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http://hdl.handle.net/2445/182755
Title: | Phase Ib study of BET inhibitor RO6870810 with venetoclax and rituximab in patients with diffuse large B-cell lymphoma |
Author: | Dickinson, Michael Briones, Javier Herrera, Alex F. González Barca, Eva Ghosh, Nilanjan Cordoba, Raúl Rutherford, Sarah C. Bournazou, Eirini Labriola Tompkins, Emily Franjkovic, Izolda Chesne, Evelyne Brouwer-Visser, Jurriaan Lechner, Katharina Brennan, Barbara Nüesch, Eveline Demario, Mark Rüttinger, Dominik Kornacker, Martin Hutchings, Martin |
Keywords: | Proteïnes Limfomes Proteins Lymphomas |
Issue Date: | 28-Sep-2021 |
Publisher: | American Society of Hematology |
Abstract: | 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1182/bloodadvances.2021004619 |
It is part of: | Blood Advances, 2021, vol. 5, num. 22, p. 4762-4770 |
URI: | http://hdl.handle.net/2445/182755 |
Related resource: | https://doi.org/10.1182/bloodadvances.2021004619 |
ISSN: | 2473-9537 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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advancesadv2021004619.pdf | 1.35 MB | Adobe PDF | View/Open |
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