Journal Article

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

DeMario, Mark, Pierceall, William E., T. Do, Khanh, Armand, Philippe, LoRusso, Patricia, Eder, Joseph Paul, Boisserie, Frédéric, Passe, Sharon, Dowlati, Afshin, Zhi, Jianguo, Shapiro, Geoffrey I., Kornacker, Martin, Jacobson, Caron A., French, Christopher A., Vaishampayan, Ulka, Labriola-Tompkins, Emily, Caimi, Paolo F., Weise, Amy

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/67/1059/602 / 692/4028 / Adverse events / Appetite loss / B-cell lymphoma / Biomedical and Life Sciences / Biomedicine / Cancer Research / Carcinogenesis / CD11b antigen / Clinical trials / Dosage / Drug Resistance / Epidemiology / Epigenetics / Erythema / Leukocytes (mononuclear) / Lymphocytes B / Lymphoma / Molecular Medicine / Myc protein / Oncology / Patients / Peripheral blood mononuclear cells / Pharmacodynamics / Pharmacokinetics / Solid tumors / Terminal protein / Tumors