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.

Details

Title
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
Author
Shapiro, Geoffrey I 1   VIAFID ORCID Logo  ; LoRusso, Patricia 2 ; Dowlati Afshin 3 ; T Do Khanh 1 ; Jacobson, Caron A 1 ; Vaishampayan Ulka 4 ; Weise, Amy 5 ; Caimi, Paolo F 3 ; Eder, Joseph Paul 2 ; French, Christopher A 6 ; Labriola-Tompkins, Emily 7 ; Boisserie Frédéric 7 ; Pierceall, William E 7 ; Zhi Jianguo 7 ; Passe, Sharon 7 ; DeMario, Mark 7 ; Kornacker, Martin 8 ; Armand, Philippe 1 

1  Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA (GRID:grid.65499.37) (ISNI:0000 0001 2106 9910) 
2  Yale University Medical Center, Early Phase Clinical Trials Program, New Haven, USA (GRID:grid.417307.6) 
3  University Hospitals Seidman Cancer Center, Department of Medicine-Hematology and Oncology, Cleveland, USA (GRID:grid.473817.e) (ISNI:0000 0004 0418 9795) 
4  Department of Oncology, Karmanos Cancer Institute, Detroit, USA (GRID:grid.477517.7) (ISNI:0000 0004 0396 4462) 
5  Medical Oncology, Karmanos Cancer Institute, Detroit, USA (GRID:grid.477517.7) (ISNI:0000 0004 0396 4462) 
6  Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA (GRID:grid.62560.37) (ISNI:0000 0004 0378 8294) 
7  Roche Pharma Research and Early Development, Roche Innovation Center New York, New York, USA (GRID:grid.62560.37) 
8  Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland (GRID:grid.62560.37) 
Pages
744-753
Publication year
2021
Publication date
Feb 2021
Publisher
Nature Publishing Group
ISSN
00070920
e-ISSN
15321827
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41416-020-01180-1
ProQuest document ID
2489438446
Copyright
© The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.