Neuro-pharmacological Properties of Repurposed Posaconazole in Glioblastoma: A Phase 0 Clinical Trial
Phase: EARLY_PHASE1
Conditions: Glioblastoma, Glioblastoma Multiforme, Glioblastoma Multiforme of Brain, Glioblastoma Multiforme, Adult
Sponsor: Milton S. Hershey Medical Center

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HRP-592 - Protocol for Human Subject 
Research with Use of Test Article(s)
Protocol Title:
Neuro-pharmacological properties of repurposed posaconazole in glioblastoma: A Phase 0 clinical trial
Principal Investigator:
Name: Alireza Mansouri, MD
Department: Neurosurgery
Telephone: (437) 215-1000
E-mail Address: amansouri@pennstatehealth.psu.edu
Version Date:
November 16, 2023
Clinicaltrials.gov Registration #:
NCT04825275
Funding Organization:
National Institutes of Health (NIH)
Table of Contents
1.0
Objectives
2.0
Background
3.0
Inclusion and Exclusion Criteria
4.0
Recruitment Methods
5.0
Consent Process and Documentation
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
7.0
Study Design and Procedures
8.0
Subject Numbers and Statistical Plan
9.0
Data and Safety Monitoring Plan
10.0
Risks
11.0
Potential Benefits to Subjects and Others
12.0
Sharing Results with Subjects
13.0
Subject Payment and/or Travel Reimbursements
14.0
Economic Burden to Subjects
15.0    Resources Available
16.0    Other Approvals
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17.0    Multi-Site Study
18.0    Adverse Event Reporting
19.0     Study Monitoring, Auditing and Inspecting
20.0     Future Undetermined Research:  Data and Specimen Banking
21.0     References
22.0     Confidentiality, Privacy and Data Management
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1.0
Objectives
1.1
Study Objectives
This study will examine the neuro-pharmacological (pharmacokinetics and pharmacodynamics) profile of 
posaconazole (PCZ), in people with primary or recurrent high-grade gliomas (HGGs) requiring open 
surgical resection.
1.2
Primary Study Endpoints
Establish the neuro-pharmacokinetic profile of posaconazole, using microdialysis catheters (MDC). This 
will be based on the assessment of the concentration versus time curves of drug in the dialysate fluid, 
collected over a 24-hour period after surgery. 
1.3
Secondary Study Endpoints
1.
Evaluate tolerability of preoperative steady-state dosing of Posaconazole, as measured through the 
Grade and Frequency of adverse events, based on the CTCAE v5.0 criteria
2.
Evaluate pharmacodynamics properties of posaconazole, based on
a)
Study drug’s effect on Hexokinase 2 activity within resected tumor tissue, as measured using a 
hexokinase assay on tumor tissue following resection 
b)
in resected tumor tissue.
c)
Study drug’s effect on tumor proliferation (using Ki-67 proliferation index), cell death (using 
TUNEL staining), and angiogenesis (based on expression of VEGF) in resected tumor tissue.
d)
Correlation of posaconazole pharmacokinetic profile with that of lactate and pyruvate, using 
MDC. This will be assessed based on the concentration versus time profile of lactate and 
pyruvate in the dialysate fluid, over the same 24-hour period used to measure the concentration 
of drug
2.0
Background 
2.1
Scientific Background and Gaps
High grade gliomas
High grade gliomas (HGGs, WHO Grade III and IV gliomas) are the most common malignant primary 
brain tumor in humans. Glioblastoma (GBM, WHO Grade IV glioma) is the most aggressive brain tumor, 
accounting for more than half of all gliomas and 17% of all primary brain and central nervous system 
(CNS) tumors[4]. Far from the importance of GBM being the most common human malignancy, GBM 
deserves attention on the basis of its universally poor prognosis. 
Decades of research has demonstrated various degrees of molecular, genetic, epigenetic, and metabolic 
heterogeneity among tumors of the same grade and even within individual tumors [7]. This 
heterogeneity has significantly hampered efforts toward developing effective therapeutic strategies for 
GBM patients. From a metabolic perspective, it is well-known that most tumor cells preferentially 
convert glucose to lactate, regardless of the levels of available oxygen; this is known as aerobic glycolysis 
(or Warburg effect) [8, 9]. 
The Warburg effect and its role in HGGs
In HGGs, as with most cancers, cells have undergone effective reprogramming of their energy 
metabolism in order to be able to survive in hypoxic conditions [8]. Rapidly proliferating cancer cells 
demonstrate a preferential bias toward aerobic glycolysis over oxidative phosphorylation for supporting 
growth and survival in hypoxic conditions. This metabolic reprogramming is referred to as the “Warburg 
effect”. Through this mechanism, tumor cells are able to produce large amounts of lactate while 
consuming very little oxygen. The dependency of cancer cell proliferation on accelerated glucose 
metabolism distinguishes them from their normal counterparts and could render them more vulnerable 
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to the disruption of glucose metabolism. Therefore, cancer cells could be selectively targeted by the 
disruption of intracellular glucose metabolism. 
Hexokinase 2 in GBM metabolism 
Hexokinases (HKs) catalyze the first committed step in glucose metabolism, which is the ATP-dependent 
phosphorylation of glucose to glucose-6-phosphate (G6P), which ensures a sustained concentration 
gradient that promotes the entry of glucose into cells. This establishes the role of HK in determining the 
magnitude and direction of intracellular glucose flux. The HK family of enzymes is comprised of 4 
isoforms (denoted as HK1, HK2, HK3, and HK4 [11]. Among these, HK1, and HK2, are associated with 
mitochondria and were also implicated in cell survival [12, 13]. While HK1 is present in most human 
adult tissues, HK2 is only expressed in embryonic tissues or a select group of adult tissues such as 
adipose and skeletal/cardiac muscles [14]. What distinguishes cancer cells from normal cells is their 
ability to express very high levels of HK2, which promotes the accelerated flux of glucose under hypoxic 
conditions [15, 16]. Over-expression of HK2 has been demonstrated in many cancer types and it has 
been associated with a poor survival [17]. 
Over-expression of HK2 has been documented in GBM cells as well [18, 19]. In addition to its role in 
promoting the influx of glucose, HK2 also inhibits apoptosis [20]. Previously, we have shown that while 
HK2 is significantly upregulated in GBM, HK1 was down-regulated [21]. Our group has also previously 
shown that a reduction of HK2 expression (but not HK1 or HK3) in vitro can inhibit aerobic glycolysis, 
increase normal oxidative respiration, and induce apoptosis (particularly under hypoxic conditions). We 
have also shown that the survival of mice injected with HK2 knockdown glioma cells is extended[19] and 
that HK2 plays a critical role in tumor cell survival at a very early stage [21].
Through microscopic analysis of tumor cells deficient of HK2, compared with controls, our group has 
also shown that HK2 has the ability to alter the tumor vasculature as well [21]. Our in vitro work has 
demonstrated a significant decrease in the density of neovasculature particularly away from the central 
necrotic core.  In vivo, we demonstrated that mice bearing intracranial GBM xenografts of HK2- knock 
down tumors had a significantly decreased vascular perfusion/permeability compared to xenografts of 
control tumor, based on measurement of the K-trans value in dynamic contrast-enhanced MR imaging 
(Figure 1). Furthermore, we have also shown that the absence of HK2 confers sensitivity to chemo-
radiation in vivo (Figure 2).
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Figure 1. HK2 knock-down models mouse models of GBM demonstrate decreased microvascular density, 
diminished vascular permeability, and less dilated/ tortuous vessels
Figure 2. HK2 knock-down mouse models of GBM have a longer average survival compared to controls. This also 
increases the tumor cells’ sensitivity to chemo-radiation (TMZ = radiation)
Therefore, it is clear that HK2 is a key driver of several oncogenic pathways in GBMs and is at least in 
part responsible for the tumor’s increased proliferation and resistance to chemo-radiation. Currently, no 
direct inhibitor of HK2 has been tested in human patients with GBMs. Given the limited progress in the 
field of therapeutics for GBMs since the establishment of the Stupp protocol as the standard of care 
[22], there is a pressing need to expand the available treatment regiments for this population by 
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introducing new approaches or therapeutic agents. One possible means to expedite initiation of GBM 
clinical trials is to examine previously established drugs with a known track record of safety in humans, 
regardless of their intended use. 
2.2
Previous Data
Identification of the potentially anti-tumor effect of azoles in patients with GBM 
Using a small drug screen targeting potential HK2 regulated gene expression networks we identified the 
azole class of antifungals as inhibitors of tumor metabolism by reducing proliferation, lactate 
production, glucose uptake in GBM cells but not primary normal human astrocytes or normal neural 
stem cells (Figure 3) [58]. 
Figure 3. Small drug screen reveals several compounds that decrease the viability of GBM tumor cell lines and 
glioma stem cell lines, including ketoconazole
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Ketoconazole and posaconazole enhance in vitro survival in part through down-regulation of HK2 
activity 
Upon identification of ketoconazole and posaconazole as potential inhibitors of HK2-regulated gene 
expression networks, we conducted dynamic metabolic flux analysis with 13C-labeling experiments 
followed by liquid chromatography-mass spectrometry (LC-MS) to assess the effect of the addition of 
