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

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  • Michael Dickinson
  • Javier Briones
  • Alex F Herrera
  • Eva González-Barca
  • Nilanjan Ghosh
  • Raul Cordoba
  • Sarah C Rutherford
  • Eirini Bournazou
  • Emily Labriola-Tompkins
  • Izolda Franjkovic
  • Evelyne Chesne
  • Jurriaan Brouwer-Visser
  • Katharina Lechner
  • Barbara Brennan
  • Eveline Nüesch
  • Mark DeMario
  • Dominik Rüttinger
  • Martin Kornacker
  • Martin Hutchings
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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 as NCT03255096.

Original languageEnglish
JournalBlood advances
Issue number22
Pages (from-to)4762-4770
Number of pages9
Publication statusPublished - 23 Nov 2021

Bibliographical note

© 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.

    Research areas

  • Antineoplastic Combined Chemotherapy Protocols/adverse effects, Bridged Bicyclo Compounds, Heterocyclic, Humans, Lymphoma, Large B-Cell, Diffuse/drug therapy, Neoplasm Recurrence, Local/drug therapy, Rituximab/therapeutic use, Sulfonamides

ID: 69977483