Conditions: Non-small Cell Lung Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine the pharmacodynamics effects of itraconazole in early-stage non-small cell lung cancer.

Detailed description:
This is a phase 0 clinical trial. While clinical data including safety will be recorded, the principal outcomes are pharmacodynamic endpoints. Specifically, the investigators seek to identify: (1) effects of itraconazole on tumor angiogenesis, (2) effects of itraconazole on the Hh pathway, (3) biomarker predictors of these effects, (4) the correlation between itraconazole pharmacokinetics and these effects, (5) the correlation between different biomarkers.

Up to 15 eligible patients with previously diagnosed or suspected NSCLC planned for resection will undergo a study-specific core needle biopsy, imaging (dynamic contrast enhanced \[DCE\]-, diffusion weighted imaging \[DWI\]-, and arterial spin labeling \[ASL\] magnetic resonance imaging \[MRI\]), skin punch biopsy, and collection of peripheral blood. Subjects will then receive itraconazole 600 mg PO daily for 7-10 days, following which they will undergo repeat imaging, skin biopsy, and blood collection. Subsequently they will undergo surgical resection. Due to the safety profile of itraconazole when used as an antifungal agent , all histologic subtypes of NSCLC will be eligible for the trial. The itraconazole dose of 600 mg, higher than an anti-angiogenic dose, has been shown to inhibit the Hedgehog (Hh) pathway.

Arms:
arm 1: 600 mg twice daily for 10-14 days

Interventions: intervention 1: Itraconazole
Intervention descriptions: intervention 1: Once on study, itraconazole will be taken twice daily for a total of 10-14 days. After being on itraconazole for 7-10 days, "Post-treatment" assessments will include a skin biopsy, blood draw for the PK (pharmacokinetics) analyses and the cytokine panel, and also MRI evaluations (anticipated to last 45-50 minutes). Toxicity assessments and laboratory checks will also be conducted during that time. Following these assessments, itraconazole will be continued until the day of surgery. At the time of surgical resection, a tissue sample (with adjacent normal tissue as per standard resection technique) will be obtained to complete the analysis. Following resection, subjects will be followed per standard post-operative procedure.

Protocol document:
Prot_SAP_000.pdf: 
 
 
Version 5 – May 1, 2017 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
 
 
 
 
 
 
 
 
 
 
Phase 0 Pharmacodynamic Study of the Effects of Itraconazole on Tumor 
Angiogenesis and the Hedgehog Pathway in Early-stage Non-small Cell Lung 
Cancer   
 
 
 
 
NCT02357836 
 
 
 
May 1, 2017 – Version 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Version 5 – May 1, 2017 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
 
 
 
 
 
 
 
 
Phase 0 pharmacodynamic study of the effects of itraconazole on tumor angiogenesis and the 
Hedgehog pathway in early-stage non-small cell lung cancer 
 
Study Chair:   
 
David E. Gerber, MD 
 
 
 
 
Division of Hematology-Oncology 
 
 
 
 
Harold C. Simmons Cancer Center 
 
 
 
 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd., Mail Code 8852 
 
 
 
 
Dallas, Texas  75390-8852 
 
 
 
 
Phone:  214-648-4180 
 
 
 
 
Fax:  214-648-1955 
 
 
 
 
E-mail:  david.gerber@utsouthwestern.edu 
 
 
Principal Investigator:  
David E. Gerber, MD  
 
 
 
 
Division of Hematology-Oncology 
 
 
 
 
Harold C. Simmons Cancer Center 
 
 
 
 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
5323 Harry Hines Blvd., Mail Code 8852 
 
 
 
 
Dallas, Texas  75390-8852 
 
 
 
 
Phone:  214-648-4180 
 
 
 
 
Fax:  214-648-1955 
 
 
 
 
E-mail:  David.Gerber@utsouthwestern.edu 
 
Sub-Investigator(s): 
 
James Kim, MD, PhD 
 
 
 
 
Hematology-Oncology 
 
 
 
 
 
Kemp Kernstine, MD, PhD 
 
 
 
 
Thoracic Surgery 
 
 
 
 
 
Scott Reznik, MD 
 
 
 
 
Thoracic Surgery 
 
 
 
 
 
Lori Watumull, M.D. 
 
 
 
 
Radiology 
 
 
 
 
 
 
 
 
Rolf Brekken, PhD 
 
 
 
 
Surgical Oncology 
 
 
 
 
 
Robert Lenkinski, PhD 
 
 
 
 
Radiology 
 
 
 
 
 
Richard Leff, PharmD 
 
 
 
 
Dallas Regional Campus 
 
 
 
 
Texas Tech School of Pharmacy 
 
 
 
 
 


 
 
Version 5 – May 1, 2017 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
 
 
Biostatistician: 
 
Chul Ahn, PhD 
 
 
 
 
Department of Clinical Sciences 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
Address 
 
 
 
 
Phone:  214-648-9418  
 
 
 
 
Fax:  214-648-3934 
 
 
 
 
Email:  chul.ahn@utsouthwestern.edu 
 
Study Monitor:  
 
Yull Arriaga, MD 
 
 
 
 
DSMC Co-Chairman 
 
 
 
 
Phone: 214-648-4180 
 
 
 
 
Email: yull.arriaga@utsouthwestern.edu 
 
Study Drug: 
 
 
Itraconazole 
 
IND Number: 
 
 
N/A (IND Exempt) 
 
Funding Source:  
Department of Defense 
 
U.S. Army Medical Research and Materiel Command 
 
Congressionally Directed Medical Research Programs  
 
2013 Lung Cancer Research Program 
 
Clinical Exploration Award 
 
CDMRP number:  LC130650 
 
 
Initial version:  
 
December 08, 2014 
Amended: 
 
 
April 29, 2015- Version 2 
 
 
 
September 01, 2015- Version 3 
 
 
 
August 23, 2016 – Version 4 
 
 
 
May 1, 2017 – Version 5 
 
 
UT Southwestern Medical Center (UTSW) 
Harold C. Simmons Cancer Center 
Attn: Clinical Research Office 
5323 Harry Hines Blvd. MC 9179 
Dallas, Texas 75390-9179 
 


 
 
Version 5 – May 1, 2017 
 
CONFIDENTIAL 
This material is the property of the UTSW Simmons Cancer Center. Do not disclose or use except as authorized in writing by the 
study sponsor. 
 
 
 
 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, including 
all statements regarding confidentiality, and according to local legal and regulatory requirements and 
applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name:   David Gerber, MD 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 
 


Study Number – 122014-038 
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i 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS............................................................................................................. 1 
STUDY SCHEMA ............................................................................................................................ 2 
STUDY SUMMARY ......................................................................................................................... 3 
1.0 
BACKGROUND AND RATIONALE ...................................................................................... 4 
1.1 
Disease Background........................................................................................................ 4 
1.2 
Rationale .......................................................................................................................... 6 
2.0 
STUDY OBJECTIVES ........................................................................................................... 7 
2.1 
Primary Objectives ........................................................................................................... 7 
2.2 
Secondary Objectives ...................................................................................................... 7 
3.0 
STUDY AGENT ...................................................................................................................... 7 
3.1 
Drug Class and Mechanism ............................................................................................ 7 
3.2 
Storage ............................................................................................................................ 8 
3.3 
Indication ......................................................................................................................... 8 
3.4 
Dosing .............................................................................................................................. 8 
3.5 
Drug Interactions ............................................................................................................. 8 
3.6 
Side effects ...................................................................................................................... 8 
3.7 
Dose reduction or interruption for toxicity ........................................................................ 8 
4.0 
SUBJECT ELIGIBILITY ......................................................................................................... 9 
4.1 
Inclusion Criteria .............................................................................................................. 9 
4.2 
Exclusion Criteria ............................................................................................................. 9 
5.0 
TREATMENT PLAN ............................................................................................................ 10 
5.1 
Treatment Dosage and Administration .......................................................................... 10 
5.2 
Toxicities and dosing delays/dose modifications ........................................................... 10 
5.3 
Concomitant Medications/Treatment ............................................................................. 11 


Study Number – 122014-038 
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ii 
5.4 
Duration of Therapy ....................................................................................................... 12 
5.5 
Duration of Follow up ..................................................................................................... 12 
5.6 
Removal of Subjects from Protocol Therapy ................................................................. 12 
5.7 
Subject Replacement..................................................................................................... 13 
5.8 
Screening/Baseline Procedures .................................................................................... 13 
5.9 
Procedures during treatment ......................................................................................... 14 
5.10 
Follow up procedures .................................................................................................... 14 
5.11 
Time and Events table ................................................................................................... 15 
5.12 
Removal of subjects from study .................................................................................... 15 
 
6.0 
ADVERSE EVENTS ............................................................................................................. 16 
6.1 
Experimental Therapy.................................................................................................... 16 
6.2 
Adverse Event Monitoring ............................................................................................. 18 
6.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting ...................... 20 
7.0 
CORRELATIVES/SPECIAL STUDIES ................................................................................ 21 
8.0 
STATISTICAL CONSIDERATIONS .................................................................................. 22 
8.1 
Sample size estimate..................................................................................................... 22 
8.2 
Statistical Analysis ......................................................................................................... 23 
9.0 
STUDY MANAGEMENT .................................................................................................... 23 
9.1 
Conflict of Interest .......................................................................................................... 23 
9.2 
Institutional Review Board (IRB) Approval and Consent ............................................... 23 
9.3 
Registration Procedures ................................................................................................ 24 
9.4 
Data Management and Monitoring/Auditing .................................................................. 24 
9.5 
Adherence to the Protocol ............................................................................................. 24 
9.6 
Amendments to the Protocol ......................................................................................... 25 
9.7 
Record Retention ........................................................................................................... 25 
9.8 
Obligations of Investigators ........................................................................................... 26 


Study Number – 122014-038 
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iii 
10.0 
REFERENCES ................................................................................................................... 27 
1.0 
APPENDICES .................................................................................................................... 31 


Study Number – 122014-038 
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1 
LIST OF ABBREVIATIONS  
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ALC 
ASCO 
Absolute Lymphocyte Count 
American Society of Clinical Oncology 
AST 
Aspartate Aminotransferase 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CMP 
Comprehensive Metabolic Panel 
CR 
Complete Response 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DOT 
Disease Oriented Team 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 
FDA 
Food and Drug Administration 
H&P 
History & Physical Exam 
HRPP 
Human Research Protections Program 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IV (or iv) 
Intravenously 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PBMCs 
Peripheral Blood Mononuclear Cells 
pCR 
Pathologic Complete Response 
PD 
Progressive Disease 
PET 
Positron Emission Tomography 
PFS 
Progression Free Survival 
p.o. 
per os/by mouth/orally 
PR 
Partial Response 
RCB 
Residual Cancer Burden 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SCCC 
Simmons Comprehensive Cancer Center 
SD 
Stable Disease 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SPGT 
Serum Glutamic Pyruvic Transaminase 
WBC 
White Blood Cells 
 
 


Study Number – 122014-038 
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2 
STUDY SCHEMA 
 
This will be a prospective phase 0 trial.  Up to 15 eligible patients with previously diagnosed or suspected NSCLC planned 
for resection will undergo collection of archived biopsy tissue, imaging (dynamic contrast enhanced [DCE]-, diffusion 
weighted imaging [DWI]-, and arterial spin labeling [ASL] magnetic resonance imaging [MRI]), skin punch biopsy, and 
collection of peripheral blood.  Subjects will then receive itraconazole 600 mg PO daily for 7-10 days, following which they 
will undergo repeat imaging, skin biopsy, and blood collection.  Subsequently they will undergo surgical resection (see 
Figure 1).  Due to the safety profile of itraconazole when used as an antifungal agent (1-3), all histologic subtypes of NSCLC 
will be eligible for the trial. The itraconazole dose of 600 mg, higher than an anti-angiogenic dose (4), has been shown to 
inhibit the Hedgehog (Hh) pathway (5). 
 
