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

Abstract

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.

A phase 1b dose-escalation/expansion study of BET inhibitor RO6870810 in patients with advanced multiple myeloma

“…While our pharmacodynamic findings provided evidence for on-target effects of RO6870810, clinical response rates with RO6870810 were infrequent and of short duration when they occurred. This is in line with the preliminary activity of RO687081 observed in the first-in-human dose-escalation trial where ORRs were 25% (2/8), 2% (1/47), and 11% (2/19) for patients with nuclear protein of the testis carcinoma (NUT carcinoma), other solid tumors, and diffuse large B-cell lymphoma (DLBCL), respectively [ 9 ]. Limited clinical data exist on the use of other BET inhibitors in multiple myeloma.…”

MYC: a multipurpose oncogene with prognostic and therapeutic implications in blood malignancies

“…However, it outperforms JQ1 in solubility, metabolic stability, and binding to serotonin receptors. Additionally, alpha assay technology shows the remarkable affinity of RO6870810 toward the acetyl-lysine recognition pocket of the BET family [ 722 , 723 ].…”

“…A novel iBET RO6870810 (also known as RG6146 and TEN-0) can dissociate the BRD-NUT oncoproteins from DNA, inhibiting the proliferation of cancer cells. RO6870810 has also been tested on DLBCL where MYC is associated with the aggressiveness of DLBCL [ 722 ]. The clinical potential of RO6870810 is now being evaluated in clinical trials.…”

Enhancers in disease: molecular basis and emerging treatment strategies

“…The role of BRD3 and BRD4 in cancer was first described in nuclear protein of testis (NUT) carcinoma, where a translocation causes BRD4 to fuse to NUT, driving cancer development [66,67]. It was then shown that BET inhibition can affect enhancer-driven oncogene expression in cancer cell lines [68] and one BET inhibitor passed Phase I in a clinical trial to treat NUT carcinoma (NCT01987362 i [69]). A study on prostate cancer found that selective inhibition of only the second bromodomain with ABBV-744 leads to fewer unwanted effects as compared with a pan-BET inhibitor, suggesting selective inhibition may be a valuable direction for treatment optimization [70].…”