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.

Conflict of interest statement

All authors have received grants and non-financial or other support from F. Hoffmann-La Roche during the conduct of the study. Editorial support, funded by the sponsor, was provided by an independent medical writer under the guidance of the authors. G.I.S. has served on advisory boards for Roche, Lilly, Pfizer, Bicycle Pharmaceuticals, Merck/EMD Serono, Sierra Oncology, G1 Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Bayer, Ipsen, Astex and Almac and has received sponsored research funding from Lilly, Pfizer, Array BioPharma, Merck, Merck/EMD Serono and Sierra Oncology. P.L. has participated in data safety monitoring boards from Chiltern, Agios, Five Prime, Parexel, Halozyme, Novella Clinical and Tyme and in advisory boards from Alexion, Ariad, CytomX, Roche/Genentech, GenMab, Glenmark, Ignyta, Menarini, Novartis, Omniox and Takeda. K.T.D. has participated in advisory boards for QED Therapeutics and Seattle Genetics. C.A.J. has received honorarium or consulting fees from Kite Pharma, Precision Biosciences, Pfizer, Bayer, Novartis, Celgene and Humanigen. U.V. has received research grants from Bristol Myers Squibb, Astellas and Pfizer and personal fees from Bayer, Bristol Myers Squibb, Astellas and Pfizer. A.W. has participated in a speaker bureau and advisory board for Array BioPharma. P.F.C. has received research funding from Roche/Genentech and ADC Therapeutics and participated in speaker bureaus from Celgene and advisory boards for Kite Pharma, Genentech, and Fate Therapeutics. C.A.F. has received research grants from National Institutes of Health, GlaxoSmithKline, C4 Therapeutics, Curis and Constellation and personal fees from GlaxoSmithKline. E.L.-T. and M.D. were employees of Roche at the time of the study and have Roche stock. F.B., W.E.P., J.Z., and S.P. were employees of Roche at the time of the study. M.K. is an employee of Roche and has Roche stock. P.A. has consulted for Merck, Bristol Myers Squibb, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, Morphosys, Daiichi Sankyo, Miltenyi, and Tessa and received institutional research funding from Merck, Bristol Myers Squibb, Affimed, Adaptive, Roche, Tensha, Otsuka, Sigma Tau, Genentech and IGM. The following authors have nothing additional to disclose beyond the support received for this work: A.D. and J.P.E.

Figures

Fig. 1. RO6870810 pharmacokinetic profile.

a Plasma concentration-time profile on days 1 and 15 of cycle 1. b Dose-exposure relationship (cycle 1, day 1).

Fig. 2. RO6870810 pharmacodynamic profiling as evidence of target engagement.

a Mean (± SD) change in CD11b by RO6870810 dose on days 1 and 15 of cycle 1 and day 1 of cycle 2. b Median of mean change in CD11b by RO6870810 dose (cycle 1, day 15). Results are based on the average of three measurements per patient. c Change in CD11b by RO6870810 concentration and LOESS curve. Results are based on three observations per patient on cycle 1, day 15.

Fig. 3. Changes from baseline to best response in measurements of target lesions.

Percentage change from baseline to best response in target lesions is shown in patients with solid tumours (a), NC (b) and diffuse large B-cell lymphoma (DLBCL) (c). Only the largest decrease in the sum of the product or longest diameters for each eligible patient is shown in each figure. For patients with solid tumours, those with missing (n = 5) responses were excluded; one patient with prostate cancer who achieved SD as best response did not have a tumour diameter measurement and is not shown. Six patients with DLBCL without postbaseline tumour assessment were excluded. Among patients with solid tumours, a PR was reported in a patient with salivary gland cancer; SD was reported in patients with salivary gland cancer (n = 4), colorectal cancer (n = 5), oesophageal carcinoma (n = 1), non-small cell lung cancer (n = 1), prostate cancer (n = 7), breast cancer (n = 2), pancreatic cancer (n = 1), uterine cancer (n = 1), ovarian cancer (n = 2) and hepatic cancer (n = 1); PD was reported in patients with squamous cell carcinoma (n = 1), colorectal cancer (n = 4), non-small cell lung cancer (n = 1), poorly differentiated carcinoma of unknown origin (n = 1), pancreatic cancer (n = 1), breast cancer (n = 2), ovarian cancer (n = 1), gastrointestinal stromal tumour (n = 1), fallopian tube cancer (n = 1), endometrial cancer (n = 1) and adenocarcinoma pancreas (n = 1); and a patient with colorectal cancer had an unknown response.