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

  • Br J Cancer. 2021 Feb;124(4):744-753. doi: 10.1038/s41416-020-01180-1.
Geoffrey I Shapiro  1 ,  Patricia LoRusso  2 ,  Afshin Dowlati  3 ,  Khanh T Do  4 ,  Caron A Jacobson  4 ,  Ulka Vaishampayan  5 ,  Amy Weise  6 ,  Paolo F Caimi  3 ,  Joseph Paul Eder  2 ,  Christopher A French  7 ,  Emily Labriola-Tompkins  8 ,  Frédéric Boisserie  8 ,  William E Pierceall  8 ,  Jianguo Zhi  8 ,  Sharon Passe  8 ,  Mark DeMario  8 ,  Martin Kornacker  9 ,  Philippe Armand  4
Affiliations
  • 1. Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. [email protected].
  • 2. Early Phase Clinical Trials Program, Yale University Medical Center, New Haven, CT, USA.
  • 3. Department of Medicine-Hematology and Oncology, University Hospitals Seidman Cancer Center, Cleveland, OH, USA.
  • 4. Department of Medical Oncology, Dana-Farber Cancer Institute, and Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 5. Department of Oncology, Karmanos Cancer Institute, Detroit, MI, USA.
  • 6. Medical Oncology, Karmanos Cancer Institute, Detroit, MI, USA.
  • 7. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 8. Roche Pharma Research and Early Development, Roche Innovation Center New York, New York, NY, USA.
  • 9. Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland.
PMID: 33311588 DOI: 10.1038/s41416-020-01180-1
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.