ketoconazole or posaconazole, on glycolytic intermediates from GBM cell lines and Glioma stem cell 
cultures [58]. Through this approach, we demonstrated a reduction of various pro-anabolic glycolytic 
intermediates through the addition of these azoles (Figure 4A). This was shown to be at least in part due 
to the down-regulation of HK2 activity, and hence reduction of lactate production, by azoles (Figure 4 B, 
and C) Loss of HK2 in GBM cells dampened the effect of several azoles suggesting that the mechanism of 
action is mediated in part through HK2 (Figure 4D). The addition of ketoconazole or posaconazole (IC50 
= 10 μM) decreased the viability of several GBM cell lines (Figure 4E) and glioma stem cells (Figure 4F) 
but not normal human astrocytes (NHA). 
Figure 4 A. HK2 knock-down decreases the concentration of glycolysis metabolites in GBM cell lines
Figure 4 B, C; Ketoconazole and Posaconazole decrease the relative HK activity and, thus, extracellular lactate in 
glioma stem cell lines
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Figure 4 D. Glioma cell line viability is decreased following treatment with Ketoconazole and Posaconazole. This 
effect on viability is decreased in the absence of HK2 (knock-down)
Figure 4E. Increasing concentrations of Ketoconazole and Posaconazole decrease the % viability of GBM cell lines 
but not normal human astrocytes (NHA).
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Figure 4F. Increasing concentrations of ketoconazole and posaconazole decrease the viability of glioma stem cell 
lines but not normal stem cell lines (NSC).
Ketoconazole and posaconazole enhance in vivo survival in part through down-regulation of HK2 
activity
The survival of U87 xenograft mice bearing glioblastoma tumors was extended through the 
administration of either ketoconazole or posaconazole (25mg/kg daily) (Figure 5A) [58]. Histologically, a 
decrease in mitotic activity was observed following the administration of these two agents in glioma 
cells (Figure 5 B and C). The reduction of HK2 activity following the administration of ketoconazole or 
posaconazole was demonstrated in vivo as well, with concordant reduction of lactate production as well 
(Figure 5 D and E). 
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D                                                                                E
Figure 5. Enhancement of xenograft survival following the administration of ketoconazole or posaconazole (A), 
along with decreased mitotic activity as demonstrated through Ki67 staining (B and C). This is mediated through 
reduction of HK activity (D) and lactate production (E).
2.3
Study Rationale
Both ketoconazole and posaconazole are FDA-approved anti-fungal agents with a well-established side 
effect and safety profile. Ketoconazole and posaconazole have shown efficacy in reducing tumor cell 
proliferation in our in vitro studies. Furthermore, both have also shown efficacy, mediated at least in 
part through inhibition of HK2 activity, in our animal models with dosing concentration and schedules 
that are documented as safe in humans.[58] As a drug, posaconazole has a more predictable half-life 
than ketoconazole and has less off-target effects. Therefore, the proposed trial will focus on the role of 
posaconazole exclusively. As a first step, demonstration of adequate penetrance of study drug in brain 
and tumor tissue (pharmacokinetics) and biological effect (inhibition of glycolysis and subsequent tumor 
cell death) is necessary prior to large scale clinical studies. A total of 5 control participants will be 
included in this study as we specifically want to assess for pharmacodynamic differences too. The 
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addition of a control group to this study rather to both the studies (ketoconazole study is a separate 
protocol) is because we feel posaconazole may be a more promising drug for moving forward.
Plasma drug concentration measurements are an unreliable method to assess delivery of drugs across 
the blood-brain barrier. In contrast, intracerebral MDC monitoring allows for approximate 
measurements within extracellular fluid (ECF) sampling of the brain. MDC placement within the brain is 
not a novel technique and has been utilized routinely in the ICU setting to measure brain metabolism by 
sampling of ECF of traumatic brain injury patients [59-61].
MDC are now FDA-approved and are being placed routinely with intracranial pressure monitors. This 
method allows for continuous measurement of ECF within a tumor or normal tissue. The dialysis probe 
has a semipermeable membrane which is less than 1 mm in diameter into which two sections of 
microcatheter are fused. Previous studies have demonstrated the feasibility of keeping the catheters in 
place of critically injured patients for up to 2 weeks [62-64]. 
When placed at the time of surgical resection, the microcatheters are stereotactically implanted, placing 
the probe within the desired brain and/or tumor region. Externally, the catheter is connected to a 
syringe pump, which delivers a low flow rate (μl/min) of continuous perfusion fluid (Lactated Ringers or 
artificial CSF) and dialysate is collected in a microvial from the outlet tube. This sterile, single use 
catheter is minimally invasive and developed to achieve optimal diffusing characteristics similar to 
passive diffusion of a capillary blood vessel. Just as in the function of brain capillary vessel, water, 
inorganic ions and small organic molecules freely diffuse across the membrane of the probe, whereas 
proteins and protein bound compounds are impermeable. Additionally, lipophilic compounds are poorly 
recovered. Therefore, assessment of pharmacokinetics of drug using MDC provides valuable insight 
relevant to its anti-neoplastic properties. 
3.0
Inclusion and Exclusion Criteria
3.1
Inclusion Criteria
Patients eligible for enrollment in this study will be male and female adults with a presumed diagnosis of 
primary or recurrent HGG based on standard of care imaging (contrast-enhanced MRI) and clinical 
presentation and for whom surgical intervention has been selected as the most appropriate treatment 
option by the treating physician and patient.
1.
Age ≥18 years
2.
Evidence of primary or recurrent HGG that in the opinion of the treating team would require 
surgical resection
3.
Adequate liver function defined as ALT, AST, ALP within 1.5x institutional upper limit of normal 
(for study drug arm only)
4.
Ability to swallow medication (for study drug arm only)
5.
Women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) for the duration of study participation 
(for study drug arm only)
6.
Ability to understand and willingness to sign a written informed consent document
7.
Be able to comply with treatment plan, study procedures and follow-up examinations
3.2
Exclusion Criteria
1.
Patients may not be receiving any other investigational agents while on study
2.
Patients who have known allergy to posaconazole or other azoles (for study drug arm only)
3.
Patients who have previously had a severe side effect, such as agranulocytosis and neutropenia, 
in conjunction with previous azole class drugs for a parasitic infection (for study drug arm only)
4.
Patients with a history of acute or chronic hepatitis (for study drug arm only)
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5.
Patients with liver enzymes (ALT, AST, ALP) >1.5x above normal range for the laboratory 
performing the test (for study drug arm only)
6.
Patients who are taking metronidazole and cannot be safely moved to a different antibiotic 
greater than 7 days prior to starting posaconazole therapy (for study drug arm only)
7.
Patients who are taking any anti-convulsant medication that interferes with the cytochrome 
P450 pathway (e.g. phenytoin, phenobarbital, carbamazepine, etc.) and who cannot be switched 
to alternative medications such as Keppra (levetiracetam) (for study drug arm only)
8.
Uncontrolled intercurrent illness such as chronic hepatitis, acute hepatitis, or psychiatric 
illness/social situation that would limit compliance with study requirements (for study drug arm 
only)
9.
Patients with a history of Addison's disease or other forms of adrenal insufficiency (for study 
drug arm only)
10. Patient with little or no stomach acid production (achlorhydria) (for study drug arm only)
11. Pregnant and breastfeeding women)
12. Patients with a history of any medical or psychiatric condition or laboratory abnormality that in 
the opinion of the investigator may increase the risks associated with the study participation or 
investigational product administration or may interfere with the interpretation of the results.
13. Patients who are not available for follow-up assessments or unable to comply with study 
requirements
14. Patients who are currently taking medications that induce the metabolism of posaconazole, 
such as isoniazid, nevirapine, rifamycins (such as rifabutin, rifampin), or St. John's wort and 
cannot be safely discontinued off of them for the duration of the trial (for study drug arm only). 
15. Patients who are currently taking medications for which the metabolism may be affected by 
posaconazole, which include but are not limited to: benzodiazepines (such as alprazolam, 
midazolam, triazolam), domperidone, eletriptan, eplerenone, ergot drugs (such asergotamine), 
nisoldipine, drugs used to treat erectile dysfunction-ED or pulmonary hypertension (such as 
sildenafil, tadalafil), some drugs used to treat seizures (such as carbamazepine, phenytoin), 
some statin drugs (such as atorvastatin, lovastatin, simvastatin) (for study drug arm only)
16. Patients who are non-English speakers
17. Patients who are not capable of understanding the consent form and would need a legally 
authorized representative
3.3
Early Withdrawal of Subjects
3.3.1
Criteria for removal from study
A participant should be withdrawn from the trial treatment if, in the opinion of the PI, 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

