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

• ClinicalTrials.gov Identifier: NCT02282917
• Recruitment Status: Terminated
• First Posted: November 5, 2014
• Results First Posted: May 11, 2022
• Last Update Posted: May 11, 2022
• 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): D. Bradley Welling, MD, PhD, 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

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 7 participants
• Allocation: N/A
• 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: December 2015
• Actual Primary Completion Date: May 30, 2017
• Actual Study Completion Date: January 4, 2021

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. Ratio of Phospho-AKT (p-AKT) to AKT After 3 Weeks of Oral AR-42 [ Time Frame: 3 weeks ]
   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.
2. Peripheral Phospho-AKT (p-AKT) to AKT Ratio After 3 Weeks of Oral AR-42 [ Time Frame: 3 weeks ]
   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.

Secondary Outcome Measures :

1. AR-42 Plasma Concentration [ Time Frame: 1 week ]
   Steady-state plasma concentrations of AR-42 at the time of tumor resection are provided.
2. AR-42 Tumor Concentration (Capsule) [ Time Frame: 1 week ]
   Concentrations of AR-42 at the tumor capsule are provided.
3. AR-42 Tumor Concentration (Center) [ Time Frame: 1 week ]
   Intra-tumor concentrations of AR-42 at the tumor center are reported.
4. AR-42 Tumor Concentration (Capsule/Plasma) [ Time Frame: 1 week ]
   Capsule/plasma intra-tumor AR-42 concentrations are provided as a ratio.
5. AR-42 Tumor Concentration (Center/Plasma) [ Time Frame: 1 week ]
   Center/plasma intra-tumoral AR-42 concentrations are provided as a ratio.

Other Outcome Measures:

1. Number of Doses of AR-42 Received [ Time Frame: 3 weeks ]
   We report the average total number of doses of AR-42 taken per participant during this study.

Eligibility Criteria

• 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

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

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

  Study Documents (Full-Text)

Documents provided by D. Bradley Welling, MD, PhD, Massachusetts Eye and Ear Infirmary:

Study Protocol and Statistical Analysis Plan  [PDF] June 11, 2019

More Information

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

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.

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.

• Responsible Party: D. Bradley Welling, MD, PhD, Chief Otolaryngology Massachusetts Eye and Ear, Massachusetts Eye and Ear Infirmary
• ClinicalTrials.gov Identifier: NCT02282917
• Other Study ID Numbers: 14-078H
• First Posted: November 5, 2014
• Results First Posted: May 11, 2022
• Last Update Posted: May 11, 2022
• Last Verified: December 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by D. Bradley Welling, MD, PhD, Massachusetts Eye and Ear Infirmary:

NF2; Vestibular Schwannoma; Schwannoma; Meningioma

Additional relevant MeSH terms:

Meningioma; Neurofibromatoses; 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; Neurofibroma; Nerve Sheath Neoplasms; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Peripheral Nervous System Neoplasms; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Cranial Nerve Neoplasms; Vestibulocochlear Nerve Diseases; Retrocochlear Diseases; Ear Diseases