Phase Ib trial combining rapid determination of drug-drug interaction (DDI) followed by a dose finding period to assess safety and preliminary efficacy of fimepinostat plus venetoclax in patients with aggressive B-cell lymphoma
| العنوان: | Phase Ib trial combining rapid determination of drug-drug interaction (DDI) followed by a dose finding period to assess safety and preliminary efficacy of fimepinostat plus venetoclax in patients with aggressive B-cell lymphoma |
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| المؤلفون: | Anas Younes, Stefan K. Barta, Connie Lee Batlevi, Tycel Phillips, Jason R. Westin, Sven de Vos, Krish Patel, John M. Pagel, Dena Grayson, Vikram Kansra, Sonali M. Smith, Jonathon B. Cohen |
| المصدر: | Journal of Clinical Oncology. 38:8056-8056 |
| بيانات النشر: | American Society of Clinical Oncology (ASCO), 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Oncology, Cancer Research, medicine.medical_specialty, Venetoclax, business.industry, Period (gene), Drug-drug interaction, medicine.disease, Lymphoma, Dose finding, chemistry.chemical_compound, Pooled analysis, chemistry, Internal medicine, medicine, In patient, B-cell lymphoma, business |
| الوصف: | 8056 Background: Fimepinostat (F), a dual inhibitor of PI3K (α, β, δ) and HDACs type 1/2, causes suppression of MYC levels (Shulman et al., 2017). A pooled analysis of diffuse large B-cell lymphoma (DLBCL) pts treated with F in two Ph 1/2 trials revealed an objective response rate in evaluable/ITT MYC-altered DLBCL pts of 29%/23%, respectively (Landsburg et al., 2018). Based on compelling preclinical activity of F in combination with venetoclax (V) (a Bcl2 inhibitor), we initiated a Ph 1b/2 study of F + V in pts with relapsed or refractory (R/R) DLBCL or high-grade B-cell lymphoma (HGBL), with or without MYC alteration. V is metabolized primarily by CYP3A, and preclinical studies showed that F may inhibit CYP3A4 (IC50 of 13.58 and 0.28 µM for midazolam and testosterone, respectively), suggesting F could cause DDI with V. Methods: Cohorts of patients received increasing dose levels of F administered on a 5-days-on/2-days-off (5/2) schedule in combination with daily V in 21-day cycles (Cohort 1: F 30 mg QD 5/2 + V 400 mg QD; Cohort 2: F 60 mg QD, 5/2 + V 400 mg QD; Cohort 3: F 60 mg QD 5/2 + V 800 mg QD). A potential DDI was assessed during Cycle 0 (Table), where PK for V (10 mg) monotherapy was compared to that for V (10 mg) in the presence of F. Patient PK samples were collected, analyzed and reviewed in < 10 days to determine the final ramp-up dose level of V. Results: As of 1-Feb-2020, 16 pts have been enrolled in 2 dose cohorts. Intensive PK analysis of 13 pts showed only mild (≤ 2-fold) to no increase in V exposure in the presence of F. In Cohort 1 (n = 6), the mean AUC increased 1.6-fold, and mean Cmax by 1.5-fold. In Cohort 2 (n = 7), no increase in mean AUC (0.9-fold) or Cmax (1.0-fold) was observed. Accordingly, all pts ramped up V to 100% of the target dose (400 mg) upon entering Cycle 1; rapid escalation of V was well tolerated. DLT was observed in 1 pt (Grade 3 diarrhea) in Cohort 2. Overall, 75% of TEAEs have been mild or moderate (Grade 1/2), and most were of limited duration. 11 pts (69%) experienced SAEs; 4 pts (25%) had SAEs considered related to either F or V. Conclusions: Real-time PK evaluation showed that F had only a mild to no DDI with V. F + V is well tolerated at clinically active dose levels, and evaluation of higher dose-level cohorts was ongoing. Enrollment in Cohort 2 remains on-going. Clinical trial information: NCT01742988 . [Table: see text] |
| تدمد: | 1527-7755 0732-183X |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::c531d60861bad7fcf4a2f14bd423d407 https://doi.org/10.1200/jco.2020.38.15_suppl.8056 |
| رقم الأكسشن: | edsair.doi...........c531d60861bad7fcf4a2f14bd423d407 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15277755 0732183X |
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