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 (e.g. 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
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
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. All participants who receive one or more doses of study 
treatment should be included in any safety analysis.  The PI 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.
3.3.2
Follow-up for withdrawn subjects
The PI will complete all end of treatment procedures when a participant withdraws from 
treatment. All participants who discontinue treatment secondary to an AE will be followed until 
resolution, stabilization or return to a baseline condition. Participants who fail to complete 
treatment for reasons other than AE or unacceptable toxicity may be replaced.
4.0
Recruitment Methods
4.1
Identification of subjects
Potential subjects will be identified by the principal investigator when they attend their clinic 
appointment or in the emergency department if no urgent surgery or biopsy indicated.
4.2
Recruitment process
4.2.1
How potential subjects will be recruited.
Potential subjects will be approached by the physicians in clinic during their regularly scheduled 
clinic visit or in the emergency department if no urgent surgery or biopsy indicated. If at that 
time the physician feels that patient would be a good fit for the study, she/he will then 
introduce the patient to the study to gauge interest. The study will be described to the patient 
and they will be given a chance to ask any additional questions. If the patient agrees to 
volunteer for the study, informed consent will be obtained.
4.2.2
Where potential subjects will be recruited.
Patients will be recruited in the clinic or in the emergency department if no urgent surgery or 
biopsy indicated.
4.2.3
When potential subjects will be recruited.
Patients will be recruited prior to their scheduled biopsy or surgery.
4.2.4
Describe the eligibility screening process and indicate whether the screening process will 
occur before or after obtaining informed consent. Screening begins when the investigator 
obtains information about or from a prospective participant in order to determine their 
eligibility.  In some studies, these procedures may not take place unless HIPAA Authorization 
is obtained OR a waiver of HIPAA Authorization when applicable for the screening procedures 
is approved by the IRB.
Screening of subjects at is expected prior to obtaining consent to determine potential eligibility.
Once informed consent is obtained, patients will undergo additional screening to determine if 
they are eligible to participate in the study based on the inclusion/exclusion criteria. If a 
participant is ineligible for the study drug arm, they will first be considered for candidacy in the 
ketoconazole study (STUDY00014115). If enrollment in the ketoconazole study is already 
completed or if the participant is not a candidate for ketoconazole either, then they will be 
considered for possible candidacy in the control arm of this study.
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5.0
Consent Process and Documentation 
The PI and/or delegated research staff will obtain informed consent from each participant enrolled in the study, 
in accordance with FDA regulations and will 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 the 
IRB to participate in the study. Prior to the beginning of the trial, the PI 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. 
5.1
Consent Process:
Check all applicable boxes below:
Informed consent will be sought and documented with a written consent form [Complete Sections 
5.2 and 5.6] 
Implied or verbal consent will be obtained – subjects will not sign a consent form (waiver of 
written documentation of consent) [Complete Sections 5.2, 5.3 and 5.6] 
  Informed consent will be sought but some of the elements of informed consent will be omitted or 
altered (e.g., deception). [Complete section 5.2, 5.4 and 5.6]
Informed consent will not be obtained – request to completely waive the informed consent 
requirement. [Complete Section 5.5]
5.2
Obtaining Informed Consent 
As part of the initial neuro exam, it will be determined if the individual is capable of signing and 
understanding the consent and research study. A physician/investigator will determine the capability of 
any potential research subject’s ability to consent, through standard neuro and cognitive testing 
completed initially upon arrival at our institution.
After it has been 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 PI 
and/or delegated research personnel in a private setting with respect to the potential subject‘s privacy. 
The PI or delegated research staff will review and discuss details of the research study using the consent 
form as a guide. All basic elements of the consent form document, consent addendums and any 
additional relevant information will be presented in detail to the prospective subject. The information 
given to the subject will 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 and delegated research staff 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 PI or delegated research staff 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 the PI 
or delegated research staff. 
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The PI 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) 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 will not complete 
these blanks for the subject. 
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 PI will 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. 
The informed consent document will 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 PI or delegated 
staff and to decide whether or not to participate. The informed consent will be approved by the IRB 
prior to being presented to a potential patient.
Telephone Consent Process
The physician/study coordinator will talk to potential participant at their initial visit. If they express 
interest, we will send a copy of the informed consent form to them ahead of the telephone call for them 
to review. We will arrange to contact them at an agreed upon date/time.
The study coordinator will conduct the telephone consent discussion with the potential participant. A 
witness will be present with the study team member during the telephone consent discussion. A review 
of the consent will be completed. All questions and concerns will be answered prior to the end of the 
discussion. Time will be given for the potential participant to respond to the consent process, and give a 
positive response, or decline to enroll in the study.
If the potential participant says yes, they will be asked to sign, date, time, and print their name on the 
consent form, as we sign the telephone consent signature page at our site.
They will be asked to return the signed consent form to the research site via email, phone text message 
with an attached picture of the signed consent page or fax. In order to return the signed document, a 
telephone number, email address or fax number will be given to the potential participant.
Once received, we will place our signed telephone consent signature page with the participant’s signed 
consent. A copy of the entire consent will be sent by mail, email or fax to the participant.
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The phone consent procedure will be included in the note to file used to document the informed 
consent process in the research record or medical record. A copy of the signed consent form will be 
placed in the medical record.
A reminder of possible loss of confidentiality may occur with email, telephone or fax, but we will be 
careful to give and review the telephone or fax number, and/or email address of the subject.
5.3
Waiver of Written Documentation of Consent 
Not applicable
5.3.1
Indicate which of the following conditions applies to this research:
  The research presents no more that minimal risk of harm to subjects and involves no 
procedures for which written consent is normally required outside of the research context.
OR
  The only record linking the subject and the research would be the consent document and the 
principal risk would be potential harm resulting from a breach of confidentiality. Each subject 
will be asked whether the subject wants documentation linking the subject with the research, 
and the subject’s wishes will govern. 
OR
  If the subjects or legally authorized representatives are members of a distinct cultural group 
or community in which signing forms is not the norm, that the research presents no more 
than minimal risk of harm to subjects and provided there is an appropriate alternative 
mechanism for documenting that informed consent was obtained.  
Describe the alternative mechanism for documenting that informed consent was obtained:
Not applicable
5.3.2
Indicate what materials, if any, will be used to inform potential subjects about the research 
(e.g., a letter accompanying a questionnaire, verbal script, implied consent form, or summary 
explanation of the research)
Not applicable
5.4
Informed consent will be sought but some of the elements of informed consent will be omitted or 
altered (e.g., deception).
Not applicable
5.4.1
Indicate the elements of informed consent to be omitted or altered
Not applicable
5.4.2
Indicate why the research could not practicably be carried out without the omission or 
alteration of consent elements
Not applicable
5.4.3
Describe why the research involves no more than minimal risk to subjects.
Not applicable
5.4.4
Describe why the alteration/omission will not adversely affect the rights and welfare of 
subjects. 
Not applicable
5.4.5
If the research involves using identifiable private information or identifiable biospecimens, 
describe why the research could not be practicably be carried out without using such 
information or biospecimens in an identifiable format.
Not applicable
5.4.6
Debriefing 
Not applicable
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5.5
Informed consent will not be obtained – request to completely waive the informed consent 
requirement
Not applicable
5.5.1
Indicate why the research could not practicably be carried out without the waiver of consent
Not applicable
5.5.2
Describe why the research involves no more than minimal risk to subjects.
Not applicable
5.5.3
Describe why the alteration/omission will not adversely affect the rights and welfare of 
subjects. 
Not applicable
5.5.4
If the research involves using identifiable private information or identifiable biospecimens, 
describe why the research could not be practicably be carried out without using such 
information or biospecimens in an identifiable format.
Not applicable
5.5.5
Additional pertinent information after participation
Not applicable
5.6
Consent – Other Considerations 
5.6.1
Non-English-Speaking Subjects
Non-English speaking subjects will not be eligible for the trial. We do not believe that excluding 
these patients from this pilot study will impact the study results, as our Neuro-oncology 
Department does not see many non-English speakers. If the study moves into the next phase, 
we will look at including non-English speakers.
5.6.2
Cognitively Impaired Adults
Cognitively impaired adults will not be consented for this pilot study as patients are required to 
be able to understand the consent form. We do not believe that excluding these patients from 
this pilot study will impact the study results, as most of the patients our Neuro-oncology 
Department sees for biopsy or surgery are not cognitively impaired. If the study moves into the 
next phase, we will look at including cognitively impaired adults.
5.6.2.1
Capability of Providing Consent
Not applicable
5.6.2.2
Adults Unable to Consent
Not applicable
5.6.2.3
Assent of Adults Unable to Consent
Not applicable
5.6.3.1
Parental Permission
Not applicable
5.6.3.2
Assent of subjects who are not yet adults
Not applicable
6.0
HIPAA Research Authorization and/or Waiver or Alteration of Authorization
6.1
Authorization and/or Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
Check all that apply:
Not applicable, no identifiable protected health information (PHI) is accessed, used or 
disclosed in this study. [Mark all parts of sections 6.2 and 6.3 as not applicable]
Authorization will be obtained and documented as part of the consent process. [If this is the 
only box checked, mark sections 6.2 and 6.3 as not applicable]
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Partial waiver is requested for recruitment purposes only (Check this box if patients’ medical 
records will be accessed to determine eligibility before consent/authorization has been 
obtained). [Complete all parts of sections 6.2 and 6.3]
Full waiver is requested for entire research study (e.g., medical record review studies).
[Complete all parts of sections 6.2 and 6.3]
Alteration is requested to waive requirement for written documentation of authorization 
(verbal authorization will be obtained). [Complete all parts of sections 6.2 and 6.3]
6.2
Waiver or Alteration of Authorization for the Uses and Disclosures of PHI
6.2.1
Access, use or disclosure of PHI representing no more than a minimal risk to the privacy of the 
individual
6.2.1.1
Plan to protect PHI from improper use or disclosure
Information is included in the “Confidentiality, Privacy and Data 
Management” section of this protocol.
6.2.1.2
Plan to destroy identifiers or a justification for retaining identifiers 
Minimal screening activities prior to consent may include accessing patient 
charts to confirm eligibility. No identifiers will be retained for any patient 
who does not meet eligibility requirements or provide consent to 
participate in the study.
6.2.2
Explanation for why the research could not practicably be conducted without access to and 
use of PHI
Potential study participants are expected to be identified by study clinical investigators, as part 
of their routine clinical duties. Once identified, other members of the study team may access the 
patient chart to confirm eligibility and/or identity of the subject.
6.2.3
Explanation for why the research could not practicably be conducted without the waiver or 
alteration of authorization
Access to the patient chart prior to consent is required in order to adequately identify subjects 
and avoid unnecessary consent discussions (ineligible patients).
6.3
Waiver or alteration of authorization statements of agreement
Protected health information obtained as part of this research will not be reused or disclosed to any 
other person or entity, except as required by law, for authorized oversight of the research study, or for 
other permitted uses and disclosures according to federal regulations. 
The research team will collect only information essential to the study and in accord with the ‘Minimum 
Necessary’ standard (information reasonably necessary to accomplish the objectives of the research) 
per federal regulations. 
Access to the information will be limited, to the greatest extent possible, within the research team. All 
disclosures or releases of identifiable information granted under this waiver will be accounted for and 
documented.
7.0
Study Design and Procedures
7.1
Study Design
This will be a single-center, open label, non-randomized Phase 0 feasibility trial to determine the neuro-
pharmacokinetic/pharmacodynamic profile of posaconazole for HGGs. We will enroll 10 (5 for study 
group and 5 for control group) evaluable patients over 12 months with recent MRI findings suggestive of 
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high grade gliomas with need for surgical resection. Our historical surgical volume supports the 
feasibility of this proposal.
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Study Schema
* Study drug arm only
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7.2
Study Procedures
If the patient appears to be eligible for the study, based on the initial evaluation, the study will be 
described to the patient and they will be given a chance to ask any additional questions. If the patient 
agrees to volunteer for the study, informed consent will be obtained. 
If the patient is not eligible for enrollment in the study drug arm (e.g. contraindications to posaconazole, 
possible drug-drug interactions), they will be assessed for candidacy in the ketoconazole study, which 
has a separate IRB-approved protocol (IRB# STUDY00014115). If enrollment in the ketoconazole study is 
already completed or if the participant is not a candidate for ketoconazole either, then they will be 
considered for possible candidacy in the control arm. If, in this scenario, 5 participants have already 
been enrolled in the control arm, then the patient will not be a candidate for this study. 
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.
A screening log will be used to store information from all potential participants screened. Information 
collected on the screening log will include participant initials, demographics (gender, race), date of 
consent, checkbox to note if signed informed consent given 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 by the study principal investigator to monitor study accrual. 
7.2.1
Visit 1 (Screening and baseline)
Once informed consent has been obtained, the following are performed as routine (standard) care
or data collected from the EMR if they were performed within 31 days of consent:

