Phase 1b study of the BET protein inhibitor RO6870810 with venetoclax and rituximab in patients with diffuse large B-cell lymphoma
Dickinson, Michael (University of Melbourne. Sir Peter MacCallum Department of Oncology)
Briones Meijide, Javier (Institut d'Investigació Biomèdica Sant Pau)
Herrera, Álex F. (Department of Hematology and Hematopoietic Cell Transplantation. City of Hope National Medical Center)
Gonzalez-Barca, Eva (Institut d'Investigació Biomèdica de Bellvitge)
Ghosh, Nilanjan (Department of Hematologic Oncology and Blood Disorders. Levine Cancer Institute. Atrium Health)
Cordoba, Raul (Hospital Universitario Fundación Jiménez Díaz)
Rutherford, Sarah C. (Meyer Cancer Center. Division of Hematology and Medical Oncology. Weill Department of Medicine. New York-Presbyterian Hospital. Weill Cornell Medicine)
Bournazou, Eirini (Roche Innovation Center New York. Roche Pharma Research and Early Development)
Labriola-Tompkins, Emily (Roche Innovation Center New York. Roche Pharma Research and Early Development)
Franjkovic, Izolda (Roche Innovation Center Munich. Roche Pharma Research and Early Development)
Chesne, Evelyne (Roche Innovation Center Basel. Roche Pharma Research and Early Development)
Brouwer-Visser, Jurriaan (Roche Innovation Center New York. Roche Pharma Research and Early Development)
Lechner, Katharina (Roche Innovation Center Munich. Roche Pharma Research and Early Development)
Brennan, Barbara (Roche Innovation Center New York. Roche Pharma Research and Early Development)
Nüesch, Eveline (Roche Innovation Center Basel. Roche Pharma Research and Early Development)
DeMario, Mark (Roche Innovation Center New York. Roche Pharma Research and Early Development)
Rüttinger, Dominik (Roche Innovation Center Munich. Roche Pharma Research and Early Development)
Kornacker, Martin (Roche Innovation Center Basel. Roche Pharma Research and Early Development)
Hutchings, Martin (Rigshospitalet. Copenhagen University Hospital)
Universitat Autònoma de Barcelona

Fecha:	2021
Resumen:	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 313 escalation design was used to determine the safety of the RO1venetoclax doublet; rituximab was added in later cohorts. Thirtynine 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 RO1600 mg venetoclax; for RO1venetoclax1rituximab, 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.
Nota:	Altres ajuts: F. Hoffmann-La Roche Ltd.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	Blood advances, Vol. 5 Núm. 22 (November 2021) , p. 4762-4770, ISSN 2473-9537

DOI: 10.1182/bloodadvances.2021004619
PMID: 34581757

9 p, 1.3 MB

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