A phase 1 trial of the histone deacetylase inhibitor AR-42 in patients with neurofibromatosis type 2-associated tumors and advanced solid malignancies.

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.

• Authors: Katharine A Collier, Hugo Valencia, Herbert Newton, Erinn M Hade, Douglas W Sborov, Robert Cavaliere, Ming Poi, Mitch A Phelps, Sophia G Liva, Christopher C Coss, Jiang Wang, Soun Khountham, Paul Monk, Charles L Shapiro, Richard Piekarz, Craig C Hofmeister, D Bradley Welling, Amir Mortazavi
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 87 Issue 5 Pg. 599-611 (05 2021) ISSN: 1432-0843 [Electronic] Germany
• PMID: 33492438 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Histone Deacetylase Inhibitors
• OSU-HDAC42 compound
• Phenylbutyrates

Topics

• Adult
• Aged
• Aged, 80 and over
• Female
• Histone Deacetylase Inhibitors (therapeutic use)
• Humans
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy, mortality)
• Neurofibromatosis 2 (drug therapy, mortality)
• Phenylbutyrates (adverse effects, pharmacokinetics, therapeutic use)
• Young Adult