Demographics.

CBC and Comprehensive Metabolic Panel (which includes electrolytes, renal function 
and liver function) (approximately 2 teaspoons of blood).

Medical history.

Neurological examination.

Baseline MRI Brain +/- Gadolinium contrast scan will be reviewed.

Concomitant medications are reviewed.

A 12-lead ECG.

If a female of childbearing age, a pregnancy test will be performed.
Blood will be drawn for Comprehensive Metabolic Panel (CMP) for the study drug group only 
(approximately 2 teaspoons of blood). Patients will wait at the clinic or emergency department if no 
urgent surgery or biopsy is indicated until these results are available (usually within 4 hours).
If the participant’s routine tests show that they are eligible and their liver function tests are 
acceptable, they will be able to continue in the study. 
If the patient is pregnant, confirmed by the pregnancy test, the medical team can take appropriate 
steps to ensure the safety of both the mother and the fetus, and the patient will not be able to 
continue study and will be considered a screen fail.
If any of routine tests or liver function tests are outside the acceptable ranges for the study, they 
will be assessed for candidacy in the ketoconazole study, which has a separate IRB-approved 
protocol (IRB# STUDY00014115). If enrollment in the ketoconazole study is already completed 
or if the participant is not a candidate for ketoconazole either, then they will be considered for 
possible candidacy in the control arm. If, in this scenario, 5 participants have already been 
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enrolled in the control arm then the patient will not be a candidate for this study and they will 
be considered a screen fail for this study. The study doctor will follow-up regarding any abnormal 
results for clinical purposes. 
Control group
Participants will first be considered for enrolment in the posaconazole arm. If there are 
contraindications to posaconazole, or if enrolment in posaconazole arm has been completed, then 
subjects will be enrolled in the ketoconazole study, which has a separate IRB-approved protocol 
(IRB# STUDY00014115). If enrollment in the ketoconazole study is already completed or if the 
participant is not a candidate for ketoconazole either, then they will be considered for possible 
candidacy in the control arm.
Study drug group
Participants will be given 12 days’ worth of the study drug (pills) and verbally instructed how 
and when to take them. The prescription bottle will have a label with this information on it as 
well.
The timing of study drug administration will be based on the scheduled date and time of 
biopsy or surgery, which will occur within 7-10 days of Visit 1. The latter parameter is based 
on the drug half-life, as follows:

Participants will be taking posaconazole as 300mg PO BID in the first day, followed 
by 300mg PO once daily thereafter.

The mean elimination half-life of posaconazole is 26-31 hours (product monograph). 
Therefore, posaconazole will reach steady state at approximately 130-155 hours 
following the first dose (5 half-lives). As such, we will work backwards from the 
scheduled date and time of biopsy or surgery such that participants in the 
posaconazole arm will receive drug for 168-240 hours. The upper range of the 
dosing (240 hours) is to minimize potentially unnecessary exposure to drug while 
accounting for variability in half-life measurements. 
In order to maintain steady-state concentrations, study drug will be administered at the 
following times as well:
1.
Pre-operatively on the morning of the planned surgical intervention
2.
On the morning of postoperative day 1, at 8:00AM +/- 4 hours *
*Only if postoperative CT rules out complications and the MDC(s) are correctly positioned.
Concurrent treatment considerations and restrictions:

Patients with HGGs will often have peri-tumoral edema for which corticosteroids are 
often effective. Given the influence of posaconazole on suppressing adrenal 
function, this exogenous steroid will also help to replace affected adrenal function 
and, therefore, concomitant use will be allowed. The corticosteroid of choice is 
dexamethasone, at a dose of 4mg PO QID. Stress dosing at time of biopsy or surgery 
will be at discretion of surgical and anesthesia teams. 

Due to the possible adverse effect of corticosteroids on the protective gastric lining, 
patients are often required to concomitantly take H2 blockers such as ranitidine 
(150mg po BID) during their course of corticosteroids. This could adversely affect 
the absorption of posaconazole. Therefore, patients will take posaconazole at least 
2 hours before taking ranitidine. 

Other drugs that decrease the amount of stomach acid include over-the-counter 
antacids, proton pump inhibitors, sucralfate. Drugs that slow down gut movement 
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include anticholinergics such as dicyclomine, propantheline. Patients taking either 
class of drugs will be advised to take posaconazole at least 2 hours before. 

Patients will be asked to avoid alcohol for at least 3 days after finishing the drug. 
7.2.2
Visit 2 (3 days +/-2 days after starting the study drug)
This visit is ONLY for the study drug arm. Participants will return to the clinic for a research-only 
visit. At this visit, the following will be performed:

Collection of adverse events.

A 12-lead ECG to rule out QTc prolongation

Comprehensive Metabolic Panel (which includes electrolytes, renal function and liver 
function). Lab values within 1.5x institutional upper limit of normal are acceptable and not 
considered adverse events.
7.2.3
Visit 3 (Day of biopsy or surgery)
Control group
The following will be performed for the research only:

Collection of adverse events.
Study drug group
Participants will bring their study drug prescription bottle with them.
The following will be performed for the research only:

Patient will take study drug at 8am (+/- 4 hours)

Collection of adverse events.

Study Medication Compliance and checking of medication diary.

Record date and time of study medication of this day for the research records and 
to confirm it was taken in the morning.

If HGG diagnosis verified, record date and time of tissue sample collection, blood 
sample collection and microdialysis catheter placement.
Intra-operative procedure 
Assessments common to both control and study drug groups 
After surgical resection, frozen pathology will be reviewed to verify the diagnosis of HGG. 
Once pathology has been verified, and it is determined there is adequate tissue for clinical 
diagnosis, we will take our research sample will be taken and prepared for assessment of 
intra-tumoral drug concentration (study drug arm only) and assessment of HK2 activity, 
downstream glycolysis metabolites, tumor cell proliferation, and angiogenesis. 
Where an open surgical resection has been planned, one (1) tissue sample will be from the 
center of the tumor and one (1) from the tumor capsule and snap-frozen immediately in the 
operating room (<15 minutes). No individual sample will be greater than 1cm x 1cm. These 
will then be divided for individual research-specific analyses.
As noted below for postoperative plasma collection schedule, blood samples will be 
obtained at the time of tumor sampling as well to determine and compare tumor: blood 
drug concentration ratios. The exact time of tumor resection and blood sampling will be 
recorded.
For patients in whom the intraoperative diagnosis is not consistent with HGG, no additional 
blood will be drawn and the patient will not be able to continue study and will be considered a 
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screen fail. Furthermore, no MDC will be inserted. Surgical procedures necessary for the 
management for the particular diagnosis will be undertaken as per standard protocol for the 
surgeon. 
Upon satisfactory resection of tumor bulk, the neurosurgeon will place two CMA 70 MDCs 
with Gold Tip - (ref. no. P000050, CMA, Solna, Sweden) with a membrane length of 10mm, 
and shaft length 100mm - in accordance with pre-op MRI. For patients with a subtotal 
resection of enhancing tumor, one MDC will be placed in a contrast enhancing area of the 
tumor and another will be placed in a non-contrast enhancing region (normal brain) within 
5mm of tumor resection cavity. For patients with a complete resection of contrast-
enhancing tumor, only one MDC will be placed in the non-enhancing tumor resection 
boundary, within 5mm of resection cavity. Ultimately, the decision on number of catheters 
inserted will be at the discretion of the surgeon. Upon completion of the surgical procedure, 
the wound will then be irrigated and closed in standard fashion and lastly the catheter will 
be anchored to the scalp with sutures and sterile dressings.
7.2.4
Visit 4 (Post-operative, Day 0)
Control group
After biopsy or surgery is completed, patients will have the following as routine (standard 
care):

Computed tomography (CT) of the head.

