Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma
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|ClinicalTrials.gov Identifier: NCT02282917|
Recruitment Status : Recruiting
First Posted : November 5, 2014
Last Update Posted : December 13, 2017
|Condition or disease||Intervention/treatment||Phase|
|Vestibular Schwannoma Meningioma Acoustic Neuroma Neurofibromatosis Type 2||Drug: AR-42||Early Phase 1|
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||20 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma|
|Study Start Date :||September 2015|
|Estimated Primary Completion Date :||August 2018|
|Estimated Study Completion Date :||August 2018|
Experimental: AR-42 Administration
AR-42 will be administered three times per week beginning 3 weeks prior to surgery.
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
- 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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02282917
|Contact: Amy Quinkertfirstname.lastname@example.org|
|United States, California|
|Stanford, California, United States, 94305|
|Contact: Robert Jackler, MD|
|United States, Maryland|
|Johns Hopkins University||Not yet recruiting|
|Baltimore, Maryland, United States, 21287|
|Contact: Jaishri Blakeley, MD 410-955-8837|
|United States, Massachusetts|
|Massachusetts Eye and Ear||Recruiting|
|Boston, Massachusetts, United States, 02214|
|Contact: D. B. Welling, M.D., PhD 617-573-4075 email@example.com|
|Contact: Amy Quinkert 617-573-4192 firstname.lastname@example.org|
|United States, Minnesota|
|Rochester, Minnesota, United States, 55905|
|Contact: Nicole Tombers, RN 507-538-1392 Tombers.Nicole@mayo.edu|
|Principal Investigator:||Brad Welling, MD, PhD||Massachusetts Eye and Ear|