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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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

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.

Detailed Summary: 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.
Sponsor: Massachusetts Eye and Ear Infirmary

Current Primary Outcome: 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.


Original Primary Outcome: Same as current

Current Secondary Outcome:

  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.


Original Secondary Outcome: Same as current

Information By: Massachusetts Eye and Ear Infirmary

Dates:
Date Received: October 31, 2014
Date Started: September 2015
Date Completion: December 2017
Last Updated: May 2, 2017
Last Verified: May 2017