Neurological examination.
The following will be performed for the research only:

Collection of adverse events experienced during biopsy or surgery as they relate to 
insertion of microdialysis catheter, if any.
Study drug group
After biopsy or surgery is completed, patients will have the following as routine (standard 
care):

Computed tomography (CT) of the head.

Neurological examination.
The following will be performed for the research only:

Collection of adverse events experienced during biopsy or surgery as they relate to 
insertion of microdialysis catheter.
A postoperative CT scan will be performed, as part of the standard of care to rule out 
immediate postoperative complications such as hemorrhage at catheter tip or misplaced 
catheter. Other surgical changes will not be considered to be related to the catheter 
insertion. This will also help confirm the position of the MDC tip: the postoperative CT image 
is fused with preoperative contrast-enhanced MRI to confirm position within enhancing vs 
non-enhancing regions. It should be performed after the surgery, prior to the dialysate 
sample collection the following morning. Per neurosurgical discretion, if the catheter 
appears malpositioned on imaging or significant tumor bed hemorrhage is present, the 
microdialysis studies will not be performed. The CT study will be considered abnormal for 
study purposes if related to the catheter insertion.
7.2.5
Visit 5 (Post-operative, Day 1)
Control group
The following will be performed as routine (standard care):

Neurological examination.
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The following will be performed for the research only:

Dialysate collection and blood sample collection. 

Collection of adverse events.
Study drug group
The following will be performed as routine (standard care):

Neurological examination.
The following will be performed for the research only:

Patient will take study medication at 8am +/- 4 hours and then study medication will be 
discontinued.

Comprehensive Metabolic Panel (which includes electrolytes, renal function and 
liver function) (approximately 1 teaspoon of blood). Lab values within 1.5x 
institutional upper limit of normal are acceptable and not considered adverse events.

Dialysate and blood sample collection. 

Collection of adverse events.
Microdialysis collection/monitoring 
After the imaging confirms proper placement of the MDC tip, the inlet tubing will be 
connected to a portable syringe pump to perfuse artificial CSF (Perfusion Fluid CNS, ref. no. 
P000151, CMA, Solna, Sweden) at a rate of 1.0 μl/min. The inlet tubing of the catheter will 
be connected to a CMA 107 Microdialysis Pump (ref. no. P000127, CMA, Solna Sweden). A 
microvial will be connected at the end of the outlet tubing to collect perfusate. 
Concurrently, a plastic microvial (Ref. No. P000001, CMA, Solna, Sweden) will be placed in 
the vial holder at the end of the outlet tubing to collect dialysate. This microvial can hold up 
to 200μL of fluid. It will need to be replaced with a new one every 3 hours. During daytime 
work week hours, trained research coordinators, in coordination with nursing team will 
collect dialysate and replace the microvials. At all other times, these tasks will be performed 
by the study PI, Dr Mansouri.
Dialysate sample collection will begin in the morning of postoperative day 1. If the 
participant was able to tolerate the AM dose of study drug (study drug group only), sample 
collection will begin immediately after drug administration. Otherwise, sample collection 
will begin within the same allotted time period (i.e. 8AM +/- 4 hours). For the control group, 
sample collection will be at 8 AM +/- 4 hours. The initial sample will be labeled as the ‘Time 
0’ sample. Additional samples will be collected at 15 and 30 minutes, along with 1, 2, 4, 6, 8, 
and 24 hours after ‘Time 0’. 
Microvials containing the dialysate should be stored in an ultralow temperature freezer (≤-
70°C) until they can be batch analyzed by LC/MS/MS.
Plasma collection 
As part of the standard of care, patients will have an arterial line placed at the time of 
biopsy or surgery, which is usually discontinued 24-48 hours postoperatively, upon evidence 
of hemodynamic stability. 
Blood samples will be collected from the arterial line at the following times: At time of 
biopsy or tumor resection (day of surgery), ‘Time 0’ (aligned with dialysate sample collection 
time above), then 15 and 30 minutes, along with 1, 2, 4, 6, 8, and 24 hours after ‘Time 0’. 
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Blood (3 mL) will be collected in green top tubes containing sodium heparin anticoagulant. 
The plasma collection tube will be promptly mixed by gently inverting 6-times, then placing 
it on wet ice, until centrifuged at 1,300 x g for 10 min at 4°C. Samples will be centrifuged for 
harvesting plasma as soon as possible after collection (within 1 hour). Upon centrifugation, 
the plasma will be separated from the blood cells using a pipette and transferred into an 
appropriately labeled polypropylene freezer vial. The samples should be processed to 
plasma within 30 minutes from centrifugation and the pH adjusted to <4 with the use of 
8.5% phosphoric acid (15μL of 8.5% phosphoric acid per 0.5mL of plasma). Plasma will then 
be stored frozen at -70°C until subsequent batch analysis.
7.2.6
Visit 6 (Post-operative, Day 2)
Control group
The following will be performed for the research only:

Dialysate and blood collection will end at 8 am +/- 4 hours on post-op Day 2.

Removal of microcatheters.

Collection of adverse events.
Following completion of dialysate collection, the infusion pump use will cease and the MDC 
will be removed percutaneously at the bedside by a study team physician. The entry site of 
the catheter will be closed with a suture or steri-strip as necessary and a clean dressing 
applied. The patient will be kept in the hospital for observation until discharged by the 
primary neurosurgical team. 
Study drug group
The following will be performed for the research only:

Dialysate and blood sample collection will end at 8 am +/- 4 hours on post-op Day 2.

Removal of microcatheters.

Collection of adverse events.
Following completion of dialysate collection, the infusion pump use will cease and the MDC 
will be removed percutaneously at the bedside by a study team physician. The entry site of 
the catheter will be closed with a suture or steri-strip as necessary and a clean dressing 
applied. The patient will be kept in the hospital for observation until discharged by the 
primary neurosurgical team. 
7.2.7
Visit 7 (Post-operative follow-up 14+/-7 days)
Control group
The following will be performed as routine (standard care):

Neurological exam
The following will be performed for the research only:

Collection of adverse events.
Study drug group
The following will be performed as routine (standard care):

Neurological exam
The following will be performed for the research only:

Collection of adverse events.
Samples collected during the study for research-only purposes will be sent for analysis as shown below:
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Sample
Analysis location
Comprehensive Metabolic Panel (which includes 
electrolytes, renal function and liver function) at Visits 1, 2, 
and 5
Clinical laboratory
Dr. Connor’s laboratory (pharmacodynamics)
Tissue from biopsy or surgery
Mass Spectrometry core at Penn State Hershey 
Cancer Institute (PSHCI) (metabolites and drug 
concentration)
Plasma at Visits 5 and 6
Mass Spectrometry core at PSHCI (drug 
concentration)
Dialysate at Visits 5 and 6
Mass Spectrometry core at Penn State Hershey 
Cancer Institute (PSHCI) (metabolites and drug 
concentration)
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Schedule of events
+Performed as routine, standard care (see note about Visit 2) and used for research as well. Any investigations or clinical documentation within 31 days prior to screening are 
acceptable
* Previously performed MRI Brain +/- Gadolinium contrast scan within 45 days prior visit 1 will be reviewed as baseline MRI
**Only required for women who, in the investigator’s opinion, are of childbearing potential
***Only performed for study drug group participants who do not have biopsy or surgery within 3 days. This is a research-only visit and all activities at this visit are for research only.
^Only applicable to those participants in the study drug group.
#As inpatient. Study drug will be dispensed as inpatient on Visit 1 if patient already hospitalized; otherwise it will be outpatient
Visit 1
(Screening and 
baseline)
Visit 2
(Day 3 +/-2 days 
of azole)***^
Visit 3
(morning of and 
during biopsy or 
surgery)
Visit 4 
(post-op 
Day 0)
Visit 5 
(post-op 
Day 1)
Visit 6 
(post-op 
Day 2)
Visit 7
(14 days +/- 7 days post-op)
Informed consent process
X
Demographics+
X
Medical history+
X
Neurological Exam+
X
X
X
X
Concomitant medication review+
X
X^
Women only: Pregnancy test+, **
X
12-lead ECG+
X
X
MRI Brain+
X*
Comprehensive Metabolic Panel (which 
includes electrolytes, renal function and 
liver function)^
X
X
X
CBCˆ
X
Study drug (posaconazole) dispensed^
X
X#
X#
X#
Adverse Events (if any)
X
X
X
X
X
X
Microdialysis catheter placement
X
Intraoperative blood and tissue 
collection
X
CT scan of head+
X
Dialysate collection
X
X
Blood sample collection
X
X
Microdialysis catheter removal
X
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7.3
Duration of Participation
It will take participants a maximum of 31 days to complete this research study. They will be asked to 
attend the research site a maximum of 4 separate times.
7.4
Test Article(s) (Study Drug(s) and/or Study Device(s))
7.4.1
Description
Classification:
Posaconazole is a second-generation triazole agent with a potent and broad antifungal activity. 
Posaconazole is available as concentrated solution to be diluted before intravenous 
administration, delayed-release tablet, or suspension for oral administration. Posaconazole is 
designated chemically as 4-[4-[4-[4-[[ (3R,5R)-5- (2,4-difluorophenyl)tetrahydro-5- (1H-1,2,4-
triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[(1S,2S)-1-ethyl-2- 
hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one with an empirical formula of C37H42F2N8O4 
and a molecular weight of 700.8.
Pharmacokinetics of delayed-release Posaconazole tablets:
When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed 
with a median Tmax of 4 to 5 hours. The elimination half-life of posaconazole has been 
estimated to vary between 15-35 hours [56]. Steady-state plasma concentrations are attained 
by Day 6 at the 300 mg dose (QD after BID loading dose at Day 1). 
The absolute bioavailability of the oral delayed-release tablet is approximately 54% under fasted 
conditions. The Cmax and AUC of posaconazole following administration of posaconazole 
delayed-release tablets is increased 16% and 51%, respectively, when given with a high fat meal 
compared to a fasted state. In order to enhance the oral absorption of posaconazole and 
optimize plasma concentrations, posaconazole delayed-release tablets should be administered 
with food.
7.4.2
Treatment Regimen
The timing of study drug administration will be based on the scheduled date and time of biopsy 
or surgery, which will occur within 7-10 days of Visit 1. The latter parameter is based on the drug 
half-life, as follows:

Participants will be taking posaconazole as 300mg PO BID in the first day, followed by 
300mg PO once daily thereafter.

