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.
Adult
Aged
Aged, 80 and over
Azepines
/ administration & dosage
Dose-Response Relationship, Drug
Female
Humans
Lymphoma, Large B-Cell, Diffuse
/ blood
Male
Middle Aged
Neoplasm Proteins
/ metabolism
Neoplasms
/ blood
Nuclear Proteins
/ metabolism
Proteins
/ antagonists & inhibitors
Small Molecule Libraries
/ administration & dosage
Journal
British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635
Informations de publication
Date de publication:
02 2021
02 2021
Historique:
received:
24
04
2020
accepted:
05
11
2020
revised:
19
10
2020
pubmed:
15
12
2020
medline:
15
7
2021
entrez:
14
12
2020
Statut:
ppublish
Résumé
Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor. 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. 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. 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. NCT01987362.
Sections du résumé
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.
Identifiants
pubmed: 33311588
doi: 10.1038/s41416-020-01180-1
pii: 10.1038/s41416-020-01180-1
pmc: PMC7884382
doi:
Substances chimiques
Azepines
0
NUTM1 protein, human
0
Neoplasm Proteins
0
Nuclear Proteins
0
Proteins
0
Small Molecule Libraries
0
bromodomain and extra-terminal domain protein, human
0
Banques de données
ClinicalTrials.gov
['NCT01987362']
Types de publication
Clinical Trial, Phase I
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
744-753Subventions
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
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