Clinical and immune correlate results from a phase 1b study of the histone deacetylase inhibitor mocetinostat with ipilimumab and nivolumab in unresectable stage III/IV melanoma.
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Benzamides
Histone Deacetylase Inhibitors
/ adverse effects
Humans
Ipilimumab
/ pharmacology
Leukocytes, Mononuclear
/ pathology
Melanoma
/ pathology
Nivolumab
/ pharmacology
Pyrimidines
Skin Neoplasms
/ pathology
Melanoma, Cutaneous Malignant
Journal
Melanoma research
ISSN: 1473-5636
Titre abrégé: Melanoma Res
Pays: England
ID NLM: 9109623
Informations de publication
Date de publication:
01 10 2022
01 10 2022
Historique:
pubmed:
10
6
2022
medline:
9
9
2022
entrez:
9
6
2022
Statut:
ppublish
Résumé
Checkpoint immunotherapies (CPIs) have improved outcomes for metastatic melanoma patients, with objective response rates to combination ipilimumab and nivolumab of ~58%. Preclinical data suggest that histone deacetylase (HDAC) inhibition enhances antitumor immune activity and may augment CPI. In a phase Ib open-label pilot trial (NCT03565406), patients with therapy-naive metastatic melanoma were treated with the class I/IV HDAC inhibitor mocetinostat orally three times a week in combination with nivolumab and ipilimumab every 3 weeks for 12 weeks followed by 12-week maintenance cycles of nivolumab every 2 weeks and mocetinostat at the same dose and schedule as induction. The endpoints of the trial were safety, definition of a recommended phase 2 dose, preliminary assessment of response, and correlative marker determination. Patient PBMC and serum samples collected at baseline and on-treatment were assessed by flow cytometry and Luminex assays for immune correlates. Ten patients were treated: nine with 70-mg and one with 50-mg mocetinostat. In the 70-mg cohort, eight patients had objective responses. The patient in the 50-mg cohort had an early progression of disease. All patients had grade 2 or higher toxicities, and six had grades 3 and 4 toxicities. Patient PBMC showed significant decreases in myeloid-derived suppressor cells and trends towards reduced anti-inflammatory monocyte phenotypes. Patient serum showed significant upregulation of granzyme A and TNF and trends towards increased granzyme B and IFNγ. Collectively, combining CPI and mocetinostat had favorable response rates but with high levels of toxicity. Assessment of immune correlates supports a shift away from immunosuppressive phenotypes towards enhanced immune responses.
Identifiants
pubmed: 35678233
doi: 10.1097/CMR.0000000000000818
pii: 00008390-202210000-00004
pmc: PMC9444873
mid: NIHMS1787237
doi:
Substances chimiques
Benzamides
0
Histone Deacetylase Inhibitors
0
Ipilimumab
0
Pyrimidines
0
Nivolumab
31YO63LBSN
mocetinostat
A6GWB8T96J
Banques de données
ClinicalTrials.gov
['NCT03565406']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
324-333Subventions
Organisme : NCI NIH HHS
ID : K99 CA230201
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA230201
Pays : United States
Informations de copyright
Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.
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