The mean elimination half-life of posaconazole is 26-31 hours (product monograph). 
Therefore, posaconazole will reach steady state at approximately 130-155 hours 
following the first dose (5 half-lives). As such, we will work backwards from the 
scheduled date and time of biopsy or surgery such that participants in the posaconazole 
arm will receive drug for 168-240 hours. The upper range of the dosing (240 hours) is to 
minimize potentially unnecessary exposure to drug while accounting for variability in 
half-life measurements. 
In order to maintain steady-state concentrations, study drug will be administered at the 
following times as well:
1.
On the morning prior to planned surgical intervention
2.
On the morning of postoperative day 1, at 8:00AM +/- 4 hours *
*Only if postoperative CT rules out complications and the MDC(s) are correctly positioned.
7.4.3
Method for Assigning Subject to Treatment Groups
Not applicable, as this is an open label, non-randomized Phase 0 feasibility trial.
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7.4.4
Subject Compliance Monitoring
Nursing staff will chart administration of study drug into the patient’s EMR and study personnel 
will monitor and document the completion of all study procedures. In the outpatient setting, 
participants will be provided with a medication diary. 
7.4.5
Blinding of the Test Article
Not applicable, as this is an open label, non-randomized Phase 0 feasibility trial.
7.4.6
Receiving, Storage, Dispensing and Return 
7.4.6.1
Receipt of Test Article 
A study specific supply of FDA-approved posaconazole 100mg tablets will 
be purchased from a pharmacy wholesaler for use in this study. The 
manufacturer, lot number, and expiration date of the purchased 
posaconazole tablets will be maintained in the drug accountability records 
kept by the IDS pharmacy.
7.4.6.2
Storage
IDS pharmacy will store the posaconazole tablets at controlled room 
temperature as per the USP guidelines for controlled room temperature.  
7.4.6.3
Preparation and Dispensing
Once an enrolled subject’s biopsy or surgery date is scheduled, subjects will 
receive an outpatient supply of the posaconazole tablets to take beginning 
~130-155 hours prior to biopsy or surgery. Subjects will take six 
posaconazole 100mg tablets by mouth, once in the morning and once in the 
evening, on the first day followed by three 100mg tablets by mouth daily. 
The last dose from the outpatient supply will be taken on the morning of 
the biopsy or surgery. Subjects should return any study medication 
remaining when they arrive the day of biopsy or surgery. Post-biopsy or 
surgery subjects will receive one additional dose of posaconazole 300mg 
(three 100mg tablets) from the study supply, in the morning after biopsy or 
surgery. These doses will also be dispensed from a study specific supply. The 
medication vial should be return to IDS for accountability.  
7.4.6.4
Return or Destruction of the Test Article
Any dispensed but not administered tablets will be noted in the 
accountability records and subsequently destroyed.
7.4.6.5
Prior and Concomitant Therapy
A concomitant therapy is any medication which is administered between 
study enrollment and the end of the study drug treatment phase that could 
achieve a synergistic/antagonistic effect or increase the risk of adverse drug 
interactions. Situational medications or dose required during the surgical 
procedures will not be logged. All other therapies will be monitored daily 
and recorded by study team members during the duration of the treatment 
phase with the study drug.
The following is a list of contra-indications to the use of posaconazole, as 
obtained from the product monograph (this list is not all-inclusive): 

Patients who are hypersensitive to this drug or to any ingredient 
in the formulation or component of the container. For a complete 
listing, see the Dosage Forms, Composition and Packaging section 
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of the product monograph. There is no information regarding 
cross-sensitivity between NOXAFIL® and other azole antifungal 
agents. Caution should be used when prescribing NOXAFIL® to 
patients with hypersensitivity to other azoles. 

Co-administration of NOXAFIL® and ergot alkaloids. NOXAFIL® 
may increase the plasma concentrations of ergot alkaloids, which 
may lead to ergotism. 

Co-administration of NOXAFIL® and certain medicinal products 
metabolized through the CYP3A4 system: terfenadine, astemizole, 
cisapride, pimozide, and quinidine. Although not studied in vitro 
or in vivo, co-administration of these CYP3A4 substrates may 
result in increased plasma concentrations of those medicinal 
products, leading to potentially serious and/or life-threatening 
adverse events, such as QT prolongation and rare occurrences of 
torsade de pointes. 

Co-administration of NOXAFIL® and HMG-CoA reductase 
inhibitors (statins) that are primarily metabolized through 
CYP3A4, since increased plasma concentration of these drugs can 
lead to rhabdomyolysis. 

Co-administration of NOXAFIL® and sirolimus. Concomitant 
administration of NOXAFIL® with sirolimus increases the sirolimus 
blood concentrations by approximately 9-fold and can result in 
sirolimus toxicity. 
The following is a full list of drugs that alter the plasma concentration of 
posaconazole obtained from the product monograph:

Rifabutin 

Phenytoin 

Efavirenz 

Fosamprenavir 

Glipizide

Loperamide

Antacids/H2 receptor antagonists 

Cimetidine 

Esomeprazole 

Metoclopramide 
8.0
Subject Numbers and Statistical Plan
8.1
Number of Subjects
Ten (10) subjects will be enrolled in the study.
8.2
Sample size determination
Design
This is an exploratory (pilot) study to assess whether posaconazole can penetrate brain tissue at 
sufficient enough levels to result in expected downstream biological effects on glycolysis and tumor cell 
survival. Five evaluable patients will be studied for this trial. The sample size justification is not based on 
statistical rationale but clinical affordability. 
The following metrics will be used to define success and support the decision to proceed with advanced 
phase trials:
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
Detection of ≥ 5uM concentration of either drug in resected tumor in at least 2 of 5 patients in 
each arm – a value that is within the range needed to achieve efficacy for CNS fungal infections 
and to achieve 50% glioma tumor cell kill in vitro based on our prior published report (ref 58); 
AND

Reduction in average lactate and pyruvate concentrations in both resected tumor and dialysate 
fluid (using MDCs) in the treated cohorts compared to controls; AND

Steady concentration of lactate and pyruvate over 24 hours of monitoring with MDCs in control 
participants. 
The rationale for the above is based on the notion that any tumor penetration by drug, with 
concomitant effect on glycolysis, warrants further in-depth analysis as our therapeutic options for these 
deadly tumors are currently very limited. Intra-tumoral drug concentration on the lower range would 
still be promising and warrant dose-escalation studies, as the currently selected dosing is based on anti-
fungal regimens that are known to be safe. Phase II studies for assessing tumor response would be 
warranted if substantial tumor penetration together with expected biological effect is observed. A 
negative trial would nonetheless have value as it would serve as an efficient means of determining 
whether or not either of ketoconazole or posaconazole hold promise against GBMs, as part of a “fail 
early” approach to drug-development, while minimizing the human and financial cost investment.  
Study Population
Only patients who are eligible and take posaconazole according to protocol specifications (study drug 
arm only) and have undergone successful MDC implantation will be considered evaluable and included 
in the study analysis. Otherwise, enrolled patients will be replaced. All eligible patients for whom 
analyzable dialysate samples were obtained for at least 7 of the 9 time points will be considered 
evaluable for the primary study endpoint. Patients who are not evaluable will be replaced. 
8.3
Statistical methods
Primary Objectives
The outcome measure for primary endpoint will be the pharmacokinetics of posaconazole, measured as 
the area under the curve of the concentration vs time gradient over the first 24 hours (AUC0-24). We 
will be measuring the concentration of posaconazole (AUC-Drug) in brain interstitium using the MDC. 
The AUC-Drug will be estimated by the trapezoid rule, based on the number of timepoints available for 
the particular evaluable patient. Brain posaconazole concentration at steady-state will also be 
summarized using descriptive statistics. The AUC-Drug will be estimated by standard noncompartmental 
or compartmental analysis as performed by Phoenix® WinNonlin version 6.3 (Pharsight Corporation, 
Mountain View, CA, USA).
The PK variables will be tabulated and descriptive statistics calculated. The AUCs will be summarized by 
mean and standard deviation or median and range if there is large variation from patient to patient. 
Means and standard deviation or mean and range will be presented for Cmax and AUC.
Secondary Objectives 

Tolerability: Adverse experiences observed over the 7-21 days of protocol follow-up will be 
characterized in CTCAE v5.0. Frequency and severity of AEs 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 5.0 criteria, with separate descriptions for grade 3 or 4 laboratory 
abnormalities. Clinically significant laboratory abnormalities will be described as well.

