Clinical trial NCT02282917
Conditions: Vestibular Schwannoma Meningioma Acoustic Neuroma Neurofibromatosis Type 2
Keywords: NF2 Vestibular Schwannoma Schwannoma Meningioma
Sponsor: Massachusetts Eye and Ear Infirmary
Start date: 2015-12-01; Completion date: 2021-01-04
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Arms: arm 1: AR-42 will be administered three times per week beginning 3 weeks prior to surgery.
Interventions: intervention 1: AR-42
Intervention descriptions: intervention 1: 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.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
EXPLORATORY EVALUATION OF AR-42 
HISTONE DEACETYLASE INHIBITOR IN 
THE TREATMENT OF VESTIBULAR 
SCHWANNOMA AND MENINGIOMA 
 
 
 
 
 
 
 
IRBNet ID : 596699/14-078H 
 
Version 8: 11 JUN 2019 
Phase 0 
IND Number: 114227 
Drug : AR-42 
 
 
 


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Coordinating Center: 
The Massachusetts Eye and Ear Infirmary  
 
 
 
PRINCIPAL 
INVESTIGATOR 
D. Bradley Welling, M.D., Ph.D. 
Walter Augustus LeCompte Professor and Chair Harvard 
Department of OtolaryngologyDepartment of Otolaryngology-
Head and Neck Surgery 
The Massachusetts Eye and Ear Infirmary 
Chief of Otolaryngology The Massachusetts General Hospital  
243 Charles Street 
Boston, MA 02115 
Administrative assistant: Suzanne Walker 
617-573-4075 
E-mail: brad_welling@meei.harvard.edu 
CO-INVESTIGATORS 
Jaishri Blakeley, M.D., Johns Hopkins University  
Robert Jackler, M.D., Stanford University 
Brian Neff, M.D., Mayo Clinic, Rochester 
COLLABORATORS 
Ruwan Kiringoda, M.D., The Massachusetts Eye and Ear 
Infirmary 
LAB INVESTIGATORS 
Long-Sheng Chang, Ph.D., Nationwide Children’s Res. Inst. 
Zhongfa Liu, Ph.D., The Ohio State University 
BIOSTATISTICIAN 
Rong Guo, M.S. 
 
 
 


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Table of Contents 
 
 
1. 
STUDY OBJECTIVES ............................................................................................................................................ 5 
1.1   
PRIMARY OBJECTIVES .......................................................................................................................................... 5 
1.2   
SECONDARY OBJECTIVES ..................................................................................................................................... 5 
2.  INTRODUCTION AND RATIONALE ..................................................................................................................... 5 
2.1  
NEUROFIBROMATOSIS TYPE 2 (NF2) IS A DEBILITATING DISEASE .......................................................................... 5 
3. 
STUDY DESIGN AND DURATION .................................................................................................................... 15 
3.1 
STUDY DESIGN .................................................................................................................................................. 15 
3.2 
DEFINITION OF UNACCEPTABLE TOXICITY ......................................................................................................... 15 
3.3 
STUDY ACCRUAL ............................................................................................................................................... 16 
3.4 
DURATION OF STUDY FOR EACH PATIENT .......................................................................................................... 16 
4. 
STUDY POPULATION ......................................................................................................................................... 17 
4.1 
INCLUSION CRITERIA ......................................................................................................................................... 17 
4.2 
EXCLUSION CRITERIA ........................................................................................................................................ 18 
5. 
STUDY PROCEDURES ........................................................................................................................................ 19 
5.1 
AR-42 ............................................................................................................................................................... 19 
5.1.1 
Dosing schedule and cohorts .................................................................................................................... 19 
5.1.2 
Supportive care for patients receiving AR-42 ........................................................................................... 19 
5.2 
DOSE DELAYS AND MODIFICATIONS .................................................................................................................. 20 
5.3 
CONCOMITANT TREATMENT RESTRICTIONS ....................................................................................................... 20 
5.4 
SCHEDULE OF TESTS AND OBSERVATIONS ......................................................................................................... 20 
5.4.1 
Screening .................................................................................................................................................. 20 
5.4.2 
Evaluation during treatment ..................................................................................................................... 21 
5.4.3 
Post-treatment follow-up .......................................................................................................................... 21 
5.4.4 
Schedule of events ..................................................................................................................................... 22 
5.4.5 
Tumor resection and sample collection .................................................................................................... 23 
5.5 
STUDY RECORDS ............................................................................................................................................... 24 
5.6 
SELECTION PROCEDURES .................................................................................................................................. 24 
6. 
PHARMACOKINETIC STUDIES ....................................................................................................................... 25 
7. 
AR-42 ....................................................................................................................................................................... 26 
7.1 
CLASSIFICATION ................................................................................................................................................ 26 
7.2 
CHEMICAL STRUCTURE ...................................................................................................................................... 26 
7.3 
SOLUBILITY AND MELTING POINT ...................................................................................................................... 27 
7.4 
SUPPLY, HANDLING AND DISPOSITION, STORAGE, AND ADMINISTRATION .......................................................... 27 
7.5 
PHARMACOKINETICS IN CANINES ...................................................................................................................... 28 
7.6 
TOXICOLOGY IN RATS AND CANINES.................................................................................................................. 28 
8. 
STATISTICAL CONSIDERATIONS .................................................................................................................. 29 
8.1 
SAFETY ENDPOINTS ........................................................................................................................................... 29 
8.2 
STUDY DESIGN AND SAMPLE SIZE ...................................................................................................................... 30 
8.3 
INTERIM ANALYSIS AND EARLY STOPPING RULES .............................................................................................. 30 
8.4 
STATISTICAL METHODS ..................................................................................................................................... 30 
8.5 
PATIENT DISPOSITION AND DRUG EXPOSURE ..................................................................................................... 31 
9. 
PATIENT SAFETY ................................................................................................................................................ 31 
9.1 
MONITORING OF ADVERSE EVENTS .................................................................................................................... 31 
9.2 
DEFINITIONS OF ADVERSE EVENTS AND CAUSALITY .......................................................................................... 32 
9.3 
SERIOUS ADVERSE EVENTS ................................................................................................................................ 33 
9.4 
DATA SAFETY MONITORING PLAN ...................................................................................................................... 34 
9.5 
REPORTING OF ADVERSE EVENT INFORMATION FOLLOWING STUDY COMPLETION ............................................. 35 
9.6 
PREGNANCY STATEMENT AND USE IN NURSING WOMEN .................................................................................... 35 
9.7 
PATIENT WITHDRAWAL AND STUDY TERMINATION............................................................................................ 36 
9.8 
RESEARCH MONITOR ......................................................................................................................................... 37 
10. ETHICAL AND REGULATORY STANDARDS ............................................................................................... 37 
10.1 
ETHICAL PRINCIPLES ......................................................................................................................................... 37 


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10.2 
PROTOCOL COMPLIANCE AND PROTOCOL REVISIONS ......................................................................................... 38 
10.3 
INFORMED CONSENT .......................................................................................................................................... 38 
10.4 
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL ............................................................................................ 39 
10.5 
ADDITIONAL RESPONSIBILITIES OF THE INVESTIGATOR ..................................................................................... 39 
10.6 
CONFIDENTIALITY ............................................................................................................................................. 39 
10.7 
CONFLICT OF INTEREST ..................................................................................................................................... 40 
11. REFERENCES ....................................................................................................................................................... 41 
12. APPENDIX A: QT PROLONGATION – HISTORY, RATIONALE, MONITORING .................................. 46 
13. APPENDIX B:  MEDICATION LOG .................................................................................................................. 49 
14. APPENDIX C:  ELIGIBILITY/SCREENING CHECKLIST ............................................................................ 50 
15. APPENDIX D:  ELIGIBILITY/SCREENING LOG .......................................................................................... 53 
 


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1.  STUDY OBJECTIVES 
 
1.1   
Primary objectives 
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 vestibular schwannomas (VS), meningiomas, and cutaneous 
schwannomas and control tissue samples from patients enrolled in the control group. This endpoint was chosen 
based on prior data from our published preclinical work and others showing marked reduction of phosphor-AKT 
in AR-42 treated VS and meningiomas in vivo.  
 
1.2   
Secondary objectives 
The secondary objectives are: 
 
1) 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 control 
patients.  
 
2) 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 control patients.    
 
3) 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 (Khan et al., 2010). 
 
4) 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. 
 
5) 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. 
 
6) 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. 
 
7) Determine the steady-state plasma and intra-tumoral concentrations of AR-42 at the time of surgical resection. 
 
2. INTRODUCTION AND RATIONALE 
 
2.1  
Neurofibromatosis type 2 (NF2) is a debilitating disease 
NF2 is highly penetrant, autosomal dominant disorder with an incidence of approximately 1/40,000 (Bull. World 
Health Org. 1992).  Patients with NF2 are at risk for multiple nervous system tumors.  One-hundred percent of 
NF2 patients develop vestibular schwannomas (VS) and up to 60% develop meningiomas. Approximately 50% 


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develop subcutaneous schwannomas.  NF2 is an extremely debilitating disease, leading to decreased life 
expectancy in those afflicted. Individuals with NF2 often show 8th-nerve dysfunction beginning in early childhood, 
including tinnitus, bilateral profound deafness, and ataxia.  The mean age at presentation for NF2-associated 
vestibular schwannomas is 20-21 years of age (Evans et al., 1992; Parry et al., 1994). Due to deafness and bilateral 
facial nerve paralysis NF2 patients are socially isolated and employment is difficult, if not impossible.   Brainstem 
compression and loss of lower cranial nerves which protect the airway are leading causes of death in NF2 patients.  
 
2.2 
NF2 tumor suppressor role remains elusive 
The human NF2 tumor suppressor gene was identified on chromosome 22q12 and mutations have been identified 
within the NF2 gene in patients with VS, including both sporadic unilateral schwannomas and the less common 
NF2-associated bilateral schwannomas (Welling et al., 2008).  Additionally, NF2 mutations are frequently found 
in meningiomas (Bianchi et al., 1994, 1995).  The NF2 gene encodes a protein named ‘merlin’ for moesin, ezrin, 
and radixin-like protein (Rouleau et al., 1993; Trofatter et al., 1993).  Unlike other tumor suppressors, merlin does 
not have any catalytic or DNA-binding domains.  It belongs to the ezrin-radixin-moesin (ERM) family of 
cytoskeleton-associated proteins, but merlin is the only member of this family to possess tumor suppressor 
functions.  Conditional biallelic inactivation of Nf2 in Schwann cells or arachnoidal cells in mice leads to 
schwannomas or meningiomas, respectively (Giovannini et al., 2000; Kalamarides et al., 2002, 2011).  In addition, 
merlin mediates contact-dependent inhibition of proliferation in confluent cells by restraining the membrane levels 
of multiple pro-mitogenic receptors, such as the epidermal growth factor receptor (EGFR) in fibroblasts and 
keratinocytes and ErbB2/3 in Schwann cells (Curto et al., 2007; Lallemand et al., 2009).  Since the growth control 
of certain Schwann cells and meningeal cells is abrogated by NF2 loss, it has been suggested that NF2 deficiency 
disrupts some aspect of intracellular signaling that leads to a signal to proliferate, albeit slowly (McClatchey and 
Giovannini, 2005).  However, the mechanism underlying the molecular pathogenesis of NF2-associated tumors is 
not completely understood. We (Welling et al., 2002; Lasak et al., 2002; Jacob et al., 2008) and others (Hanemann 
et al., 2006; Hansen et al., 2006; Rong et al., 2004; Doherty et al., 2008; Hilton et al., 2009; Lallemand et al., 2009) 
have identified several signaling pathways that are frequently deregulated in VS, including the 
phosphatidylinositol 3-kinase (PI3K)/AKT pathway. In addition to slightly elevated AKT mRNA and protein 
levels, VS tumors express substantially higher levels of phosphorylated, activated AKT than paired vestibular 
nerve specimens (Jacob et al., 2008).  Furthermore, activation of the PI3K/AKT pathway has been reported in 
meningiomas (Johnson et al., 2002; Mawrin et al., 2005).  Since the PI3K/AKT pathway serves as a convergence 
point for many growth stimuli and, through its downstream substrates, controls cellular processes and responses 
such as cell survival, cell proliferation, insulin response, stress response, and differentiation (LoPiccolo et al., 
2008), its activation likely contributes to tumorigenesis.  Thus, the PI3K/AKT pathway is an attractive therapeutic 
target for VS, and small-molecule inhibitors of AKT signaling may have therapeutic potential in suppressing the 
growth of these tumors. 
 
2.3 
Like NF2-associated VS, sporadic VS can cause significant morbidity, and in some cases, 
mortality, due to brain stem compression 
VS are histologically benign nerve sheath tumors that originate on the superior or inferior vestibular branches of 
cranial nerve VIII.  The hallmark of NF2 is the development of bilateral VS, however, VS most commonly occur 
as sporadic unilateral solid tumors with an incidence of 40/100,000 (Evans et al. 1992).  Patients with VS present 
with tinnitus, hearing loss and imbalance.  The tumors may lead to deafness, facial nerve paralysis and brainstem 
compression, hydrocephalus, and death, if left untreated. The mean age at onset in our series is 49 years of age 
and there is a slight female predominance without ethnic predilection (Welling et al., 1998). 
 
2.4 
NF2-associated meningiomas are associated with a high risk of mortality 
Meningiomas, which arise from meningothelial or arachnoid cap cells, constitute approximately 34% of primary 
intracranial brain tumors (Wiemels et al., 2010; Central Brain tumor Registry of the United States [CBTRUS], 
2011).  Meningiomas occur in up to 60% of NF2 patients and are often multiple.  Meningiomas in NF2 patients 
are associated with a 2- to 3-fold increased risk of mortality, and their treatment is challenging (Goutagny and 


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Kalamarides, 2010; Baser et. al., 2002).  Location-dependent cranial nerve palsy, seizures and brainstem 
compression may lead to paralysis, aspiration pneumonia and death.  While NF2 patients develop both VS and 
meningiomas synchronously, these tumors can also occur sporadically in non-NF2 patients.  Meningiomas affect 
lower cranial nerves by compression or invasion and may have similar devastating effects to VS. 
 
2.5 
Development of a medical therapy for VS and meningiomas  
General principles to consider in treatment of VS and meningiomas include the importance of preservation of 
function of the brainstem, the facial nerve and lower cranial nerves for swallowing and airway protection, hearing 
and balance. Long-term quality of life is greatly affected.  Current level of evidence in the literature regarding 
treatment outcomes in NF2 is predominantly grade IV (retrospective case series) (Bassim et al., 2010). Treatment 
options for NF2-associated tumors are presently limited to observation, surgical removal or stereotactic radiation.   
 
Observation 
Watchful waiting may be advocated with MRI to assess tumor growth rate along with audiometric studies to 
monitor hearing loss.  Both VS and meningiomas are usually slow growing. The first complication associated with 
observation of VS is most often increased tinnitus and decreased hearing (Massick et. al., 2000).  There is not good 
correlation with tumor size relative to hearing loss.  Some tumors originate in the cerebellopontine angle where 
the tumors may grow without direct pressure being placed on the adjacent cranial nerves.  If, however, the tumor 
growth occurs within the internal auditory canal, hearing may decline rapidly from pressure on the cochlear nerve 
or vascular compromise to the cochlea.  At present, there are no good predictors or biomarkers of tumor growth.  
 
