Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma

• Sponsor: Massachusetts Eye and Ear Infirmary
• Collaborators: Johns Hopkins University; Mayo Clinic; Stanford University; Ohio State University; Nationwide Children's Hospital
• Information provided by (Responsible Party): Dr. Bradley Welling, Massachusetts Eye and Ear Infirmary

Study Description

Brief Summary:

This will be a multi-center, proof of concept phase 0 study to assess the suppression of p-AKT in Vestibular Schwannoma (VS) and meningiomas by AR-42 in adult patients undergoing tumor resection. AR-42 is a small molecule which crosses the blood brain barrier (BBB) in rodents, but the investigators are not certain yet if it will penetrate human VS. Meningiomas are outside the BBB, but seem to be unusually resistant to all current medical treatments. The primary endpoint of the bioactivity of suppression of p-AKT by AR-42 was selected as drug activity seems more informative than bioavailability. Our preclinical data and others have shown dose dependent suppression of p-AKT by AR-42 in both VS and meningiomas.

Condition or disease	Intervention/treatment	Phase
Vestibular Schwannoma; Meningioma; Acoustic Neuroma; Neurofibromatosis Type 2	Drug: AR-42	Early Phase 1

Detailed Description:

This is a multi-center, proof of concept phase 0 study to assess the suppression of p-AKT in VS and meningiomas by AR-42 in adult patients undergoing NF2-tumor resection. AR-42 will be administered three times per week beginning 3 weeks prior to surgery. A total of ten doses, +/- 1 dose at 40 mg/dose, will be self-administered orally by study participants at approximately the same time every day (+/- 1 hour, preferably in the evening) 3 times per week for 3 weeks pre-operatively, with the last dose taken the night before surgery. Patients will be evaluated within the context of their standard post-operative follow up which includes within 2 days of surgery and again at 2 weeks (+/- 10 days) after surgery. Samples will be shipped to the participating laboratories (OSU Comprehensive Cancer Center (CCC) Pharmacoanalytical Shared Resource (PhASR) and Nationwide Children's Research Institute) for assessment of intratumoral drug concentration and assessment of intratumoral disease markers. During surgery, four blood samples will also be obtained and sent to the cooperating laboratory (PhASR) for determination of drug concentration and molecular analysis.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	5 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma
Actual Study Start Date :	September 2015
Estimated Primary Completion Date :	October 2020
Estimated Study Completion Date :	October 2022

Arms and Interventions

Arm

Intervention/treatment

Experimental: AR-42 Administration; AR-42 will be administered three times per week beginning 3 weeks prior to surgery.

Drug: AR-42; AR-42 will be administered in a total of ten oral doses, +/- 1 dose, at 40 mg/dose, will be self-administered by study participants at approximately 8:00pm (+/- 1 hour) for 3 weeks pre-operatively, with the last dose being administered the night before surgery. The treating surgeon will perform the clinically indicated surgical procedure 3 weeks post-initial dose of medication as well as the specimen collection.; Other Name: OSU-HDAC42

Outcome Measures

Primary Outcome Measures :

1. Expression levels of phospho-Akt (p-AKT) and p16INKA after 3 weeks of oral AR-42 [ Time Frame: 3 weeks ]
   The primary objective of this study is to estimate the expression levels of phospho-Akt (p-AKT) and p16INKA after 3 weeks of oral AR-42 at 40 mg every other day, 3 times per a week for 3 weeks preceding surgery, as determined by immunohistochemistry in NF2-related vestibular schwannomas (VS), sporadic VS, NF2-related meningiomas and sporadic meningiomas and control tissue samples from a tumor bank.

Secondary Outcome Measures :

1. Biological effects onPI3K (including levels of p-AKT, total AKT, p-PRAS-40, total PRAS-40, p-S6 ribosomal protein, and p-4E-BP-1) [ Time Frame: 1 week ]
   Assess biological effects of AR-42 on the phosphoinositide 3 kinase (PI3K)/AKT signaling pathway, including the levels of p-AKT, total AKT, p-PRAS-40, total PRAS-40, p-S6 ribosomal protein, and p-4E-BP-1 by immunoblot and immunohistochemistry and compare to untreated samples from our tumor bank.
2. Biological effects on tumor proliferation (as assessed by Ki-67 proliferation index), etc. [ Time Frame: 1 week ]
   Assess biological effects of AR-42 on tumor proliferation (as assessed by Ki-67 proliferation index), cell cycle (as assessed by the expression of cyclins, CDK inhibitors, and mitotic checkpoint kinases), cell death (as assessed by cleaved caspase-3 and TUNEL staining), and angiogenesis (as assessed by the expression of VEGF and CD31) by immunohistochemistry and immunoblot after exposure to AR-42 and compare to untreated samples from our tumor bank.
3. The utility of HR23B as a biomarker for sensitivity of VS and meningiomas [ Time Frame: 1 week ]
   Explore the utility of HR23B as a biomarker for sensitivity of VS and meningiomas to AR-42. HR23B was previously shown to be a biomarker for tumor sensitivity to HDACi-based therapy in cutaneous T cell lymphomas
4. Gene sequencing (tumor and germ-line DNA) [ Time Frame: 1 week ]
   Perform NF2 gene sequencing (tumor and germ-line DNA) and Merlin protein expression in all VS and meningiomas and explore possible differences between sporadic and NF2-related tumors and baseline p-AKT activation and biological response to AR-42 based on NF2 mutational status and Merlin protein expression.
5. Audiometric changes by conventional pure tone and speech discrimination testing [ Time Frame: 6 weeks ]
   Assess any audiometric changes pre- and post AR-42 administration by conventional pure tone and speech discrimination testing. A difference of 20% speech discrimination will be considered significant on a 50-word recorded NU word list.
6. Volumetric tumor reduction by magnetic resonance imaging. [ Time Frame: 1 week ]
   Evaluate any volumetric tumor reduction after 10 doses of AR-42 in 10 study participants by magnetic resonance imaging. A decline of 20% by volumetric analysis will be considered a clinically significant reduction. Tumor reduction will not be assessed in additional participants if no tumor response is noted in these first 10 participants.
7. Steady-state plasma and intra-tumoral concentrations of AR-42 [ Time Frame: 1 week ]
   Determine the steady-state plasma and intra-tumoral concentrations of AR-42 at the time of surgical resection.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Patients with vestibular schwannoma and/or meningioma diagnosed by MRI where surgical resection has been selected as treatment.
• Patients diagnosed with NF2 must meet Manchester Criteria.
• Age > 18 years of age
• Prior biologic therapy, chemotherapy, surgery or radiation is permitted.
• At the time of screening, the patient must have normal organ and marrow function.
• Eastern Cooperative Oncology Group/World Health Organization (ECOG/WHO) performance status of 0-1.
• Patients must be able to swallow capsules.
• Patients or their legal representatives must be able to read, understand and provide informed consent to participate in the trial.
• Tumor type will be confirmed by a neuropathologist.
• Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL prior to starting AR-42.
• The patient must be willing to comply with fertility requirements

