Not provided
Not provided
Not provided
Not provided
Not provided
Drug manufacturing logistics; lack of access to drug supply
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| Johns Hopkins University | OTHER |
| Stanford University | OTHER |
| Ohio State University | OTHER |
| Nationwide Children's Hospital |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| AR-42 Administration | Experimental | AR-42 will be administered three times per week beginning 3 weeks prior to surgery. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| AR-42 | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 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. | 3 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| AR-42 Plasma Concentration | Steady-state plasma concentrations of AR-42 at the time of tumor resection are provided. | 1 week |
| AR-42 Tumor Concentration (Capsule) | Concentrations of AR-42 at the tumor capsule are provided. |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Doses of AR-42 Received | We report the average total number of doses of AR-42 taken per participant during this study. | 3 weeks |
Inclusion Criteria:
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:
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.
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Brad Welling, MD, PhD | Massachusetts Eye and Ear | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stanford University | Stanford | California | 94305 | United States | ||
| Johns Hopkins University |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34667843 | Derived | 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. | |
| 26943915 |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
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.
Not provided
| ID | Title | Description |
|---|---|---|
| FG000 | AR-42 Administration | There was no randomization in this trial and all participants completed study procedures uniformly. 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, which 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. All participants were instructed to take the study medication at least 1 hour before, or 2 hours after, a meal. The principal investigator performed the clinically indicated surgical procedure 3 weeks post-initial dose of medication as well as the specimen collection. |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
|
Not provided
| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jun 11, 2019 |
Not provided
| OTHER |
| Mayo Clinic | OTHER |
Not provided
Not provided
Not provided
Not provided
Not provided
|
|
| 1 week |
| AR-42 Tumor Concentration (Center) | Intra-tumor concentrations of AR-42 at the tumor center are reported. | 1 week |
| AR-42 Tumor Concentration (Capsule/Plasma) | Capsule/plasma intra-tumor AR-42 concentrations are provided as a ratio. | 1 week |
| AR-42 Tumor Concentration (Center/Plasma) | Center/plasma intra-tumoral AR-42 concentrations are provided as a ratio. | 1 week |
| Baltimore |
| Maryland |
| 21287 |
| United States |
| Massachusetts Eye and Ear | Boston | Massachusetts | 02214 | United States |
| Mayo Clinic | Rochester | Minnesota | 55905 | United States |
| Derived |
| 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. |
| COMPLETED |
|
| NOT COMPLETED |
|
|
Two participants were withdrawn from the study prior to the administration of the study drug: one was deemed ineligible, and one chose not to participate.
Not provided
| ID | Title | Description |
|---|---|---|
| BG000 | 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants | Participants |
| ||||||||||||||||||
| Age, Continuous | Mean | Full Range | years |
| |||||||||||||||||
| Sex: Female, Male | Count of Participants | Participants |
| ||||||||||||||||||
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||||
| Race (NIH/OMB) | Count of Participants | Participants |
| ||||||||||||||||||
| Region of Enrollment | Number | participants |
| ||||||||||||||||||
| Weight | Two participants were withdrawn from the study prior to baseline weight measurement. | Mean | Full Range | kilograms (kg) |
| ||||||||||||||||
| Prior tumor biopsy or debulking | Count of Participants | Participants |
| ||||||||||||||||||
| Relevant diagnosis | Count of Participants | Participants |
| ||||||||||||||||||
| ECOG Grade | The ECOG Scale of Performance Status grades a patient's level of functioning in terms of their ability to care for themselves and other activities of daily living. Grading is done from 0 (zero) to 5 (five). An ECOG grade of 0 (zero) is defined as "fully active, able to carry on all pre-disease performance without restriction." An ECOG grade of 4 (four) is defined as "completely disabled; cannot carry on any selfcare; totally confined to bed or chair." An ECOG grade of 5 (five) is defined as death. | Count of Participants | Participants |
| |||||||||||||||||
| Baseline plasma concentration of AR-42 | Plasma concentrations of AR-42 at baseline (before tumor resection) are reported individually for each of the 5 participants. | Mean | Full Range | nanomolar (nM) |
|
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Mean | Full Range | percent (%) | 3 weeks |
|
|
| ||||||||||||||||||||||||||
| 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. | Posted | Mean | Full Range | percent (%) | 3 weeks |
|
| |||||||||||||||||||||||||||
| Secondary | AR-42 Plasma Concentration | Steady-state plasma concentrations of AR-42 at the time of tumor resection are provided. | Posted | Mean | Full Range | nanomolar (nM) | 1 week |
|
| |||||||||||||||||||||||||||
| Secondary | AR-42 Tumor Concentration (Capsule) | Concentrations of AR-42 at the tumor capsule are provided. | Posted | Mean | Full Range | nanomolar (nM) | 1 week |
|
| |||||||||||||||||||||||||||
| Secondary | AR-42 Tumor Concentration (Center) | Intra-tumor concentrations of AR-42 at the tumor center are reported. | Posted | Mean | Full Range | nanomolar (nM) | 1 week |
|
| |||||||||||||||||||||||||||
| Secondary | AR-42 Tumor Concentration (Capsule/Plasma) | Capsule/plasma intra-tumor AR-42 concentrations are provided as a ratio. | Posted | Mean | Full Range | ratio | 1 week |
|
| |||||||||||||||||||||||||||
| Secondary | AR-42 Tumor Concentration (Center/Plasma) | Center/plasma intra-tumoral AR-42 concentrations are provided as a ratio. | Posted | Mean | Full Range | ratio | 1 week |
|
| |||||||||||||||||||||||||||
| 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. | Posted | Median | Full Range | total doses | 3 weeks |
|
|
Participants were observed for adverse events over 5 weeks, beginning 3 weeks prior to surgery and ending 2 weeks after surgery. This interval included perioperative adverse events and surgical complications associated with AR-42.