Projected Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This is a phase 0 clinical trial.  While clinical data including safety will be recorded, the principal outcomes are 
pharmacodynamic endpoints.  Specifically, we seek to identify: (1) effects of itraconazole on tumor angiogenesis, (2) effects 
of itraconazole on the Hh pathway, (3) biomarker predictors of these effects, (4) the correlation between itraconazole 
pharmacokinetics and these effects, (5) the correlation between different biomarkers. 
 
 
 
 
 
 
 
 
 
 1.  Schema for phase 0 trial of itraconazole for early-stage NSCLC
Baseline assessments
• 
Archived tissue collection 
(angiogenesis markers, GLI1, Hh)
• 
Skin biopsy (GLI1, Hh) 
• 
Blood sample (multiplex 
angiogenic cytokine panel) 
• 
Imaging (DCE- , DWI- , ASL-MRI)
Surgical resection
• Tissue analyzed for 
angiogenesis markers,
GLI1,  Hh, intratumoral
PK
 
Post-treatment assessments
• 
Skin biopsy (GLI1, Hh)
• 
Blood sample (multiplex 
angiogenic cytokine panel, PK) 
• 
Imaging (DCE -, DWI - , ASL-MRI)
Itraconazole 
x 7-10 days 
Itraconazole 
x 4 -7 days
(for 10 --14
days total of 
itraconazole 
treatment) 
• Blood Sample (PK) 


Study Number – 122014-038 
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3 
 
 
STUDY SUMMARY 
Title 
Phase 0 pharmacodynamic study of the effects of itraconazole on tumor 
angiogenesis and the Hedgehog pathway in early-stage non-small cell 
lung cancer 
Short Title 
Neoadjuvant Itraconazole in NSCLC 
Protocol Number 
STU 122011-038 
Phase 
Phase 0 
Methodology 
Prospective, open-label  
Study Duration 
3 years 
Study Center(s) 
Single-center  
Objectives 
Determine the pharmacodynamics effects of itraconazole in early-stage 
NSCLC 
Number of Subjects 
15 
Diagnosis and Main 
Inclusion Criteria 
Early-stage NSCLC  
Study Product(s), Dose, 
Route, Regimen 
Itraconazole 600 mg  PO daily for 10-14 days  
Duration of administration 
10-14 days 
Reference therapy 
N/A 
Statistical Methodology 
Paired t-tests or Wilcoxon signed rank-tests will be used to investigate if 
there is a significant change in the values of tissue and peripheral 
samples, and imaging from pre-treatment to post-treatment in terms of 
itraconazole effects on tumor angiogenesis and hedgehog pathway 
signaling.   The nonlinear mixed effects model will be used to determine 
the effect of itraconazole pharmacokinetics on the pharmacodynamic 
profile of itraconazole.  
 
 
 


Study Number – 122014-038 
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4 
 
1.0 
BACKGROUND AND RATIONALE 
 
1.1 Background 
Itraconazole, an orally available azole antifungal in clinical use for decades, has emerged as a promising, safe, convenient, 
and inexpensive treatment for lung cancer.  In preclinical models, itraconazole has demonstrated inhibition of (1) tumor 
angiogenesis and (2) the Hedgehog (Hh) pathway, a critical axis in cancer stem cell development (see Figure 2).  In multiple 
primary xenograft models, itraconazole demonstrates potent inhibition of endothelial cell proliferation and angiogenesis, 
resulting in over 50% reduction in micro vessel density and tumor vascular area. (6-9)   
 
Itraconazole effects on angiogenesis 
 
Itraconazole may have both mechanistic and clinical advantages over bevacizumab (Avastin), the anti-vascular endothelial 
growth factor (VEGF) monoclonal antibody approved by the U.S. Food and Drug Administration (FDA) for advanced non-
squamous non-small cell lung cancer (NSCLC) and the only antiangiogenic agent approved to date for any lung cancer 
indication.  In contrast to bevacizumab, itraconazole appears to affect multiple antiangiogenic pathways, including sterol 
biosynthesis, disruption of cholesterol trafficking, intratumoral induction of hypoxia inducible factor 1 (HIF1α), and inhibition 
of VEGF receptor 2 (VEGFR2) and mammalian target of rapamycin (mTOR) pathways(6, 8, 10).  Conceivably, an agent 
with multi-targeted effects may be less susceptible to acquired resistance than are drugs with highly selective mechanisms 
such as VEGF inhibition.  Indeed, in clinical settings, bevacizumab has demonstrated modest and inconsistent clinical 
benefit (11, 12), conveyed substantial toxicities (including fatal hemoptysis), has had restricted clinical use due to safety 
concerns (13), and results in a dramatic increase in the cost of care (incremental cost-utility ratio of more than $500,000 per 
quality adjusted life year [QALY]) (14).    
 
Itraconazole effects on Hedgehog (Hh) pathway 
 
The Hedgehog (Hh) pathway has been implicated in oncogenesis, maintenance of tumor progenitor cells, and tumor-stromal 
interactions in multiple tumor types (15).  These include sporadic cancers such as lung cancer, pancreatic cancer, and 
prostate cancer(16-23), as well as malignancies with Hh pathway mutations such as basal cell carcinoma (BCC) and 
medulloblastoma (24, 25).  Given the longstanding need for therapies targeting cancer stem cells, preclinical studies 
demonstrating efficacy in several cancer models, and cases of dramatic clinical benefit in BCC and medulloblastoma, the 
pharmaceutical industry has recently seen several large-scale efforts to develop Hh pathway antagonists for clinical use, 
including vismodegib (Erivedge), the first FDA-approved Hh pathway inhibitor, indicated for metastatic BCC. 
 
Although inhibitors of Sonic Hedgehog (SHH) (26), GLI proteins (9, 27, 28), Smoothened (SMO) localization to primary cilia 
(29), and trafficking of ciliary motors (30) have been reported, these antagonists 
have been used only for research purposes thus far. SMO, as a central 
regulator of the pathway and an accessible cell membrane component, has 
been the primary focus for development of small molecule Hh pathway 
inhibitors (31). Cyclopamine, the archetypical SMO antagonist, was first 
described as a steroidal alkaloid teratogen associated with cyclopic lambs (32) 
and subsequently determined to be a SMO antagonist (33-36). All subsequent 
small-molecule SMO antagonists have been derived from the structural 
scaffold of cyclopamine or designed to mimic its mode of binding. In addition to 
vismodegib (GDC-0449; Genentech), a number of SMO inhibitors are in 
development and clinical trials, including NVP-LDE225 (Novartis), BMS-
833923/XL-139 (BMS/Exelixis), and TAK-441 (Millenium). All of these inhibitors 
have been designed to be cyclopamine-competitive (36-38). 
 
Itraconazole may have mechanistic advantages over vismodegib and other Hh 
pathway antagonists.   
Due to their limited mechanistic diversity resistance to these cyclopamine-
competitive antagonists has already emerged (39-42). While efforts are 
underway to develop new small compounds to inhibit drug-resistant SMO mutants (40, 41), there is no clear time-line for 
when these drugs will enter into clinical trials.  In contrast, UT Southwestern researchers have demonstrated that 
 
Figure 2. Hh signaling pathway. A 
simplified schematic view of the Hh 
signaling pathway. Small compound 
agonists (green font) and antagonists 
(red font) are shown.  


Study Number – 122014-038 
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5 
itraconazole acts on SMO to inhibit the Hh pathway at a site distinct from cyclopamine (see Figure 2).  Itraconazole inhibits 
in vivo tumor growth of Hh-dependent BCC and medulloblastoma in mice and inhibits the Hh pathway in human BCC (9, 
43).  We have also shown that itraconazole inhibits the activity of vismodegib-resistant SMO in vitro and in vivo and has 
inhibitory activity against all other drug-resistant SMO mutants that have been described (see Figure 3).  The cyclopamine-
independent mechanism by which itraconzole inhibits SMO appears distinct from its anti-fungal target of 14-α-lanosterol 
demethylase (14LDM) and from its activity as an anti-angiogenic agent (43, 44).   
 
 
 
The Hh pathway appears to be a relevant target in lung cancer.   
 
Although most studies investigating the Hh pathway in lung cancer have focused on small cell histology (approximately 15% 
of lung cancers), we and others have demonstrated that transgenic mouse models of non-small cell lung cancer (NSCLC, 
approximately 85% of cases) and human NSCLC express high levels of Hh compared to normal bronchial epithelial tissue 
(see Figure 4) (22, 23, 45, 46).  In pancreatic cancer cell lines, Hh pathway activation has been noted in tumor stroma.  
Treatment of these mice with SMO antagonists prolonged survival and decreased tumor-associated stroma, suggesting 
that the Hh pathway may act through a paracrine process (18, 45, 47).  The recognition that Hh targeting may be relevant 
to NSCLC is beneficial not only because this histologic subtype is far more common, but also because early-stage NSCLC 
cases undergo surgical resection, permitting tumor-level pharmacodynamic assessment of target inhibition, as described in 
this proposal.   
 
