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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 : Terminated (Drug manufacturing logistics; lack of access to drug supply)
First Posted : November 5, 2014
Results First Posted : May 11, 2022
Last Update Posted : May 11, 2022
Sponsor:
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

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.

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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


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




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.



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

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


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