We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
A phase 1 trial of the histone deacetylase inhibitor AR-42 in patients with neurofibromatosis type 2-associated tumors and advanced solid malignancies.
- Authors
Collier, Katharine A.; Valencia, Hugo; Newton, Herbert; Hade, Erinn M.; Sborov, Douglas W.; Cavaliere, Robert; Poi, Ming; Phelps, Mitch A.; Liva, Sophia G.; Coss, Christopher C.; Wang, Jiang; Khountham, Soun; Monk, Paul; Shapiro, Charles L.; Piekarz, Richard; Hofmeister, Craig C.; Welling, D. Bradley; Mortazavi, Amir
- 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. 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. 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). 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. Trial registration: NCT01129193, registered 5/24/2010.
- Subjects
HISTONE deacetylase inhibitors; HISTONES; SMALL cell lung cancer; NEUROFIBROMATOSIS; ADVERSE health care events; HISTONE deacetylase; TUMORS
- Publication
Cancer Chemotherapy & Pharmacology, 2021, Vol 87, Issue 5, p599
- ISSN
0344-5704
- Publication type
Article
- DOI
10.1007/s00280-020-04229-3