 
Clinical experience with itraconazole 
 
Itraconazole has a number of favorable characteristics compared to existing antiangiogenic agents and Hh pathway 
antagonists.  Decades of use have shown it to be well tolerated.  Well before the agent was recognized for potential effects 
on angiogenesis, stem cells, and cancer growth, it was administered to lung cancer patients with invasive aspergillus 
infections without complications (1).  Notably, most of these patients had cavitary squamous tumors and underwent invasive 
procedures while receiving itraconazole, suggesting that—in contrast to bevacizumab—this agent may be safely given to 
all histologic subtypes of lung cancer, even in the perioperative period.(2, 3)  Principal toxicities of itraconazole include 
gastrointestinal events (nausea, vomiting, and diarrhea in ≤5%) and concern for drug-drug interactions via effects on 
CYP3A4 (48), PGP1 (48, 49), and protein glycosylation (10, 50).  Importantly, adverse effects of vismodegib—which include 
taste loss, muscle cramps, hair loss, and weight loss—were noted to result in discontinuation of vismodegib treatment in 
Figure 4. NSCLC expresses sonic 
hedgehog (Shh).(A) H&E section of lung 
tumors from an LSL-K-rasG12D/+; 
Trp53fl/fl mouse infected with adenovirus-
Cre via nasal inhalation. 10x objective.  
(B,C) Shh expression (green) and pERK 
expression (red) at 20x (B) and 40x (C) 
magnification.   
Figure 3. Itraconazole has inhibitory 
activity 
against 
mutant 
drug-
resistant SMO (SMOD477G). Smo-/- 
cells expressing mouse SMOWT or 
SMOD477G 
and 
stimulated 
with 
SHHN-conditioned 
medium 
were 
treated 
with 
(A) 
GDC-0449 
(vismodegib) 
or 
(B) 
itraconazole. 
Itraconazole has inhibitory activity 
against SMOWT and SMOD477G 
mediated 
Hh 
pathway 
activation 
whereas GDC-0449 cannot inhibit 
mutant SMOD477G activity (A). 


Study Number – 122014-038 
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6 
approximately half of subjects in a pivotal BCC trial (51).  Finally, in an era of increasing attention to health care costs, 
itraconazole ($975/month when dosed 600 mg PO daily) presents a far less costly option than bevacizumab ($8,500/month) 
or vismodegib ($7,500/month).(52-54)     
 
Clinical studies of itraconazole as an antineoplastic agent have been performed in prostate cancer, NSCLC, and BCC.  A 
recent study using itraconazole 600 mg/day for castrate resistant prostate cancer resulted in decreased Hh pathway activity 
that correlated with decreased prostate-specific antigen (PSA) levels (5).  In a preliminary phase 2 clinical trial, the addition 
of itraconazole to pemetrexed chemotherapy for second-line treatment of advanced nonsquamous NSCLC resulted in a 
doubling of progression-free survival (PFS) and a four-fold increase in overall survival (OS) (4).  The survival difference 
reached statistical significance even though the trial was closed to enrollment before reaching target accrual.  Based on our 
results that itraconazole inhibits the growth of endogenous Ptch+/-; p53-/- murine BCC and increases tumor necrosis (43), 
in collaboration with colleagues at Stanford University, members of this study team (Dr. James Kim) conducted an 
exploratory open label biomarker proof-of-concept study of itraconazole in BCC (NCT01108094), in which itraconazole 
demonstrated anti-tumor effects and antagonism of Hh pathway (see Figure 5).  In that study, treatment with itraconazole 
400 mg daily for one month produced decreases in Hh pathway activation, tumor size, and proliferation.  Specifically, 
fourteen untreated patients and 15 patients treated with itraconazole 200 mg PO bid for 1 month, all with multiple BCCs, 
were monitored. Patients who received itraconazole showed decreases in tumor growth on average of 23%. The tumors 
showed a decrease in Hh pathway activity by 63% as measured by GLI1 mRNA levels. Itraconazole decreased cell 
proliferation, measured by Ki-67 staining, by 45% in vismodegib-naïve subjects (P=0.04).  In aggregate, this pilot trial 
showed that itraconazole inhibits the Hh pathway of BCCs in humans. 
 
1.2 Rationale  
 
Critical to the further development of itraconazole as a therapeutic agent in lung cancer is a clear understanding of its 
pharmacodynamic profile in patients.  While a small phase 2 trial has demonstrated possible clinical benefit in this patient 
population (4), neither the mechanism nor predictors of this effect has been demonstrated in humans.  The proposed phase 
0 study will provide much needed and unprecedented insight via intensive and integrated real-time pharmacodynamic and 
pharmacokinetic analyses of tumor samples and surrogate tissues.  These results will inform subsequent trials, both in 
terms of treatment selection and also biomarker implementation.  Such studies are particularly essential in lung cancer, 
where perceived challenges to tissue acquisition may hinder implementation of essential bio correlatives.  The molecular 
proof-of-concept investigations we propose may guide large-scale development of itraconazole for lung cancer therapy.  
Furthermore, because the Hh pathway and angiogenesis are relevant to multiple cancer types, our findings may be more 
broadly applicable to the field of medical oncology. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 5. Itraconazole has activity against human BCC. (A) Nodular BCC at baseline and after treatment with 
itraconazole.  (B) During itraconazole treatment, tumor area decreased by an average of 23% (95% CI: 17.2%, 28.1%). 
(C) Unpaired analysis of individual tumors of treated subjects showed inhibition of Hh pathway as measured by GLI1 
mRNA expression. “GDC-0449 Treated” patients had been treated with and were resistant to GDC-0449 (vismodegib) 
prior to itraconazole treatment.  (D) Paired analysis of patient Ki67 (proliferation marker) averages and Ki67 tumor 
staining (brown) among itraconazole-treated GDC-0449 (vismodegib)-naïve subjects. 
D


Study Number – 122014-038 
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7 
The design of this study incorporates the clinical and preclinical experience to date of itraconazole as a cancer therapeutic.  
The itraconazole dose was selected based on pharmacodynamic analyses in earlier human studies, suggesting that 600 
mg daily provided optimal Hh pathway antagonism (5).  The duration of itraconazole therapy is designed to provide sufficient 
drug exposure to reach steady-stage pharmacokinetics in plasma and tissues, and is also expected to be sufficient for target 
pharmacodynamic effects, as tumor Gli1 mRNA has been shown to decrease after as little as 3 days of itraconazole 
treatment in a medulloblastoma xenograft model (43).  
 
1.3 Correlative Studies 
 
We hypothesize that itraconazole will inhibit tumor angiogenesis and will inhibit Hh pathway activation.  The proposed trial 
will determine the impact of itraconazole on tumor angiogenesis and on the Hh pathway in lung cancer.    For the first time 
in patients, we will determine itraconazole effects on (1) tumor vessel density, (2) tumor perfusion and cellular density, and 
(3) Hh pathway components including GLI1, SHH, and PTCH1.  We will also investigate potential mechanisms of treatment 
resistance (SMO gene mutations, GLI2 and CCND1 copy number, PI3K-mTOR pathway activation), which have been 
demonstrated in other tumor types but not previously evaluated in lung cancer.   
 
Separately, this will demonstrate the applicability of new molecular and imaging technologies to the clinical study of lung 
cancer.  Specifically, we will evaluate use of RNAScope (Advanced Cell Diagnostics), a technology for detecting Hh pathway 
components that could be applied to patient selection in future clinical trials.  We will also evaluate use of dynamic contrast 
enhanced (DCE)-, diffusion weighted imaging (DWI)-, and arterial spin labeling (ASL)-MRI.  There has been limited 
experience in lung cancer with these start-of-the-art imaging techniques due to concerns for motion artifact.  However, we 
have developed motion correction algorithms to address these limitations.  Such imaging studies might be applied to patient 
selection and/or early determination of treatment efficacy in future trials. 
 
2.0 
STUDY OBJECTIVES 
 
 
Primary Objective 
 
Determine the pharmacodynamic effects of itraconazole on tumor angiogenesis (assessed by changes in tumor 
tissue microvessel density [MVD]) 
 
 
Secondary Objectives  
o 
Determine the pharmacodynamic effects of itraconazole on tumor angiogenesis (assessed by changes 
in HIF1α, VEGFR2, phospho-VEGFR2, and other plasma cytokine and angiogenic factor levels) 
o 
Determine the pharmacodynamic effects of itraconazole on tumor angiogenesis (assessed by dynamic 
contrast enhanced [DCE], diffusion weighted imaging [DWI], and arterial spin labeling [ASL] MRI) 
o 
Determine the pharmacodynamic effects of itraconazole on tumor Hedgehog (Hh) pathway (assessed 
by changes in tumor tissue GLI1, SHH, and PTCH1 levels) 
o 
Assess predictors of effects of itraconazole on tumor Hedgehog (Hh) pathway (assessed by tumor 
SMO gene mutations, GLI2 and CCND1 copy number, PI3K-mTOR pathway activation) 
o 
Determine the pharmacodynamic effects of itraconazole on systemic Hedgehog (Hh) pathway 
(assessed by changes in skin biopsy GLI1, SHH, and PTCH1 levels) 
o 
Determine the effects of itraconazole on tumor cell proliferation and apoptosis (assessed by tumor Ki67 
and cleaved caspase 3 levels) and correlate with pharmacodynamic effects on Hh pathway 
components 
o 
Determine the effects of itraconazole pharmacokinetics on the pharmacodynamic profile of itraconazole 
(assessed by post-treatment serum, tumor tissue, and skin biopsy itraconazole levels) 
3.0 
STUDY AGENT 
 
3.1  Drug class and Mechanism  
 
Itraconazole is an anti-fungal drug in the same class of drugs as fluconazole (Diflucan), 
ketoconazole (Nizoral), and miconazole (Micatin, Monistat). Itraconazole inhibits the cytochrome 
P450-dependent synthesis of ergosterol and prevents growth of several types of fungi by 


Study Number – 122014-038 
________________________________________________________________________ 
8 
preventing the fungi from producing the membranes that surround the fungal cells The FDA 
approved Itraconazole in September 1992.  Itraconazole is commercially available as Sporanox® 
capsules 100 mg. 
 
3.2 Storage  
 
Capsules and itraconazole patch should be stored at room temperature, 15-25 C (59-77 F) and 
protected from light and moisture.  
 
3.3  Indication  
 
Itraconazole is used for the treatment of fungal infections. It is active against fungal infections 
such as aspergillosis, blastomycosis, histoplasmosis, and candidiasis, as well as fungal infection 
localized to the toenails and fingernails (onychomycosis). It also is used for treating patients with 
fever and low white blood cell counts who are likely to develop a fungal infection.    Do not take 
itraconazole if pregnant or nursing. 
 
3.4  Dosing 
 
The usual recommended dose is 400-600 mg daily as a single dose or two divided doses. 
Capsules should be taken with a full meal because food improves absorption. For systemic fungal 
infections, patients have been treated for one year without serious toxicities.  For this study, 
patients will be treated with itraconazole 300 mg bid (600 mg/day total) for a total of10-14 days. 
Drug will be provided by the investigators. 
 