Stereotactic radiation 
Stereotactic radiation treatment has been proposed as a treatment for NF2-associated tumors with control rates 
of vestibular schwannomas from 66% to 81%.  Hearing preservation rates at five years were reported at 48% 
(Mathieu et al., 2007) and serviceable hearing at 33% (Phi et al., 2009). In a consensus conference of 36 experts, 
we recommended caution in recommending radiation for NF2 patients given the young age of the NF2 patient 
population and the reports of secondary radiation induced malignancy (Evans, et. al., 2009; Mut et al., 2004; 
Balasubramaniam et al., 2007).  The incidence of malignant change following stereotactic radiation to benign VS 
is presently less than 1%, however a disproportionate number of these are found in NF2 patients.  Resulting 
malignant sarcomas or triton tumors are universally fatal when they occur.  Twenty to 30 year follow up will be 
necessary to determine the true incidence of malignant change as shown with prior studies of radiation to the scalp 
for acne and to the tonsils for hypertrophy (Albright and Allday, 1967; Palmer et al., 1980).  NF2 patients are 
predisposed by their tumor suppressor mutation to further malignancy.  Radiation induced meningiomas are also 
a concern. Additionally, Friedman et al. (2005) reported much poorer surgical outcome in patients who failed 
stereotactic radiation.  Fifty-percent of patients that had surgery following radiation suffered severe or complete 
facial paralysis.   
 
Surgical resection 
For VS, the advantages of surgical resection may include brainstem decompression, hearing and facial nerve 
preservation, but the success rate is variable depending upon a number of factors, including the aggressiveness 
and adherence of the tumor to the brainstem and cranial nerves, the preoperative hearing, the experience of the 
surgical team and the tumor size.  Early removal of small tumors is more likely to succeed in functional 
preservation.  However, hearing preservation in NF2-associated VS is not as high as non-NF2 associated VS and 
is reported between 35 and 65% (Welling et al., 1998; Slattery et al., 2007; Samii et al., 2008).  Tumor recurrence 
or new cranial nerve schwannomas are more common in NF2.  Complications of surgery include brainstem injury, 
facial nerve paralysis, hearing loss, cerebrospinal fluid leak, meningitis, post-operative bleeding, pneumocephalus, 
and death. 
Surgical excision of meningiomas is complicated by the structures to which they are adherent.  Complete 
excision can be very challenging.  Recurrence occurs in up to 30% of meningiomas following resection as 
extensive dural attachments and the attempts to preserve adherent or encased vital structures may result in 
incomplete extirpation.  Similar complications of surgical craniotomy occur with surgical excision of menigiomas 


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as with VS.  Tumors located along the skull base are more likely to be incompletely excised and are associated 
with higher morbidity than tumors along the convexity of the cranial vault.  Lower cranial nerve palsy and shared 
blood supply to the brainstem are especially hazardous.   
 
Chemotherapy 
At the present time, no FDA-approved drugs are available for the treatment of NF2-associated VS or 
meningiomas.  A case series by Plotkin et al. (2009) with bevacizumab for VS shows some tumor shrinkage and 
hearing improvement in a portion of patients.  Meningiomas do not appear to respond well to bevacizumab.  Only 
seven of 40 meningiomas in 14 patients showed decreased volume over the course of treatment (Nunes et. al., 
2011).  Meningiomas are less radio-sensitive than VS.  Together, these factors underscore the importance of 
developing an effective chemotherapeutic agent which will stop tumor growth or completely eradicate NF2-
associated and sporadic VS and meningiomas.  The ideal chemotherapeutic agent would target both. 
 
2.6 
Histone deacetylase inhibition as a potential therapy for VS and Meningiomas 
Histone acetylation is critical to epigenetic modifications occurring in many solid and hematological tumors (Cress 
and Seto, 2000; Marks et al., 2001).  Histone proteins condense eukaryotic DNA 10,000 fold via the nucleosome, 
a histone octamer consisting of a histone H3 and H4 tetramer and two histone H2A and H2B dimers.  These histone 
proteins are subject to post-translational modifications that regulate gene transcription by either inhibiting or 
facilitating tight interactions between the nucleosome and the DNA. Histone deacetylases (HDACs) remove acetyl 
groups from histone lysines and neutralize the positive charge on histone tails, thereby weakening interactions 
with negatively-charged DNA, creating a more “open” chromatin conformation, and altering transcription of 
growth-regulatory genes (Drummond et al., 2005; Bolden et al., 2006).  Over-expressed or sustained HDAC 
activity has been reported in leukemia, lymphomas, and other types of cancers (Johnstone and Licht, 2003; 
Minucci and Pelicci, 2006).  The aberrant HDAC activity in human neoplasms deacetylates the N-termini of core 
histones, resulting in a tightly-closed chromatin structure; therefore, tumor suppressor genes can be silenced by 
abnormal HDAC activity. Inhibitors of HDACs reverse this histone deacetylation, thus reactivating expression of 
silenced genes (Santini et al., 2007).  Presently, more than a dozen HDAC inhibitors are being investigated in 
phase I/II clinical trials for solid and hematological tumors, with some showing efficacy and low pharmacotoxicity, 
including AR-42 (Drummond et al., 2005; Bolden et al., 2006; Minucci and Pelicci, 2006; Marks and Breslow, 
2007; Lucas et al., 2010; Johnson et al., 2011). 
 
AR-42 was developed at The Ohio State University (OSU) and was licensed to Arno Therapeutics, Inc.  It is a 
novel hydroxamate-tethered phenylbutyrate derivative.  AR-42 also down-regulates the AKT pathway by 
disrupting interactions between protein phosphatase-1 (PP1) and HDAC6, consequently allowing free PP1 to 
interact with and dephosphorylate AKT (Kulp et al., 2006).  AR-42 has shown potent antitumor effects in multiple 
tumor types, at least in part, by inhibition of the PI3K/AKT pathway (Chen et al., 2005; Kulp et al., 2006; Lu et 
al., 2007; Sargeant et al., 2008; Yang et al., 2009; Bai et al., 2011; Lin et al., 2010; Zhang et al., 2011).  We also 
found it to induce pro-apoptotic Bim and to decrease anti-apoptotic Bcl.  AR-42 also induces cell cycle arrest by 
cyclin-dependent kinase inhibitors. 
 
We recently reported AR-42 inhibition of the growth of human VS and Nf2-deficient mouse schwannoma cells 
with an IC50 of 500 nM and 250-350 nM, respectively (Bush et al., 2011). AR-42 also inhibited primary 
meningioma cells and benign meningioma Ben-Men-1 cells with IC50 values of 1.5 M and 1.0 M, respectively. 
AR-42 treatment induced cell cycle arrest at G2 and apoptosis in both VS and meningioma cells.  Also, AR-42 
exposure decreased phosphorylated AKT in schwannoma and meningioma cells.  In vivo treatment with AR-42 
inhibited the growth of schwannoma xenografts, induced apoptosis, and decreased AKT activation (Figure 1).  
These results demonstrate a high potency of AR-42 against NF2-associated VS and meningiomas (Bush et al., 
2011). 
 


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Figure 1.AR-42 treatment induced apoptosis and decreased phospho-AKT (p-AKT) staining in malignant 
schwannoma xenografts.  (A,B) Hematoxylin/eosin (H/E) staining of untreated or AR-42-treated xenograft tumor 
sections.  (C,D) Cleaved caspase 3 (CC3) staining.  (E,F) TUNEL staining.  (G,H) p-AKT staining. 
 
 
We created a benign meningioma model by stereotactically implanting the skull base of SCID mice with a 
telomerase immortalized cell line, Ben-Men-1 (Puttmann et al., 2005) with a luciferase-expressing lentiviral vector 
(Burns et al., 2011).  By bioluminescence imaging (BLI) we detected increasing luciferase activity in the brain 
region of these mice over time (Figure 2), establishing an intracranial meningioma model. 
 
 
 
Figure 2. Ben-Men-1-LucB cells establish intracranial 
tumors that grow over time.  Mice with Ben-Men-1-LucB 
cells (5X105) stereotactically injected into the skull base 
region were imaged at the indicated time. 


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2.7 
AR-42 potently inhibits the growth of Ben-Men-1-LucB benign meningioma xenografts  
To compare the in vivo efficacy of AR-42, we divided mice bearing intracranial Ben-Men-1-LucB xenografts into 
three groups one week after injection.  The first group was fed normal diet, the second group received AR-42 at 
25 mg/kg/day formulated into mouse chow, and the third group ate chow formulated with AR-12, a celecoxib 
derivative which we have also shown to inhibit the PI3K/AKT pathway, at 200 mg/kg/day (Research Diets, New 
Brunswick, NJ).  We performed BLI to monitor tumor growth every month following treatment.  Figure 3 showed 
that AR-42 potently inhibits the growth of Ben-Men-1-LucB benign meningioma xenografts.  AR-42 treatment 
reduced the size of luciferase-expressing Ben-Men-1 meningioma xenografts by about 80~98% after five months.  
Importantly, the size of the Ben-Men-1-LucB xenograft was substantially reduced following AR-42 treatment for 
just one month.  AR-12 also showed growth inhibitory activity on Ben-Men-1-LucB xenografts by 34~51% after 
one month of treatment; however, the tumors in mice receiving AR-12 continued to grow, albeit at a slower rate 
than the normal diet control group.  We also performed MRI on mice treated for three months to confirm the 
growth inhibitory effect of AR-42 and AR-12 on intracranial Ben-Men-1-LucB xenografts (Figure 4).  
Histopathological examination showed that Ben-Men-1-LucB xenograft tumors grow along the meninges like 
benign meningiomas.  The drug-treated tumors appeared much smaller than the untreated control (Figure 5).  We 
are presently performing immunostaining for cleaved caspase 3 and terminal deoxynucleotidyl transferase dUTP 
nick end labeling (TUNEL) assay to confirm that the inhibition of tumor growth by AR-42 is mediated by 
apoptosis as that seen in schwannoma xenografts (Lee et al., 2009; Bush et al., 2011). 
 
Figure 3. Growth inhibition of intracranial Ben-Men-1 benign meningioma xenografts by AR-42 and AR-12.  
SCID mice with established intracranial Ben-Men-1-LucB xenografts were divided into three groups (N=5).  The 
first group (mouse #1 shown) was fed chow formulated with AR-42, the second group (mouse #2) ate normal diet, 
and the third group (mouse #3 and #4) received chow containing AR-12.  At each indicated time points, BLI was 
performed. 
 
 


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Figure 4. The effect of AR-42 and AR-12 
on Ben-Men-1-LucB intracranial 
xenografts was  confirmed by MRI.  
Multi-planar tumor volumes were 
calculated from manually-traced tumor 
areas on axial and coronal images.  
Comparing with total flux emitted from 
the tumor detected by BLI, a trend of 
reduction of tumor volumes in AR-42 or 
AR-12 treated mice was seen by MRI. 
 


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To examine whether AR-42 effectively eliminated Ben-Men-1-LucB cells, xenograft-bearing mice that had been 
treated with AR-42 for six months were fed normal diet, and the residual tumor imaged every following month for 
four months.  Although a residual tumor was detected and appeared to regrow over time (Figure 6), the tumor 
remained very small after four months on a normal diet.  
 
Collectively, our results indicate that AR-42 possesses potent growth inhibitory activity in both schwannomas and 
meningiomas. 
 
Figure 6. Minimal regrowth of Ben-Men-1-LucB xenografts after AR-42 treatment. 
 
 
2.8 
AR-42 passes blood-brain barrier and shows low toxicity profile  
The dose of AR-42 which best corresponds to the severe toxic dose in 10% of rats (rat STD10) is 30 mg/kg (180 
mg/m2). In 28-day repeat dose toxicology studies in rats, a dose of 30 mg/kg administered orally every other day 
caused slight changes in bodyweight, significant decreases in red and all lineages of white blood cells (returned to 
control values after recovery) and histopathological changes (bone marrow, lymph nodes, spleen, thymus and 
Figure 5. Ben-Men-1-LucB xenograft tumors 
grow along the meninges like benign meningiomas.  
Hematoxylin-eosin 
staining 
of 
sections 
of 
decalcified heads of xenograft-bearing mice fed 
normal diet or chow formulated with AR-42 for three 
months.  Note that the xenograft tumor was much 
smaller in the mouse fed AR-42-containing chow.  
 


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female and male reproductive tract). All histopathological changes, with the exception of testicular findings, 
showed evidence of total or partial recovery after 2 weeks.  One-tenth of the rat STD10, or 18 mg/m2, corresponds 
to a human dose of approximately 30 mg in an adult human.   
 
A similar dose in beagle dogs of 1 mg/kg (20 mg/m2) was not associated with severe toxicity when given p.o. 
q.o.d. for 7 or 28 days. However, dogs were determined to be a more sensitive species overall. The no observable 
effect levels (NOELs) in the 28-day dog study were 1 mg/kg in females and 0.3 mg/kg in males.  The dose of AR-
42 which best corresponds to the Highest Non Severe Toxic Dose (HNSTD) is 3 mg/kg (60 mg/m2). In repeat dose 
studies in dogs, administration of 3 mg/kg p.o. every other day resulted in a slight decrease in body weight, 
decreases in red and white blood cell variables, vomiting and liquid feces. One-sixth of the dog HNSTD, or 10 
mg/m2, corresponds to a human dose of approximately 20 mg in an adult human.  Preclinical pharmacology 
conducted at OSU also showed that AR-42 passed the blood brain barrier in mice.  In addition, mice fed AR-42 
for 6 months behaved normally and did not showed overt weight loss. Blood-chemistry studies and organ histology 
performed after 3 and 6 months of AR-42 treatment demonstrated no clinically significant abnormalities (Jacob et 
al., 2012).   
 
2.9 
Clinical studies of AR-42  
AR-42 is currently being studied in a phase I dose escalation study for relapsed or refractory multiple myeloma, 
chronic lymphocytic leukemia, and lymphoma and recurrent or advanced solid tumors.  This is the first study of 
AR-42 in humans, and the study has demonstrated bioavailability of AR-42 in these patient populations.  To date, 
15 participants have been enrolled in the study.  The study is currently enrolling participants into the 50 mg dose 
cohort in the hematologic malignancies arm.  At this dose level, one patient experienced a grade 4 
thrombocytopenia and therefore, this arm is now expanded to 3 more patients (a total of 6 patients). 
 
Dose (mg) 
 
 
Number of Participants 
20 
 
 
 
 
3 
30 
 
 
 
 
3 
40 
 
 
 
 
6 
 
50 
 
 
 
 
3 
 
The recommended starting dose level for the solid tumors arm is one dose level less than the maximum tolerated 
dose (MTD) for the hematologic malignancies arm.  At prior dose level (40 mg), a total of 6 patients were treated 
and one experienced a dose limiting toxicity (DLT) (Grade 3 thrombocytopenia).  Based on these preliminary 
results to this point, 40 mg is proposed as the starting dose for the solid tumors arm, which may change to a higher 
starting dose, when the MTD for the hematologic malignancies arm is defined.  
 
Serious adverse events (SAEs) have been reported.  In the 40mg dosing cohort, one SAE was reported that was 
possibly related to AR-42, a grade 3 thrombocytopenia.  Below is a summary of all SAEs reported in any dosing 
cohort, with SAEs possibly related to AR-42 listed in bold. 
 
 
33 y Hodgkin’s lymphoma patient on dose level 1a (20mg) had grade 3 blood bilirubin increase; 
unlikely r/t AR42 and r/t disease progression as evidence of CT scans and was removed from study for 
progressive disease. 
 
