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A phase 1 trial of the histone deacetylase inhibitor AR-42 in patients with neurofibromatosis type 2-associated tumors and advanced solid malignancies.
- Source :
-
Cancer chemotherapy and pharmacology [Cancer Chemother Pharmacol] 2021 May; Vol. 87 (5), pp. 599-611. Date of Electronic Publication: 2021 Jan 25. - Publication Year :
- 2021
-
Abstract
- Purpose: Given clinical activity of AR-42, an oral histone deacetylase inhibitor, in hematologic malignancies and preclinical activity in solid tumors, this phase 1 trial investigated the safety and tolerability of AR-42 in patients with advanced solid tumors, including neurofibromatosis type 2-associated meningiomas and schwannomas (NF2). The primary objective was to define the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). Secondary objectives included determining pharmacokinetics and clinical activity.<br />Methods: This phase I trial was an open-label, single-center, dose-escalation study of single-agent AR-42 in primary central nervous system and advanced solid tumors. The study followed a 3 + 3 design with an expansion cohort at the MTD.<br />Results: Seventeen patients were enrolled with NF2 (n = 5), urothelial carcinoma (n = 3), breast cancer (n = 2), non-NF2-related meningioma (n = 2), carcinoma of unknown primary (n = 2), small cell lung cancer (n = 1), Sertoli cell carcinoma (n = 1), and uveal melanoma (n = 1). The recommended phase II dose is 60 mg three times weekly, for 3 weeks of a 28-day cycle. DLTs included grade 3 thrombocytopenia and grade 4 psychosis. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. The best response was stable disease in 53% of patients (95% CI 26.6-78.7). Median progression-free survival (PFS) was 3.6 months (95% CI 1.2-9.1). Among evaluable patients with NF2 or meningioma (n = 5), median PFS was 9.1 months (95% CI 1.9-not reached).<br />Conclusion: Single-agent AR-42 is safe and well tolerated. Further studies may consider AR-42 in a larger cohort of patients with NF2 or in combination with other agents in advanced solid tumors.<br />Trial Registration: NCT01129193, registered 5/24/2010.
- Subjects :
- Adult
Aged
Aged, 80 and over
Female
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms mortality
Neurofibromatosis 2 mortality
Phenylbutyrates adverse effects
Phenylbutyrates pharmacokinetics
Young Adult
Histone Deacetylase Inhibitors therapeutic use
Neoplasms drug therapy
Neurofibromatosis 2 drug therapy
Phenylbutyrates therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0843
- Volume :
- 87
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cancer chemotherapy and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 33492438
- Full Text :
- https://doi.org/10.1007/s00280-020-04229-3