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.

Keywords: Histone deacetylase inhibitor; Neurofibromatosis type 2; Pharmacokinetics; Phase 1; Solid tumor.

Conflict of interest statement

Conflicts of interest:

Christopher C. Coss, Sophia G. Liva, and Mitch A. Phelps are listed as inventors on a provisional patent for AR-42 for cancer-related cachexia (U.S. Patent Application No. 62/898,992).

The other authors declare no potential conflict of interest.

The Ohio State University (OSU) holds the patent on the investigational drug AR-42 (US 10/597,022). The Technology Commercialization Office has licensed AR-42 (now called REC-2282) to Recursion Pharmaceuticals using the institution’s standard terms, conditions and approval process, in which no author participated. To assure absence of institutional conflict of interest in assessment of response and attribution of toxicity, both were reviewed by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) prior to reporting results. Safety issues related to dose increases and attribution of response were monitored by the Ohio State University Data Safety Monitoring Committee and the OSU Cancer Center Institutional Review Board (IRB).

Figures

Figure 1.

Median PFS of primary CNS and advanced solid tumors treated with AR-42.

Figure 2.

Pharmacokinetics by dose on a) Day 1 and b) Day 19.