74y multiple myeloma patient on dose level 1b (40mg) had grade 3 lung infection; unlikely r/t AR42 and 
r/t disease progression; was removed from protocol for disease progression and started on new 
treatment. 
 
59y multiple myeloma patient on dose level 2b (50mg) had grade 4 platelet count decrease that was 
r/t AR42 (Dose Limiting Toxicity) and grade 2 confusion r/t his narcotic regimen.  Was removed from 
study per PI decision for ongoing confusion and inability to obtain pain control with narcotic regimen. 


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 
67y multiple myeloma patient on dose level 2b (50mg) had grade 3 pain in extremity; unlikely r/t AR42 
and r/t disease, she was continued on study as surgery was not an option and pain improved on pain 
medication. 
 
71y multiple myeloma patient on dose level 2b (50mg) had grade 2 blurred vision, diplopia, muscle 
cramps and memory impairment that was possibly related to AR42; she remained on study with 
dose reduction as toxicities reduced to grade 1 after AR42 was held. 
 
61y multiple myeloma patient on dose level 2a (40mg) hospitalized with grade 3 diarrhea, grade 2 
increased creatinine, and grade 3 dehydration; unlikely r/t AR42 and probable related to gastroenteritis, 
likely foodborne.  He remains on study. 
 
61y multiple myeloma patient on dose level 2a (40mg) hospitalized with grade 2 sinus bradycardia, 
grade 3 non-cardiac chest pain, grade 2 creatinine increase unlikely related to AR42 and grade 3 
platelet count decrease possibly related to AR42;  He remains on study.  
 
Other adverse events have been reported in the dosing cohorts (all Grade 1 or 2), but it is unknown if they are 
related to AR-42.   These include:   
 
 
Anorexia 
 
Anemia 
 
Electrolyte abnormalities (hyponatremia, hypophosphatemia, hypoalbuminemia, hypermagnesemia, 
hyperglycemia, hypokalemia, hypercalcemia) 
 
Nausea, vomiting, diarrhea 
 
Dysgeusia 
 
Dry mouth 
 
Limb edema 
 
Pain (back, urinary tract, abdominal, extremities, myalgia, arthralgia) 
 
Increased creatinine, liver enzymes 
 
Neutropenia 
 
Leukopenia 
 
Thrombocytopenia 
 
Fatigue 
 
Prolonged QTc intervals  
 
Hyperhidrosis 
 
Constipation 
 
Insomnia 
 
Dyspnea 
 
Confusion 
 
Preclinical and clinical results lead us to believe that an exploratory study to assess the potential of AR-42 in the 
treatment of the intracranial tumors associated with NF2 would be very useful.  We have full support from ARNO 
Therapeutics who will provide us good manufacturing practice (GMP)-quality AR-42 for the proposed study.  An 
IND application to the FDA for the exploratory evaluation of AR-42 in meningiomas and VS was filed by Dr. 
Brad Welling, and on January 20, 2012, the FDA concluded that it was reasonably safe to proceed with the study. 
 
2.10 
NF2 presents unique challenges for clinical testing 
 
NF2-associated VS, meningiomas, and cutaneous schwannomas present several unique challenges. First, there are 
relatively few NF2 patients. Their tumors are primarily intracranial or along the spinal axis and thus are difficult to 
access for study; though a significant subset of NF2 patients do have peripheral nerve involvement and develop 
cutaneous schwannomas (Sperfield et al., 2002). Second, in spite of severe morbidity and mortality associated with 


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NF2, NF2 patients are unlikely to develop malignant diseases. The treatment aims and endpoints must be selected 
accordingly. We have experience in measuring not only volumetric tumor growth (Walz et al., 2012) with an 
outstanding imaging core, but also in measuring other surrogates, such as hearing (Massick et al., 2000).  Hearing 
loss can result from vascular compromise or from an increased pressure on the cochlear nerve without demonstrated 
tumor growth, and thus is an important surrogate of functional significance.  Third, the length of successful treatment 
is likely to be quite prolonged; therefore, drug safety and an extremely low side effect profile must be sought. 
Fortunately, the preliminary phase I data for AR-42 show a well-tolerated profile.  Fourth, we have selected AR-42 
to move forward to clinical trial very carefully because the patients are few and resources are precious, but this 
unique combination of histone mediated and non-histone mediated AKT pathway targeting by a single drug is 
entirely novel to the treatment of NF2-associated tumors.  The preclinical and toxicity data to date is also very 
encouraging. 
 
If AR-42 is found to have biological activity by showing suppressed p-AKT in VS, meningiomas, and cutaneous 
schwannomas and if the current Phase I AR-42 study continues to demonstrate minimal toxicity, we will seek to 
move forward into a Phase II study for efficacy.  Successful completion of this study would aid in understanding 
the effects of AR-42 in NF2-associated tumor regulation in humans and may lead to substantial improvement over 
today’s current approach to the treatment of NF2 with resulting improvement in the quality of life and longevity 
of our NF2 patients.  
 
3. STUDY DESIGN AND DURATION 
3.1 
Study Design 
This will be a multi-center, proof of concept phase 0 study to assess the suppression of p-AKT in VS, meningiomas, 
and cutaneous schwannomas 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 we 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.    
 
Addendum:  Early results demonstrate intratumoral VS concentration of AR-42, therefore exploring the mechanism 
of action of AR-42 in peripheral schwannomas in patients with NF2 will add information of value and may allow 
more patient participation. 
 
3.2 
Definition of unacceptable toxicity  
An unacceptable toxicity is defined as one of the following toxicities occurring during the cycle of AR-42. 
 
Hematologic unacceptable toxicity criteria: 
 
 
Grade 3 thrombocytopenia (platelet count <50,000/µL) or anemia or grade 3 neutropenia (absolute 
neutrophil count [ANC] <1000/µL; as described by 1996 National Cancer Institute [NCI] Working Group 
Criteria) that does not resolve within 5 days.   
 
Non-hematologic unacceptable toxicity:  Any grade 3-4 non-hematologic adverse event (AE) (NCI Common 
Toxicity Criteria for Adverse Events [CTCAE] version 4) except as follows:   
 
 
Grade 3 or 4 laboratory abnormalities not associated with clinical sequelae, correctable within 24 hours, that 
does not lead to missing more than one dose of study drug. 
 
Grade 3 or 4 nausea or vomiting that resolves to grade 2 or less within 24 hours that does not lead to missing 
more than one dose of study drug. 


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 
Liver function test abnormalities (aspartate transaminase [AST], alanine transaminase [ALT], bilirubin, or 
alkaline phosphatase) that resolve to <grade 1 within 5 days and that does not lead to missing more than one 
dose of study drug 
 
Any AE with clear evidence per the study PI to support an alternative causality other than study drug that 
does not lead to missing more than one dose of study drug. 
 
3.3 
Study accrual 
p-AKT expression will be determined in up to 20 specimens total from AR-42 treated patients with the following 
tumor types: vestibular schwannomas (either NF2-associated or sporadic), meningiomas, and cutaneous 
schwannomas.  A total of 20 subjects will be enrolled in the study.  Control tissues of non-treated vestibular 
schwannomas and meningiomas will serve as comparators. 
 
Given that NF2-associated VS and NF2-associated meningioma patients are rare, we plan to recruit patients from 
four high volume institutions with clinical trial expertise.  We are expecting to enroll between 8-10 patients per year 
based upon current center surgical volume estimates.  Patient recruitment should be completed within three years.  
Should these targets lag, we have another four centers who have agreed to participate if needed.  We anticipate 
patient support from the NF2 communities and support groups also for this venture. 
 
3.4 
Duration of study for each patient 
AR-42 will be administered three times per week beginning 3 weeks prior to resection.  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 resection.  AR-42 should be taken at least 1 hour before or 2 hours after meals.  The starting dose 
of 40 mg for this study of solid tumors was selected by pre-clinical and ongoing phase I data.  The recommended 
starting dose level for the solid tumors arm in the ongoing phase I trial is one dose level less than the maximum 
tolerated dose (MTD) for the hematologic malignancies arm, which is currently 50 mg.  Based on these preliminary 
results to this point, 40 mg is proposed as the starting dose for the solid tumors arm, which may change to a higher 
starting dose, when the MTD for the hematologic malignancies arm is defined.    
 
Baseline assessments will all be done within 30 days of the start of AR-42 and will include:  medical history, 
clinical examination, vital signs, concomitant medications, appropriate assessment of inclusion and exclusion 
criteria, comprehensive metabolic panel which includes liver function tests, serum chemistries including calcium, 
magnesium, and phosphorous, complete blood count, coagulation panel (PT/PTT), , pregnancy test, chest x-ray, 
ECG, audiogram, and Eastern Cooperative Oncology Group/World Health Organization (ECOG/WHO) 
performance status.  A baseline MRI will also be required within 60 days of day 1 dosing of AR-42.   
 
To monitor participant safety, a total of three monitoring assessments will be performed beginning one week after 
the first dose of AR-42, concluding with the last monitoring assessment at the pre-surgery visit.  These assessments 
will include 12-lead ECGs at each visit, complete blood counts, and a monitoring of adverse events.  A 
comprehensive metabolic panel (i.e. Chem 7) to also include liver function tests and serum chemistries for calcium, 
magnesium, and potassium will be completed at the last monitoring/ pre-surgery visit.  To ensure that AR-42 
administration will not adversely affect outcomes of surgical resection, subjects will undergo the last assessments 
within 4 days of the scheduled surgical resection.  These assessments include clinical examination, vital signs, 
comprehensive metabolic panel which also includes liver function tests and serum chemistries for calcium, 
magnesium, and potassium, complete blood count, coagulation panel (PT/PTT), , pregnancy test, ECG, audiogram, 
and Eastern Cooperative Oncology Group/World Health Organization (ECOG/WHO) performance status.  For the 
first 10 study participants enrolled in the study, an MRI will also be done within 4 days of the scheduled surgery.  
If no tumor reduction is noted in these participants, a MRI at this time point will not be required for the additional 
study participants that will be enrolled.  Toxicity will be monitored and adverse event information collected.  
Toxicity will be assessed according to the NCI CTCAE V 4.0.  If any changes in health status are noted that may 
affect a subject’s safety and outcomes during surgery, surgery will be delayed. 


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During surgical resection of the tumor, tissue will be resected per clinical indications.  The tumor tissue will first 
be sent to diagnostic pathology and when it is determined there is adequate tissue for diagnosis, additional 
samples will be taken and prepared as described in the study procedures section.  The 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.  Two 
blood samples will be taken prior to tumor removal and two will be taken at the time of tumor removal (while in 
the operating room).  There will be no charge for collection of the blood and tumor samples since the collection 
will be done by study investigators who are also the treating surgeon/physician.  The blood sample taken at the 
time of anesthesia induction will serve as the steady state measure as this will be drawn after 10 doses of AR-42.  
The sample taken at time of tumor resection will be used to confirm that essentially the same plasma levels are 
achieved indicating steady state.  The plasma AR-42 concentration determined from the blood sample taken at 
the time of tumor resection will also be used to calculate the plasma to brain drug concentration ratio.  The exact 
time of tumor resection and blood sampling will be recorded. 
 
Subjects will take their last dose of AR-42 the night before surgery and no additional laboratory and surveillance 
studies will be completed after surgical resection.  Patients will be evaluated within the context of their standard 
post-operative follow up which includes within 4 days of surgery and again at 2 weeks (+/- 10 days) after 
surgery.  Toxicity will be monitored and adverse event information collected at within 4 days and 2 weeks (+/- 
10 days) after surgery.  Toxicity will be assessed according to the NCI CTCAE V 4.0.  The total observation 
window for adverse events will be 2 weeks post-surgery.  If there are any adverse events, the subject will be 
followed until recovery or stabilization or return to baseline condition if at all possible.   
 
4. STUDY POPULATION 
Patients eligible for enrollment in this study will be male and female adults diagnosed with a cutaneous 
schwannoma, a vestibular schwannoma, or a meningioma by MRI where surgical resection has been selected as 
the most appropriate treatment option by the treating physician and patient. 
 
4.1 
Inclusion criteria 
 
Patients with a cutaneous schwannoma, or a vestibular schwannoma, or a 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.  
o Chemotherapy: Up to three prior cytotoxic chemotherapy treatments, in the metastatic setting, are 
allowed.  Prior hormonal, biological or targeted therapies are not limited. At least 4 weeks need to have 
elapsed since last treatment and the patient must have recuperated from acute toxicities from the prior 
treatment.  
o Radiation Therapy: Prior radiation therapy is allowed.  At least 1 year must have elapsed since last 
treatment, and the patient must have recovered from all toxicities to Grade 1 or less. 
o Surgery:  Prior curative and palliative intent surgery is allowed.  At least 3 weeks must have elapsed 
since last major surgical treatment and the patient must have recovered from surgery and any post-
surgical complications.  If photodynamic therapy has been performed, at least 4 weeks must have 
elapsed (to allow for full clearance of the photosensitizing agent).  Minor surgical procedures, such as 
removal of skin lesions or MediPort and nephrostomy tube placements are not considered major surgery 
and treatment can start as soon as the surgical site is healed, per the treating physician’s discretion. 
 
At the time of screening, the PI will review the patient’s lab work to determine that the patient meets the eligibility 
criteria. The patient must have normal organ and marrow function  as described below*: 


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o Leukocytes ≥ 3,000/mcL  
o Absolute neutrophil count ≥ 1,500/mcL  
o Platelets ≥ 100,000/mcL  
o Total bilirubin < 1.5 mg/dL  
o AST(SGOT)/ALT(SGPT) ≤ 5 x institutional upper limit of normal (ULN);  
o Creatinine ≤ 1.5 x ULN OR creatinine clearance ≥ 50 mL/min by MDRD (original or abbreviated), OR 
measured creatinine clearance ≥ 50 ml/min  
o Hemoglobin of at least 9 g/dL 
o Normal serum magnesium (1.6 – 2.6 mg/dL), calcium (8.6 – 10.0 mg/dL), and potassium (3.5 – 5.1 
mmol/L) levels. 
*Any abnormal laboratory values will be reviewed by the PI to determine the appropriate treatment and 
continued study eligibility.  
 
Eastern Cooperative Oncology Group/World Health Organization (ECOG/WHO) performance status of 0-1. 
 
Patients must be able to swallow capsules. 
 
Patients must be able to read, understand and provide informed consent to participate in the trial. 
 
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 effects of AR-42 on the developing human 
fetus are unknown.  For this reason women of child-bearing potential and men must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation.  Should a woman become pregnant or suspect she is pregnant while she or 
her partner is participating in this study, she should inform her treating physician immediately.   
 
A female of childbearing potential (FCBP) is a sexually mature woman who: 1) has not undergone a 
hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months). 
 
 
The patient must be willing to comply with fertility requirements as below: 
 
A. Male patients must agree to use an adequate method of contraception for the duration of the study and 
for 28 days afterwards 
B. Female patients must be either postmenopausal, free from menses ≥ 2 yrs, surgically sterilized, willing 
to use two adequate barrier methods of contraception to prevent pregnancy, or agree to abstain from 
heterosexual activity starting with screening and for 90 days afterwards.   
C. Patients must agree not to donate blood, sperm/ova during study participation and for at least 4 weeks 
after stopping treatment 
 
4.2 
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. 


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 
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: 
o Any other anti-neoplastic chemotherapy or biologic therapy during the study  
o Concomitant radiotherapy 
o Concomitant HDAC inhibitors (e.g. valproic acid) as class-specific adverse reactions may be additive 
o 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. 
o 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. 
 
