Abstract B065: A phase 1 study of abemaciclib, a CDK 4/6 inhibitor, with radiation in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG)
Notice bibliographique
Résumé
Abstract BACKGROUND: Cyclin-dependent kinases 4 and 6 (CDK 4/6) control cell cycle progression through phosphorylation of Rb. Tumor tissue studies in diffuse intrinsic pontine glioma (DIPG) demonstrate frequent alterations in cell cycle regulatory proteins, including CDK 4/6, and infrequent deletions in Rb1. Preclinical DIPG studies have demonstrated prolonged survival when CDK 4/6 inhibition is added to radiation therapy (RT) compared to RT alone. Abemaciclib is a selective and potent, orally bioavailable small molecule CDK 4/6 inhibitor that crosses the blood brain barrier. We conducted a Phase 1 trial to determine the maximum tolerated dose (MTD) of abemaciclib administered concurrently with RT, and to describe the toxicity and pharmacokinetic (PK) profile, in patients with newly diagnosed DIPG. METHODS: Patients 2-25 years of age with newly diagnosed DIPG were eligible. A CDK 4/6 pathway alteration was not required, and patients with known RB1 mutations were excluded. Abemaciclib was administered orally twice daily on days 1-28 of a 28-day cycle. Four dose levels (DLs) were evaluated using a rolling-six design: 75 (DL0), 100 (DL1), 130 (DL2), and 170 (DL3) mg/m2/dose. Abemaciclib started concurrently with RT and was continued as maintenance after completion of RT until the patient experienced progression or unacceptable toxicity. The 6-week duration of RT (54 Gy in 30 fractions) constituted the dose-limiting toxicity (DLT) evaluation period. The PKs of abemaciclib were evaluated at serial timepoints. RESULTS: Median age of the 22 enrolled patients was 7.1 years (range: 2.6 - 20.1). Eleven (50%) patients were biopsied; 10 were histologically defined as H3K27M mutant diffuse midline glioma. In seventeen DLT-evaluable patients, there was 1 DLT during the DLT evaluation period, grade 3 nausea that occurred on DL3. There were 5 DLTs during maintenance: 3 episodes of prolonged grade 3 neutropenia (DL1=1 and DL2=2) and one episode of grade 4 neutropenia (DL0), and grade 3 weight loss (DL3). The predominant abemaciclib-related toxicities were low-grade and hematologic in nature, including leukopenia (80%), lymphopenia (70%), neutropenia (65%), diarrhea (60%), anemia (50%), and nausea (45%). PK analysis demonstrated that abemaciclib exposure increased with increasing dose. The apparent clearance (CL/F) increased with increasing weight/body surface area, and there was extensive variability in exposure across doses and weight ranges. Mean abemaciclib trough concentrations achieved the target associated with preclinical and clinical efficacy (200 ng/mL) at the 130 and 170 mg/m2 dose levels. The median progression-free survival for all patients was 7.5 months (range: 3.0-21.3) and median overall survival was 12.4 months (range: 2.6-29.0); 2 (10%) patients survived > 24 months. CONCLUSIONS: The MTD of abemaciclib administered concurrently with RT to pediatric patients with newly diagnosed DIPG was 170 mg/m2/dose administered orally twice daily on a 28-day cycle. Abemaciclib was well-tolerated with mainly low-grade hematologic toxicity and diarrhea. Citation Format: Thomas Cash, Dolly Aguilera, Zhulin He, Melissa Schink, Amanda Sykes, Celine Pitou, Erin Connelly, Bree Eaton, Natia Esiashvili, Ross Mangum, Margaret E. Macy, Robert C. Castellino, Jason Fangusaro, Tobey J. MacDonald, Cynthia Wetmore, Lindsey Hoffman. A phase 1 study of abemaciclib, a CDK 4/6 inhibitor, with radiation in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B065.
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 | 0,001 | 0,002 |
| 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 ».