 
3.5  Drug Interactions 
 
Itraconazole reduces the liver metabolism (breakdown) of some drugs, resulting in increased 
blood levels and side effects from the affected drugs. Life threatening adverse effects occurred 
when Itraconazole was combined with cisapride (no longer available in the U.S.), pimozide 
(Orap), quinidine (Quinaglute, Quinidex), dofetilide (Tikosyn), or levomethadyl (Orlaam). 
Therefore, Itraconazole should not be combined with these drugs. Other drugs whose blood 
levels are increased by Itraconazole include warfarin (Coumadin), tolbutamide, glyburide 
(Micronase, Diabeta, Glynase), glipizide (Glucotrol), protease inhibitors [for example, indinavir 
(Crixivan), ritonavir (Norvir), saquinavir (Invirase, Fortovase)], midazolam (Versed), triazolam 
(Halcion), "statins" (for example, simvastatin or Zocor) and several others. Itraconazole increases 
blood levels of certain calcium channel blockers, for example, nisoldipine (Sular) and verapamil 
(Calan). Such combinations increase the occurrence of heart failure.  
 
3.6  Side Effects 
 
Stomach upset, diarrhea, headache, or dizziness may occur the first few days in adjustment to 
the medication. Other side effects reported include ringing in the ears, fever, sexual performance 
problems, depression, drowsiness, or trouble sleeping, severe nausea, yellowing eyes/skin, 
unusual weakness, dark urine, pale stools, numbness or tingling of the hands/feet. Symptoms of 
a serious allergic reaction include: rash, itching, swelling, dizziness, trouble breathing. Symptoms 
such as trouble breathing or ankle/foot swelling could also be due to a rare side effect—
congestive heart failure. 
 
3.7 Dose Reduction or Interruption for Toxicity 
 
Subjects experiencing one or more AEs due to study treatment may require reductions in their 
doses or dosing interruptions in order to continue with study treatment. See section 5.2 for further 
details. 
 


Study Number – 122014-038 
________________________________________________________________________ 
9 
4.0 
SUBJECT ELIGIBILITY 
 
Eligibility waivers will be permitted on a case-by-case basis upon discussion with the Principal 
Investigator. Study treatment may not begin until a subject is registered. 
4.1 
Inclusion Criteria 
 
4.1.1 Histologically or cytologically proven NSCLC planned for surgical resection.  All NSCLC histologic 
subtypes are eligible.  Alternatively, patients in whom a diagnosis of NSCLC is highly suspected based on 
history and imaging studies and who are, therefore, scheduled for diagnostic biopsy and/or surgical 
resection will also be eligible for screening, enrollment, and study treatment if they meet all additional 
eligibility criteria.  In the event that biopsies do not confirm NSCLC, such patients will be removed from 
study but monitored for any adverse events resulting from study participation. 
 
4.1.2 No prior therapy, but planned for surgical resection. Prior therapy for NSCLC is allowed, as long as 
no systemic or local therapy has been administered for the disease site planned for resection since the 
most recent biopsy was performed. 
 
 
 
4.1.3 Age ≥ 18 years. 
 
 
 
4.1.4 ECOG 0-2 performance status 
 
 
 
4.1.5 Adequate organ function as defined below: 
 
 
- total bilirubin within normal institutional limits 
 
 
- AST(SGOT)/ALT(SPGT) ≤ 2.5 X institutional upper limit of normal 
 
 
- creatinine ≤ 2 X institutional upper limit of normal  
 
 
 
 
4.1.6 
Women of child-bearing potential and men must agree to use adequate contraception (hormonal 
or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, 
and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is 
pregnant while participating in this study, she should inform her treating physician immediately. 
 
4.1.6.1 A female of child-bearing potential is any woman (regardless of sexual orientation, having 
undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria: 
 
• 
Has not undergone a hysterectomy or bilateral oophorectomy; or 
• 
Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses 
at any time in the preceding 12 consecutive months). 
4.2 
Exclusion Criteria 
 
4.2.1 Subjects may not be receiving any investigational agents that would confound interpretation of study 
pharmacodynamic endpoints. 
  
 
 
4.2.2 
History of allergic reactions attributed to itraconazole or to compounds of similar chemical or 
biologic composition to itraconazole. 
 
 
 
4.2.3   Uncontrolled, concurrent medical illness. 
 
 
 
4.2.4 Active hepatitis or symptomatic liver disease. 
 
4.2.5. History of or current evidence of uncontrolled cardiac ventricular dysfunction (congestive heart failure) 
or NYHA Class III or IV heart failure. 
 


Study Number – 122014-038 
________________________________________________________________________ 
10 
4.2.6  Patients currently taking any contraindicated medication listed in Appendix A.  If a patient is already 
taking such a medication, a 4-5 half-life washout period is needed for enrollment. 
 
 
4.2.7 Current evidence of hyperthyroidism (which would increase metabolism of itraconazole). 
 
 
 
4.2.8 Pregnant or lactating female or any female trying to get pregnant. 
 
5.0 
TREATMENT PLAN 
 
5.1 
Treatment Dosage and Administration 
 
Itraconazole is commercially available as Sporanox® capsules 100 mg. Patients will be treated with itraconazole 
300 mg bid (600 mg/day total) for a total of10-14 days. Drug will be provided by the investigators.  Itraconazole 
should be taken during or right after a full meal. 
 
 
 
Agent 
Premedications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
Itraconazole 
take during or 
right after a full 
meal 
300 mg bid 
PO 
10-14 
days total 
(see 
schema, 
Figure 1, 
above) 
 
 
 
 
A study medication diary will be provided.  For missed or vomited doses, if the missed dosed is within 6 
hours of the next scheduled dose, the dose should be skipped and the patient should return to his/her 
regular schedule. Otherwise, the dose should be taken and the next scheduled dose should be pushed 
back slightly in an attempt to get the doses back on track. 
 
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any subject who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
table (Section 5.11). Toxicity will be assessed according to the NCI Common Toxicity 
Criteria for Adverse Events (CTCAE), version 4.0. Dose adjustments should be made 
according to the system showing the greatest degree of toxicity.  
 
If a subject misses more than 3 doses, the subject may be replaced.   
 
 
 
 
Non-hematological Toxicity Dose Reductions 
Event 
Action 
Nausea/Vomiting 
Grade 1-2 
Allow attempt at control, e.g., with anti-emetics 
Grade 3 
Hold dose and use antiemetics until resolution or 
improvement to Grade 1-2.  
Grade 4 
Discontinue itraconazole and monitor. 


Study Number – 122014-038 
________________________________________________________________________ 
11 
Diarrhea 
Grade 1-2 
Allow attempt at control, e.g., with anti-diarrheal 
agents 
Grade 3 
Hold dose and use anti-diarrheal agents until 
resolution or improvement to Grade 1-2. 
Grade 4 
Discontinue itraconazole and monitor. 
Elevations in ALT or AST 
Grade 1-2 
Decrease dose to 300mg PO qday. 
Grade 3 
Hold dose until resolution. 
Grade 4 
Discontinue itraconazole and monitor. 
Rash 
Grade 1-2 
Allow attempt at control, e.g. with topical agents 
or anti-histamines 
Grade 3 
Hold dose until resolution or improvement to 
Grade 1-2. 
Grade 4 
Discontinue itraconazole and monitor. 
Headache 
Grade 1-2 
Allow attempt at control with medication 
Grade 3 
Hold dose until resolution or improvement to 
Grade 1-2. 
Edema 
Grade 1-2 
Allow attempt at control with medication. 
Grade 3 
Hold dose until resolution or improvement to 
Grade 1-2. 
 
5.3 
Concomitant Medications/Treatments 
 
Itraconazole reduces the liver metabolism (breakdown) of some drugs, resulting in increased 
blood levels and side effects from the affected drugs. Life threatening adverse effects occurred 
when Itraconazole was combined with cisapride (no longer available in the U.S.), pimozide 
(Orap), quinidine (Quinaglute, Quinidex), dofetilide (Tikosyn), or levomethadyl (Orlaam). 
Therefore, Itraconazole should not be combined with these drugs.  
Other drugs whose blood levels are increased by Itraconazole include warfarin (Coumadin), 
tolbutamide, glyburide (Micronase, Diabeta, Glynase), glipizide (Glucotrol), protease inhibitors [for 
example, indinavir (Crixivan), ritonavir (Norvir), saquinavir (Invirase, Fortovase)], midazolam 
(Versed), triazolam (Halcion), "statins" (for example, simvastatin or Zocor) and several others. 
Itraconazole increases blood levels of certain calcium channel blockers, for example, nisoldipine 
(Sular) and verapamil (Calan). Such combinations increase the occurrence of congestive heart 
failure due to Itraconazole.  
 
Additionally, itraconazole should be used with caution in patients also taking 
immunosuppressive drugs such as cyclosporin (due to increased plasma levels of these drugs 
when taken in conjunction with itraconazole).  These patients require extra monitoring by the 
treatment team prescribing the immunosuppressive agent(s). 
Drugs that may decrease itraconazole plasma concentrations 
 
It is recommended that itraconazole capsules be administered with an acidic beverage (such as 
non-diet cola) upon co-treatment with drugs reducing gastric acidity. 
It is recommended that acid neutralizing medicines (e.g. aluminum hydroxide) be administered at 
least 1 hour before or 2 hours after the intake of Itraconazole Capsules. 
 


Study Number – 122014-038 
________________________________________________________________________ 
12 
Coadministration of itraconazole with potent enzyme inducers of CYP3A4 may decrease the 
bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be 
reduced. Examples include: 
Antibacterials: isoniazid, rifabutin, rifampicin  
Anticonvulsants: carbamazepine, phenobarbital, phenytoin  
Antivirals: efavirenz, nevirapine 
Therefore, administration of potent enzyme inducers of CYP3A4 with itraconazole is not 
recommended. It is recommended that the use of these drugs be avoided from 2 weeks before 
and during treatment with itraconazole, unless the benefits outweigh the risk of potentially 
reduced itraconazole efficacy.  
Drugs that may increase itraconazole plasma concentrations 
 
Potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole. Examples include: 
Antibacterials: ciprofloxacin, clarithromycin, erythromycin 
Antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, ritonavir.  
It is recommended that these drugs be used with caution when coadministered with Itraconazole 
Capsules. It is recommended that patients who must take itraconazole concomitantly with potent 
inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged 
pharmacologic effects of itraconazole. 
 
 
See Appendix A (Drugs that may have their plasma concentrations increased by itraconazole).  
 
5.4 
Duration of Therapy 
Treatment will be for 10-14 days total with the last dose taken ≤ 12 hours prior to surgical 
resection OR until the event of  
 
Inter-current illness that prevents further administration of treatment 
 
Unacceptable adverse event(s) 
 
Subject  decides to withdraw from the study, OR 
 
General or specific changes in the patient’s condition render the subject  
unacceptable for further treatment in the judgment of the investigator 
In the event that surgical resection is delayed, patients may continue taking itraconazole if 
tolerated up until ≤ 12 hours prior to surgical resection 
5.5 
Duration of Follow Up 
All subjects will be followed for 3 weeks following resection. Subjects who experience 
study-related adverse events will be followed until resolution or stabilization of the 
adverse event.  
 
