- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02282917
Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma
February 22, 2022 updated by: D. Bradley Welling, MD, PhD, Massachusetts Eye and Ear Infirmary
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.
Study Overview
Status
Terminated
Intervention / Treatment
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.
Study Type
Interventional
Enrollment (Actual)
7
Phase
- Early Phase 1
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
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California
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Stanford, California, United States, 94305
- Stanford University
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Maryland
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Baltimore, Maryland, United States, 21287
- Johns Hopkins University
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Massachusetts
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Boston, Massachusetts, United States, 02214
- Massachusetts Eye and Ear
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Minnesota
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Rochester, Minnesota, United States, 55905
- Mayo Clinic
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
18 years and older (Adult, Older Adult)
Accepts Healthy Volunteers
No
Genders Eligible for Study
All
Description
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.
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: AR-42 Administration
AR-42 will be administered three times per week beginning 3 weeks prior to surgery.
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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 Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
3 weeks
|
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.
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3 weeks
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
AR-42 Plasma Concentration
Time Frame: 1 week
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Steady-state plasma concentrations of AR-42 at the time of tumor resection are provided.
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1 week
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AR-42 Tumor Concentration (Capsule)
Time Frame: 1 week
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Concentrations of AR-42 at the tumor capsule are provided.
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1 week
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AR-42 Tumor Concentration (Center)
Time Frame: 1 week
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Intra-tumor concentrations of AR-42 at the tumor center are reported.
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1 week
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AR-42 Tumor Concentration (Capsule/Plasma)
Time Frame: 1 week
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Capsule/plasma intra-tumor AR-42 concentrations are provided as a ratio.
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1 week
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AR-42 Tumor Concentration (Center/Plasma)
Time Frame: 1 week
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Center/plasma intra-tumoral AR-42 concentrations are provided as a ratio.
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1 week
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Number of Doses of AR-42 Received
Time Frame: 3 weeks
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We report the average total number of doses of AR-42 taken per participant during this study.
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3 weeks
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Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Collaborators
Investigators
- Principal Investigator: Brad Welling, MD, PhD, Massachusetts Eye and Ear
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- Welling DB, Collier KA, Burns SS, Oblinger JL, Shu E, Miles-Markley BA, Hofmeister CC, Makary MS, Slone HW, Blakeley JO, Mansouri SA, Neff BA, Jackler RK, Mortazavi A, Chang LS. Early phase clinical studies of AR-42, a histone deacetylase inhibitor, for neurofibromatosis type 2-associated vestibular schwannomas and meningiomas. Laryngoscope Investig Otolaryngol. 2021 Aug 20;6(5):1008-1019. doi: 10.1002/lio2.643. eCollection 2021 Oct.
- Cheng H, Xie Z, Jones WP, Wei XT, Liu Z, Wang D, Kulp SK, Wang J, Coss CC, Chen CS, Marcucci G, Garzon R, Covey JM, Phelps MA, Chan KK. Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents. AAPS J. 2016 May;18(3):737-45. doi: 10.1208/s12248-016-9876-3. Epub 2016 Mar 4.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
December 1, 2015
Primary Completion (Actual)
May 30, 2017
Study Completion (Actual)
January 4, 2021
Study Registration Dates
First Submitted
October 31, 2014
First Submitted That Met QC Criteria
November 4, 2014
First Posted (Estimate)
November 5, 2014
Study Record Updates
Last Update Posted (Actual)
May 11, 2022
Last Update Submitted That Met QC Criteria
February 22, 2022
Last Verified
December 1, 2021
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Nervous System Diseases
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Genetic Diseases, Inborn
- Otorhinolaryngologic Neoplasms
- Otorhinolaryngologic Diseases
- Neurodegenerative Diseases
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Ear Diseases
- Central Nervous System Neoplasms
- Nervous System Neoplasms
- Heredodegenerative Disorders, Nervous System
- Neoplastic Syndromes, Hereditary
- Cranial Nerve Diseases
- Neuroendocrine Tumors
- Neoplasms, Vascular Tissue
- Nerve Sheath Neoplasms
- Neurocutaneous Syndromes
- Peripheral Nervous System Neoplasms
- Meningeal Neoplasms
- Cranial Nerve Neoplasms
- Neurofibroma
- Vestibulocochlear Nerve Diseases
- Retrocochlear Diseases
- Neurofibromatoses
- Meningioma
- Neuroma
- Neurofibromatosis 2
- Neurilemmoma
- Neuroma, Acoustic
Other Study ID Numbers
- 14-078H
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
No
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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