A Phase 1 study of RO6870810, a novel bromodomain and extra-terminal protein inhibitor, in patients with NUT carcinoma, other solid tumours, or diffuse large B-cell lymphoma.

Autor: Shapiro GI; Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. geoffrey_shapiro@dfci.harvard.edu., LoRusso P; Early Phase Clinical Trials Program, Yale University Medical Center, New Haven, CT, USA., Dowlati A; Department of Medicine-Hematology and Oncology, University Hospitals Seidman Cancer Center, Cleveland, OH, USA., T Do K; Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Jacobson CA; Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Vaishampayan U; Department of Oncology, Karmanos Cancer Institute, Detroit, MI, USA., Weise A; Medical Oncology, Karmanos Cancer Institute, Detroit, MI, USA., Caimi PF; Department of Medicine-Hematology and Oncology, University Hospitals Seidman Cancer Center, Cleveland, OH, USA., Eder JP; Early Phase Clinical Trials Program, Yale University Medical Center, New Haven, CT, USA., French CA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Labriola-Tompkins E; Roche Pharma Research and Early Development, Roche Innovation Center New York, New York, NY, USA., Boisserie F; Roche Pharma Research and Early Development, Roche Innovation Center New York, New York, NY, USA., Pierceall WE; Roche Pharma Research and Early Development, Roche Innovation Center New York, New York, NY, USA., Zhi J; Roche Pharma Research and Early Development, Roche Innovation Center New York, New York, NY, USA., Passe S; Roche Pharma Research and Early Development, Roche Innovation Center New York, New York, NY, USA., DeMario M; Roche Pharma Research and Early Development, Roche Innovation Center New York, New York, NY, USA., Kornacker M; Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland., Armand P; Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Jazyk: angličtina
Zdroj: British journal of cancer [Br J Cancer] 2021 Feb; Vol. 124 (4), pp. 744-753. Date of Electronic Publication: 2020 Dec 14.
DOI: 10.1038/s41416-020-01180-1
Abstrakt: Background: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor.
Methods: We conducted a Phase 1 study of RO6870810 administered subcutaneously for 21 or 14 days of 28- or 21-day cycles, respectively, in patients with the nuclear protein of the testis carcinoma (NC), other solid tumours, or diffuse large B-cell lymphoma (DLBCL) with MYC deregulation.
Results: Fatigue (42%), decreased appetite (35%) and injection-site erythema (35%) were the most common treatment-related adverse events. Pharmacokinetic parameters demonstrated linearity over the dose range tested and support once-daily dosing. Pharmacodynamic assessments demonstrated sustained decreases in CD11b levels in peripheral blood mononuclear cells. Objective response rates were 25% (2/8), 2% (1/47) and 11% (2/19) for patients with NC, other solid tumours and DLBCL, respectively. Responding tumours had evidence of deregulated MYC expression.
Conclusions: This trial establishes the safety, favourable pharmacokinetics, evidence of target engagement and preliminary single-agent activity of RO6870810. Responses in patients with NC, other solid tumours and DLBCL provide proof-of-principle for BET inhibition in MYC-driven cancers. The results support further exploration of RO6870810 as monotherapy and in combinations.
Clinical Trials Registration: NCT01987362.
Databáze: MEDLINE
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