Additionally, every year medical records will be evaluated and/or subjects will be 
contacted regarding disease recurrence and survival information. 
 
5.6 
Removal of Subjects from Protocol Therapy 
Subjects will be removed from therapy when any of the criteria listed in Section 5.4 apply. 
Notify the Principal Investigator, and document the reason for study removal and the date 
the subject was removed in the Case Report Form. The subject should be followed-up 
according to protocol.  


Study Number – 122014-038 
________________________________________________________________________ 
13 
5.7 
Subject  Replacement 
Subjects may be replaced if they do not complete study-directed therapy and surgical 
resection, or if their biospecimens are not evaluable for study endpoints  
 
STUDY PROCEDURES 
5.8 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only 
after obtaining informed consent. Assessments performed for clinical indications (not 
exclusively to determine study eligibility) may be used for baseline values even if the 
studies were done before informed consent was obtained. 
 
All screening procedures must be performed within 21 days prior to registration unless 
otherwise stated. The screening procedures include: 
5.8.1 Informed Consent 
5.8.2 Medical history 
Complete medical and surgical history, history of infections 
5.8.3 Demographics 
Age, gender, race, ethnicity 
5.8.4 Review subject eligibility criteria 
5.8.5 Review previous and concomitant medications 
5.8.6 Physical exam including vital signs, height and weight 
Vital signs (temperature, pulse, respirations, blood pressure), height, weight 
5.8.7 Performance status 
Performance status evaluated prior to study entry according to Appendix D. 
5.8.8 Adverse event assessment 
Baseline adverse events will be assessed. See section 6 for Adverse Event 
monitoring and reporting. 
5.8.9 Hematology 
 
 
CBC with differential, PT/INR, aPTT 
5.8.10 Blood draw for correlative studies 
See Section 5.9 for details. 
5.8.11 
Serum chemistries 
Comprehensive metabolic panel (CMP) to include: albumin, alkaline 
phosphatase, ALT/SGPT, AST/SGOT, BUN, creatinine, electrolytes (sodium, 
potassium, calcium, chloride, bicarbonate), glucose, and total bilirubin. 
5.8.12 
Pregnancy test (for females of child bearing potential) 
See section 4.1.6.1 for definition.  


Study Number – 122014-038 
________________________________________________________________________ 
14 
5.9 
Procedures During Treatment 
 
All screening procedures must take place within 21 days of trial registration unless otherwise stated.   
 
 
Following screening, pre-study (“Baseline”) assessments will include history and physical exam, 
performance status evaluation, laboratory studies including a blood draw for the cytokine panelarchived 
tumor collection from diagnostic biopsy, skin biopsy, and the MRI evaluations (anticipated to last 45-50 
minutes).  In certain cases when there is a high suspicion of cancer prior to the diagnostic biopsy, the 
collection of study-required tissue can occur at the time of the diagnostic biopsy (see Inclusion Criteria 
4.1.1).  
 
 
Once on study, itraconazole will be taken twice daily for a total of 10-14 days, After being on itraconazole 
for 7-10 days, “Post-treatment” assessments will include a skin biopsy, blood draw for the PK analyses and 
the cytokine panel, and also MRI evaluations (anticipated to last 45-50 minutes). Toxicity assessments and 
laboratory checks will also be conducted during that time. Following these assessments, itraconazole will 
be continued until the day of surgery.   
 
 
At the time of surgical resection, a tissue sample (with adjacent normal tissue as per standard resection 
technique) will be obtained to complete the analysis.   
 
 
Following resection, subjects will be followed per standard post-operative procedure.  
 
Samples will be collected at the following time points per patient: 
Baseline prior to study treatment:  
 
Collection of archive tissue from the diagnostic biopsy.  A core-
needle biopsy must have been completed.  A fine needle aspiration 
(FNA) will not be sufficient. 12 unstained slides are needed for this 
study.  Fresh tumor may be collected in cases where the diagnosis 
of NSCLC is highly suspected and the patient will be sent for a 
diagnostic biopsy.  
 
Skin biopsy- one 4mm punch biopsy 
 
Blood sample  
o 
One 3mL EDTA-containing tube for multiplex cytokine panel 
7-10 days post itraconazole initiation: 
 
Skin biopsy- one 4mm punch biopsy 
 
Blood samples 
o 
One 3mL EDTA-containing tube for multiplex cytokine panel 
o 
One 3mL EDTA-containing tubes at each of the following PK 
time points:  4, 6, 8 (or as late as possible prior to discharge) 
hours. 
Surgical Resection: 
 
1 tissue sample will be obtained for analysis of itraconazole content 
(PK) 
 
1 3mL EDTA containing tube  for Itraconazole PK 
5.10 
Follow-up Procedures 
            Following resection, subjects will be followed per standard post-operative 
            procedure. Subjects who experience study-related adverse events will be 
 
followed until  
resolution or stabilization of the adverse event.  
 
 
Additionally, every year medical records will be evaluated and/or subjects will be 
contacted regarding disease recurrence and survival information. 
 
 
 


Study Number – 122014-038 
________________________________________________________________________ 
15 
 
5.11 
Time and Events Table  
 
Event   
Pre-study 
Days 
1-10* 
post-treatment 
assessments (after 
7-10 days of 
itraconazole bid) 
Day 
8-
14** 
Resection 
(Non-
study) 
 
Screen-
ing 
Base- 
line 
Archived 
tumor 
tissue^  
X 
 
 
 
 
 
Phone assessment 
(to 
evaluate 
for 
adherence and any 
symptoms) 
 
 
on day 
3 
 
 
 
Informed Consent 
X 
 
 
 
 
 
History and PE 
X 
 
 
X 
 
 
Performance Status 
X 
 
 
 
 
 
Toxicity Evaluations 
 
 
 
X 
 
 
Labs# 
X 
 
X (on 
day 5, 
6, 7, or 
8) 
 
 
 
Skin biopsy 
X 
 
 
X 
 
 
Blood draw for 
multiplex 
correlative studies 
X 
 
 
X 
 
 
Blood draw for PK 
studies 
 
 
 
X 
 
X 
Imaging Studies § 
X 
 
 
X 
 
 
Itraconazole bid 
 
 
X 
X 
X 
 
Tissue sample from 
non-study surgical 
biopsy 
 
 
 
 
 
X  
 
^ 12 unstained slides will be collected from the diagnostic core-needle biopsy.  In 
 
cases where malignancy is highly suspected, tissue may be collected from the diagnostic 
biopsy to be performed. 
 
 
* To allow for scheduling, this phase will last between 7 and 10 days. 
 
** To allow for scheduling, this phase will last between 4 and 7 days.  
 #Hematology and chemistry labs as detailed in Section 6.1; on day 5, 6, 7 or 8 only 
chemistry is required 
§ MRI studies may be not be performed if the tumor is too small for imaging 
assessments. Patients may also be excluded from the imaging portion of the study 
for safety reasons. See section 7.0 for additional information.  
5.12 
Removal of Subjects from Study 
Subjects can be taken off the study treatment and/or study at any time at their own 
request, or they may be withdrawn at the discretion of the investigator for safety, 
behavioral or administrative reasons. The specific reason(s) for discontinuation will be 
documented and may include: 
 


Study Number – 122014-038 
________________________________________________________________________ 
16 
5.12.1 Subject voluntarily withdraws from treatment (follow-up permitted); 
5.12.2 Subject withdraws consent (termination of treatment and follow-up); 
5.12.3 Subject is unable to comply with protocol requirements; 
 
5.12.4 Subject experiences toxicity that makes continuation in the protocol unsafe; 
5.12.5 Treating physician deems continuation on the study would not be in the subject’s 
best interest; 
5.12.6 Subject becomes pregnant (pregnancy to be reported along same timelines as a 
 
 serious adverse event); 
5.12.7 Development of second malignancy (except for basal cell carcinoma or 
squamous cell carcinoma of the skin) that requires treatment, which would 
interfere with this study; 
 
5.13. Safety/tolerability 
 
 Analyses will be performed for all subjects having received at least one dose of study 
drug. The study will use the CTCAE version 4.0 for reporting of adverse events 
(http://ctep.cancer.gov/reporting/ctc.html)  
 
6.0 
ADVERSE EVENTS 
6.1 
Experimental Therapy 
Please see Section 3.0 and 5.3 for information on Itraconazole.  For the most recent 
safety update, please refer to the Itraconazole drug packet insert. 
 
6.1.1 
Contraindications 
 
Itraconazole reduces the liver metabolism (breakdown) of some drugs, resulting in increased 
blood levels and side effects from the affected drugs. Life threatening adverse effects occurred 
when Itraconazole was combined with cisapride (no longer available in the U.S.), pimozide 
(Orap), quinidine (Quinaglute, Quinidex), dofetilide (Tikosyn), or levomethadyl (Orlaam). 
Therefore, Itraconazole should not be combined with these drugs.  
 
Itraconazole should not be administered to pregnant patients or to women contemplating 
pregnancy. 
 
Itraconazole Capsules should not be administered in patients with evidence of ventricular 
dysfunction such as congestive heart failure (CHF) or a history of CHF. 
 
Itraconazole is contraindicated for patients who have shown hypersensitivity to itraconazole. 
There is limited information regarding cross-hypersensitivity between itraconazole and other 
azole antifungal agents. Caution should be used when prescribing itraconazole to patients with 
hypersensitivity to other azoles. 
 
6.1.2 
Special Warnings and Precautions for Use 
 
Itraconazole Capsules should not be used for other indications in patients with evidence of 
ventricular dysfunction unless the benefit clearly outweighs the risk. 


Study Number – 122014-038 
________________________________________________________________________ 
17 
 
Rare cases of serious hepatotoxicity have been observed with itraconazole treatment, including 
some cases within the first week. It is recommended that liver function monitoring be considered 
in all patients receiving itraconazole. Treatment should be stopped immediately and liver function 
testing should be conducted in patients who develop signs and symptoms suggestive of liver 
dysfunction. 
 
If neuropathy occurs that may be attributable to Itraconazole Capsules, the treatment should be 
discontinued. 
 
Transient or permanent hearing loss has been reported in patients receiving treatment with 
itraconazole. Several of these reports included concurrent administration of quinidine which is 
contraindicated. The hearing loss usually resolves when treatment is stopped, but can persist in 
some patients 
 
6.1.3 
Interaction with other medications 
 
It is recommended that itraconazole capsules be administered with an acidic beverage (such as 
non-diet cola) upon co-treatment with drugs reducing gastric acidity. 
It is recommended that acid neutralizing medicines (e.g. aluminum hydroxide) be administered at 
least 1 hour before or 2 hours after the intake of Itraconazole Capsules. 
Upon coadministration, it is recommended that the antifungal activity be monitored and the 
itraconazole dose increased as deemed necessary. 
 