5. STUDY PROCEDURES 
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. The PI will instruct the patient on their medication regimen throughout the study. AR-42 
should be taken at least 1 hour before or 2 hours after meals.  The starting dose of 40 mg for this study of solid 
tumors was selected by pre-clinical and ongoing phase I data. 
 
5.1 
AR-42 
 
5.1.1 Dosing schedule and cohorts 
Treatment 
AR-42 will be administered orally three times per week beginning 3 weeks prior to surgery for removal of a 
vestibular schwannoma, meningioma, or cutaneous schwannoma.  A total of ten 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.   For example, if surgery were scheduled for 
Tuesday, study participants would take the study drug on Mondays, Wednesdays, and Fridays for 3 weeks pre-
operatively and one final dose on Monday, the evening before surgery.  The PI is responsible for determining the 
dosing schedule and will include this in written directions. Study participants will receive written instructions 
regarding the correct dosing schedule and a Medication Log to record date and time medication was taken.   
 
Doses of AR-42 should be taken on an empty stomach.  Doses should be taken at least 1 hour before or 2 hours 
after meals.  If a dose is missed or vomited up, the dose will not be made up.  Study participants will be asked to 
record any missed doses or doses that were vomited up on the Medication Log. 
 
5.1.2 Supportive care for patients receiving AR-42 
Prophylactic use of growth factors is not allowed.   
 
Nausea:  Treat nausea with appropriate supportive care as required. The following are suggestions:  
 
Benzodiazepines:  
Lorazepam 0.25-1 mg PO or IV 
 
Dopamine blockade:  
Prochlorperazine 5-10 mg or Promethazine 12.5-25 mg by PO, IV, or IM.   


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 
Steroid:  
 
Dexamethasone 4 mg PO or IV 
 
Diarrhea: Treat diarrhea promptly with appropriate supportive care, including loperamide. Instruct patients to 
begin taking loperamide at the first signs of: 1) poorly formed or loose stool, 2) occurrence of more bowel 
movements than usual in one day, or 3) unusually high volume of stool. Loperamide should be taken in the 
following manner: 4 mg at first onset of diarrhea, then 2 mg after each unformed stool. Daily dose should not 
exceed 16 mg/day. Advise patients to drink plenty of fluids to help prevent dehydration caused by diarrhea. 
Avoid loperamide if there is the presence of blood or mucus in the stool or if diarrhea is accompanied by fever. 
If grade 3 or 4 diarrhea develops, hold treatment with AR-42.  
 
Dysgeusia: Therapy will be provided to assure maintenance of adequate hydration in the setting of dysgeusia.  
Hydration with intravenous fluid may be given.  Additionally, the use of popsicles and Gatorade may be helpful. 
Additional anti-emetics therapy may be given.  If a dose is missed or vomited up, the dose will not be made up.   
 
Hypokalemia or hypomagnesemia should be corrected to within normal limits prior to administration of AR-
42, and weekly assessments during dosing of AR-42 will be conducted to monitor potassium and magnesium 
levels.  
 
5.2 
Dose delays and modifications  
During treatment, patients who miss 2 or more doses of study drug due to non-compliance or AR-42 toxicity will 
discontinue study therapy, regardless of whether the toxicity causing the missed does is related or unrelated to 
AR-42.  If there is any Unacceptable Toxicity (as defined in Section 3.2), the AR-42 will be stopped and the 
patient will be removed from the study. 
 
5.3 
Concomitant treatment restrictions 
All patients should be treated for any medical conditions according to the best interests of the patients and 
acceptable community medical standards. 
 
The following treatments are not permitted during the study: 
 
 
Any other anti-neoplastic chemotherapy or biologic therapy  
 
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) 
 
The following are permitted: 
 
 
Anti-emetic treatment, with ativan, corticosteroids, and anti-5 HT3 agents.   
 
All supportive and palliative treatment if necessary (nutritional, transfusional support, pain control, etc.).   
 
5.4 
Schedule of tests and observations 
 
5.4.1 Screening 
Baseline assessments will all be done within 30 days of the start of AR-42 and will include:  medical history, 
clinical examination, vital signs, concomitant medications, appropriate assessment of inclusion and exclusion 
criteria, comprehensive metabolic panel which includes liver function tests and serum chemistries for calcium, 
magnesium and potassium, complete blood count, coagulation panel (PT/PTT), urine or serum pregnancy test, 
chest x-ray, ECG, audiogram, and Eastern Cooperative Oncology Group/World Health Organization 


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(ECOG/WHO) performance status.  A baseline MRI will also be required within 60 days of day 1 dosing of AR-
42.   
 
It should be noted that before a patient has been consented for the study, standard of care procedures may have 
been already conducted within 30 days prior to the screening visit. These results may then be used for baseline 
assessments in order to determine the patient’s eligibility for the study. A standard of care MRI within 60 days 
prior to scheduled day 1 dosing of study drug may be used for screening/baseline assessments. 
 
5.4.2 Evaluation during treatment 
To monitor participant safety, a total of three monitoring assessments will be performed beginning one week 
after the first dose of AR-42 including the last assessment at the pre-surgery visit.  The first two monitoring 
visits will include the following assessments: 12-lead ECGs at each visit, complete blood counts, comprehensive 
metabolic panel, review of concomitant medications, and monitoring of adverse events. These lab assessments 
may be accomplished locally to the patient with a phone interview for conmed review and AE assessment. To 
ensure that AR-42 administration will not adversely affect outcomes of surgical resection, subjects will undergo 
additional assessments at the third monitoring visit / pre-surgery visit within 4 days of the scheduled surgical 
resection.  These assessments (to be accomplished at the research site) include clinical examination, vital signs, 
comprehensive metabolic panel which also includes liver function tests and serum chemistries for calcium, 
magnesium, and potassium, complete blood count, coagulation panel (PT/PTT), urine or serum pregnancy test, 
ECG, audiogram, and Eastern Cooperative Oncology Group/World Health Organization (ECOG/WHO) 
performance status.   
 
For the first 10 study participants enrolled in the study, a MRI will also be done within 4 days of the scheduled 
surgery.  If no tumor reduction is noted in these participants, a MRI at this time point will not be required for the 
additional study participants that will be enrolled.   
 
If any changes in health status are noted that may affect a subject’s safety and outcomes during surgery, surgery 
will be delayed.  Tumor specimens will still be collected at the time of surgery to determine expression levels of 
phosphor-Akt (p-AKT) and p16INKA and assess biological effects of AR-42 on the phosphoinositide 3 kinase 
(PI3K)/AKT signaling pathway, tumor proliferation, cell cycle, cell death, and angiogenesis.  Toxicity will be 
monitored and adverse event information collected at this visit.  Toxicity will be assessed according to the NCI 
CTCAE V 4.0.   
 
If the QTcB is prolonged to CTCAE grade 3 or higher, the patient will discontinue study drug and will be 
monitored until QTc intervals return to baseline. 
 
5.4.3 Post-treatment follow-up 
Patients will be evaluated within the context of their standard post-operative follow up which includes within 4 
days of surgery and again at 2 weeks (+/- 10 days) after surgery.  Evaluations include a clinical exam, vital signs, 
and ECOG/WHO performance status. Toxicity will be monitored and adverse event information collected at 4 
days and 2 weeks after surgery.  Toxicity will be assessed according to the NCI CTCAE V 4.0.  The total 
observation window for adverse events will be 2 weeks post-surgery.  If there are any adverse events, the subject 
will be followed until recovery or stabilization or return to baseline condition if at all possible. 
 
All patients who discontinue the trial secondary to an adverse event thought to be related to protocol therapy 
(probably, possible, or definite) should be followed until resolution, stabilization, return to a baseline condition, 
or death.   
 
 


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5.4.4 Schedule of events 
 
STUDY SCHEDULE OF EVENTS 
 
Baseline1 
Monitoring 
Visit #12 
Monitoring 
Visit #22 
Monitoring 
Visit #3/ 
Pre-
Surgery3 
Surgery 
Post-
Surgery4 
Off-
Study5 
CBC w/ differential 
and platelets 
X 
X 
X 
X 
 
 
 
Comprehensive 
Metabolic Panel6  
X 
X 
X 
X 
 
 
 
Serum or Urine 
Pregnancy Test7  
X 
 
 
X 
 
 
 
AE8 Reporting 
X 
X 
X 
X 
 
X 
X 
Concomitant 
Medication Review 
X 
X 
X 
X 
 
 
 
12-lead ECG 
X9 
X9 
X9 
X9 
 
 
 
Coagulation panel 
(PT/PTT) 
X 
 
 
X 
 
 
 
Chest x-ray 
X 
 
 
 
 
 
 
H&P, Neuro Exam, 
Vital Signs 
X 
 
 
X 
 
X 
X 
ECOG performance 
status 
X 
 
 
X 
 
X 
X 
Audiogram 
X 
 
 
X 
 
 
 
MRI (CPT 70553) 
X10 
 
 
X11 
 
 
 
Intraoperative 
Blood and Tissue 
Collection 
 
 
 
 
X12 
 
 
1 –Within 30 days prior to starting AR-42 
2 –There will be three monitoring visits after the first dose of AR-42 has been taken. The third monitoring visit 
is combined with the pre-surgery visit.  
3 –Within 4 days prior to surgery for the monitoring visit #3/ pre-surgery visit  
4 –Within 4 days after surgery for the post-surgery visit 
5 –Two weeks ± 10 days after surgery 
6 –Standard peri-operative evaluations; comprehensive metabolic panel (i.e. Chem 12) to also include liver 
function tests and serum chemistries for calcium, magnesium, and potassium 
7 –Only required for females that are, in the investigator’s opinion, of childbearing potential 
8 –AE= Adverse Events 
9 –If the QTcB is prolonged to CTCAE grade 3 or higher, the patient will discontinue study drug and will be 
monitored until QTc intervals return to baseline.  
10 -Done within 60 days of day 1 dosing of AR-42.   
11 – Performed in first 10 study participants.  Will not be required of additional study participants if tumor 
reduction not noted in the first 10  
12 –Intraoperative blood (for steady state) and tumor sampling will be collected at the time of surgery 
 


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5.4.5 Tumor resection and sample collection 
The treating surgeon will perform the clinically indicated surgical procedure as well as the specimen collection.  
To monitor the risk of increased surgical complications associated with AR-42, the treating surgeon will record 
any noted differences during surgical resection such as increased bleeding, tumor adherence to adjacent nerves, or 
increased difficulty in tumor removal.  After tissue required for diagnostic pathology has been resected, additional 
tumor samples will be prepared for tissue sampling.  Four tissue samples will be taken per tumor, two from the 
center of the tumor and two from the tumor capsule and snap-frozen immediately in the operating room (<15 
minutes).  Each sample will be approximately 5 mm3 in size and will be placed into an individual cryotube labeled 
with a unique study number, time of collection, sampling location and then snap-frozen in liquid nitrogen.  Efforts 
will be made to ensure only tumor tissue (not surrounding adjacent tissues) are frozen in the vials. The samples 
will be stored in a liquid nitrogen tank or -70ºC to a -80 ºC freezer until shipment.  Tissue acquisition forms will 
be completed and shipped with the specimen.  Shipment from the originating institution will occur only after the 
final diagnostic pathology has been reported.  Once ready for shipment, the sample will be sent via overnight 
express on dry ice.  Two samples will be sent to the OSU Pharmacoanalytical Shared Resource (PhASR) where 
they will be maintained at -70ºC to -80 ºC until used for drug concentration analysis and two will be sent to 
Nationwide Children’s Research Institute for molecular analysis.  Twelve unstained paraffin fixed slides will also 
be requested from each tumor sample as well.  These will be used for standard histologic analysis and 
immunohistochemisty assessment to be performed at Nationwide Children’s Research Institute.  These specimens 
will be processed as soon as possible, and at least within the year from sample collection.  Expression of proteins 
by immunoblot and immunohistochemistry to be measured will include 1) the PI3K/AKT signaling pathway 
including total AKT, phospho-Akt, p-PRAS40, total PRAS-40, p-S6 ribosomal protein, and p-4E-BP-1; 2) other 
implicated pathways such as the MAPK, ERK and total ERK, 3) cell cycle regulators Ac-Lysine, acetylated histone 
2B (Ac-H2B), p16INK4A, p21, other suspected HDAC regulators such as HSP90; 4) HR23B as a potential biomarker 
for tumor sensitivity to AR-42; and 5) merlin.  The biological effects of AR-42 on tumor proliferation (assessed 
by Ki-67 proliferation index), cell death (assessed by cleaved caspase-3 and TUNEL staining), and angiogenesis 
(assessed by expression of VEGF and CD31) will also be investigated.  Protein expression levels and biological 
effects of AR-42 determined from study samples will be compared to untreated samples from our control patients.  
Tumor specimens will be examined according to our previous study (Bush et al., 2011).  
 
NF2 gene mutation analysis will be performed via exon scanning and multiplex ligation-dependent probe 
amplification (MLPA), and merlin protein expression will be determined by immunoblot and 
immunohistochemistry.  
 
Additionally, during tumor resection, four venous blood samples will be taken, two at the start of anesthesia on 
the day of surgery and two at the time of tumor removal (while in the operating room).  The blood samples at the 
induction of anesthesia will serve as the steady state serum measure, and the samples taken at the time of tumor 
resection will be used to confirm that essentially the same plasma levels are achieved indicating steady state.   
The plasma AR-42 concentration determined from the blood samples taken at the time of tumor resection will be 
used to calculate the plasma to in-tumor drug concentration ratio.  Each sample will be 6mL of blood, which will 
be drawn into heparinized plasma collection tubes.  The specimens will be promptly mixed by gently inverting 
the Vacutainer tube several times and then be placed on wet ice.  
 
The samples will be centrifuged at 1,100-1,300 x g for 10 min at 4°C within 15-30 min after collection. The plasma 
in each individual Vacutainer will be removed from the blood cells using a pipette and transferred into a separate 
labeled 4.5 mL self-standing polypropylene cryogenic tubes with external threads. The tubes will be placed on 
crushed dry ice until stored in a freezer maintained at -70°C.  Complete sets of samples from one or more patients 
will be sent by batch by overnight mail on dry ice.  The pharmacokinetic tissue and plasma assays will be 
performed at the Ohio State PhASR where assays for PK analysis of AR-42 in tumor and blood have been 
established and validated.  
 


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5.5 
Study Records 
Study data will be collected in a standardized case report form (CRF). The investigator or authorized study 
personnel will record all pertinent patient information, including patient identification number, tumor type and 
size, health history as well as information concerning drug administration, results of laboratory tests and 
audiograms, and toxicity data.  
 
MEEI will be the central location for data processing and management utilizing the biostatistician on site.  
 
All protocol-required information collected during the study will be entered by the investigator, or designated 
representative, in the appropriate study forms.  The investigator, or designated representative, should complete the 
forms as soon as possible after information is collected, preferably on the same day that a study subject is seen for 
an examination, treatment, or any other study procedure.  Any outstanding entries will be completed immediately 
after the final examination.  By design, an explanation must be provided for all missing data, altered data, and/or 
out of range data.  The completed case report form will be reviewed and signed by the investigator named in the 
study protocol or by a designated sub investigator. 
 
 The Case Report Form will be provided for each subject; subjects will not be identified by name on any study 
documents.  Any requested information that is not obtained as specified in the protocol should have an explanation 
for the omission noted on the applicable study form.   
 
