Exploratory Evaluation of AR-42 for Vestibular Schwannoma and Meningioma


Title

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

MEEI Protocol ID

14-078H

National Clinical Trial (NCT) Number

NCT02282917

Condition

NF2; Vestibular Schwannoma; Meningioma

Sponsor

DOD

Principal Investigator

Brad Welling, MD, PhD

Study Design

Phase 0, Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment

Study Objective

Primary Objective:
1)     Evaluate levels of phospho-Akt (p-AKT) and p16INKA  in subjects with NF2-related vestibular schwannomas (VS), sporadic VS, NF2-related meningiomas, and sporadic meningiomas after AR-42 has been taken per study protocol (40 mg every other day, 3 times per a week for 3 weeks preceding surgery). Levels will be compared to control tissue samples from a tumor bank.

Secondary Objectives:
1)     Assess biological effects of AR-42 on the phosphoinositide 3 kinase (PI3K)/AKT signaling pathway, p-4E-BP-1 by immunoblot and immunohistochemistry and compare to untreated samples from our tumor bank.
2)   Assess biological effects of AR-42 on tumor proliferation, cell cycle, cell death, and angiogenesis by immunohistochemistry, immunoblot after exposure to AR-42 and compare to untreated samples from our tumor bank.
3)     Explore utility of HR23B as a biomarker for sensitivity of VS and meningiomas to AR-42.
4)     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)     Assess any audiometric changes pre- and post AR-42 administration by conventional pure tone and speech discrimination testing.
6)     Evaluate any volumetric tumor reduction after 10 doses of AR-42 in 10 study participants by magnetic resonance imaging.  Tumor reduction will not be assessed in additional participants if no tumor response is noted in first 10 participants.
7)     Determine steady-state plasma and intra-tumoral concentrations of AR-42 at time of surgical resection.

Who is Eligible

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
  • Patients must have normal organ and marrow function; be able to swallow capsules; and patients/legal representatives must be able to read, understand and provide informed consent.
  • Females with childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50mIU/mL and be willing to comply with fertility requirements.
  • Breastfeeding should be discontinued if mother is treated with AR-42.
  • Eastern Cooperative Oncology Group/World Health Organization (ECOG/WHO) performance status of 0-1.
  • Tumor type will be confirmed by a neuropathologist.

Exclusion Criteria:

  • Pregnant women and pediatric patients are excluded from this study.
  • Patients with malabsorption or any other condition that could cause difficulty in absorption.
  • Patients requiring chronic corticosteroids (dose equivalent > 20mg prednisolone).
  • Concurrent use of complementary or alternative medicines that could confound interpretation of toxicities and/or antitumor activity of the study drug.
  • Patients who are receiving concurrent anti-neoplastic therapy.
  • Patients with a second malignancy that could interfere with patient participation, increase patient risk, or confound data interpretation.
  • Patients with long QT syndrome or a mean QTcB > 450 msec in males and > 470 msec in females.
  • Patients who are being treated for an active infection.
  • Patients with significant cardiovascular disease, including a myocardial infarction or unstable angina, within 6 months or unstable cardiac.
  • Known HIV infection.
  • Patients receiving the following concomitant medications:
  • Any other anti-neoplastic chemotherapy or biologic therapy during the study
  • Radiotherapy
  • 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
  • Any medical condition, including mental illness or substance abuse, deemed likely interfere with a patient's ability to cooperate and participate in the study, or interfere with interpretation of the results.

Subject Enrollment

20 subjects across 4 sites (MEEI N=10, Stanford University, Mayo Clinic, Johns Hopkins University)

Study Procedures

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 with weekly monitoring visits prior to surgery and 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 for assessment of intratumoral drug concentration and assessment of intratumoral disease markers. During surgery, four blood samples will be obtained and sent to the cooperating laboratory for determination of drug concentration and molecular analysis.

For More Information

Sybil_Murphy@meei.harvard.edu

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