Abstract
BackgroundBromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor.MethodsWe 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.ResultsFatigue (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.ConclusionsThis 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 registrationNCT01987362.
Highlights
Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance
The BET inhibitor RO6870810 had an acceptable and manageable safety profile in patients with NC and other solid tumours and diffuse large B-cell lymphoma (DLBCL), which was confirmed in an expansion cohort enrolled at the recommended phase 2 dose of 0.65 mg/kg administered for 14 of every 21 days
Toxicities encountered with RO6870810 demonstrated commonalities with those reported for orally administered birabresib (MK8628; OTX015) and molibresib (GSK525762), such as fatigue, anaemia and thrombocytopenia, as well as gastrointestinal side effects, including diarrhoea, nausea, vomiting, reduced appetite, dysgeusia and increases in both indirect and direct bilirubin.[31,32]
Summary
Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. Direct-acting BET inhibitors utilise acetyl-lysine competitive binding to displace BET proteins from chromatin, resulting in preclinical activity in several solid tumour models, including those derived from colon, pancreatic and breast cancers.[4] The selectivity of these compounds for transformed cells arises from the localisation of BET proteins to super-enhancers that regulate cell-specifying and oncogenic transcriptional programs, including those governed by the oncogene encoding the transcription factor c-MYC.[8] In addition to MYC downregulation, BET inhibition has been shown to decrease oncogenic nuclear factor-κB activity, reduce ERK1/2 protein levels and decrease programmed death-ligand 1 and CXCL12 expression, thereby affecting immunity and cancer cell metastasis.[9,10,11,12,13,14]
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