Abstract
Bromodomain and extra-terminal (BET) proteins can drive carcinogenesis and therapy resistance. RO6870810 (RO) is a novel, small-molecule BET inhibitor. We conducted a study in 32 patients with relapsed/refractory acute myeloid leukemia and hypomethylating agent–refractory myelodysplastic syndrome (NCT02308761). Pharmacodynamic assessments showed decreases in CD11b in peripheral blood mononuclear cells at RO concentrations above 120 ng/mL. Treatment emergent adverse events were generally mild and the most frequent were fatigue, injection site reactions, diarrhea, decreased appetite and nausea. There were no treatment-related deaths. Potential drug-related dose limiting toxicities included decreased appetite, congestive cardiac failure, hypertension, fatigue, increased conjugated bilirubin and increased gamma glutamyltransferase. One AML patient achieved complete remission after withdrawal from study. Eleven AML patients experienced SD. For AML, the median OS was 72.0 days. For MDS, two patients experienced SD. Further development of RO as monotherapy was discontinued due to lack of efficacy, but combinations with other agents are under consideration.
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Disclosure statement
Dr. Roboz reports grants and non-financial support from Roche, during the conduct of the study; personal fees from Abbvie, personal fees from Actinium, personal fees from Agios, personal fees from Amphivena, personal fees from Argenx, personal fees from Array Biopharma, personal fees from Astex, personal fees from Astellas, personal fees from AstraZeneca, personal fees from Bayer, personal fees from Celgene, personal fees from Celltrion, personal fees from Daiichi Sankyo, personal fees from Eisai, personal fees from Epizyme, personal fees from Helsinn, personal fees from Janssen, personal fees from Jasper Therapeutics, personal fees from Jazz, personal fees from MEI Pharma, personal fees from Mesoblast, personal fees from Novartis, personal fees from Orsenix, personal fees from Otsuka, personal fees from Roche, personal fees from Sandoz, personal fees from Takeda, personal fees from Trovagene, grants from Celgene, outside the submitted work; Dr. Desai reports personal fees from BMS/Celgene, personal fees from Kura Oncology, grants from Astex, grants from Janssen Research Alliance, outside the submitted work; Dr. Lee reports personal fees from BMS, personal fees from Helsinn, personal fees from Innate Pharma, personal fees from Jazz Pharmaceuticals, personal fees from Pin Therapeutics, personal fees from Roche Diagnostics, personal fees from AstraZeneca, grants from Lam Therapeutics, outside the submitted work; Dr. Ritchie reports grants from Novartis, grants from Pfizer, grants from Celgene, grants from Jazz, outside the submitted work; Dr. Winer reports personal fees from Jazz Pharmaceuticals, personal fees from Takeda Pharmaceutical Company, personal fees from Novartis, personal fees from Pfizer, outside the submitted work; Dr. DeMario reports personal fees from Roche, during the conduct of the study; Dr. Brennan reports personal fees from Roche, during the conduct of the study; Dr. Nüesch reports personal fees from Roche, during the conduct of the study; Dr. Chesne reports personal fees from Roche, during the conduct of the study; Dr. Brennan reports personal fees from Roche, during the conduct of the study; Dr. Lechner reports personal fees from Roche, during the conduct of the study; Dr. Kornacker reports personal fees and other from Roche, outside the submitted work; Dr. DeAngelo reports personal fees from Amgen, personal fees from Agios, grants and personal fees from Blueprint, personal fees from Incyte, personal fees from Jazz, personal fees from Novartis, personal fees from Pfizer, personal fees from Shire, personal fees from Takeda, grants from Abbvie, grants from Glycomimetics, outside the submitted work.