Pharmacodynamics: Descriptive statistics, using means/ median, will be used to report drug 
effect on:
a)
HK2 activity in resected tumor tissue
b)
Concentration of downstream glycolysis metabolites in resected tumor tissue
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c)
Tumor cell proliferation, cell death, and angiogenesis in resected tumor tissue
d)
Concentration vs time profile of lactate and pyruvate, based on MDC studies, in relation 
to the concentration vs time profile of posaconazole. 
** The above values will be compared to levels in the control arm. 
Off Study Criteria
Follow-up for this protocol will be considered complete when: (1) intraoperative pathology not 
consistent with glioma; (2) the patient dies; (3) the patient refuses posaconazole during the 
preoperative steady-state dosing period; (4) misses more than 3 doses; or (5) completes the 14 +/-7 day 
follow-up after surgical resection of tumor. If a drug/ procedure-related complication has occurred, the 
patient will be clinically followed and managed accordingly until resolution. 
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. 
9.0
Data and Safety Monitoring Plan
9.1
Periodic evaluation of data
To monitor safety throughout the course of the study, every effort will be made to remain alert to 
possible AEs/SAEs. If an AE/SAE occurs, the first concern should be for the safety of the subject. If 
necessary, appropriate medical intervention will be provided. At the signing of the written consent form, 
each subject or his/her legally authorized representative and/or main caregiver must be given the 
names and telephone numbers of study site staff for reporting AEs/SAEs and medical emergencies. In 
this study, any AE/SAE experienced by the subject between the time of first dose of study treatment and 
24 hours after the last dose will be recorded on the electronic case report form, regardless of the 
severity of the event or its relationship to study treatment. During study treatment and visit after 14 
days, the research team will assess the subject for AEs and will record any new AEs/SAEs or updates to 
previously reported AEs on the electronic case report form.
9.2
Data that are reviewed
Data reviewed are described below. 

Retrieved tumor sample:
o
Drug concentration
o
Hexokinase 2 enzyme activity assay
o
TUNEL staining for assessment of apoptosis
o
Glycolysis metabolites (lactate and pyruvate)
o
Immunohistochemistry – Ki67 staining for assessment of cell proliferation

Blood and dialysate:

Drug concentration

Glycolysis metabolites (lactate and pyruvate)

Clinical safety data:

Adverse events, as per NCI CTCAE v 5.0 criteria
9.3
Method of collection of safety information
Safety information will be collected in the research database throughout the study. The safety of the 
study drug will be evaluated by clinical assessments and laboratory tests (see section 7.2).
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9.4
Frequency of data collection
Data collection will occur as follows:

Laboratory data:
o
Once – Resected tumor, blood samples, and dialysate samples will be analyzed in batch

Clinical safety data:

Monitored at every study visit (please refer to schedule of events)
9.5
Individuals reviewing the data
The following individuals will review the data: 

Dr. Alireza Mansouri (PI)

Dr. Brad Zacharia (Co-investigator; Co-I)

Additional research personnel as required
9.6
Frequency of review of cumulative data
Cumulative data will be reviewed once, upon conclusion of the study.
9.7
Statistical tests
For details, see the statistical section under 8.3.
9.8
Suspension of research
This is pilot study, but after periodic evaluation of study result and safety profile, the PI can terminate 
the research anytime based on outcomes of periodic safety monitoring and benefit/risk outcomes and 
will inform the IRB if such a decision is being made.
10.0
Risks
Risk of drug
While this drug has never been tested specifically in the HGG population, it is an FDA-approved drug. The 
potential side effects are:
Common side effects (occurring in at least 1 in 100 patients) are:

Headache

Dizziness

numbness or tingling;

sleepiness

feeling or being sick

loss of appetite

stomach pain

diarrhea

upset stomach

nausea

vomiting

flatulence (excessive gas in the digestive tract)

dry mouth

abnormal liver function tests

rash

weakness

tiredness

a decrease in white blood cells (that can increase the risk of infections)

fever
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
abnormal amounts of salts in the blood
Infrequent

Liver problems, including liver failure, with symptoms such as:
o
dark colored urine
o
pale stools
o
yellowing of the skin and eyes
o
abdominal pain
o
nausea
o
vomiting
Uncommon

Heart problems such as very slow, fast or irregular heartbeat
Rare

Severe allergic reaction with symptoms such as

severe skin blistering

peeling rash

swollen lips, mouth and throat

difficulty in breathing
Risks of microdialysis
Microdialysis is an invasive surgical procedure with a small risk of bleeding at the site of insertion and discomfort 
for the patient. Removal of the catheter can result in minor discomfort as well.  There is a chance that the 
catheter may break or get stuck in the brain that would require surgical intervention to remove it.
There is also a small risk of infection (1%), but pre-operative antibiotics are used to reduce the risk. However, 
this is a small device and it is removed early postoperatively, similar to other surgical drains placed 
postoperatively. There is also a very small possibility of bleeding along the catheter tip.
Risks of venipuncture
The discomfort associated with removing blood by venipuncture (by a needle from a vein) is a slight pinch or pin 
prick when the sterile needle enters the skin. The risks include mild discomfort and/or a black and blue mark at 
the site of puncture. Less common risks include a small blood clot, infection or bleeding at the puncture site, and 
on rare occasions fainting during the procedure.
Risks of electrocardiogram (ECG): 
The patches that the study staff will stick to your chest and other areas of your body to monitor your heart may 
irritate your skin and cause itching and redness. The study staff might need to shave your body hair so that they 
can stick the pads to your skin. The shaving may cause some irritation (depending on the tools and soap used); 
also, a local allergic reaction could occur. When the sticky patches are removed, it might sting for a few seconds. 
The test itself is painless.
Reproductive risks
The class of drugs, azoles, which the study drug is part of, can cause birth defects. There is only limited 
information regarding their effect on infants of breastfeeding mothers. For this reason, all women of 
childbearing potential MUST have a negative pregnancy test. 
The study doctor will discuss methods with participants to ensure that they do not become pregnant or father a 
baby during the study. Women should not breastfeed a baby while taking study treatment and for 30 days after 
the last dose because the drug used in this study might be present in breast milk and could be harmful to a baby.
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Pregnancy statement and use in nursing women
Azoles can be teratogenic.[57] Information regarding adverse effects on infants of breastfeeding mothers taking 
azoles is limited. 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. 
We will request that female participants wait 30 days after the last dose of drug before considering becoming 
pregnant or starting breastfeeding.
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 30 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 30 days afterwards. 

Participants must agree not to donate blood, sperm/ova during study participation and for at least 30 
days after stopping treatment. 
During the course of the trial, if a participant suspects that they may have conceived a child, they will be 
instructed to contact the study doctor named at the top of this form immediately. In addition, a missed or late 
menstrual period during the course of the trial should be also reported to the study doctor 
If a male patient is suspected of having fathered a child while on study drug, 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 
30 days. 
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.
Risk of loss of confidentiality
There is a risk of loss of confidentiality if participant information or identity is obtained by someone other than 
the investigators, but precautions will be taken to prevent this from happening. The confidentiality of participant 
electronic data created by the participant or by the researchers will be maintained as required by applicable law 
and to the degree permitted by the technology used. Absolute confidentiality cannot be guaranteed.
11.0
Potential Benefits to Subjects and Others 
11.1
Potential Benefits to Subjects
There will be no direct benefit to study participants.
11.2
Potential Benefits to Others
The use of posaconazole as a drug against HGGs has never been formally studied and this is a unique 
opportunity to study this possible indication. If posaconazole successfully demonstrates effective 
accumulation in brain and tumor interstitium and result in the expected pharmacodynamics changes, it 
could be of major importance in improving the outcome of patients with HGGs.
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12.0
Sharing Results with Subjects
If the research with the participants identifiable information or samples gives results that do have meaning for 
their health, the researchers will contact the participants to let them know the findings and discuss the potential 
implications with them. 
13.0
Subject Payment and/or Travel Reimbursements
Participants will receive a $50.00 gift card (via Greenphire) for completing the research-only visit (Visit 2) if it is 
performed. No compensation will be provided for any other study visits.
14.0
Economic Burden to Subjects
14.1
Costs
There will be no additional costs to the participants for enrolling on the trial.

The study drug, posaconazole, will be provided at no cost to the study drug group participants 
while they take part in this study. 