Coadministration of itraconazole with potent enzyme inducers of CYP3A4 may decrease the 
bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy may be 
reduced. Examples include: 
Antibacterials: isoniazid, rifabutin, rifampicin  
Anticonvulsants: carbamazepine, phenobarbital, phenytoin  
Antivirals: efavirenz, nevirapine 
Therefore, administration of potent enzyme inducers of CYP3A4 with itraconazole is not 
recommended. It is recommended that the use of these drugs be avoided from 2 weeks before 
and during treatment with itraconazole, unless the benefits outweigh the risk of potentially 
reduced itraconazole efficacy. Upon coadministration, it is recommended that the antifungal 
activity be monitored and the itraconazole dose increased as deemed necessary. 
 
Potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole. Examples include: 
Antibacterials: ciprofloxacin, clarithromycin, erythromycin 
Antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir, ritonavir.  
It is recommended that these drugs be used with caution when coadministered with Itraconazole 
Capsules. It is recommended that patients who must take itraconazole concomitantly with potent 
inhibitors of CYP3A4 be monitored closely for signs or symptoms of increased or prolonged 
pharmacologic effects of itraconazole, and the itraconazole dose be decreased as deemed 
necessary. 
 
Drugs whose blood levels are increased by Itraconazole include warfarin (Coumadin), 
tolbutamide, glyburide (Micronase, Diabeta, Glynase), glipizide (Glucotrol), protease inhibitors [for 
example, indinavir (Crixivan), ritonavir (Norvir), saquinavir (Invirase, Fortovase)], midazolam 
(Versed), triazolam (Halcion), "statins" (for example, simvastatin or Zocor) and several others. 
Itraconazole increases blood levels of certain calcium channel blockers, for example, nisoldipine 
(Sular) and verapamil (Calan). Such combinations increase the occurrence of congestive heart 
failure due to Itraconazole.   Please also see Appendix A: Drugs that may have their plasma 
concentrations increased by itraconazole 
 


Study Number – 122014-038 
________________________________________________________________________ 
18 
6.1.4 
Adverse Reactions 
 
Please see Section 3.6. 
6.2 
Adverse Event Monitoring 
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of subjects enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Adverse events are reported in a 
routine manner at scheduled times during a trial. Additionally, certain adverse events 
must be reported in an expedited manner to allow for optimal monitoring of subject  
safety and care.  
 
All subjects experiencing an adverse event, regardless of its relationship to study drug, 
will be monitored until:  
 the adverse event resolves or the symptoms or signs that constitute the adverse 
event return to baseline;  
 any abnormal laboratory values have returned to baseline;  
 there is a satisfactory explanation other than the study drug for the changes 
observed; or 
 death. 
6.2.1 
Definition  
An adverse event is defined as any untoward or unfavorable medical occurrence in a 
human research study participant, including any abnormal sign (for example, abnormal 
physical exam or laboratory finding), symptom, clinical event, or disease, temporarily 
associated with the subject’s participation in the research, whether or not it is considered 
related to the subject’s participation in the research. 
Adverse events encompass clinical, physical and psychological harms. Adverse events 
occur most commonly in the context of biomedical research, although on occasion, they 
can occur in the context of social and behavioral research. Adverse events may be 
expected or unexpected. 
Severity  
Adverse events will be graded by a numerical score according to the defined NCI 
Common Terminology Criteria for Adverse Events (NCI CTCAE) and version number 
specified in the protocol. Adverse events not specifically defined in the NCI CTCAE will 
be scored on the Adverse Event log according to the general guidelines provided by the 
NCI CTCAE and as outlined below.   
 
Grade 1: Mild  
 
Grade 2: Moderate 
 
Grade 3: Severe or medically significant but not immediately life threatening 
 
Grade 4: Life threatening consequences 
 
Grade 5: Death related to the adverse event 
 
Serious Adverse Events  
ICH Guideline E2A and the UTSW IRB define serious adverse events as those events, 
occurring at any dose, which meets any of the following criteria:  
 
Results in death   
 
Immediately life-threatening  


Study Number – 122014-038 
________________________________________________________________________ 
19 
 
Results in inpatient hospitalization or prolongation of existing hospitalization  
 
Results in persistent or significant disability/incapacity  
 
Results in a congenital anomaly/birth defect  
 
Based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other outcomes 
listed in this definition. 
Note: A “Serious adverse event” is by definition an event that meets any of the above 
criteria. Serious adverse events may or may not be related to the research project. A 
serious adverse event determination does not require the event to be related to the 
research. That is, both events completely unrelated to the condition under study and 
events that are expected in the context of the condition under study may be serious 
adverse events, independent of relatedness to the study itself. As examples, a car 
accident requiring overnight hospitalization would be a serious adverse event for any 
research participant; likewise, in a study investigating end-stage cancer care, any 
hospitalization or death would be a serious adverse event, even if the event observed is a 
primary clinical endpoint of the study. Refer to the UTSW IRB website at 
http://www.utsouthwestern.net/intranet/research/research-administration/irb/study-
management/adverse-events.html to determine when a serious adverse event requires 
reporting to the IRB. 
Unanticipated Problems 
The term “unanticipated problem” is found, but not defined in the regulations for the 
Protection of Human Subjects at 45 CFR 46, and the FDA regulations at 21 CFR 56. 
Guidance from the regulatory agencies considers unanticipated problems to include any 
incident, experience, or outcome that meets each of the following criteria: 
• 
Unexpected (in terms of nature, severity or frequency) AND 
• 
Definitely, probably, or possibly related to participation in the research AND  
• 
Serious or a possible unexpected problem in that the research places subjects or 
others at greater risk of harm than was previously known or recognized. Note: Any 
serious adverse event would always suggest a greater risk of harm. 
 
Follow-up  
All adverse events will be followed up according to good medical practices.  
  
6.2.2 
Reporting 
Local unanticipated problems require expedited reporting, and are submitted to the 
UTSW IRB through the UTSW eIRB and to the SCC DSMC Coordinator.  Hardcopies or 
electronic versions of the eIRB report; FDA Form #3500A forms, or other sponsor forms, 
if applicable; and/or any other supporting documentation available should be forwarded to 
the DSMC Coordinator.  The DSMC Coordinator forwards the information onto the DSMC 
Chairman who determines if immediate action is required.  Follow-up eIRB reports, and 
all subsequent SAE documentation that is available are also submitted to the DSMC 
Chair who determines if further action is required.    
  
All local serious adverse events which occur on research subjects on protocols for which 
the SCC is the DSMC of record require reporting to the DSMC regardless of whether IRB 
reporting is required. Hardcopies or electronic versions of the FDA Form #3500A forms, 
or other sponsor forms, if applicable; and/or any other supporting documentation 
available should be forwarded to the DSMC Coordinator.   


Study Number – 122014-038 
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20 
 
If the event occurs on a multi-institutional clinical trial coordinated by the Cancer Center, 
the DOT Manager or lead coordinator ensures that all participating sites are notified of 
the event and resulting action, according to FDA guidance for expedited reporting. DSMC 
Chairperson reviews all serious adverse events within upon receipt from the DSMC 
Coordinator.  The DSMC Chairperson determines whether action is required and either 
takes action immediately, convenes a special DSMC session (physical or electronic), or 
defers the action until a regularly scheduled DSMC meeting.  
  
Telephone reports to: 
(David Gerber) 
 
UTSW SCC Data Safety Monitoring Committee Coordinator (if fax report is not 
available) within 2 working days to 214-648-7097. 
 
Written reports to: 
(David Gerber ) 
 
UTSW SCC Data Safety Monitoring Committee Coordinator 
Email: SCCDSMC@utsouthwestern.edu 
Fax: 214-648-7018 or deliver to NB 2.418 
 
UTSW Institutional Review Board (IRB) 
Submit via eIRB with a copy of the final sponsor report as attached supporting 
documentation 
 
1. 
SAEs 
 
Serious adverse events (SAEs) will be reported to the DSMC coordinator within 2 
working days of PI awareness.   
 
2. 
Unanticipated Problems  
Unanticipated problems will be reported to the UTSW IRB within 2 working days of PI 
awareness of the event.   
For further guidance for Investigators regarding safety reporting requirements for INDs 
and BA/BE studies, refer to FDA Draft Guidance document: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/UCM227351.pdf 
6.3 
Steps to Determine If an Adverse Event Requires Expedited Reporting 
Step 1: Identify the type of adverse event using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE v4).  
 
Step 2: Grade the adverse event using the NCI CTCAE v4. 
 
Step 3: Determine whether the adverse event is related to the protocol therapy  
Attribution categories are as follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 


Study Number – 122014-038 
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21 
Note: This includes all events that occur within 30 days of the last dose of protocol 
treatment. Any event that occurs more than 30 days after the last dose of treatment and 
is attributed (possibly, probably, or definitely) to the agent(s) must also be reported 
accordingly. 
 
Step 4: Determine the prior experience of the adverse event.  
Expected events are those that have been previously identified as resulting from 
administration of the agent. An adverse event is considered unexpected, for expedited 
reporting purposes only, when either the type of event or the severity of the event is not 
listed in: 
 
the current known adverse events listed in the Agent Information Section of this 
protocol; 
 
the drug package insert; 
 
the current Investigator’s Brochure 
 
6.4 
Role of the Research Monitor 
 
The role and responsibilities of the research monitor will include: 
1. May discuss the protocol with the investigators, interview subjects, and consult with others 
outside the study about the research. 
2.  Shall have the authority to stop the protocol, remove subjects from the protocol, and take 
any necessary steps to protect the safety and well-being of subjects until the IRB can assess the 
Monitor's report. 
3. Shall have the responsibility to promptly report their observations and findings to the IRB or 
other designated official. 
4.  Is required to review all unanticipated problems involving risks to subjects or others, serious 
adverse events and all subject deaths associated with the protocol and provide an unbiased  
written report of the event.  At a minimum, the research monitor must comment on the 
outcomes of the event or problem and in the case of a serious adverse event or death, comment 
on the relationship to participation in the study.  The research monitor must also indicate 
whether he/she concurs with the details of the report provided by the principal investigator.  
Reports for events determined by either the investigator or research monitor to be possibly or 
definitely related to participation and report of events resulting in death must be promptly 
forwarded to the USAMRMC ORP HRPO. 
7.0 
CORRELATIVES/SPECIAL STUDIES 
 
Angiogenesis endpoints 
 
Tissue (tumor):  The proposed tissue correlates include multiple angiogenic biomarkers which will be assessed by 
standard immunohistochemical methods.  The Brekken Lab has extensive experience in immunohistochemical 
analysis of human clinical tissue specimens) and in immunohistochemical analysis of angiogenic biomarkers in 
several preclinical tumor models (55-58).  
 
Blood:  As described previously (59), we will employ a commercially available kit to measure plasma cytokine and 
angiogenic factor levels.  Plasma will be collected as detailed in “Biospecimen collection and processing.”   
 
