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.
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
- ORG STUDY ID:
14-078H
- NCT ID:
NCT02282917
Conditions
- Vestibular Schwannoma
- Meningioma
- Acoustic Neuroma
- Neurofibromatosis Type 2
Interventions
| Drug | Synonyms | Arms |
|---|
| AR-42 | OSU-HDAC42 | AR-42 Administration |
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
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. | |
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.
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Expression levels of phospho-Akt (p-AKT) and p16INKA after 3 weeks of oral AR-42 |
| Time Frame: | 3 weeks |
| Safety Issue: | |
| Description: | 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. |
Secondary Outcome Measures
| Measure: | 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 |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Biological effects on tumor proliferation (as assessed by Ki-67 proliferation index), etc. |
| Time Frame: | 1 week |
| Safety Issue: | |
| Description: | 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. |
| Measure: | The utility of HR23B as a biomarker for sensitivity of VS and meningiomas |
| Time Frame: | 1 week |
| Safety Issue: | |
| Description: | 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 |
| Measure: | Gene sequencing (tumor and germ-line DNA) |
| Time Frame: | 1 week |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Audiometric changes by conventional pure tone and speech discrimination testing |
| Time Frame: | 6 weeks |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Volumetric tumor reduction by magnetic resonance imaging. |
| Time Frame: | 1 week |
| Safety Issue: | |
| Description: | 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. |
| Measure: | Steady-state plasma and intra-tumoral concentrations of AR-42 |
| Time Frame: | 1 week |
| Safety Issue: | |
| Description: | Determine the steady-state plasma and intra-tumoral concentrations of AR-42 at the time of surgical resection. |
Details
| Phase: | Early Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Active, not recruiting |
| Lead Sponsor: | Massachusetts Eye and Ear Infirmary |
Trial Keywords
- NF2
- Vestibular Schwannoma
- Schwannoma
- Meningioma
Last Updated
May 8, 2020
