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

Primary Purpose

Vestibular Schwannoma, Meningioma, Acoustic Neuroma

Status
Terminated
Phase
Early Phase 1
Locations
United States
Study Type
Interventional
Intervention
AR-42
Sponsored by
Massachusetts Eye and Ear Infirmary
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Vestibular Schwannoma focused on measuring NF2, Vestibular Schwannoma, Schwannoma, Meningioma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Stanford University
  • Johns Hopkins University
  • Massachusetts Eye and Ear
  • Mayo Clinic

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

AR-42 Administration

Arm Description

AR-42 will be administered three times per week beginning 3 weeks prior to surgery.

Outcomes

Primary Outcome Measures

Ratio of Phospho-AKT (p-AKT) to AKT After 3 Weeks of Oral AR-42
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.
Peripheral Phospho-AKT (p-AKT) to AKT Ratio After 3 Weeks of Oral AR-42
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

AR-42 Plasma Concentration
Steady-state plasma concentrations of AR-42 at the time of tumor resection are provided.
AR-42 Tumor Concentration (Capsule)
Concentrations of AR-42 at the tumor capsule are provided.
AR-42 Tumor Concentration (Center)
Intra-tumor concentrations of AR-42 at the tumor center are reported.
AR-42 Tumor Concentration (Capsule/Plasma)
Capsule/plasma intra-tumor AR-42 concentrations are provided as a ratio.
AR-42 Tumor Concentration (Center/Plasma)
Center/plasma intra-tumoral AR-42 concentrations are provided as a ratio.

Full Information

First Posted
October 31, 2014
Last Updated
February 22, 2022
Sponsor
Massachusetts Eye and Ear Infirmary
Collaborators
Johns Hopkins University, Mayo Clinic, Stanford University, Ohio State University, Nationwide Children's Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT02282917
Brief Title
Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma
Official Title
Exploratory Evaluation of AR-42 Histone Deacetylase Inhibitor in the Treatment of Vestibular Schwannoma and Meningioma
Study Type
Interventional

2. Study Status

Record Verification Date
December 2021
Overall Recruitment Status
Terminated
Why Stopped
Drug manufacturing logistics; lack of access to drug supply
Study Start Date
December 2015 (Actual)
Primary Completion Date
May 30, 2017 (Actual)
Study Completion Date
January 4, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts Eye and Ear Infirmary
Collaborators
Johns Hopkins University, Mayo Clinic, Stanford University, Ohio State University, Nationwide Children's Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Vestibular Schwannoma, Meningioma, Acoustic Neuroma, Neurofibromatosis Type 2
Keywords
NF2, Vestibular Schwannoma, Schwannoma, Meningioma

7. Study Design

Primary Purpose
Treatment
Study Phase
Early Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
7 (Actual)

8. Arms, Groups, and Interventions

Arm Title
AR-42 Administration
Arm Type
Experimental
Arm Description
AR-42 will be administered three times per week beginning 3 weeks prior to surgery.
Intervention Type
Drug
Intervention Name(s)
AR-42
Other Intervention Name(s)
OSU-HDAC42
Intervention Description
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.
Primary Outcome Measure Information:
Title
Ratio of Phospho-AKT (p-AKT) to AKT After 3 Weeks of Oral AR-42
Description
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.
Time Frame
3 weeks
Title
Peripheral Phospho-AKT (p-AKT) to AKT Ratio After 3 Weeks of Oral AR-42
Description
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.
Time Frame
3 weeks
Secondary Outcome Measure Information:
Title
AR-42 Plasma Concentration
Description
Steady-state plasma concentrations of AR-42 at the time of tumor resection are provided.
Time Frame
1 week
Title
AR-42 Tumor Concentration (Capsule)
Description
Concentrations of AR-42 at the tumor capsule are provided.
Time Frame
1 week
Title
AR-42 Tumor Concentration (Center)
Description
Intra-tumor concentrations of AR-42 at the tumor center are reported.
Time Frame
1 week
Title
AR-42 Tumor Concentration (Capsule/Plasma)
Description
Capsule/plasma intra-tumor AR-42 concentrations are provided as a ratio.
Time Frame
1 week
Title
AR-42 Tumor Concentration (Center/Plasma)
Description
Center/plasma intra-tumoral AR-42 concentrations are provided as a ratio.
Time Frame
1 week
Other Pre-specified Outcome Measures:
Title
Number of Doses of AR-42 Received
Description
We report the average total number of doses of AR-42 taken per participant during this study.
Time Frame
3 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Brad Welling, MD, PhD
Organizational Affiliation
Massachusetts Eye and Ear
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Massachusetts Eye and Ear
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02214
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34667843
Citation
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.
Results Reference
derived
PubMed Identifier
26943915
Citation
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.
Results Reference
derived

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

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