Source data are all the information in original records and certified copies of original records of clinical findings, 
observations, laboratory reports, data sheets provided by the sponsor or other activities in the study, which are 
necessary for the reconstruction and evaluation of the study. The investigator will permit study-related monitoring, 
audit(s), IRB review(s) and regulatory inspection(s), with direct access to all the required source records.  Hard 
copies of any individual’s study documents will be kept in separate subject binders in the locked office of the study 
coordinator at each site.   
 
5.6 
Selection Procedures 
Potential participants will be identified and recruited by the study investigators and/or study coordinators at MEEI 
and any of the approved participating sites from their patient populations seen clinically for 
evaluation/management of their vestibular schwannomas, meningiomas, cutaneous schwannomas, and/or 
Neurofibromatosis Type 2.  After clinical consultation with their physician, patients that elect surgical removal 
for management of their tumors will be informed of the study.  If these patients are interested in participating, 
they will come to the clinical office for a screening visit and further discussion of the study.  All treatment options 
including observation, surgical repair, and study participation will be presented to all eligible participants prior 
to obtaining informed consent.  Recruitment and discussion of the study will be done in private, clinical offices. 
Physicians not included as study investigators may refer patients to approved study sites for enrollment in the 
study.  If a physician identifies a potential participant, the physician can provide the participant’s contact 
information to study team members (only after they have received the participant’s permission) so that the study 
team can contact the potential participant and discuss the study.   
 
Screening Procedures: 
An inclusion/exclusion checklist worksheet for the study with detailed guidelines for the pre-study/screening 
evaluation to determine patient eligibility will be used by all participating sites.  When a potential participant is 
screened for the study, the checklist will be completed and placed in the individual subject binder at the 
participating site where the participant was screened.  A copy of the completed screening checklist will be 
forwarded to the study coordinator at the primary institution (MEEI).   
 
A screening log will be distributed to all participating sites, and information from all potential participants screened 
must be documented on the screening log.  Information collected on the screening log will include participant 
initials, demographics (gender, race, ethnicity), date of consent, checkbox to note if signed informed consent given 


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to subject, checkbox to indicate if subject enrolled, and reason for exclusion if subject not enrolled.  The screening 
log will be kept in the regulatory binder for each site and will be sent to MEEI monthly for review by the study 
principal investigator (Dr. Welling) to monitor study accrual. 
 
Determining Eligibility:  
After all screening procedures are complete, the site investigator or delegated research staff will review the 
subject’s full medical history to determine the subject’s eligibility. There must be source documentation to support 
all requirements for determining eligibility.  The subject’s medical history and all relevant research screening tests 
and procedures must meet inclusion criteria and not meet exclusion criteria.  
 
All tests, assessments, and procedures must be done within the protocol specified timeline.  If the subject is deemed 
ineligible or wishes to not proceed with enrollment, then the delegated research coordinator or specialist will 
document the reason the subject was not enrolled in the trial and will update the site screening log appropriately.  
 
6. PHARMACOKINETIC STUDIES 
In the current Phase I study of AR-42, plasma PK studies and kidney excretion in all patients were conducted to 
assess inter-individual variability.  Detailed pharmacokinetics with rich sampling (full profiles days 1-2 and 19-
20, trough level on day 3 pre-dose) were conducted in all patients.  Briefly, venous blood samples (6-mL 
heparinized tubes) have been collected in pre-chilled heparinized tubes and immediately placed in an ice/water 
mixture until centrifuged at the following specific time points: 15, 30 min, 1, 1.5, 2, 4, 8, 10 and 24 hours on day 
1 cycle 1, and the pre-dose on day 3, 15, 30 min, 1, 1.5, 2, 4, 8, 10 and 24 hours on day 19 cycle 1.  To understand 
the kidney excretion in the AR-42 elimination, the excretion of AR-42 in urine on day 1 has been collected at the 
following intervals: 0-4, 4-8, 8-10 and 10-24 hours after cycle 1 day 1 only.  For patient’s enrolled on the first two 
cohorts, pharmacokinetic profiling has revealed day 1 (Top plot) and day 19 (Bottom plot) profiles as shown 
below: 
 
 
 


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As a secondary endpoint, we will determine the steady-state plasma and intra-tumoral concentrations of AR-42 at 
the time of surgical resection after 10 days of dosing of AR-42. 
 
7. AR-42 
 
7.1 
Classification 
Histone deacetylase inhibitor  
 
7.2 
Chemical structure 
AR-42, a free base formerly known as OSU-HDAC42 and NSC-D736012, is an orally bioavailable small 
molecule.  The chemical name of AR-42 is N-Hydroxy-4-(3-methyl-2-(S)-phenyl-butyrylamino) benzamide.  AR-
42 is the chirally pure S-enantiomer of this compound.  The empirical formula is C18H20N2O3 , the molecular 
weight is 312.36, and the chemical structure is shown below: 
 
 


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7.3 
Solubility and melting point  
An equilibrium solubility study with the AR-42 free base in water produced a concentration of 0.16 mg/mL.  The 
solubility of AR-42 free base in 50 mM aqueous buffer systems across the pH range from 1 to 10 was determined.  
The results of this study are depicted below: 
 
 
Organic solubility: 
The solubility of AR-42 was determined in common solvents and is summarized below. 
Solvent 
Solubility (mg/mL) 
Acetonitrile 
8.62 
Isopropyl Alcohol 
25.52 
Methanol 
54.27 
Ethanol 
37.10 
 
Melting point: The melting point of AR-42 was determined by differential scanning calorimetry (DSC) and found 
to be 206.93°C.   
 
7.4 
Supply, handling and disposition, storage, and administration  
ARNO Therapeutics, Flemingtion, NJ, will provide an adequate supply of AR-42 (histone deacetylase inhibitor) 
clinical trial material to conduct this clinical study.  AR-42, capsules will be supplied in the dosage strengths 
below: 
 
 
10 mg capsules:  Forty-eight size 3 white opaque Coni-Snap capsules will be packaged into 120 cc wide 
mouth round high density polyethylene (HDPE) bottles.  Each bottle will be capped with a 38 mm child 
resistant closure with FS M1/.035 pulp liner, induction sealed, and labeled.  Study participants will take 
four 10 mg capsules per dose to achieve the study dose of 40 mg. 
 
Handling and Disposition of Study Drug:  All packaging and labeling operations will be performed according 
to the requirements of Directive 2001/20/EC1 and in accordance with Good Manufacturing Practice for 
Medicinal Products.  Each investigational site will work with their Investigational Drug Pharmacy Services to 
coordinate receipt, storage, dispensing, and return of AR-42.   
 
Storage: The product is to be stored at 25C and protected from moisture and light.  Temperature excursions in the 
range from 15-30C will be permitted. 


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Route of Administration: Oral.  A one cycle supply of AR-42 will be dispensed at the start of treatment and study 
participants will receive written instructions regarding the correct dosing schedule. Study participants will also receive 
a medication dose log to record date and time medication was taken.    
   
7.5 
Pharmacokinetics in canines 
A single non-Good Laboratory Practice (GLP) study to assess the comparative bioavailability of single (1 mg/kg) 
doses of orally or intravenously (iv) administered AR-42 was conducted in male dogs.  Following both IV and oral 
administration, plasma concentrations of AR-42 were generally quantifiable up to 24 hours post-dose (i.e. the last 
sampling time point post-dose). 
 
Following IV administration to 4 animals, the maximum plasma concentrations (Cmax) ranged from 651 to 1140 
ng/mL and were observed (Tmax) at 0.0830 to 0.220 hours post-dose.  Thereafter, plasma concentrations declined 
with a geometric mean apparent terminal half-life (t1/2) of approximately 3.59 hours.  The geometric mean apparent 
volume of distribution (Vss) of AR-42 at steady-state was approximately 1280 mL/kg, which is considerably greater 
than total body water in dogs, indicating extensive distribution of AR-42 into tissues.  The clearance (CL) of AR-42 
was estimated to be approximately 406 mL/hour/kg, which is lower than hepatic and renal blood flow rates in dogs. 
 
Following oral administration to 4 animals, Cmax of AR-42 ranged from 147 to 398 ng/mL and were attained (Tmax) 
at 0.480 to 4.00 hours post-dose in all animals.  Thereafter, plasma concentrations declined with a geometric mean 
apparent terminal half-life of approximately 4.20 hours.  The geometric mean bioavailability (F) of the oral 
formulation was estimated to be approximately 57.9%.  The geometric mean absorption time (MAT) was 1.03 hours. 
 
7.6 
Toxicology in rats and canines 
Rats 
The MTD in rats receiving a single dose of AR-42 by oral gavage was determined to be 100 mg/kg in a 
non-GLP study.  The MTD in rats dosed with AR-42 by oral gavage every other day for 7 days was 
determined to be 30 mg/kg in a non-GLP study.   
 
A 28-day GLP toxicity study in rats determined that the no adverse effect level (NOAEL) of AR-42 
dosed orally by gavage once every other day for 4 weeks was 3 mg/kg in female animals.  Due mainly 
to findings in the male reproductive system, neither a no effect level (NOEL) nor a NOAEL was 
established in this study for male animals.  The severity of the findings noted in males when compared 
to females may have been a consequence of the increased systemic exposure noted in males over the 
4-week dosing period. 
 
Canines 
(non-GLP) 
 
Two non-GLP studies of single and repeated (7-day) oral dosing of 1, 3, 10 and 30 mg/kg/day AR-42 
to male and female dogs were completed.  Plasma concentrations were generally measurable up to the 
last sampling time of 24 hours post-dose.  Cmax of AR-42 in male and female dogs were observed 
(Tmax) at 0.5 to 2 hours post-dose.  Thereafter, plasma concentrations of AR-42 declined with apparent 
t1/2 ranging from 2.48 to 7.57 hours.  Systemic exposure to AR-42, as measured by AUC and Cmax, 
increased in an approximately dose-proportional manner.  Following repeated administration, there was 
no appreciable accumulation of AR-42 in plasma, consistent with the short half-life measured in 
plasma relative to the dosing interval.  There appeared to be no consistent or appreciable sex-related 
difference in systemic exposure to AR-42.  The maximum tolerated single dose was considered to be 
10 mg/kg.  A 1 mg/kg dose of AR-42 was determined to be suitable for a subsequent multiple dose, 
28-day toxicity study. 
Canines 
(GLP) 
 
In dogs dosed every other day for 28 days followed by a two week recovery period, the systemic 
exposure (Cmax and AUC0-48) to AR-42 increased in an approximately dose-proportional manner, and 
following repeated administration of AR-42 once every other day, there was no appreciable 
accumulation of AR-42 in male or female dogs.  There also appeared to be no consistent or appreciable 
sex-related difference in the extent of systemic exposure to AR-42. 
 


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Based on the changes in relative spleen and testes weight at 1.0 mg/kg, the oral NOEL in male dogs 
was considered to be 0.3 mg/kg/day. Based on the lack of any treatment-related findings in females, the 
NOEL was considered to be 1.0 mg/kg, the highest dose tested. 
 
 
Cardiovascular, respiratory, and CNS safety:   
 
Cardiovascular safety 
(in vitro, canine)  
Study ZNA20087.011 (in vitro):  A study to assess the effect of AR-42, vehicle, or 
the reference substance E-4031 on hERG tail current recorded from HEK293 cells 
stably transfected with hERG cDNA was conducted using standard whole cell patch 
clamp methods.  Compounds that inhibit hERG current have been shown to prolong 
the cardiac action potential and hence QT interval in man.  AR-42 produced a 
concentration-dependent effect on hERG tail current recorded from stably transfected 
HEK293 cells.  Exposure to 30 µM AR-42 produced no effect compared to the 
vehicle on hERG tail current; however, exposure to 100 µM produced an average 
25% inhibition of tail current and exposure to 300 µM produced a transient 
potentiation of tail current followed by moderate inhibition (up to 50% in individual 
cell preparations).  The decrease in tail current following treatment with 100 and 300 
µM was found to be reversible.  It is anticipated that 300 µM AR-42 is well in excess 
of the anticipated plasma levels that may be achieved in humans.  The reference 
substance, E-4031, inhibited hERG tail current by approximately 90%, an effect 
consistent with its known activity. 
Study ZNA20087.008 (canine):  A cardiovascular safety study with telemetry in 
conscious dogs was conducted to assess the potential effects of ascending doses of 
AR-42 on arterial blood pressure, heart rate, and lead II electrocardiogram (ECG).  
Prolonged increases in heart rate (maximum increase approximately 64%) were noted 
after all dose levels of AR-42.  There was no effect on blood pressure after 
administration of 1 mg/kg; however higher doses tended to produce decreases in 
arterial blood pressure of up to 20%.  Evaluation of ECG parameters showed that 
QRS duration was not affected by AR-42 administration.  Doses of 1 mg/kg AR-42 
also had no effect on other parameters studied; however, higher doses were associated 
with decreases in RR interval and PR interval.  The duration of the decreases in PR 
interval was dose-dependent, with a maximum decrease of approximately 16%.  At 
doses of 10 mg/kg AR-42, QTcF intervals were prolonged up to approximately 
16%.  The ECG waveform and rhythm was unaffected by the administration AR-42. 
Respiratory safety (rat) 
A single study of AR-42 on the respiration rate and tidal volume in conscious rats was 
conducted.  Oral administration of AR-42 at 10, 30 and 100 mg/kg did not 
significantly affect the respiration rate or tidal volume of male rats at any time point 
tested up to 1440 minutes post-dose. 
 
Central nervous system 
safety (rat) 
A single study was conducted to assess the effects of AR-42 in a ‘Primary Observation 
Test’ designed to detect effects on the gross behavioral and physiological state of rats.  
Oral administration of AR-42 at doses of 10 and 30 mg/kg did not cause rats to exhibit 
any changes from normal.  Male Sprague-Dawley rats dosed orally with AR-42 at a 
dose of 100 mg/kg showed mild, transient CNS depression-like signs. 
 
8. STATISTICAL CONSIDERATIONS 
 
8.1 
Safety endpoints 
Safety will be assessed by evaluation of adverse events and clinical laboratory results and derived as data sets and 
frequency methods.  The following safety measurements will be used. 
 
 
Adverse events by severity and causality as described below. 


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 
Laboratory evaluations including comprehensive metabolic panel (which includes serum chemistries 
for magnesium, calcium, and potassium, and liver function tests), coagulation panel (PT/PTT), and 
CBC with differentials. 
 
Routine ECGs to monitor changes in QTc intervals. 
 
Clinically meaningful changes in vital signs including temperature, blood pressure, weight, pulse, and 
respiratory rate. 
 
Adverse events will be described using the NCI CTCAE, V 4.0 criteria.  Frequency and severity of adverse events 
according to body system and severity criteria will be described.  In addition, frequency of grade 3 or 4 adverse 
events will be described separately.  Causality will also be noted.    
 
Laboratory assessments will also be described according to the NCI CTCAE, V 4.0 criteria, with separate 
descriptions for grade 3 or 4 laboratory abnormalities.  Clinically significant laboratory abnormalities will be 
described as well. 
 
