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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 www.clinicaltrials.gov as NCT03255096.

Original languageEnglish
JournalBlood advances
Volume5
Issue number22
Pages (from-to)4762-4770
Number of pages9
ISSN2473-9529
DOIs
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