once daily [qd] up to the maximum tolerated dose of 10 mg qd established with INCB057643 monotherapy; during dose expansion: starting dose 4 mg qd or 8 mg qd given continuously) as add-on to RUX in adults with MF and suboptimal response to RUX or who were JAK inhibitor (JAKi) naive. The INCB057643 starting dose for each patient was selected based on baseline platelet count, and intra-patient dose upward titration was allowed based on protocol-defined criteria (up to 10 mg qd). Safety and tolerability is the primary endpoint; secondary endpoints include spleen volume response (≥35% reduction from baseline [SVR35] at Week 24), symptom response (≥50% reduction from baseline in Myeloproliferative Neoplasm Symptom Assessment Form total symptom score [TSS50] at Week 24), and anemia response (sustained hemoglobin increase ≥1.5 g/dL [if transfusion independent at baseline] or transfusion independence [if dependent at baseline] for ≥12 weeks). Results:As of March 17, 2025,23 patients were treated in dose escalation (all with suboptimal response to RUX; 11 ongoing) and 13 in dose expansion (all ongoing; suboptimal response to RUX, n=9; JAKi-naive, n=4). Median (range) INCB057643 exposure was 334 (85–749) days in dose escalation; in dose expansion, exposure was 112 (12–172) days in suboptimal response to RUX and 27 (19–34) in newly enrolled JAKi-naive patients. All patients were evaluable for safety. Thrombocytopenia (50%, n=18/36) was the most common treatment-emergent adverse event (TEAE). Grade ≥3 TEAEs occurred in 39% (n=14/36) of patients, with the most common (≥20%) being thrombocytopenia (22%, n=8/36) and anemia (22%, n=8/36). Serious TEAEs occurred in 25% (n=9/36) of patients, with 6% (n=2/36; grade 3 hematoma and grade 3 pyrexia) considered related to INCB057643 treatment. Gastrointestinal (17%, n=6/36) and hepatic (alanine aminotransferase increased, 8% [n=3/36]; aspartate aminotransferase increased, 8% [n=3/36]) TEAEs related to INCB057643 treatment were uncommon and manageable (all were grade 1–2). There were no fatal events that were considered related to INCB057643 treatment. One patient experienced a dose-limiting toxicity (6 mg, thrombocytopenia), and 2 patients had leukemic transformation (4 mg and 8 mg; both with suboptimal response to RUX and multiple high-risk factors for leukemic transformation, with 1 in accelerated phase at baseline). Among patients with a Week 24 efficacy assessment (all of which were in the suboptimal response to RUX group), SVR35 was achieved by 5 of 23 (22%) evaluable patients at Week 24 and by 8 of 28 (29%) patients as best overall response (BOR) at any time. SVR25 at Week 24 was reached by 8 of 23 (35%) patients, and 10 of 28 (36%) patients had a BOR of SVR25. At Week 24, 11 of 21 (52%) evaluable patients achieved a TSS50; 20 of 29 (69%) patients had a BOR of TSS50, and 21 of 29 (72%) had TSS30. Durable anemia response lasting ≥12 weeks occurred in 7 of 28 (25%) evaluable patients, regardless of transfusion status at baseline. Conclusions:INCB057643 combination therapy with RUX was generally well tolerated on a continuous dosing schedule, with few treatment-related serious TEAEs and no treatment-related fatal events, and was associated with improvement in spleen size, marked improvement in symptom burden, and anemia responses. Dose expansion is ongoing for the 4- and 8-mg combination in both the add-on therapy group and in JAKi-naive patients.
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 | 0,002 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
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 ».