Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT02282917|
Recruitment Status : Active, not recruiting
First Posted : November 5, 2014
Last Update Posted : November 20, 2018
|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)|
|Actual Enrollment :||5 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|
|Actual Study Start Date :||September 2015|
|Estimated Primary Completion Date :||October 2020|
|Estimated Study Completion Date :||October 2022|
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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02282917
|United States, California|
|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|
|Rochester, Minnesota, United States, 55905|
|Principal Investigator:||Brad Welling, MD, PhD||Massachusetts Eye and Ear|