Exclusion Criteria:

• Pregnant women are excluded from this study because the potential for teratogenic or abortifacient effects of AR-42 are not known. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with AR-42, breastfeeding should be discontinued if the mother is treated with AR-42.
• Pediatric patients are excluded from the phase 0 study as the effects of AR-42 are not known on children and there is no potential direct benefit to them.
• Patients with malabsorption or any other condition that in the opinion of the principal investigator could cause difficulty in absorption of drug.
• Patients requiring chronic corticosteroids (dose equivalent > 20mg prednisolone).
• Concurrent use of complementary or alternative medicines that in the opinion of the principal investigator would confound the interpretation of toxicities and/or antitumor activity of the study drug.
• Patients with a "currently active" second malignancy that, in the opinion of the principal investigator, will interfere with patient participation, increase patient risk, or confound data interpretation.
• Patients with a mean QTcB > 450 msec in males and > 470 msec in females.
• Patients with long QT syndrome.
• Patients who are being treated for an active infection.

• Patients receiving the following concomitant medications:

  • Any other anti-neoplastic chemotherapy or biologic therapy during the study
  • Concomitant radiotherapy
  • Concomitant HDAC inhibitors (e.g. valproic acid) as class-specific adverse reactions may be additive
  • Use of granulocyte colony-stimulating factors including G-CSF, pegylated G-CSF or GM-CSF should follow ASCO guidelines for patients receiving anti-cancer therapy.
  • Drugs associated with QT/QTc prolongation (see Appendix A)
• Patients who are receiving concurrent anti-neoplastic therapy.
• Any other medical condition, including mental illness or substance abuse, deemed by the principal investigator to likely interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results.
• Patients with significant cardiovascular disease, including a myocardial infarction or unstable angina within 6 months or unstable cardiac arrhythmias are not eligible for the study.
• Known HIV infection, as their immunosuppressive conditions may complicate potential pancytopenias seen with HDAC inhibitors and complicate evaluation of drug effect.

Contacts and Locations

Locations

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United States, California
Stanford University
Stanford, California, United States, 94305
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Massachusetts Eye and Ear
Boston, Massachusetts, United States, 02214
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905

Sponsors and Collaborators

Massachusetts Eye and Ear Infirmary

Johns Hopkins University

Mayo Clinic

Stanford University

Ohio State University

Nationwide Children's Hospital

Investigators

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Principal Investigator:	Brad Welling, MD, PhD	Massachusetts Eye and Ear

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Cheng H, Xie Z, Jones WP, Wei XT, Liu Z, Wang D, Kulp SK, Wang J, Coss CC, Chen CS, Marcucci G, Garzon R, Covey JM, Phelps MA, Chan KK. Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents. AAPS J. 2016 May;18(3):737-45. doi: 10.1208/s12248-016-9876-3. Epub 2016 Mar 4.

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Responsible Party:	Dr. Bradley Welling, Chief Otolaryngology Massachusetts Eye and Ear, Massachusetts Eye and Ear Infirmary
ClinicalTrials.gov Identifier:	NCT02282917 History of Changes
Other Study ID Numbers:	14-078H
First Posted:	November 5, 2014
Last Update Posted:	March 28, 2019
Last Verified:	March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Keywords provided by Dr. Bradley Welling, Massachusetts Eye and Ear Infirmary:

NF2; Vestibular Schwannoma; Schwannoma; Meningioma

Additional relevant MeSH terms:

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Meningioma; Neurofibromatoses; Neurofibromatosis 1; Neurofibroma; Neurilemmoma; Neuroma; Neuroma, Acoustic; Neurofibromatosis 2; Neoplasms, Nerve Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Vascular Tissue; Meningeal Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms

Neoplasms by Site; Nervous System Diseases; Nerve Sheath Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Peripheral Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Cranial Nerve Neoplasms