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.
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
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
7
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.
Stanford University
Stanford, California, United States
Johns Hopkins University
Baltimore, Maryland, United States
Massachusetts Eye and Ear
Boston, Massachusetts, United States
Mayo Clinic
Rochester, Minnesota, United States
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.
Time frame: 3 weeks
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.
Time frame: 3 weeks
AR-42 Plasma Concentration
Steady-state plasma concentrations of AR-42 at the time of tumor resection are provided.
Time frame: 1 week
AR-42 Tumor Concentration (Capsule)
Concentrations of AR-42 at the tumor capsule are provided.
Time frame: 1 week
AR-42 Tumor Concentration (Center)
Intra-tumor concentrations of AR-42 at the tumor center are reported.
Time frame: 1 week
AR-42 Tumor Concentration (Capsule/Plasma)
Capsule/plasma intra-tumor AR-42 concentrations are provided as a ratio.
Time frame: 1 week
AR-42 Tumor Concentration (Center/Plasma)
Center/plasma intra-tumoral AR-42 concentrations are provided as a ratio.
Time frame: 1 week
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