8.2 
Study design and sample size 
For this multi-center, Phase 0 proof of concept study, 20 subjects will be enrolled in the treatment group.  
Differences in expression levels of phospho-Akt (p-AKT) and p16INK4A will be determined in five specimens from 
each of the following tumor types: 1) Non-NF2 associated VS tumors, 2) NF2-associated VS tumors, 3) Non-NF2 
associated meningiomas, and 4) NF2-associated meningiomas. Additionally 10 control tissue from our control 
patients not receiving AR-42 will be analyzed. These sample sizes are consistent with phase 0 study designs.  With 
5 patients per group, we will have approximately 80% power to detect a 2 fold change, assuming a coefficient of 
variation of 0.30, and a type I error rate of 0.05.  Since our analyses are exploratory we will not adjust for multiple 
comparisons. 
 
Study enrollment and study treatment administration will be temporarily suspended if any patient dies from a drug-
related AE.  After a thorough review of the data by the study PI, investigational site PIs, and Data and Safety 
Monitoring Board, the study will be terminated if the death is determined to be drug-related. 
 
8.3 
Interim analysis and early stopping rules 
Any unexpected deaths or SAEs possibly related to study treatment will be reported to the local Institutional 
Review Board (IRB).  Trial accrual will be prematurely stopped if two or more unacceptable toxicities occur. 
 
8.4 
Statistical methods 
The primary objective of this study is to estimate the expression levels of phospho-Akt (p-AKT) and p16INK4A in 
each of the four tumor types 1) NF2-related VS, 2) sporadic VS, 3) NF2-related meningiomas and 4) 
sporadic meningiomas after the described dosing of oral AR-42 as well as control samples from our control 
patients.  Statistical analysis on the tumor samples for PK/PD will be descriptive and exploratory for this proof of 
concept study including summary statistics overall and by group for each variable as well as graphical displays for 
trend identification for use in planning future trials.  P-AKT and p16INK4A will be evaluated as continuous variables 
in both AR-42 treated tumor samples and control samples.  Of particular interest is the proportion of samples with 
complete inhibition of p-AKT and the increase in p16INK4A in AR-42 treated subjects.    Because this is a phase 0 
proof of concept trial with a small sample size we do not anticipate enough having enough power to see statistically 
significant differences between the groups and the controls.  However, sufficient data will be gleaned to be 
extremely valuable in determining whether or not to move forward to the phase II clinical trial.  
 
The secondary aims in this study include investigating the effect of AR-42 on acetylation of lysine (Ac-Lysine) 
and acetylated histone 2B (Ac-H2B) and on the phosphoinositide 3 kinase (PI3K)/AKT signaling pathway; tumor 
proliferation, cell cycle, cell death and angiogenesis; exploring HR23B as a biomarker for tumor sensitivity; 
performing NF2 gene mutation analyses; assessing audiometric changes pre and post AR-42; evaluating 


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volumetric changes in tumor size of the first 10 subjects; and determining the steady-state plasma and intra-tumoral 
concentrations of AR-42 at the time of surgical resection.  For each of these secondary aims as well as baseline 
assessment variables we will use the appropriate summary statistics and graphical displays to summarize the 
variables collected for each of the four tumor types and the control samples.  Since these are secondary aims no 
statistical testing will be performed.    
 
8.5 
Patient disposition and drug exposure 
 
Patients’ disposition will be summarized in the following manner: 
 
 
The number and percentage of patients selected, included, completed, withdrawn and lost to follow-up will 
be summarized using descriptive statistics. 
 
Major protocol deviations will be summarized. 
 
The reason for withdrawal (adverse events, major protocol deviation, non-medical reason) will be 
summarized. 
 
9. PATIENT SAFETY 
 
9.1 
Monitoring of adverse events 
Patients will be evaluated for toxicity if they have received at least one dose of AR-42.  Significant adverse events 
(AEs) should be identified and recorded, then seriousness, expectedness, and causality will be assessed using the 
definitions that follow.  The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
 
An Adverse Event will be considered any unfavorable or unintended change in structure, function, signs, or 
symptoms temporally associated with the use of a medicinal product experienced by a person administered a 
pharmaceutical product, whether or not a causal relationship with the product has been established.  Clinically 
significant laboratory abnormalities may be considered AEs if deemed appropriate by the Investigator.  Worsening 
of a pre-existing condition is also considered an AE as is the discovery of an abnormal finding during physical 
exam that was not included in the medical history. 
 
Subjects will be encouraged to spontaneously report any AE.  Study personnel will ask open-ended questions to 
obtain information about AEs at every visit.  Date and time of onset and resolution (if applicable) of the AE will 
be documented.  All adverse events occurring after the initiation of the study treatment (treatment emergent 
adverse events) will be reported, including events present at baseline that worsened during the study. 
      
Safety will be assessed by the investigator in the form of evaluation of adverse events and clinical laboratory 
results and derived as data sets and frequency methods.  The following safety measurements will be used and 
conducted prior to AR-42 dosing and surgery. 
 
Adverse events by severity and causality as described below. 
 
Laboratory evaluations including comprehensive metabolic panel (which includes serum chemistries 
for magnesium, calcium, and potassium, and liver function tests) and CBC with differentials.  For 
participants whose platelets decrease to less than 50,000/µL, AR-42 will be discontinued.  Surgery 
may be delayed until platelet count is above 50,000/µL. 
 
Clinically meaningful changes in vital signs including temperature, blood pressure, weight, pulse, and 
respiratory rate.  
 
12-lead ECG (triplicate).   
 
To monitor any risk of increased surgical complications associated with AR-42, the treating surgeons will evaluate 
and record any noted intra-operative, short-term post-operative or intermediate post-operative differences and/or 


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complications such as increased bleeding, tumor adherence to adjacent nerves, or increased difficulty in tumor 
removal. A summary report of this information will be provided to the IRB after 5 participants have been accrued 
to the study.  This information will also be provided to the research monitor for review.   
 
9.2 
Definitions of adverse events and causality 
 
An Adverse Event is any untoward medical occurrence in a patient administered a pharmaceutical product and 
which does not necessarily have to have a causal relationship with the treatment.  Clinically significant 
laboratory abnormalities may be considered AEs if deemed appropriate by the Investigator.  Worsening of a pre-
existing condition is also considered an AE as is the discovery of an abnormal finding during physical exam that 
was not included in the medical history.  For marketed products in the U.S., a Serious Adverse Event is any 
untoward medical occurrence that at any dose:  
 
 
Results in death (if the patient’s death is suspected as being a direct outcome of the adverse event) 
 
Is life-threatening (the patient was at substantial risk of dying at the time of the adverse event or it is 
suspected that the use or continued use of the product would result in the patient’s death) 
 
Requires inpatient hospitalization or prolongation of existing hospitalization   
 
Results in persistent or significant disability/incapacity 
 
Results in a congenital anomaly/birth defect (i.e., exposure to a medical product prior to conception or 
during pregnancy resulted in an adverse outcome in a child) 
 
Results in the development of drug dependency or drug abuse 
 
Requires intervention to prevent permanent impairment or damage 
 
Overdosage (regardless of adverse outcome) of any study medication.  An overdose is defined as the 
accidental or intentional ingestion of any dose of a product that is considered both excessive and medically 
important. 
 
Pregnancy 
 
Is an important medical event, defined as a medical event(s) that may not be immediately life threatening 
or result in death or hospitalization but, based upon appropriate medical and scientific judgment, may 
jeopardize the patient or may require medical or surgical intervention to prevent one of the other serious 
outcomes listed in the definition above.  Examples of such events include, but are not limited to, intensive 
treatment in an emergency room or at home for allergic bronchospasm, or blood dyscrasias or convulsions 
that do not result in hospitalization.   
 
The SAE reporting period begins once study drug treatment is initiated to within 30 days following cessation of 
treatment.  AEs should be followed to resolution or stabilization, and reported as SAEs if they become serious.  
This also applies to patients experiencing AEs that cause interruption or discontinuation of investigational product, 
or those experiencing AEs that are present at the end of their participation in the study.  Such patients should 
receive post-treatment follow-up as appropriate.  If an ongoing AE changes in its severity or in its perceived 
relationship to study drug, a new AE entry for the event should be completed. 
 
Additionally, any serious adverse event considered by an investigator to be possibly, probably, or definitely related 
to the investigational product that is brought to the attention of the investigator at any time outside of the time 
period specified in the previous paragraph also must be reported immediately to the IRB. 
 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in 
other situations, such as important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed in the definition above. These should also usually be considered serious. 
 


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Note: The term "life-threatening" in the definition of "Serious Adverse Event" refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe. 
 
An Unexpected Adverse Event would either be unexpected for a similar HDAC inhibitor or differs because of 
greater severity or specificity.  
 
Causality is a determination of whether there is a reasonable possibility that the drug may have caused or 
contributed to an adverse event. It includes assessing temporal relationships dechallenge/rechallenge information, 
association (or lack of association) with underlying diseases, and the presence (or absence) or a lack of one or 
more likely causes. 
 
The Investigator must attempt to determine if an adverse event is in some way related to the use of the study drug.  
This relationship should be described as follows: 
 
Unlikely:   The event is clearly due to causes distinct from the use of the study drug, such as a documented pre-
existing condition, the effect of a concomitant medication, a new condition which, based on the 
pathophysiology of the condition, and the pharmacology of the study drug, would be unlikely related 
to the use of the study drug. 
 
Possible: 
The event follows a reasonable temporal sequence from administration of the study drug or the event 
follows a known response pattern to the study drug BUT the event could have been produced by an 
intercurrent medical condition which, based on the pathophysiology of the condition, and the 
pharmacology of the study drug, would be unlikely related to the use of the study drug or the event 
could be the effect of a concomitant medication 
 
Probable: The event follows a reasonable temporal sequence from administration of the study drug and the event 
follows a known response pattern to the study drug AND the event cannot have been reasonably 
explained by an intercurrent medical condition or the event cannot be the effect of a concomitant 
medication 
 
Definite: 
The event follows a reasonable temporal sequence from administration of the study drug, the event 
follows a known response pattern to the study drug and based on the known pharmacology of the 
study drug, the event is clearly related to the effect of the study drug 
 
Unknown: Based on the evidence available, causality cannot be ascribed 
    
9.3 
Serious adverse events 
 
Any Serious Adverse Events (SAE) as described in Section 9.2, including death due to any cause, which occurs 
during this study, must be reported immediately (within 24 hours) by confirmed email or phone call  to the principal 
investigator or study coordinator in  the central study office: 
 
D. Bradley Welling, M.D., Ph.D. 
 
Amy Quinkert, PhD, CCRP 
Principal Investigator 
 
 
 
Study Coordinator 
The Massachusetts Eye and Ear Infirmary 
The Massachusetts Eye and Ear Infirmary 
Phone:  617-573-3632  
 
 
Phone: 617-573-4192 
Fax:  617-573-3415 
 
 
 
Fax: 614-293-7292 
Email:  brad_welling@meei.harvard.edu 
Email: amy_quinkert@meei.harvard.edu 
 


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When the principal investigator has determined that a Serious Adverse Event has occurred, the principal 
investigator is responsible for providing all Serious Adverse Events to the IRB within two working days of this 
determination.  Additionally, the principal investigator will inform all participating investigators of an 
unacceptable toxicity or SAE at least possible related to AR-42 within 48-72 hours of its occurrence.  This applies 
to initial and follow-up information. 
 
Follow-up reports: 
 
 
The Investigator should take all appropriate measures to ensure the safety of the patients, notably he/she should 
follow up the outcome of any Serious Adverse Event and complete follow-up forms as necessary.  The patient 
must be followed up until recovery, stabilization or return to baseline. This may mean that follow-up will 
continue after the patient has completed the trial and that additional investigations may be necessary.  
 
Any reportable Serious Adverse Events brought to the attention of the Investigator at any time after cessation 
of the trial and considered by him/her to be reasonably associated with medication administered during the 
period should also be submitted to the IRB.   
 
As with the initial submission to the IRB, the principal investigator is also responsible for providing all follow-
ups of Serious Adverse Events to the IRB. 
 
A copy of all 15 Day Reports and Annual Progress Reports will be submitted as required by FDA, or other local 
regulators. In addition, the FDA should be notified as soon as possible and in no case later than 7 calendar days 
after initial receipt, of all unexpected fatal or life-threatening suspected adverse reactions. 
 
9.4 
Data safety monitoring plan 
The Data and Safety Monitoring Board (DSMB) as outlined in the DSMB charter will serve as the independent 
data and safety monitoring board for this study. The DSMB will meet annually to review progress of the study and 
will be available for emergent meetings if serious or unanticipated adverse events occur.  The serious adverse 
events and responses will be reviewed by the DSMB.  
 
 
 
The Data and Safety Monitoring Plan will involve the continuous evaluation of safety, data quality and data 
timeliness.  Investigators will conduct continuous review of data and patient safety at their regular Disease Group 
meetings and the discussion will be documented in the minutes.  The PI of the trial will review toxicities and 
responses of the trial, where applicable, at these disease center meetings and determine if the risk/benefit ratio of 
the trial changes.  Frequency and severity of adverse events will be reviewed by the PI and compared to what is 
known about the agent/device from other sources; including published literature, scientific meetings and 
discussions with the sponsors, to determine if the trial should be terminated before completion.  Serious adverse 
events and responses will also be reviewed by DSMB.  The PI will also submit a progress report (biannually for 
Phase II and quarterly for Phase I) that will be reviewed by the committee per the IRB of record as per the policies 
of the IRB. The DSMB Membership List is as follows: 
 
Edwin Choy, MD, Chair and Research Monitor 
MGH, Dana Farber/Harvard Cancer Center 
Division of Hematology Oncology 
55 Fruit Street 
Boston MA 02114 
Phone: (617) 643-0230 
Fax: (617) 724-3166 
Email: echoy@partners.org 
 


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Christopher Moertel, MD, Member 
University of Minnesota 
Department of Pediatrics 
MMC 484 
420 Delaware Street S.E.  
Minneapolis, MN 55455 
Phone: (612) 625-3229 
Fax: (612) 626-2815 
Email: moert001@umn.edu 
 
Domenic Reda, PhD, Member (Statistician) 
Director, Cooperative Studies Program Coordinating Center 
Hines VA Hospital, CSPCC (151K) 
5000 South 5th Avenue, Building 1, Room B240, 
Hines, IL 60141-3030 
Phone: 708-202-5853 
Fax: 708-202-2116 
Email: domenic.reda@va.gov 
 
9.5 
Reporting of adverse event information following study completion  
 
Collection of safety information following the end of investigational product administration is important in 
assisting in the identification of possible delayed toxicities or withdrawal effects.  All SAEs must be collected 
which occur within 30 days of discontinuation of dosing or completion of the patient’s participation in the study 
if the last scheduled visit occurs at a later time.   
 
9.6 
Pregnancy statement and use in nursing women 
 
All women of childbearing potential MUST have a negative pregnancy test.  If the pregnancy test is positive, the 
patient must not receive any investigational product and must not be enrolled in the study. 
 
Definition of childbearing potential: For the purposes of this study, a female of childbearing potential is a 
sexually mature female who: 1) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral 
oophorectomy (the surgical removal of both ovaries) or 2) has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time during the preceding 24 consecutive months). 
 
Study participants must be willing to comply with fertility requirements as described below: 
 
 
Male participants must agree to use an adequate method of contraception for the duration of the study and 
for 28 days afterwards. 
 
Female participants must be either postmenopausal, free from menses ≥ 2 yrs, surgically sterilized, willing 
to use two adequate barrier methods of contraception to prevent pregnancy, or agree to abstain from 
heterosexual activity starting with screening and for 90 days afterwards.   
 
Participants must agree not to donate blood, sperm/ova during study participation and for at least 4 weeks 
after stopping treatment. 
 