Adverse events were graded according to Common Terminology Criteria for Adverse Events (CTCAE) and were also recorded according to severity, expectedness, and relatedness to the investigational treatment. Participants were encouraged throughout the study to spontaneously report all adverse events promptly to their physician-investigator.
Not provided
| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. | 0 | 5 | 0 | 5 | 4 | 5 |
Not provided
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Thrombocytopenia | Blood and lymphatic system disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Fatigue | General disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Nausea | General disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Diarrhea | Gastrointestinal disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Anemia | Blood and lymphatic system disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Leukopenia | Blood and lymphatic system disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Neutropenia | Blood and lymphatic system disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Confusion | Psychiatric disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Lymphopenia | Blood and lymphatic system disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Myalgia | Musculoskeletal and connective tissue disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Taste change | Nervous system disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Headache | General disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Dyspepsia | Gastrointestinal disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Facial weakness | Nervous system disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Rash | Skin and subcutaneous tissue disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Leukocytosis | Blood and lymphatic system disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Non-cardiac chest pain | General disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| CSF leak | Nervous system disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Tremor | Nervous system disorders | CTCAE (4.0) | Non-systematic Assessment |
| |
| Scleral disorder | Eye disorders | CTCAE (4.0) | Non-systematic Assessment |
|
The supplier of AR-42 was unable to continue to supply drugs after 2017. We elected to present the data on five of the originally planned 20 patients. Accrual was also limited by patient willingness to accept potential additional peri-operative risk without a reasonable likelihood of benefit from only 3 weeks of therapy with AR-42. Other limitations include possible selection bias, lack of control subjects, and the inability to perform meaningful statistical analysis.
Not provided
Not provided
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Matthew E Stenerson, MSc, Clinical Research Project Manager | Mass General Brigham | 7155721100 | matthew_stenerson@meei.harvard.edu |
| Oct 20, 2021 |
| Prot_SAP_000.pdf |
| ID | Term |
|---|---|
| D009464 | Neuroma, Acoustic |
| D008579 | Meningioma |
| D016518 | Neurofibromatosis 2 |
| D009442 | Neurilemmoma |
| ID | Term |
|---|---|
| D018358 | Neuroendocrine Tumors |
| D017599 | Neuroectodermal Tumors |
| D009373 | Neoplasms, Germ Cell and Embryonal |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D009463 | Neuroma |
| D018317 | Nerve Sheath Neoplasms |
| D009380 | Neoplasms, Nerve Tissue |
| D003390 | Cranial Nerve Neoplasms |
| D009423 | Nervous System Neoplasms |
| D009371 | Neoplasms by Site |
| D010524 | Peripheral Nervous System Neoplasms |
| D000160 | Vestibulocochlear Nerve Diseases |
| D012181 | Retrocochlear Diseases |
| D004427 | Ear Diseases |
| D010038 | Otorhinolaryngologic Diseases |
| D010039 | Otorhinolaryngologic Neoplasms |
| D003389 | Cranial Nerve Diseases |
| D009422 | Nervous System Diseases |
| D009383 | Neoplasms, Vascular Tissue |
| D008577 | Meningeal Neoplasms |
| D016543 | Central Nervous System Neoplasms |
| D017253 | Neurofibromatoses |
| D009455 | Neurofibroma |
| D009386 | Neoplastic Syndromes, Hereditary |
| D020752 | Neurocutaneous Syndromes |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
Not provided
Not provided
| ID | Term |
|---|---|
| C524513 | HDAC-42 |
Not provided
Not provided
Not provided
| >=65 years |
|
|
| Unknown or Not Reported |
|
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
|
|
|
| ECOG not assessed at baseline |
|
|
|
|
|
|
|
|
|