The research-related tests and procedures that will be provided at no cost to the participants 
include: 
o
CMP at Visits 1, 2, and 5, including blood draws (study drug group only_
o
12-lead ECG at Visit 2 (study drug group)
o
Physical examination at Visit 2 (study drug group)
o
Microdialysis catheter and related reagents, and catheter monitoring at visits 3 through 6 both 
groups)
o
The removal of the microdialysis catheter will also be at no charge, performed at the bedside 
(both groups)
14.2
Compensation for research-related injury
It is the policy of the institution to provide neither financial compensation nor free medical treatment 
for research-related injury. In the event of injury resulting from this research, medical treatment is 
available but will be provided at the usual charge. Costs for the treatment of research-related injuries 
will be charged to subjects or their insurance carriers.
15.0
Resources Available 
15.1
Facilities and locations
The study will be conducted in the Neurosurgery Clinic, operating room (collection of samples, 
placement of MDCs), and in post-operative rooms in the hospital at the Penn State Hershey Medical 
Center.
15.2
Feasibility of recruiting the required number of subjects
The clinical investigators are involved in the care of any patient diagnosed with glioblastoma. Not all will 
be appropriate study candidates, but the likelihood of identifying and recruiting 10 subjects is high.
15.3
PI Time devoted to conducting the research
The PI and other clinical co-investigators will screen and identify appropriate subjects as part of their 
routine clinical activity of caring for patients. The clinical investigators are supported by a team of 
clinical research staff who will assist in the completion of the research procedures. All clinical members 
of the research team are experienced clinicians and researchers, who have successfully balanced their 
clinical and research responsibilities.
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15.4
Availability of medical or psychological resources
All resources and facilities of the HMC are available to subjects on study, as part of their routine 
standard of care. No additional resources are anticipated to be needed specifically due to participation 
in this study.
15.5
Process for informing Study Team
Members of the research team will be required to undergo protocol training and to sign a delegation of 
duties log prior to participation in the study. During the study, the PI and/or study coordinator will 
communicate updates to all team members as they become aware of any changes or updates.
16.0
Other Approvals
16.1
Other Approvals from External Entities
Will need approval from grant funders.
16.2
Internal PSU Committee Approvals
Check all that apply:
  Anatomic Pathology – Penn State Health only – Research involves the collection of tissues or use of 
pathologic specimens. Upload a copy of “HRP-902 - Human Tissue For Research Form” in CATS IRB. 
  Animal Care and Use – All campuses – Human research involves animals and humans or the use of 
human tissues in animals
  Biosafety – All campuses – Research involves biohazardous materials (human biological specimens 
in a PSU research lab, biological toxins, carcinogens, infectious agents, recombinant viruses or DNA 
or gene therapy).
  Clinical Laboratories – Penn State Health only – Collection, processing and/or storage of extra tubes 
of body fluid specimens for research purposes by the Clinical Laboratories; and/or use of body fluids 
that had been collected for clinical purposes but are no longer needed for clinical use. Upload a copy 
of “HRP-901 - Human Body Fluids for Research Form” in CATS IRB. 
  Clinical Research Center (CRC) Advisory Committee – All campuses – Research involves the use of 
CRC services in any way.
  Conflict of Interest Review – All campuses – Research has one or more of study team members 
indicated as having a financial interest.
  Radiation Safety – Penn State Health only – Research involves research-related radiation 
procedures. All research involving radiation procedures (standard of care and/or research-related) 
must upload a copy of “HRP-903 - Radiation Review Form” in CATS IRB. 
  IND/IDE Audit – All campuses – Research in which the PSU researcher holds the IND or IDE or 
intends to hold the IND or IDE.
  Scientific Review – Penn State Health only – All investigator-written research studies requiring 
review by the convened IRB must provide documentation of scientific review with the IRB 
submission. The scientific review requirement may be fulfilled by one of the following: (1) external 
peer-review process; (2) department/institute scientific review committee; or (3) scientific review by 
the Clinical Research Center Advisory committee.  NOTE: Review by the Penn State Health Cancer 
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Institute (PSCI) Protocol Review Committee or the PSCI Disease Team is required if the study 
involves cancer prevention studies or cancer patients, records and/or tissues. For more information 
about this requirement see the IRB website.
17.0
Multi-Site Study
17.1
Other sites 
Not applicable
17.2
Communication Plans
Not applicable
17.3
Data Submission and Security Plan
Not applicable
17.4
Subject Enrollment
Not applicable
17.5
Reporting of Adverse Events and New Information
Not applicable
17.6
Audit and Monitoring Plans
Not applicable
18.0
Adverse Event Reporting
18.1
Adverse Event Definitions
For drug studies, incorporate the following definitions into the below responses, as written:
Adverse event
Any untoward medical occurrence associated with the use of the drug in 
humans, whether or not considered drug related
Adverse reaction
Any adverse event caused by a drug
Suspected adverse 
reaction
Any adverse event for which there is a reasonable possibility that the drug 
caused the adverse event.  Suspected adverse reaction implies a lesser degree 
of certainty about causality than “adverse reaction”.

Reasonable possibility.  For the purpose of IND safety reporting, 
“reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.
Serious adverse 
event or Serious 
suspected adverse 
reaction
Serious adverse event or Serious suspected adverse reaction: An adverse event 
or suspected adverse reaction that in the view of either the investigator or 
sponsor, it results in any of the following outcomes: Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth 
defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. 
Life-threatening 
adverse event or 
life-threatening 
suspected adverse 
reaction
An adverse event or suspected adverse reaction is considered “life-
threatening” if, in the view of either the Investigator (i.e., the study site 
principal investigator) or Sponsor, its occurrence places the patient or research 
subject at immediate risk of death.  It does not include an adverse event or 
suspected adverse reaction that had it occurred in a more severe form, might 
have caused death.
Unexpected 
adverse event or 
Unexpected 
An adverse event or suspected adverse reaction is considered “unexpected” if 
it is not listed in the investigator brochure, general investigational plan, clinical 
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suspected adverse 
reaction.  
protocol, or elsewhere in the current IND application; or is not listed at the 
specificity or severity that has been previously observed and/or specified.
For device studies, incorporate the following definitions into the below responses, as written:
Unanticipated 
adverse device 
effect
Any serious adverse effect on health or safety or any life-threatening problem 
or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or IDE application (including a supplementary plan 
or application), or any other unanticipated serious problem associated with a 
device that relates to the rights, safety, or welfare of subjects.
18.2
Recording of Adverse Events
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 AEs 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, recorded for this study. AEs by 
severity and causality as described below: 

Laboratory evaluations including liver function tests. Laboratory values within 1.5x the 
institutional upper limit of normal are considered acceptable and not as AEs 
To monitor any risk of increased surgical complications associated with posaconazole, the treating 
surgeons will make a Note-to-File recording any unexpected events that occurred during surgery.
Patients unable to tolerate posaconazole due to AE grade 3-4 (hepatic, gastroenterological, and/or renal 
toxicity) will have a dose reduction. Posaconazole will be reduced to 33% of schedule dose (200 mg per 
dose, see table below). If the AE does not resolve within 24 hours, it will be discontinued.  However, 
tumor tissue will still be collected and analyzed.
Posaconazole Dose Modification for Adverse Reactions
Dose Level
Posaconazole dose 
Starting Dose
300 mg once daily
Dose Reduction (33%)
200 mg once daily
Pregnancy statement
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 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 30 days. 
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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 30 days. 
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. 
18.3
Causality and Severity Assessments
The investigator will promptly review documented adverse events and abnormal test findings to 
determine 1) if the abnormal test finding should be classified as an adverse event; 2) if there is a 
reasonable possibility that the adverse event was caused by the study drug(s) or device(s); and 3) if the 
adverse event meets the criteria for a serious adverse event.
If the investigator’s final determination of causality is “unknown and of questionable relationship to the 
study drug(s) or device(s)”, the adverse event will be classified as associated with the use of the study 
drug(s) or device(s) for reporting purposes.  If the investigator’s final determination of causality is 
“unknown but not related to the study drug(s) or device(s)”, this determination and the rationale for the 
determination will be documented in the respective subject’s case history.
18.4
Reporting of Adverse Reactions and Unanticipated Problems to the FDA  
Not applicable
18.4.1 Written IND/IDE Safety Reports
Not applicable
18.4.2 Telephoned IND Safety Reports – Fatal or Life-threatening Suspected Adverse Reactions
Not applicable
18.5
Reporting Adverse Reactions and Unanticipated Problems to the Responsible IRB
In accordance with applicable policies of The Pennsylvania State University Institutional Review Board 
(IRB), the investigator will report, to the IRB, any observed or reported harm (adverse event) 
experienced by a subject or other individual, which in the opinion of the investigator is determined to be 
(1) unexpected; and (2) probably related to the research procedures. Harms (adverse events) will be 
submitted to the IRB in accordance with the IRB policies and procedures.
18.6
Unblinding Procedures
Not applicable
18.7
Stopping Rules
Trial accrual will be prematurely stopped if two or more unacceptable toxicities occur. Unacceptable 
toxicity is defined as mortality or grade 4 toxicity directly attributed to drug.
19.0
Study Monitoring, Auditing and Inspecting
19.1
Study Monitoring Plan
19.1.1 Quality Assurance and Quality Control
The study will be monitored by Clinical Trial Monitoring Team from the Department of Public 
Health Sciences at Penn State Hershey College of Medicine.
Staff within the Department of Public Health Sciences will be monitoring the study for protocol 
compliance, data quality, and regulatory compliance. This will include reviewing the informed 
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Page 42 of 45 (V.05/19/2022) 
consent process and completed forms, verifying the presence of essential documents in the 
study regulatory binder, completing source document verification for data entered into REDCap, 
ensuring the study is implemented as planned, reviewing adverse events and the reporting of 
serious adverse events, and ensuring that all data quality rules have been executed and resolved 
and all data queries are resolved and closed.
The monitor will create a detailed report following each scheduled monitoring session to 
forward to the PI and will verify that proposed action items are addressed and completed. The 
monitoring will occur at regular intervals as specified in the monitoring plan developed by Public 
Health Sciences and PSU Sponsor Investigator.
19.1.2 Safety Monitoring
Data and safety will be monitored by the Cancer Institute Data Safety Monitoring Committee (CI 
DSMC).
The Principal Investigator will confirm that all adverse events (AE) are correctly entered into the 
AE case report forms by the coordinator; be available to answer any questions that the 
coordinators may have concerning AEs; and will notify the IRB, FDA, and/or DSMB of all 
applicable AEs as appropriate. All assessments of AEs will be made by a licensed medical 
professional who is an investigator on the research.
The Research Coordinator will complete the appropriate report form and logs; assist the PI to 
prepare reports and notify the IRB, and CI DSMC of all Unanticipated Problems/SAE’s.
The Monitor will confirm that the AEs are correctly entered into the case report forms. The 
Monitor will also confirm that the adverse events are consistent with the source documents and 
are reported to the appropriate regulatory bodies as required.
20.0
Future Undetermined Research: Data and Specimen Banking
20.1
Data and/or specimens being stored
Not applicable
20.2
Location of storage
Not applicable
20.3
Duration of storage
Not applicable
20.4
Access to data and/or specimens
Not applicable
20.5
Procedures to release data or specimens
Not applicable
20.6
Process for returning results
Not applicable
21.0
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22.0
Confidentiality, Privacy and Data Management 
See the Research Data Plan Review Form
STUDY00015948
Approval: 8/13/2025