Clinical Trials /

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

NCT02282917

Description:

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.

Related Conditions:
  • Meningioma
  • Schwannoma
Recruiting Status:

Active, not recruiting

Phase:

Early Phase 1

Trial Eligibility

Document

Exploratory Evaluation of <span class="go-doc-concept go-doc-biomarker">AR</span>-42 <span class="go-doc-concept go-doc-intervention">Histone Deacetylase Inhibitor</span> in the Treatment of Vestibular Schwannoma and Meningioma

Title

  • 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
  • Clinical Trial IDs

    NCT ID: NCT02282917

    ORG ID: 14-078H

    Trial Conditions

    Vestibular Schwannoma

    Meningioma

    Acoustic Neuroma

    Neurofibromatosis Type 2

    Trial Interventions

    Drug Synonyms Arms
    AR-42 OSU-HDAC42 AR-42 Administration

    Trial Purpose

    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
    NF2-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.

    Trial Arms

    Name Type Description Interventions
    AR-42 Administration Experimental AR-42 will be administered three times per week beginning 3 weeks prior to surgery. AR-42

    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.

    Minimum Eligible Age: 18 Years

    Maximum Eligible Age: N/A

    Eligible Gender: Both

    Primary Outcome Measures

    Expression levels of phospho-Akt (p-AKT) and p16INKA after 3 weeks of oral AR-42

    Secondary Outcome Measures

    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)

    Biological effects on tumor proliferation (as assessed by Ki-67 proliferation index), etc.

    The utility of HR23B as a biomarker for sensitivity of VS and meningiomas

    Gene sequencing (tumor and germ-line DNA)

    Audiometric changes by conventional pure tone and speech discrimination testing

    Volumetric tumor reduction by magnetic resonance imaging.

    Steady-state plasma and intra-tumoral concentrations of AR-42

    Trial Keywords

    NF2

    Vestibular Schwannoma

    Schwannoma

    Meningioma