Acoustic Neuroma, Meningioma, Neurofibromatosis Type 2, Vestibular Schwannoma
Conditions
Keywords
NF2, Vestibular Schwannoma, Schwannoma, Meningioma
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.
Interventions
DRUGAR-42
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.
Sponsors
Johns Hopkins University
Stanford University
Ohio State University
Nationwide Children's Hospital
Mayo Clinic
Massachusetts Eye and Ear Infirmary
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Peripheral Phospho-AKT (p-AKT) to AKT Ratio After 3 Weeks of Oral AR-42 | 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. |
| Ratio of Phospho-AKT (p-AKT) to AKT After 3 Weeks of Oral AR-42 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AR-42 Plasma Concentration | 1 week | Steady-state plasma concentrations of AR-42 at the time of tumor resection are provided. |
| AR-42 Tumor Concentration (Capsule) | 1 week | Concentrations of AR-42 at the tumor capsule are provided. |
| AR-42 Tumor Concentration (Center) | 1 week | Intra-tumor concentrations of AR-42 at the tumor center are reported. |
| AR-42 Tumor Concentration (Capsule/Plasma) | 1 week | Capsule/plasma intra-tumor AR-42 concentrations are provided as a ratio. |
| AR-42 Tumor Concentration (Center/Plasma) | 1 week | Center/plasma intra-tumoral AR-42 concentrations are provided as a ratio. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Doses of AR-42 Received | 3 weeks | We report the average total number of doses of AR-42 taken per participant during this study. |
Countries
United States
Participant flow
Recruitment details
Seven participants were identified and recruited by the study investigators and/or study coordinators within the Department of Otolaryngology at Massachusetts Eye and Ear, Boston, MA. Participants were identified by their clinical history with vestibular schwannomas, meningiomas, cutaneous schwannomas, and/or Neurofibromatosis Type 2. The first enrollment took place in December 2015, and the final enrollment took place in July 2017.
Pre-assignment details
Following all participant enrollments (consent), baseline procedures to determine eligibility included: complete blood count with differential and platelets, comprehensive metabolic panel, coagulation panel (PT/PTT), chest x-ray, neurological exam, pregnancy testing, 12-lead ECG, audiogram, and MRI (CPT 70553). Participants were terminated from the study after their baseline visit if they did not meet all eligibility requirements.
Participants by arm
| Arm | Count |
|---|---|
| AR-42 Administration AR-42 was administered three times per week beginning 3 weeks prior to surgery. AR-42 was administered in a total of ten oral doses, +/- 1 dose, at 40 mg/dose, and was 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. A study investigator performed the clinically indicated surgical procedure 3 weeks post-initial dose of medication as well as the specimen collection. | 5 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Screen Failure/Not Eligible | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | AR-42 Administration |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 54.9 years |
| Baseline plasma concentration of AR-42 | 150.18 nanomolar (nM) |
| ECOG Grade ECOG = 0 | 4 Participants |
| ECOG Grade ECOG not assessed at baseline | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Prior tumor biopsy or debulking No | 5 Participants |
| Prior tumor biopsy or debulking Yes | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment United States | 5 participants |
| Relevant diagnosis Sporadic meningioma | 1 Participants |
| Relevant diagnosis Sporadic vestibular schwannoma | 4 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 4 Participants |
| Weight | 98.22 kilograms (kg) |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 5 |
| other Total, other adverse events | 4 / 5 |
| serious Total, serious adverse events | 0 / 5 |
Outcome results
Primary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AR-42 Administration | Peripheral Phospho-AKT (p-AKT) to AKT Ratio After 3 Weeks of Oral AR-42 | 61.2 percent (%) |
Primary
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AR-42 Administration | Ratio of Phospho-AKT (p-AKT) to AKT After 3 Weeks of Oral AR-42 | 53.6 percent (%) |
Secondary
AR-42 Plasma Concentration
Steady-state plasma concentrations of AR-42 at the time of tumor resection are provided.
Time frame: 1 week
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AR-42 Administration | AR-42 Plasma Concentration | 107.58 nanomolar (nM) |
Secondary
AR-42 Tumor Concentration (Capsule)
Concentrations of AR-42 at the tumor capsule are provided.
Time frame: 1 week
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AR-42 Administration | AR-42 Tumor Concentration (Capsule) | 325.1 nanomolar (nM) |
Secondary
AR-42 Tumor Concentration (Capsule/Plasma)
Capsule/plasma intra-tumor AR-42 concentrations are provided as a ratio.
Time frame: 1 week
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AR-42 Administration | AR-42 Tumor Concentration (Capsule/Plasma) | 13.078 ratio |
Secondary
AR-42 Tumor Concentration (Center)
Intra-tumor concentrations of AR-42 at the tumor center are reported.
Time frame: 1 week
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AR-42 Administration | AR-42 Tumor Concentration (Center) | 645.18 nanomolar (nM) |
Secondary
AR-42 Tumor Concentration (Center/Plasma)
Center/plasma intra-tumoral AR-42 concentrations are provided as a ratio.
Time frame: 1 week
| Arm | Measure | Value (MEAN) |
|---|---|---|
| AR-42 Administration | AR-42 Tumor Concentration (Center/Plasma) | 5.748 ratio |
Other Pre-specified
Number of Doses of AR-42 Received
We report the average total number of doses of AR-42 taken per participant during this study.
Time frame: 3 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AR-42 Administration | Number of Doses of AR-42 Received | 9 total doses |