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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

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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.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article and/or supplementary materials. Further data are available on request from the corresponding author, Amir Mortazavi. The data are not publicly available to prevent compromise of the privacy of the research participants.

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Funding

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U01CA076576 and R01CA201382. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Internal Medicine, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH, USA

    Katharine A. Collier, Hugo Valencia, Paul Monk, Charles L. Shapiro & Amir Mortazavi

  2. Division of Hematology, Department of Internal Medicine, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH, USA

    Katharine A. Collier, Hugo Valencia & Soun Khountham

  3. Division of Neuro-Oncology, Departments of Neurology and Neurosurgery, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH, USA

    Herbert Newton

  4. Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA

    Erinn M. Hade

  5. Division of Hematology and Hematologic Malignancies, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA

    Douglas W. Sborov

  6. Division Neuro-Oncology, Department of Cancer Medicine, Baptist MD Anderson, Jacksonville, FL, USA

    Robert Cavaliere

  7. College of Pharmacy, The Ohio State University and The Comprehensive Cancer Center, Columbus, OH, USA

    Ming Poi, Mitch A. Phelps, Sophia G. Liva, Christopher C. Coss & Jiang Wang

  8. National Cancer Institute/Cancer Therapy Evaluation Program, Bethesda, MD, USA

    Richard Piekarz

  9. Division of Hematology, Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA

    Craig C. Hofmeister

  10. Department of Otolaryngology Head and Neck Surgery, Harvard Medical School, Massachusetts Eye and Ear Infirmary and Massachusetts General Hospital, Boston, MA, USA

    D. Bradley Welling

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  1. Katharine A. Collier
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  2. Hugo Valencia
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  3. Herbert Newton
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  18. Amir Mortazavi
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Contributions

Conceptualization and design: CCH and AM; methodology: EMH, CCH, and AM; data collection and analysis: KAC, CCC, EMH, SGL, AM, MAP, HV, and DBW; draft preparation: KAC, EMH, SGL, AM, MAP, DWS, HV, and DBW; funding acquisition: CCH and AM; provided resources, patient referral/management: RC, PM, AM, HN, CLS, and DBW; supervision: AM, RP, MP, and DBW. All the authors read, reviewed, edited, and approved the final manuscript.

Corresponding author

Correspondence to Amir Mortazavi.

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Conflict 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). 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. D. Bradley Welling is a consultant for CereXis who is a subsidiary of Recursion Pharmaceuticals. Amir Mortazavi is on the advisory board for Seattle Genetics and Pfizer and is on the scientific advisory board for Debiopharm Group. His institution (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 10/597,022). 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).

Ethics approval

This study was performed under the principles of the Declaration of Helsinki. Approval was granted by the Institutional Review Board of the Ohio State University (Protocol 2010C0006, approval date 3/24/2010).

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Written informed consent was obtained from all patients.

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Not applicable. There is no patient identifying information or image included in this article.

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Collier, K.A., Valencia, H., Newton, H. et al. A phase 1 trial of the histone deacetylase inhibitor AR-42 in patients with neurofibromatosis type 2-associated tumors and advanced solid malignancies. Cancer Chemother Pharmacol 87, 599–611 (2021). https://doi.org/10.1007/s00280-020-04229-3

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