Early phase clinical studies of AR-42, a histone deacetylase inhibitor, for neurofibromatosis type 2-associated vestibular schwannomas and meningiomas

Abstract

Objectives: Two pilot studies of AR-42, a pan-histone deacetylase inhibitor, in human neurofibromatosis type 2 (NF2), vestibular schwannomas (VS), and meningiomas are presented. Primary endpoints included safety, and intra-tumoral pharmacokinetics (PK) and pharmacodynamics (PD).

Methods: Pilot 1 is a subset analysis of a phase 1 study of AR-42 in solid tumors, which included NF2 or sporadic meningiomas. Tumor volumes and treatment-related adverse events (TRAEs) are reported (NCT01129193).Pilot 2 is a phase 0 surgical study of AR-42 assessing intra-tumoral PK and PD. AR-42 was administered for 3 weeks pre-operatively. Plasma and tumor drug concentrations and p-AKT expression were measured (NCT02282917).

Results: Pilot 1: Five patients with NF2 and two with sporadic meningiomas experienced a similar incidence of TRAEs to the overall phase I trial. The six evaluable patients had 15 tumors (8 VS, 7 meningiomas). On AR-42, tumor volume increased in six, remained stable in eight, and decreased in one tumor. The annual percent growth rate decreased in eight, remained stable in three, and increased in four tumors. Pilot 2: Four patients with sporadic VS and one patient with meningioma experienced no grade 3/4 toxicities. Expression of p-AKT decreased in three of four VS. All tumors had higher AR-42 concentrations than plasma.

Conclusions: AR-42 is safe. Tumor volumes showed a mixed response, but most slowed growth. On a 40-mg regimen, drug concentrated in tumors and growth pathways were suppressed in most tumors, suggesting this may be a well-tolerated and effective dose. A phase 2 study of AR-42 for NF2-associated tumors appears warranted.

Level of evidence: 1b, 4.

Keywords: AR‐42; histone deacetylase inhibitor; meningioma; neurofibromatosis type 2; vestibular schwannoma.

Conflict of interest statement

D. Bradley Welling is a consultant for CereXis, Science 24/7, NFBio, NF2 Biosolutions, and Mulberry Bio. Craig C. Hofmeister has received research grants from Takeda and Oncolytics Biotech; research and personal grants from Janssen, BMS, Sanofi, Nektar, Karyopharm, Imbrium, and Oncopeptides, all outside the submitted work. Amir Mortazavi is on the advisory board for Seattle Genetics and Pfizer and is on the scientific advisory board for Debiopharm Group. His institution (but not him) has received research funding from Acerta Pharma, Genentech, Roche, Merck, Novartis, Seattle Genetics, Astellas Pharma, Mirati Therapeutics, and Bristol‐Myers Squibb. The other authors declare no potential conflict of interest. The Ohio State University (OSU) holds the patent on the investigational drug AR‐42 (US 10/597022). 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 of the National Cancer Institute prior to reporting results for the phase I study. Safety issues related to dose increases and attribution of response were monitored by The OSU Data Safety Monitoring Committee and The OSU Cancer Center Institutional Review Board for the phase 1 pilot. A separate Data Safety and Monitoring Board of Massachusetts Eye and Ear oversaw pilot study 2.

© 2021 The Authors. Laryngoscope Investigative Otolaryngology published by Wiley Periodicals LLC on behalf of The Triological Society.

Figures

FIGURE 1

Pilot 1—Change in tumor volumes and annual rate of tumor growth. A, Change in 3‐D tumor volume in cm3 over time. Vertical black lines indicate initiation and discontinuation of AR‐42. B, Annual estimated rate of growth, in percent per year, pre‐treatment, on AR‐42, and post‐treatment

FIGURE 2

Pilot 2—AR‐42 suppressed the AKT and ERK pathways in VS. A, AR‐42 (or REC‐2282) decreased p‐AKT levels in three of four treated VS compared to untreated tumors VS1 and VS2. B, Patient 2.4 did not have reduced p‐AKT in the tumor, compared with seven untreated VS controls. Quantitation of the normalized p‐AKT/AKT ratio is depicted as percentage relative to the untreated VS2 set as 100%. C, AR‐42‐treated VS also showed reduced levels of p‐S6, downstream of the AKT/mTOR pathway, as well as p‐ERKs. Quantitation shown is a percentage of p‐S6/S6 or p‐ERKs/ERKs relative to VS2 set as 100%. D, Suppression of p‐S6 was also observed in an AR‐42‐treated meningioma compared to untreated tumors (MEN1 and MEN2); however, reduction of p‐AKT was not detected. Shown below the blot is the relative percentage of p‐AKT/AKT or p‐S6/S6 relative to the untreated MEN2 set as 100%. C, core of tumor; MEN, meningioma; P, periphery of tumor; VS, vestibular schwannoma