PF291 A PHASE 1B/2 CLINICAL STUDY OF TARGETED IDH1 INHIBITION WITH IVOSIDENIB, IN COMBINATION WITH THE BCL‐2 INHIBITOR VENETOCLAX, FOR PATIENTS WITH IDH1‐MUTATED (MIDH1) MYELOID MALIGNANCIES
Notice bibliographique
Résumé
Background: IDH1 mutations (mIDH1) occur in 5–12% of patients with high‐risk MDS and AML. IDH mutations sensitize AML cells to BCL2 inhibition, and pre‐clinical evidence demonstrates the synergistic activity of targeted mIDH‐inhibition with BCL2 inhibition in mIDH PDX models. Ivosidenib (IVO) is an oral potent targeted inhibitor approved for relapsed/refractory mIDH1 AML. Venetoclax (VEN) is an oral targeted BCL2 inhibitor approved in combination for patients with newly diagnosed AML, ineligible for intensive chemotherapy. Aims: We report the first clinical results from an ongoing open label Phase 1b/2 study evaluating the safety, tolerability, pharmacokinetic profiles, and efficacy of IVO and VEN in combination for patients with mIDH1 myeloid malignancy (NCT03471260). Methods: Eligible patients include adults ≥ 18 years with IDH1‐R132 mutated high‐risk MDS or AML. Prior therapy with ivosidenib or venetoclax was exclusionary; receipt of other targeted mutant IDH1 inhibitors was allowed. Patients receive VEN on days 1–14 of each treatment cycle. IVO is given continuously daily starting on cycle 1 day 15. Each cycle is 28 days. Patients in the Phase 1b study portion are enrolled of cohorts of 6; we report results from patients treated on dose level 0 (VEN 400 mg and IVO 500 mg) and level +1 (VEN 800 mg and IVO 500 mg). Results: As of Feb 26 2019, 11 IDH1‐mutated patients have been enrolled on study; 10 AML and 1 MDS patient with excess blasts refractory to hypomethylating agent therapy. The study opened to enrollment in March 2018; median follow‐up time is 6 months. Median patient age is 65 yrs (range 37–83 yrs), and 6 patients are male. Patients had received a median of 2 prior therapies (range 0–5); two patients were treatment naïve. Additional clinicopathologic details are provided in Table 1. Grade ≥ 3 adverse events (AEs) occurring on study regardless of attribution included lung infection (n = 7), febrile neutropenia (n = 3), other infection (n = 2), differentiation syndrome (n = 1), stroke (n = 1), TLS (n = 1), leukocytosis (n = 1) and acute kidney injury (n = 1). The only Grade 1–2 AE occurring in ≥ 2 patients was diarrhea (n = 3). Grade 2 QTc prolongation occurred in one patient. One patient was enrolled in Feb 2019 and remains too early for response assessment, and one refractory AML patient received ten VEN doses prior to death from complications of infection, and was inevaluable for efficacy of the combination. Of 9 evaluable patients, responses include CR in 44% (n = 4), CRi in 33% (n = 3), and no response/progressive disease in 22% (n = 2). One responding CRi patient progressed with extramedullary disease, and discontinued study treatment for cytarabine‐based therapy. All other responders (n = 6) remain on study with a median of six cycles received to date (range 1–9, all ongoing). Of the seven patients achieving CR/CRi, 3 patients, all in CR, obtained negative measurable residual disease (MRD) by multiparameter flow cytometry (0.01% sensitivity). Analysis for IDH mutational clearance at remission, as well as BCL2 family expression and BH3 profiling for all patients is ongoing. Summary/Conclusion: IVO + VEN is a well‐tolerated regimen with a safety profile consistent with single‐agent IVO and VEN. The preliminary response rate of this combination appears favorable with a CR rate of 44% and CR/CRi rate of 78% in evaluable patients, with 43% of responding patients attaining MRD negativity by flow cytometry. This study continues to enroll and a future cohort will evaluate the “triplet” of IVO + VEN with azacitidine. image
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 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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| 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 | 0,001 |
| 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 ».