دورية أكاديمية
أعرض في EDS

Phase 1b study of the BET protein inhibitor RO6870810 with venetoclax and rituximab in patients with diffuse large B-cell lymphoma.

التفاصيل البيبلوغرافية
العنوان: Phase 1b study of the BET protein inhibitor RO6870810 with venetoclax and rituximab in patients with diffuse large B-cell lymphoma.
المؤلفون: Dickinson M; Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia., Briones J; Hematology Department, Hospital de la Santa Creu i Sant Pau, Sant Pau, Spain.; Jose Carreras Leukemia Research Institutes, Autonomous University of Barcelona, Barcelona, Spain., Herrera AF; Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA., González-Barca E; Department of Hematology, Institut Català d'Oncologia, Hospital duran i Reynals, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Universitat de Barcelona, L'Hospitalet de LLobregat, Barcelona, Spain., Ghosh N; Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, NC., Cordoba R; Department of Hematology, Fundacion Jimenez Diaz University Hospital, Madrid, Spain., Rutherford SC; Meyer Cancer Center, Division of Hematology and Medical Oncology, Weill Department of Medicine, NewYork-Presbyterian Hospital, Weill Cornell Medicine, New York, NY., Bournazou E; Roche Innovation Center New York, Roche Pharma Research and Early Development, New York, NY., Labriola-Tompkins E; Roche Innovation Center New York, Roche Pharma Research and Early Development, New York, NY., Franjkovic I; Roche Innovation Center Munich, Roche Pharma Research and Early Development, Penzberg, Germany., Chesne E; Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland., Brouwer-Visser J; Roche Innovation Center New York, Roche Pharma Research and Early Development, New York, NY., Lechner K; Roche Innovation Center Munich, Roche Pharma Research and Early Development, Penzberg, Germany., Brennan B; Roche Innovation Center New York, Roche Pharma Research and Early Development, New York, NY., Nüesch E; Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland., DeMario M; Roche Innovation Center New York, Roche Pharma Research and Early Development, New York, NY., Rüttinger D; Roche Innovation Center Munich, Roche Pharma Research and Early Development, Penzberg, Germany., Kornacker M; Roche Innovation Center Basel, Roche Pharma Research and Early Development, Basel, Switzerland., Hutchings M; Department of Hematology and.; Phase 1 Unit, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
المصدر: Blood advances [Blood Adv] 2021 Nov 23; Vol. 5 (22), pp. 4762-4770.
نوع المنشور: Clinical Trial, Phase I; Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Society of Hematology Country of Publication: United States NLM ID: 101698425 Publication Model: Print Cited Medium: Internet ISSN: 2473-9537 (Electronic) Linking ISSN: 24739529 NLM ISO Abbreviation: Blood Adv Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : American Society of Hematology, [2016]-
مواضيع طبية MeSH: Antineoplastic Combined Chemotherapy Protocols*/adverse effects , Lymphoma, Large B-Cell, Diffuse*/drug therapy, Bridged Bicyclo Compounds, Heterocyclic ; Humans ; Neoplasm Recurrence, Local/drug therapy ; Rituximab/therapeutic use ; Sulfonamides
مستخلص: Bromodomain and extraterminal (BET) proteins are transcriptional activators for multiple oncogenic processes in diffuse large B-cell lymphoma (DLBCL), including MYC, BCL2, E2F, and toll-like receptor signaling. We report results of a phase 1b dose-escalation study of the novel, subcutaneous BET inhibitor RO6870810 (RO) combined with the BCL-2 inhibitor venetoclax, and rituximab, in recurrent/refractory DLBCL. RO was delivered for 14 days of a 21-day cycle, whereas venetoclax was delivered continuously. A 3 + 3 escalation design was used to determine the safety of the RO+venetoclax doublet; rituximab was added in later cohorts. Thirty-nine patients were treated with a median of 2.8 cycles (range, 1-11). Dose-limiting toxicities included grade 3 febrile neutropenia, grade 4 diarrhea, and hypomagnesemia for the doublet; and grade 3 hyperbilirubinemia and grade 4 diarrhea when rituximab was added. The doublet maximum tolerated dose (MTD) was determined to be 0.65 mg/kg RO+600 mg venetoclax; for RO+venetoclax+rituximab, the MTDs were 0.45 mg/kg, 600 mg, and 375 mg/m2, respectively. The most frequent grade 3 and 4 adverse events were neutropenia (28%) and anemia and thrombocytopenia (23% each). Responses were seen in all cohorts and molecular subtypes. Sustained decreases in CD11b on monocytes indicated pharmacodynamic activity of RO. Overall response rate according to modified Lugano criteria was 38.5%; 48% of responses lasted for ≥180 days. Complete response was observed in 8 patients (20.5%). Optimization of the treatment schedule and a better understanding of predictors of response would be needed to support broader clinical use. This trial is registered on www.clinicaltrials.gov as NCT03255096.
(© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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سلسلة جزيئية: ClinicalTrials.gov NCT03255096
المشرفين على المادة: 0 (Bridged Bicyclo Compounds, Heterocyclic)
0 (Sulfonamides)
4F4X42SYQ6 (Rituximab)
N54AIC43PW (venetoclax)
تواريخ الأحداث: Date Created: 20210928 Date Completed: 20211129 Latest Revision: 20220115
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC8759125
DOI: 10.1182/bloodadvances.2021004619
PMID: 34581757
قاعدة البيانات: MEDLINE
الوصف
تدمد:2473-9537
DOI:10.1182/bloodadvances.2021004619