During the course of the trial, all patients of childbearing potential should be instructed to contact the treating 
physician immediately if they suspect they might have conceived a child.  In addition, a missed or late menstrual 
period should be reported to the treating physician.  If a female patient or the treating physician suspects that the 
female patient may be pregnant prior to administration of study drugs, the study drugs must be withheld until the 


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results of a pregnancy test are available. If pregnancy is confirmed the patient must not receive study medications 
and must be withdrawn from the study.  Throughout the entire pregnancy, additional contact should be made with 
the patient, and in some cases with the healthcare provider, to identify spontaneous abortions and elective 
terminations, as well as any medical reasons for elective termination. In addition, the study investigator should 
include perinatal and neonatal outcome. Infants should be followed for a minimum of 4 weeks. 
 
If a male patient is suspected of having fathered a child while on study drugs, the pregnant female partner must be 
notified and counseled regarding the risk to the fetus. In addition, the treating physician must follow the course of 
the pregnancy, including prenatal and neonatal outcome. Infants should be followed for a minimum of eight weeks. 
 
Upon live-birth delivery, the minimum information that should be collected includes date of birth, length of 
pregnancy, sex of infant, major and minor anomalies identified at birth. Outcomes can be obtained via mailed 
questionnaires, maternal interviews, medical record abstraction, or a combination of these methods. All serious 
adverse event reports relating to the pregnancy, including spontaneous abortion, elective abortion and congenital 
anomalies, should be forwarded to the FDA. 
 
It is not known whether AR-42 is excreted in human milk. Because many drugs are excreted in human milk and 
because of the potential for serious adverse reactions in nursing infants from AR-42, a decision should be made 
whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the 
mother.   
 
9.7 
Patient withdrawal and study termination 
 
A participant should be withdrawn from the trial treatment if, in the opinion of the investigator, it is medically 
necessary, or if it is the wish of the participant.  If a participant does not return for a scheduled visit, every effort 
will be made to contact the participant.  In any circumstance, every effort will be made to document participant 
outcome, if possible. 
 
Participants should be removed from therapy if any of the following occurs: 
 
 
Adverse event: The occurrence of unacceptable toxicity indicating the need for cessation of treatment, 
defined as grade 3/4 arrhythmia. 
 
The physician feels it is in the best interest of the patient to stop treatment.  
 
The participant desired to withdraw from further participation in the study in the absence of an 
investigator-determined medical need to withdraw.  If a reason for withdrawal is given, it should be 
recorded in the case report form. 
 
Protocol violation: The participant’s findings or conduct failed to meet the protocol entry criteria or failed 
to adhere to the protocol requirements (eg. study drug compliance, returning for the specified number of 
visits).   
 
Participant is lost to follow-up.  If a participant does not return for scheduled visits, every effort should be 
made to re-establish contact.  In any circumstance, every effort should be made to document participant 
outcome, if possible. 
 
Participant becomes pregnant. 
 
Termination of the study. 
 
The reason and date of discontinuation are to be documented in the participant’s medical record and in the case 
report form.  
 


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The investigator should complete all end of treatment procedures when a participant withdraws from treatment.  
All participants who discontinue the trial secondary to an adverse event should be followed until resolution, 
stabilization or return to a baseline condition. 
 
Participants who fail to complete treatment for reasons other than adverse event or unacceptable toxicity may be 
replaced.  All participants who receive one or more doses of study treatment should be included in any safety 
analysis. 
 
The investigator may discontinue the trial at any time.  Reasons for early trial discontinuation may include, but 
are not limited to, unacceptable toxicity of study treatment, a request to discontinue the trial from a regulatory 
authority, or poor enrollment. 
 
9.8 
Research monitor 
 
Edwin Choy, MD, will serve as the Chair of the DSMB and Research Monitor.  Dr. Choy serves as an Assistant 
Professor of Medicine at the Harvard Medical School. Dr. Choy has several years of experience serving on a 
DSMB for similar research studies.  Dr. Choy is the Director of Sarcoma Research at the Division of Hematology 
Oncology at MGH. He specialized in the medical management of patients with sarcomas, gastrointestinal stromal 
tumors, chordomas, and desmoid tumors.  He works closely with a team of world class surgical, orthopedic, and 
radiation oncologists as well as connective tissue pathologists and radiologists to provide optimal care for his 
patients.  He directs a clinical trials program at the MGH Center for Sarcoma and Connective Tissue Oncology 
that includes 9-12 active phase I-III clinical trials.  He also maintains an active scientific research program that 
investigates diverse areas of sarcoma therapy ranging from the use of nanotechnology and other translational 
research tools aimed at developing new targeted therapies for treating cancers to preclinical studies using cell lines 
and animal models to better understand the molecular basis of sarcoma biology.  His clinical expertise matched 
with his experience in data safety monitoring has equipped him to take on the position of Research Monitor for 
this study. In addition to attending the regular meetings of the DSMB, assessing any adverse events presented, and 
overseeing the overall maintenance of DSMB records and reporting, Dr. Choy is responsible for identifying and 
following through with the need to report to the IRB, when appropriate. Dr. Choy will work with the Principal 
Investigator, Dr. Welling, to ensure all reports are filed to the IRB in a timely and efficient manner in order to 
protect the safety of human subjects. As Research Monitor, Dr. Choy has the authority to stop the research protocol 
in progress, remove individual human subjects from the research protocol, and take whatever steps are necessary 
to protect the safety and well-being of human subjects until the IRB assesses the report filed.   
 
Dr. Choy is responsible for reviewing all unanticipated problems involving risk to subjects or others, serious 
adverse events, and all subject deaths associated with the protocol. He will provide an unbiased written report of 
any events relating to these matters.  This report will provide an overview of the event, including the outcomes of 
the event or problem and in case of a serious adverse event or death, comment on the relationship to participation 
in the study.  In these reports, Dr. Choy will indicate whether he concurs with the details of the report provided by 
the principal investigator.  Dr. Choy and Dr. Welling will ensure reports possibly or definitely related to 
participation and reports of events resulting in death are promptly forwarded to the USAMRMC ORP HRPO at 
usarmy.detrick.medcom-usamrmc.other.hrpo@mail.mil. 
 
10. ETHICAL AND REGULATORY STANDARDS 
 
10.1 
Ethical principles 
The study should be conducted according to the principles outlined by the 18th World Medical Assembly 
(Helsinki, 1964) and all applicable amendments; the International Conference on Harmonization Guidelines for 
Good Clinical Practice; and FDA regulations regarding the conduct of clinical trials and the protection of human 
subjects.  
 


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10.2 
Protocol compliance and protocol revisions 
The study must be conducted as described in this approved protocol.  The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval from the IRB of an amendment, 
except where necessary to eliminate an immediate hazard(s) to study patients.   
 
10.3 
Informed consent 
The study investigator and/or delegated research staff at each site will obtain informed consent from each 
participant enrolled in the study, in accordance with the U.S. Food and Drug Administration (FDA) regulations 21 
CFR 50.20 - 50.27, the laws and regulations of the state in which the investigation is being conducted, and should 
adhere to Good Clinical Practices and to the ethical principles that have their origin in the Declaration of Helsinki.   
Consent will only be obtained under circumstances that provide the prospective subject sufficient opportunity to 
consider whether or not to participate and that minimize the possibility of coercion or undue influence. 
 
All personnel involved with recruitment and obtaining informed consent will have completed training in the 
protection of human subjects in research and been approved by their IRB to participate in the study.  Prior to the 
beginning of the trial, the investigator will have the IRB approval of the written informed consent form and any 
other written information provided to subjects. Subjects will not be consented until final IRB approval of these 
documents is received.   
  
Obtaining Consent: 
After study investigators have determined that an individual is eligible to participate, the study protocol, including 
all risks and potential benefits and investigational nature, will be explained to the participant by the site study 
investigators in a private clinical office with respect to the potential subject’s privacy.  The investigator will review 
and discuss details of the research study using the consent form as a guide.  All basic elements of the consent form 
document, HIPAA, consent addendums and any additional relevant information will be presented in detail to the 
prospective subject.  The information given to the subject shall be in a language understandable to the subject.  No 
informed consent, whether oral or written, will include any exculpatory language through which the subject is 
made to waive or appear to waive any of the subject's legal rights, or releases or appears to release the investigator, 
the sponsor, the institution or its agents from liability for negligence.  The information presented will not include 
complex, technical, highly specialized language or medical jargon that would not be understandable to potential 
subject.  The PI will not coerce or unduly influence a subject to participate or to continue to participate in a trial.  
 
Before informed consent may be obtained, the investigator will provide the subject ample time and opportunity to 
read, inquire about the details of the study and to decide whether or not to participate.  All questions about the 
study will be answered to the satisfaction of the subject by site study investigators.  The subject can chose to 
provide consent at the time of the office visit or take the consent home for review and discussion with others and 
have an opportunity to think about participation.   
 
For patients to qualify to participate in this study, information such as the results of routine blood work necessary 
for surgery (including but not limited to chemistries, CBC, platelets, etc.) may be used to determine candidacy and 
may have been done within 30 days before the patient has consented into the study. A standard of care MRI done 
within 60 days of the scheduled day 1 of study drug may be used for screening/baseline assessments. The 
investigator or delegated research staff will obtain informed consent which will be documented by the use of a 
written consent form, approved by the IRB and signed and dated in pen, by the subject prior administering the first 
dose of the study medicine.  This form will also be signed and dated in pen by the person obtaining consent and if 
necessary a witness to the consent process and maintained in an individual subject research binder. 
 
All blanks on the consent form, consent addendum forms (if applicable) and  HIPAA authorization form (if 
applicable) for subject name, subject initials, dates, signatures, yes/no check boxes for optional research 
procedures must be completed by the subject themselves if previously approved by the IRB.  Delegated research 
staff may not complete these blanks for the subject.  


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The PI or delegated research staff will ensure that the subject expresses understanding of information presented 
on the clinical trial, that participation is voluntary, and that the subject can withdraw at any time without penalty 
or effects to their medical care.  They will ensure that all of the subject’s questions have been answered.  
Participants will also be made aware that by signing the consent form their personal health information and 
research records may be audited/reviewed by authorized study personnel. 
 
By signing the consent form, the witness attests that the information in the consent form and any other written 
information was accurately explained to and understood by the subject, and that informed consent was freely given 
by the subject.  The PI or delegated research staff will give a copy of all signed and completed forms to the subject. 
The investigational site should ensure that the subject understands that in order to participate on the clinical trial 
the subject must be eligible per the protocol’s inclusion and exclusion criteria.  
It is the responsibility of the investigator to obtain written informed consent from a patient before any study related 
procedures are performed.  The Investigator will provide an informed consent in compliance with ICH GCP and 
U.S. FDA guidelines (21 CFR 50).  The informed consent document must clearly describe the potential risks and 
benefits of the trial, and each prospective participant must be given adequate time to discuss the trial with the 
Investigator or site staff and to decide whether or not to participate.  The informed consent must be approved by 
the IRB prior to being presented to a potential patient.    
 
10.4 
Institutional Review Board (IRB) approval 
The principal investigator must obtain the approval of the protocol, the informed consent document and any other 
material used to inform the patient about the nature of the trial from the local IRB in the form of a written letter.  
On the approval letter, which must be signed by the chairperson of the IRB or the chairperson’s designee, the 
following items should be clearly stated:  trial title, protocol number and version, study-related documents 
(protocol, informed consent material, advertisement when applicable), IRB review date, and IRB decision.  The 
trial should not start until a copy of this written approval has been received by the Investigator. 
 
10.5 
Additional responsibilities of the investigator 
The investigator(s) agrees to perform the study in accordance with ICH Good Clinical Practice and FDA 
regulations.  The Investigator is required to ensure compliance with respect to the investigational drug schedule, 
visit schedule and procedures required by the protocol.  
 
The investigator should be able to recruit the required number of suitable patients and should have sufficient time 
to properly conduct and complete the trial.  The Investigator should have available an adequate number of qualified 
staff and adequate facilities for the duration of the trial, and should ensure that all persons assisting with the trial 
are adequately informed about the protocol, the protocol-defined procedures, protocol therapy and trial related 
duties and functions.. 
 
The Investigator should be responsible for all trial-related medical decisions.  During and following a patient’s 
participation in a trial, the investigator should ensure that adequate medical care is provided to a patient for any 
adverse events related to the trial.   
 
10.6 
Confidentiality 
It is the responsibility of the investigator to ensure that the confidentiality of all patients participating in the trial 
and all of their medical information is maintained.  Case report forms must never contain the name of a trial patient.  
All case report forms and any identifying information must be kept in a secure location with access limited to the 
study staff directly participating in the trial.  Personal medical information may be reviewed by a representative 
of the IRB, or of regulatory authorities in the course of auditing the trial.  Every reasonable effort will be made to 
maintain such information as confidential. 
 


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10.7 
Conflict of interest 
AR-42 is a therapeutic that was generated at OSU and for which many laboratories at this same institution have 
performed pre-clinical studies supporting its use in different types of cancer.  Ching-Shih Chen is the inventor of 
this compound.  Both the inventor and the University (OSU) have the potential to benefit financially from AR-42 
if the compound has clinical activity.  Addressing conflict of interest relative to investigators is therefore very 
important.  None of the clinical investigators involved in this trial have personal potential to financially gain from 
the success of this program.  The pharmaceutical licensee (ARNO Therapeutics) will be supplying all of the study 
drug for completion of this trial. Safety issues relative to attribution of response will also be monitored by the 
DSMB and the Cancer Center IRB.   
 


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11. 
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12. 
APPENDIX A: QT PROLONGATION – HISTORY, RATIONALE, MONITORING 
The QT interval is an important variable in oncology drug development, but its significance in early-phase 
clinical trials is still uncertain.  At least four HDAC inhibitors examined to date—including vorinostat (Olsen et 
al., 2007), panobinostat (Giles et al., 2006), and depsipeptide (Piekarz et al., 2006) have shown clinical evidence 
of QT prolongation in phase I and/or II studies. Although QT prolongation poses a risk of malignant cardiac 
arrhythmia with torsade de pointes and sudden cardiac death, it is important to note that, with a few exceptions 
such as depsipeptide, the QT abnormalities observed in HDAC inhibitor clinical trials have not translated into 
clinically meaningful events.   
 
It is important to review the experience with Depispeptide. Depsipeptide (FK228), a cyclic peptide, is an HDAC 
inhibitor that has been variably associated with QT prolongation and rarely sudden cardiac death (Ueda et al., 
1994; Bates et al., 2006).  A phase I study of depsipeptide in solid tumor malignancies reported three 
asymptomatic cardiac arrhythmic events and one symptomatic episode of dose-limiting atrial fibrillation in four 
of 37 patients (Sandor et al., 2002).  Depsipeptide's ability to induce QT toxicity appears to be heterogeneous and 
may vary based on the patient population. A phase II study at Ohio State University (PI Manisha Shah) 
investigated depsipeptide in 15 patients with metastatic neuroendocrine tumors. After the sudden death of one 
patient, the protocol was amended to include 24-hour telemetry after depsipeptide infusion. Subsequently, two 
patients had nonsustained ventricular tachycardia and prolonged QT was noted in three patients. The trial was 
terminated prematurely because of cardiac toxicity.  Of note, most patients had been previously treated with 
octreotide and received antiemetic therapy with ondansetron, both of which are associated with at least minimal 
QT prolongation (Shah et al., 2006). 
 