Imaging:  Imaging studies will include DCE- and DWI-MRI (both of which are established technologies to assess 
microvessel density and cellularity (60)) as well as ASL-MRI (an exploratory platform to assess perfusion and 
vascular density without contrast).  Motion correction techniques will be employed (61).  Together, these studies 
will take approximately 45-50 minutes per time-point.  Patients may be excluded from MRI examinations for any of 
the following reasons: 
1.  Tumor size may be too small for imaging studies. 
2.  Claustrophobia that would interfere with MRI studies anticipated to last 45-50 minutes. 


Study Number – 122014-038 
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22 
3.  Metal implants deemed at risk for migration during MRI studies. 
4.  CrCl < 45 mL/min (increased risk of nephrogenic systemic fibrosis [NSF] from MRI Gadolinium 
contrast). 
5.  Known allergy to MRI contrast. 
 
DCE-MRI. Each consented participant will undergo point of care testing for creatinine on the day of the examination. 
We will employ Gadavist, an FDA  approved macrocyclic agent in order to minimize risk of nephrogenic systemic 
fibrosis (NSF).  DCE-MRI will be carried out on a 3.0 Tesla Philips whole-body scanner using a turbo fast low-angle 
gradient echo sequence (TFE) combined with parallel acquisition SENSE technique. The images will be obtained 
in each patient so that the tumor moves along the imaging plane based on a method developed in our previous 
work (62). Images will be acquired after intravenous administration of a standard dose of 0.1 mmol per kg of body 
weight of Gadavist (Schering AG, Germany) over a 4-s period with subjects in the supine position, breathing 
normally during the scan.  
 
DWI-MRI. MRI examinations will be performed on the 3 Tesla Philips Ingenia MRI scanner using a phased-array 
body coil. Data for apparent diffusion coefficient assessment on diffusion-weighted imaging will be acquired using 
an Echoplanar Imaging Inversion Recovery sequence acquired during  either breath hold or using respiratory 
triggering in the desired plane to image the tumor.  
 
ASL-MRI.  Arterial spin labeling (ASL) has been used extensively to measure tissue perfusion in the brain (63, 64).  
ASL uses endogenous spins to measure tissue perfusion without having any complications due to permeability 
contributions. ASL in the lung has been developed and evaluated in normal volunteers (65, 66).  However, its 
evaluation in lung pathology has been limited to date,.  We will  measure tumor perfusion using either pulsed ASL 
(e.g. FAIRER) or a high labeling efficient pseudo-continuous ASL (pCASL) (67).  These  approaches offer increased 
labeling efficiency and improved SNR. These characteristics should make ASL an attractive non-invasive method 
for measuring both absolute perfusion in lung cancer and changes in perfusion upon treatment.  
 
Image data from all MRI examinations will be stored on a dedicated computer workstation for analysis. Image data 
will be correlated with other pharmacodynamic endpoints (eg, Ktrans with MVD; ADC with cellularity).   
 
Itraconazole pharmacokinetics (plasma, skin, tumor) 
 
These analyses will be performed at the Clinical Pharmacology & Experimental Therapeutics Center at Texas Tech 
University School of Pharmacy.  The Center laboratory includes a state-of-the-art mass spectrometry core including 
AB Sciex 5500 QTRAP®, AB Sciex 5600 TripleTOF™, and Agilent 7700x ICP-MS, and specializes in development 
of novel methods of analyses for analytes contained in complex biologic matrices, such as tumor tissue and skin 
biopsies.  The Center is strategically located adjacent to the Simmons Cancer Center to support collaborative 
research initiatives such as the current proposal.     
 
8.0 
STATISTICAL CONSIDERATIONS 
 
 
8.1 Sample size estimate 
 
Paired t-tests or Wilcoxon signed rank-tests will be used to investigate if there is a significant change in microvessel 
density (MVD) and angiogenic cytokine levels from pre-treatment to post-treatment. We will enroll up to 15 patients.  
A sample size of 10 patients will have 90% power to detect a 30% reduction in MVD between the pre-and post-
itraconazole tissue samples, assuming a standard deviation of 25% using a paired t-test with a two-sided 
significance level of 0.05. This is a relatively conservative estimate of effect size, as itraconazole reduces MVD by 
50-75% in preclinical lung cancer models (6). Up to 5 additional patients will be accrued as needed to ensure that 
we have 10 matched pairs of imaging, blood, and tissue data for analysis. In exploratory analyses, we will evaluate 
the association between baseline biomarkers and pharmacodynamic effects of itraconazole. 
 
The planned sample size of 15 patients is consistent with FDA recommendations for human PK 
studies.  Specifically, the number of subjects is projected to provide (1) 20% precision (SEM) 
 


Study Number – 122014-038 
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23 
within PK parameters, and (2) a reasonable understanding of intra-individual variability in 
pharmacokinetic parameters. (68)  
 
Additionally, subjects who miss more than 3 doses may be replaced with additional patients to be included in the 
analyses. 
 
8.2 Statistical analyses 
 
To determine effects of itraconazole on tumor angiogenesis, paired t-tests or Wilcoxon signed rank-tests 
will be used to investigate if there is a significant change in the values of tissue and peripheral samples, 
and imaging from pre-treatment to post-treatment.  
 
In order to determine effects of itraconazole on the Hedgehog pathway, pre- and post-treatment tissue 
samples and skin biopsies will be analyzed for GLI1 mRNA levels and compared using paired t-tests or 
Wilcoxon signed rank-tests. The nonlinear mixed effects model has been widely used to investigate the 
effect of pharmacokinetics (PK) on the pharmacodynamic profile of a drug compound.  
 
The nonlinear mixed effects model will be used to determine the effect of itraconazole pharmacokinetics 
(PK) on the pharmacodynamic profile of itraconazole. Post-treatment serum and tissue will be analyzed 
for itraconazole concentrations. Mean serum and tissue concentration-time profiles of itraconazole will be 
plotted on linear and semi-logarithmic scales based on scheduled sample times. For values recorded 
above the upper limit of quantification (ULoQ) or below the lower limit of quantification (LLoQ), the ULoQ 
or LLoQ respectively will be used for any summaries and plots. The individual serum and tissue 
concentration over actual time data will be used to derive the pharmacokinetic (PK) parameters by non-
compartmental PK analyses using Phoenix WinNonlin 6.1 or higher.  
 
The following PK parameters will be computed:  area under the concentration-time curve over the dosing 
interval (AUC), observed maximum serum and tissue concentration at steady state (Cmax,ss), average 
concentration at steady state (Cav), calculated as AUCτ/τ, minimum concentration immediately before the 
next application (Cmin), and terminal elimination half-life calculated from the pharmacokinetic profile (T1/2). 
Effects of these PK parameters will be compared to pharmacodynamic assay results using nonlinear 
mixed effects model. 
9.0 
STUDY MANAGEMENT 
9.1 
Conflict of Interest 
 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, 
or financial gain greater than the minimum allowable by their institution, etc.) must have 
the conflict reviewed by the UTSW COI Committee and IRB according to UTSW Policy 
on Conflicts of Interest.  All investigators will follow the University conflict of interest 
policy. 
 
 
9.2 
Institutional Review Board (IRB) Approval and Consent 
It is expected that the IRB will have the proper representation and function in accordance 
with federally mandated regulations. The IRB must approve the consent form and 
protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) 
and to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
Before recruitment and enrollment onto this study, the subject will be given a full 
explanation of the study and will be given the opportunity to review the consent form. 


Study Number – 122014-038 
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24 
Each consent form must include all the relevant elements currently required by the FDA 
Regulations and local or state regulations. Once this essential information has been 
provided to the subject and the investigator is assured that the subject understands the 
implications of participating in the study, the subject will be asked to give consent to 
participate in the study by signing an IRB-approved consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be 
signed and personally dated by the subject  and by the person who conducted the 
informed consent discussion. 
9.3       Registration Procedures 
 
All subjects must be registered with the Harold C. Simmons Cancer Center Clinical 
Research Office (CRO) before enrollment to study. Prior to registration, eligibility criteria 
must be confirmed with the CRO Study Coordinator.  
9.4 
Data Management and Monitoring/Auditing 
Trial monitoring will be conducted no less than annually and refers to a regular interval 
review of trial related activity and documentation performed by the DOT, which includes 
but is not limited to accuracy of case report forms, protocol compliance, timeliness and 
accuracy of Velos entries and AE/SAE management and reporting. Documentation of trial 
monitoring will be maintained along with other protocol related documents and will be 
reviewed during internal audit.   
 
 
 
The UTSW Simmons Cancer Center (SCC) Data and Safety Monitoring Committee 
(DSMC) is responsible for overall monitoring of data quality and patient safety.  As part of 
that responsibility, the DSMC reviews all local serious adverse events and unanticipated 
problems in real time as they are reported and reviews adverse events on a quarterly 
basis.   The Quality Assurance activity of the Clinical Research Office provides for 
periodic auditing of clinical research documents to ensure data integrity and regulatory 
compliance based on risk.  
 
The SCC-DSMC meets quarterly and conducts annual comprehensive reviews of 
ongoing clinical trials, for which it is the DSMC of record. 
 
Further detail may be found in the SCC-DSMC Plan.  
9.5      Adherence to the Protocol 
Except for an emergency situation in which proper care for the protection, safety, and 
well-being of the study subject requires alternative treatment, the study shall be 
conducted exactly as described in the approved protocol.  
9.5.1 Emergency Modifications 
Investigators may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval.  
 
For any such emergency modification implemented, an IRB modification form 
must be completed within five (5) business days of making the change. 


Study Number – 122014-038 
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25 
9.5.2  Other Protocol Deviations/Violations 
All other planned deviations from the protocol must have prior approval by the 
Principal Investigator and the IRB. According to the IRB, a protocol deviation is 
any unplanned variance from an IRB approved protocol that:  
 
Is generally noted or recognized after it occurs 
 
Has no substantive effect on the risks to research participants 
 
Has no substantive effect on the scientific integrity of the research plan or the 
value of the data collected  
 
Did not result from willful or knowing misconduct on the part of the 
investigator(s).  
 
An unplanned protocol variance is considered a violation if the variance: 
 
Has harmed or increased the risk of harm to one or more research 
participants. 
 
Has damaged the scientific integrity of the data collected for the study. 
 
Results from willful or knowing misconduct on the part of the investigator(s). 
 
Demonstrates serious or continuing noncompliance with federal regulations, 
State laws, or University policies. 
 
If a deviation or violation occurs without prior approval from the Principal 
Investigator, please follow the guidelines below: 
 
 
Protocol Deviations: Personnel will report to the SCC DSMC in accordance 
with their policies. Deviations should be summarized and reported to the IRB at 
the time of continuing review. 
 
