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

NCT02282917 | Terminated Early Phase 1 Results DMC

• 1 other identifier: 14-078H
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 4

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.

Conditions

Neurofibromatosis Type 2; Vestibular Schwannoma; Meningioma; Acoustic Neuroma

Keywords

NF2; Vestibular Schwannoma; Schwannoma; Meningioma

Outcome Measures

Primary Outcomes (2)

• Ratio of Phospho-AKT (p-AKT) to AKT After 3 Weeks of Oral AR-42

  The phospho-AKT/AKT ratio was used to estimate the activity of AKT, a kinase, at the core of resected tumors. Quantitation of the normalized p-AKT/AKT ratio is depicted as a percentage relative to the untreated VS2 set as 100%. For example, a value under 100% indicates a lower level of AKT activity relative to untreated VS2 tumors. Phosphorylated AKT, or phospho-AKT, is the activated form of AKT. These measurements were derived from the core of the resected tumors.

  3 weeks

• Peripheral Phospho-AKT (p-AKT) to AKT Ratio After 3 Weeks of Oral AR-42

  The phospho-AKT/AKT ratio was used to estimate the activity of AKT, a kinase, at the core of resected tumors. Quantitation of the normalized p-AKT/AKT ratio is depicted as a percentage relative to the untreated VS2 set as 100%. For example, a value under 100% indicates a lower level of AKT activity relative to untreated patients. Phosphorylated AKT, or phospho-AKT, is the activated form of AKT. These measurements were derived from the periphery of the resected tumors.

  3 weeks

Secondary Outcomes (5)

• AR-42 Plasma Concentration

  1 week

• AR-42 Tumor Concentration (Capsule)

  1 week

• AR-42 Tumor Concentration (Center)

  1 week

• AR-42 Tumor Concentration (Capsule/Plasma)

  1 week

• AR-42 Tumor Concentration (Center/Plasma)

  1 week

Other Outcomes (1)

• Number of Doses of AR-42 Received

  3 weeks

Study Arms (1)

AR-42 Administration

EXPERIMENTAL

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

Drug: AR-42

Interventions

AR-42 DRUG

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.

Also known as: OSU-HDAC42

AR-42 Administration

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Stanford University: collaborator
• Ohio State University: collaborator
• Nationwide Children's Hospital: collaborator
• Massachusetts Eye and Ear Infirmary: lead
• Johns Hopkins University: collaborator
• Mayo Clinic: collaborator

Study Sites (4)

Stanford University

Stanford, California, 94305, United States

Location

Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

Massachusetts Eye and Ear

Boston, Massachusetts, 02214, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Related Publications (2)

• Welling DB, Collier KA, Burns SS, Oblinger JL, Shu E, Miles-Markley BA, Hofmeister CC, Makary MS, Slone HW, Blakeley JO, Mansouri SA, Neff BA, Jackler RK, Mortazavi A, Chang LS. Early phase clinical studies of AR-42, a histone deacetylase inhibitor, for neurofibromatosis type 2-associated vestibular schwannomas and meningiomas. Laryngoscope Investig Otolaryngol. 2021 Aug 20;6(5):1008-1019. doi: 10.1002/lio2.643. eCollection 2021 Oct.

  PMID: 34667843 DERIVED

• 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.

  PMID: 26943915 DERIVED

MeSH Terms

Conditions

Neuroma, Acoustic; Meningioma; Neurofibromatosis 2; Neurilemmoma

Interventions

HDAC-42

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neuroma; Nerve Sheath Neoplasms; Neoplasms, Nerve Tissue; Cranial Nerve Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Peripheral Nervous System Neoplasms; Vestibulocochlear Nerve Diseases; Retrocochlear Diseases; Ear Diseases; Otorhinolaryngologic Diseases; Otorhinolaryngologic Neoplasms; Cranial Nerve Diseases; Nervous System Diseases; Neoplasms, Vascular Tissue; Meningeal Neoplasms; Central Nervous System Neoplasms; Neurofibromatoses; Neurofibroma; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Limitations and Caveats

The supplier of AR-42 was unable to continue to supply drugs after 2017. We elected to present the data on five of the originally planned 20 patients. Accrual was also limited by patient willingness to accept potential additional peri-operative risk without a reasonable likelihood of benefit from only 3 weeks of therapy with AR-42. Other limitations include possible selection bias, lack of control subjects, and the inability to perform meaningful statistical analysis.

Results Point of Contact

• Title: Matthew E Stenerson, MSc, Clinical Research Project Manager
• Organization: Mass General Brigham

matthew_stenerson@meei.harvard.edu

7155721100

Study Officials

• Brad Welling, MD, PhD

  Massachusetts Eye and Ear

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief Otolaryngology Massachusetts Eye and Ear

Study Record Dates

• First Submitted: October 31, 2014
• First Posted: November 5, 2014
• Study Start: December 1, 2015
• Primary Completion: May 30, 2017
• Study Completion: January 4, 2021
• Last Updated: December 5, 2025
• Results First Posted: May 11, 2022

Record last verified: 2021-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)