Evidence collected to date indicates that these QTc changes may be a class effect of HDAC inhibitors (Strevel et 
al., 2006) with the actual incidence and severity of QTc prolongation a function of the specific dose and 
schedule used for each HDAC inhibitor as well as the patient selection criteria. 
 
In May 2005, the ICH issued the E14 guideline for the clinical evaluation of QT interval prolongation and 
proarrhythmic potential for nonantiarrhythmic drugs (Committee IS, 2005).  The Thorough QT Study (TQTS), 
the fundamental recommendation of ICH E14, advises that every new drug undergo clinical assessment of its 
repolarization effects. The TQTS characterizes a drug's impact on the QT interval over an entire dose range 
(including maximum tolerated dose) and anticipates interactions predisposing to QT prolongation, and if a drug 
is found to prolong QT, determines its safest efficacious dose (Shah, 2005). TQTS participants are intended to be 
healthy volunteers. QTc prolongations of 60 ms or more over baseline or more than 500 ms are considered 
cautionary.  Applying these guidelines to early oncology drug development is not immediately clear. 
 
In two phase II studies, the appropriate reference values of QTc interval for adult patients with hematological or 
solid tumors, enrolled across various protocols were evaluated (Piekarz et al, 2006; Varterasian et al., 2003).  
Data indicated that the distribution of QTc interval duration was greater in these patients when compared with 
results from a trial with similar ECG methods conducted in healthy volunteers. This implies that if exclusion 
criteria of 450 ms for males and 470 ms for females (Straus et al., 2006) were considered for oncology trials, 
more than 10% of patients would be excluded from phase I or phase II studies because of marginally prolonged 
QTc interval at baseline. 
 
Because of baseline tachycardia that is often seen in hematologic malignancies, we propose using correcting the 
QT interval for heart rate.  Because heart rate is the principal determinant of repolarization length, many 
correction formulae have been developed to calculate a corrected QT interval (QTc) value corresponding to a 
QT value normalized at a heart rate of 60 beats/min (Funck-Brentano and Jaillon, 1993).  The most widely used 
formula, in particular by automatic devices, has been proposed by Bazett but is known to overcorrect the QT 
interval at high heart rate and therefore could lead to a false diagnosis of prolonged QTc interval in patients with 
baseline tachycardia as is often seen in hematologic malignanies (Puddu et al., 1988; Desai et al., 2003; Luo et 


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al., 2004).  Until other QT corrections such as the Fridericia formula are available in an automated fashion on 
ECG machines, we will use the Bazett formula (QTcB) in this protocol. 
 
 
The following drugs should be avoided if possible (http://www.azcert.org/medical-pros/drug-
lists/bycategory.cfm# obtained 28-Sep-09): 
 
Generic Name 
Brand Name 
Class/Clinical Use 
Comments 
Amiodarone  
Cordarone® 
Anti-arrhythmic / abnormal heart 
rhythm 
Females>Males,TdP risk 
regarded as low 
Amiodarone  
Pacerone® 
Anti-arrhythmic / abnormal heart 
rhythm 
Females>Males,TdP risk 
regarded as low 
Arsenic trioxide  
Trisenox® 
Anti-cancer / Leukemia 
 
Astemizole  
Hismanal® 
Antihistamine / Allergic rhinitis 
No Longer available in U.S. 
Bepridil  
Vascor® 
Anti-anginal / heart pain 
Females>Males 
Chloroquine 
Aralen® 
Anti-malarial / malaria infection 
 
Chlorpromazine  
Thorazine® 
Anti-psychotic/ Anti-emetic / 
schizophrenia/ nausea 
 
Cisapride 
Propulsid® 
GI stimulant / heartburn 
Restricted availability; 
Females>Males. 
Clarithromycin 
Biaxin® 
Antibiotic / bacterial infection 
 
Disopyramide  
Norpace® 
Anti-arrhythmic / abnormal heart 
rhythm 
Females>Males 
Dofetilide  
Tikosyn® 
Anti-arrhythmic / abnormal heart 
rhythm 
 
Domperidone 
Motilium® 
Anti-nausea / nausea 
Not available in the U.S. 
Droperidol  
Inapsine® 
Sedative;Anti-nausea / anesthesia 
adjunct, nausea 
 
Erythromycin  
Erythrocin® 
Antibiotic;GI stimulant / bacterial 
infection; increase GI motility 
Females>Males 
Erythromycin  
E.E.S.®  
Antibiotic;GI stimulant / bacterial 
infection; increase GI motility 
Females>Males 
Halofantrine  
Halfan® 
Anti-malarial / malaria infection 
Females>Males 
Haloperidol  
Haldol® 
Anti-psychotic / schizophrenia, 
agitation 
When given intravenously or at 
higher-than- recommended 
doses, risk of sudden death, QT 
prolongation and torsades 
increases.  
Ibutilide 
Corvert® 
Anti-arrhythmic / abnormal heart 
rhythm 
Females>Males 
Levomethadyl 
Orlaam® 
Opiate agonist / pain control, 
narcotic dependence 
 
Mesoridazine 
Serentil® 
Anti-psychotic / schizophrenia 
 
Methadone 
Dolophine® 
Opiate agonist / pain control, 
narcotic dependence 
Females>Males 
Methadone 
Methadose® 
Opiate agonist / pain control, 
narcotic dependence 
Females>Males 
Pentamidine  
Pentam® 
Anti-infective / pneumocystis 
pneumonia 
Females>Males 


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Pentamidine  
NebuPent® 
Anti-infective / pneumocystis 
pneumonia 
Females>Males 
Pimozide 
Orap®  
Anti-psychotic / Tourette's tics 
Females>Males 
Probucol 
Lorelco® 
Antilipemic / 
Hypercholesterolemia 
No longer available in U.S. 
Procainamide  
Pronestyl® 
Anti-arrhythmic / abnormal heart 
rhythm 
 
Procainamide  
Procan®  
Anti-arrhythmic / abnormal heart 
rhythm 
 
Quinidine 
Cardioquin®  
Anti-arrhythmic / abnormal heart 
rhythm 
Females>Males 
Quinidine 
Quinaglute® 
Anti-arrhythmic / abnormal heart 
rhythm 
Females>Males 
Sotalol  
Betapace®  
Anti-arrhythmic / abnormal heart 
rhythm 
Females>Males 
Sparfloxacin  
Zagam®  
Antibiotic / bacterial infection 
 
Terfenadine 
Seldane® 
Antihistamine / Allergic rhinitis 
No longer available in U.S. 
Thioridazine 
Mellaril®  
Anti-psychotic / schizophrenia 
 
 


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13.  
APPENDIX B:  MEDICATION LOG 
 
MEDICATION LOG 
 
Subject Study ID:_______________________ 
 
Date to Start Taking Study Medication:_______________________ 
 
1. 
AR-42 should be stored at room temperature in the bottle dispensed. 
2. 
You will take AR-42 once a day on days specified below. 
3. 
AR-42 should be taken in the evening on an empty stomach; at least 1 hour before or 2 hours 
following a meal. 
4. 
Record the date, time, and number of capsules taken at the time you take the medication. 
5. 
If you make a mistake, please do not scribble out or use white out to make corrections. Draw a 
single line through the mistake, correct the mistake, and initial next to your correction. 
Example: 1:00pm 2:30pm JD 
6. 
If you have any comments or notice any side effects, please record them in the Comments 
column. 
7. 
Please bring this form when you return the day of your surgery along with the study 
medication.  
 
 
 
 
 
 
 
 
Number of capsules dispensed________  
Number of capsules returned_______
Day 
Date  
Time  
Number of Capsules 
Taken 
Comments 
1 
 
 
 
 
3 
 
 
 
 
5 
 
 
 
 
8 
 
 
 
 
10 
 
 
 
 
12 
 
 
 
 
15 
 
 
 
 
17 
 
 
 
 
19 
 
 
 
 
22 
 
 
 
 


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14. APPENDIX C:  ELIGIBILITY/SCREENING CHECKLIST 
 
PARTICIPANT ELIGIBILITY/SCREENING CHECKLIST 
 
 
Participant Name: ______________________________________ 
DOB: __________________ 
 
Medical Record #: __________________________  
Site: __________________________ 
 
Date eligibility screened: _____________________  
 
 
 
 
American 
Indian or 
Alaskan 
Native 
Asian or 
Pacific 
Islander 
Black, not of 
Hispanic 
Origin 
Hispanic 
White, not 
of Hispanic 
Origin 
Other or 
Unknown 
Male 
 
 
 
 
 
 
Female 
 
 
 
 
 
 
 
Please ask each question to the patient being screened and circle the answer given.  If the answer 
indicates that the patient is not eligible, you may suspend screening at that point in the questionnaire. 
 
1. 
Is the patient 18 years of age or older? 
 
 
 
 
YES (continue) 
 
NO (not eligible) 
 
2. 
For which of the following does the patient meet diagnostic criteria? 
 
 
 
 
NF2-Associated Vestibular Schwannoma (continue) 
 
 
 
 
Non NF2-Associated (sporadic) Vestibular Schwannoma (continue) 
 
 
 
 
NF2-Associated Meningioma (continue) 
 
 
 
 
Non NF2-Associated Meningioma (continue) 
 
 
 
 
None of the above (not eligible) 
 
3. 
Has surgery for vestibular schwannoma or meningioma been determined to be clinically 
necessary by the treating physician? 
 
 
 
 
YES (continue) 
 
NO (not eligible) 
 
4. 
Can this patient provide written informed consent? 
 
 
 
 
YES (continue) 
 
NO (not eligible) 
 
5. 
Can this patient swallow tablets? 
 
 
 
 
YES (continue) 
 
NO (not eligible) 
 
6. 
Is this patient currently pregnant or breast-feeding? 
 
 
 
 
YES (not eligible) 
 
NO (continue) 
 
7. 
Does this patient have a known cardiovascular disease (myocardial infarction, angina, 
arrhythmia) requiring treatment? 
 
 
 
 
YES (not eligible) 
 
NO (continue) 
 


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8. 
Does the patient have a concurrent malignancy? 
 
 
 
 
YES (not eligible) 
 
NO (continue) 
 
9. 
Is the patient receiving concurrent anti-neoplastic therapy (chemotherapeutics or investigational 
agents, radiation, immunotherapy)? 
 
 
 
 
YES (not eligible) 
 
NO (continue) 
 
10. 
Has the patient received any prior biologic therapy, chemotherapy, surgery or radiation? 
 
 
 
 
YES (continue to question 11) 
 
NO (continue to question 12) 
 
11. 
For chemotherapy or biological therapy, have 4 weeks elapsed since the last treatment and 
patient has recovered from all toxicities to Grade 1 or less? 
 
 
 
 
YES (continue) 
 
NO (not eligible) 
 
 
 
For surgery, have 3 weeks elapsed since last major surgical treatment and patient has 
recovered from surgery and any post-surgical complications? 
 
 
 
 
YES (continue) 
 
NO (not eligible) 
 
 
For radiation therapy, has 1 year elapsed since last treatment and patient has recovered from 
all toxicities to Grade 1 or less? 
 
 
 
 
YES (continue) 
 
NO (not eligible) 
 
12. 
Does the patient have malabsorption or any other condition that could cause difficulty in 
absorption of the study drug? 
 
 
 
 
YES (not eligible) 
 
NO (continue) 
 
13. 
Does the patient require chronic corticosteroids (dose equivalent > 20mg prednisolone)? 
 
 
 
 
YES (not eligible) 
 
NO (continue) 
 
14. 
Is the patient receiving treatment for an active infection? 
 
 
 
 
YES (not eligible) 
 
NO (continue) 
 
15. 
Does the patient have known HIV infection? 
 
 
 
 
YES (not eligible) 
 
NO (continue) 
 
16. 
Does the patient have any medical condition or illness that is likely to interfere with the patient’s 
ability to cooperate and participate in the study (follow directions, complete study evaluations, 
etc.)? 
 
 
 
 
YES (not eligible) 
 
NO (continue) 
 
17. 
Is the patient receiving any of the following concomitant medications? 
 
 
 
 
YES (not eligible) 
 
NO (continue) 
 
 
HDAC inhibitors (e.g. valproic acid) 
 
Granulocyte colony-stimulating factors including G-CSF, pegylated G-CSF or GM-CSF 
 
Drugs associated with QT/QTc prolongation (review Appendix A in protocol) 
 
18. 
Is the patient currently using complementary or alternative medicines that in the opinion of the 
principal investigator could confound the interpretation of toxicities of the study drug? 
 
 
 
 
YES (not eligible) 
 
NO (continue) 
 


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19. 
Is the patient of childbearing potential? 
 
 
 
 
YES (continue to question 20) 
NO (continue to 22) 
 
20. 
Has the patient agreed to use birth control/contraception for the length of this trial? 
 
 
 
 
YES, method______________________ (continue) 
 
 
 
 
NO (not eligible) 
 
21. 
Does the patient have a documented negative pregnancy test? 
 
 
 
 
YES (continue) 
 
NO (not eligible) 
 
22. 
Does the patient have QT/QTc prolongation documented by ECG (mean QTcB > 450 msec in 
males and > 470 msec in females)?  
 
 
 
 
YES (not eligible) 
 
NO (continue) 
 
23. 
Does the patient have an Eastern Cooperative Oncology Group/World Health Organization 
(ECOG/WHO) performance status of 0-1? 
 
 
 
 
YES (continue) 
 
NO (not eligible) 
 
24. 
Please provide documentation of the following (if any of these lab results are outside of the 
listed ranges or cannot be documented, then the patient is not eligible for the study): 
 
 
Leukocytes > 3,000/mcL 
 
Absolute neutrophil count > 1,500/mcL 
 
Platelets > 100,000/mcL 
 
Total bilirubin < 1.5 mg/dL 
 
AST(SGOT)/ALT(SGPT) < 5x institutional upper limit of normal (ULN) 
 
Creatinine < 1.5x ULN, OR creatinine clearance > 50 mL/min by MDRD (original 
or abbreviated), OR measured creatinine clearance > 50 mL/min 
 
Hemoglobin of at least 9 g/dL 
 
Normal serum magnesium (1.6 – 2.6 mg/dL), calcium (8.6 – 10.0 mg/dL), 
potassium (3.5 – 5.1 mmol/L) levels  
 
 
 
 
*If screening questionnaire indicates that the patient is eligible for the study, please proceed to 
obtaining informed consent.  Once consent is obtained, please refer to the Study Manual for directions 
on enrolling the patient in the study. 
 
 
 
 
Eligibility screening completed by: 
_____________________________________ 
 
 
 
 
 
 
(printed name) 
 
 
 
 
 
 
 
 
_____________________________________       Date:________ 
 
 
 
 
 
(signature


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15. APPENDIX D:  ELIGIBILITY/SCREENING LOG 
 
PARTICIPANT ELIGIBILITY LOG 
 
Site: __________________________________ 
 
Page ____ of ____ 
 
In order to track enrollment numbers, please record all potential participants that are eligible for the study.  
Submit this form quarterly to the Central Study Office at The Massachusetts Eye and Ear Infirmary. 
 
Participant 
Initials 
Study ID # 
Diagnosis 
NF2/non-NF2) 
Date 
Screened 
Eligible  
(Y/N) 
If No, Why Not? 
Screened By: 
Example:  
A.B. 
Example: 
10006 
Example: 
NF2 VS, MEN 
Example: 
01/01/01 
Example: 
Y 
Example: 
Pregnant 
Example: 
John Smith