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

Dickinson, M; Briones, J; Herrera, AF; Gonzalez-Barca, E; Ghosh, N; Cordoba, R; Rutherford, SC; Bournazou, E; Labriola-Tompkins, E; Franjkovic, I; Chesne, E; Brouwer-Visser, J; Lechner, K; Brennan, B; Nuesch, E; DeMario, M; Ruttinger, D; Kornacker, M; Hutchings, M

Author(s): Dickinson, M; Briones, J; Herrera, AF; Gonzalez-Barca, E; Ghosh, N; Cordoba, R; Rutherford, SC; Bournazou, E; Labriola-Tompkins, E; Franjkovic, I; Chesne, E; Brouwer-Visser, J; Lechner, K; Brennan, B; Nuesch, E; DeMario, M; Ruttinger, D; Kornacker, M; Hutchings, M;
Details: Publication Year 2021-11-22,Volume 5,Issue #22,Page 4762-4770
Journal Title: Blood Advances
Publication Type: Research article
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.
Keywords: *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
Department(s): Haematology
PubMed ID: 34581757
Publisher's Version: https://doi.org/10.1182/bloodadvances.2021004619
Open Access at Publisher's Site: https://doi.org/10.1182/bloodadvances.2021004619
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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