Protocol Violations: Study personnel should report violations within two (2) 
week of the investigator becoming aware of the event using the same IRB online 
mechanism used to report Unanticipated Problems.  
9.6  
Amendments to the Protocol 
Should amendments to the protocol be required, the amendments will be originated and 
documented by the Principal Investigator.  A summary of changes document outlining 
proposed changes as well as rationale for changes, when appropriate, is highly 
recommended.  When an amendment to the protocol substantially alters the study design 
or the potential risk to the patient, a revised consent form might be required.  
 
The written amendment, and if required the amended consent form, must be sent to the 
IRB for approval prior to implementation.  
 
9.7 
Record Retention 
Study documentation includes all Case Report Forms, data correction forms or queries, 
source documents, Sponsor-Investigator correspondence, monitoring logs/letters, and 
regulatory documents (e.g., protocol and amendments, IRB correspondence and 
approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities 
and all reports and records necessary for the evaluation and reconstruction of the clinical 
research study. 
 
Government agency regulations and directives require that the study investigator retain 
all study documentation pertaining to the conduct of a clinical trial. In the case of a study 


Study Number – 122014-038 
________________________________________________________________________ 
26 
with a drug seeking regulatory approval and marketing, these documents shall be 
retained for at least two years after the last approval of marketing application in an 
International Conference on Harmonization (ICH) region. In all other cases, study 
documents should be kept on file until three years after the completion and final study 
report of this investigational study. 
 
9.8     Obligations of Investigators 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki. The Principal Investigator is responsible for personally overseeing the treatment 
of all study patients. The Principal Investigator must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during and 
after study completion. 
 
The Principal Investigator at each institution or site will be responsible for assuring that all 
the required data will be collected and entered onto the Case Report Forms. Periodically, 
monitoring visits may  be conducted and the Principal Investigator will provide access to 
his/her original records to permit verification of proper entry of data. At the completion of 
the study, all case report forms will be reviewed by the Principal Investigator and will 
require his/her final signature to verify the accuracy of the data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Number – 122014-038 
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27 
10.0 
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endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in 
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Holloway SE, Beck AW, Shivakumar L, Shih J, Fleming JB, Brekken RA. Selective blockade of 
vascular endothelial growth factor receptor 2 with an antibody against tumor-derived vascular endothelial 
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Nikolinakos PG, Altorki N, Yankelevitz D, Tran HT, Yan S, Rajagopalan D, et al. Plasma cytokine 
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Mamata H, Tokuda J, Gill RR, Padera RF, Lenkinski RE, Sugarbaker DJ, et al. Clinical 
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8088). 
 
 
 


Study Number – 122014-038 
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11.0 
APPENDICES 
 
Appendix A:   Drugs that may have their plasma concentrations increased by itraconazole 
 
 
Appendix B:   Biospecimen collection and processing:  
 
 
Appendix C: Pill Diary 
 
 
Appendix D: ECOG performance status scale 
 
 
 
 


Study Number – 122014-038 
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32 
Appendix A:   Drugs that may have their plasma concentrations increased by 
itraconazole 
[https://druginserts.com/lib/rx/meds/itraconazole/page/2/] 
 
Itraconazole and its major metabolite, hydroxy-itraconazole, can inhibit the metabolism of drugs 
metabolized by CYP3A4 and can inhibit the drug transport by P-glycoprotein, which may result 
in increased plasma concentrations of these drugs and/or their active metabolite(s) when they are 
administered with itraconazole. These elevated plasma concentrations may increase or prolong 
both therapeutic and adverse effects of these drugs. CYP3A4-metabolized drugs known to 
prolong the QT interval may be contraindicated with itraconazole, since the combination may 
lead to ventricular tachyarrhythmias including occurrences of torsade de pointes, a potentially 
fatal arrhythmia. Once treatment is stopped, itraconazole plasma concentrations decrease to an 
almost undetectable concentration within 7 to 14 days, depending on the dose and duration of 
treatment. In patients with hepatic cirrhosis or in subjects receiving CYP3A4 inhibitors, the 
decline in plasma concentrations may be even more gradual. This is particularly important when 
initiating therapy with drugs whose metabolism is affected by itraconazole. 
Examples of drugs that may have their plasma concentrations increased by itraconazole 
presented by drug class with advice regarding coadministration with itraconazole: 
Drug Class 
Contraindicated 
Not Recommended Use with Caution 
Comments 
 
Under no 
circumstances is the 
drug to be 
coadministered with 
itraconazole, and up 
to two weeks after 
discontinuation of 
treatment with 
itraconazole.  
It is recommended 
that the use of the 
drug be avoided 
during and up to two 
weeks after 
discontinuation of 
treatment with 
itraconazole, unless 
the benefits outweigh 
the potentially 
increased risks of 
side effects. If 
coadministration 
cannot be avoided, 
clinical monitoring 
for signs or 
symptoms of 
increased or 
prolonged effects or 
side effects of the 
interacting drug is 
recommended, and 
its dosage be 
reduced or 
interrupted as 
deemed necessary. 
When appropriate, it 
is recommended that 
plasma 
concentrations be 
measured. The label 
Careful monitoring is 
recommended when the 
drug is coadministered 
with itraconazole. Upon 
coadministration, it is 
recommended that 
patients be monitored 
closely for signs or 
symptoms of increased 
or prolonged effects or 
side effects of the 
interacting drug, and its 
dosage be reduced as 
deemed necessary. 
When appropriate, it is 
recommended that 
plasma concentrations 
be measured. The label 
of the coadministered 
drug should be 
consulted for 
information on dose 
adjustment and adverse 
effects.  
 


Study Number – 122014-038 
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33 
Drug Class 
Contraindicated 
Not Recommended Use with Caution 
Comments 
of the 
coadministered drug 
should be consulted 
for information on 
dose adjustment and 
adverse effects.  
 
Alpha Blockers 
 
tamsulosin 
 
 
Analgesics 
methadone 
 
alfentanil, 
buprenorphine IV and 
sublingual, fentanyl, 
oxycodone, sufentanil 
The potential increase 
in plasma 
concentrations of 
methadone when 
coadministered with 
itraconazole may 
increase the risk of 
serious cardiovascular 
events including QTc 
prolongation and . 
Methadone: torsade 
de pointes  
 
 
 
 
The potential increase 
in plasma 
concentrations of 
fentanyl when 
coadministered with 
itraconazole may 
increase the risk of 
potentially fatal 
respiratory depression. 
Fentanyl:  
 
 
 
 
No human 
pharmacokinetic data 
of an interaction with 
itraconazole are 
available. In vitro data 
suggest that sufentanil 
is metabolized by 
CYP3A4 and so 
potentially increased 
sufentanil plasma 
concentrations would 
be expected when 
coadministered with 
itraconazole. 
Sufentanil:  
Antiarrhythmics 
disopyramide, 
dofetilide, 
dronedarone, 
quinidine 
 
digoxin 
The potential increase 
in plasma 
concentrations of these 
drugs when 
coadministered with 
itraconazole may 
increase the risk of 
serious cardiovascular 
events including QTc 
prolongation. 
Disopyramide, 


Study Number – 122014-038 
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34 
Drug Class 
Contraindicated 
Not Recommended Use with Caution 
Comments 
dofetilide, 
dronedarone, 
quinidine:  
Antibacterials 
 
rifabutin 
 
Rifabutin:  
Anticoagulants and 
Antiplatelet Drugs 
 
rivaroxaban 
coumarins cilostazol, 
dabigatran 
Itraconazole may 
enhance the 
anticoagulant effect of 
coumarin-like drugs, 
such as warfarin. 
Coumarins:  
Anticonvulsants 
 
carbamazepine 
 
studies have 
demonstrated an 
increase in plasma 
carbamazepine 
concentrations in 
subjects concomitantly 
receiving ketoconazole. 
Although there are no 
data regarding the 
effect of itraconazole 
on carbamazepine 
metabolism, because of 
the similarities between 
ketoconazole and 
itraconazole, 
concomitant 
administration of 
itraconazole and 
carbamazepine may 
inhibit the metabolism 
of carbamazepine. 
Carbamazepine: In 
vivo  
Antidiabetics 
 
 
repaglinide, saxagliptin  
Antihelmintics and 
Antiprotozoals 
 
 
praziquantel 
 
Antimigraine Drugs 
ergot alkaloids, such 
as 
dihydroergotamine, 
ergometrine 
(ergonovine), 
ergotamine, 
methylergometrine 
(methylergonovine) 
 
eletriptan 
The potential increase 
in plasma 
concentrations of ergot 
alkaloids when 
coadministered with 
itraconazole may 
increase the risk of 
ergotism, ie. a risk for 
vasospasm potentially 
leading to cerebral 
ischemia and/or 
ischemia of the 
extremities. Ergot 
Alkaloids:  
Antineoplastics 
irinotecan 
dasatinib, nilotinib 
bortezomib, busulphan, 
docetaxel, erlotinib, 
ixabepilone, lapatinib, 
trimetrexate, vinca 
alkaloids 
The potential increase 
in plasma 
concentrations of 
irinotecan when 
coadministered with 


Study Number – 122014-038 
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35 
Drug Class 
Contraindicated 
Not Recommended Use with Caution 
Comments 
itraconazole may 
increase the risk of 
potentially fatal 
adverse events. 
Irinotecan:  
Antipsychotics, 
Anxiolytics and 
Hypnotics 
lurasidone, oral 
midazolam, 
pimozide, triazolam 
 
alprazolam, 
aripiprazole, buspirone, 
diazepam, haloperidol, 
midazolam IV, 
perospirone, quetiapine, 
ramelteon, risperidone 
Coadministration of 
itraconazole and oral 
midazolam, or 
triazolam may cause 
several-fold increases 
in plasma 
concentrations of these 
drugs. This may 
potentiate and prolong 
hypnotic and sedative 
effects, especially with 
repeated dosing or 
chronic administration 
of these agents. 
Midazolam, triazolam 
 
 
 
 
The potential increase 
in plasma 
concentrations of 
pimozide when 
coadministered with 
itraconazole may 
increase the risk of 
serious cardiovascular 
events including QTc 
prolongation and . 
Pimozide: torsade de 
pointes  
Antivirals 
 
 
maraviroc, indinavir, 
ritonavir saquinavir 
Indinavir, ritonavir 
Beta Blockers 
 
 
nadolol 
 
Calcium Channel 
Blockers 
felodipine, 
nisoldipine 
 
other dihydropyridines, 
verapamil 
can have a negative 
inotropic effect which 
may be additive to 
those of itraconazole. 
The potential increase 
in plasma 
concentrations of 
calcium channel 
blockers when co-
administered with 
itraconazole may 
increase the risk of 
congestive heart 
failure. Calcium 
channel blockers  
 
 
 
 
Concomitant 
administration of 
itraconazole may cause 
several-fold increases 
in plasma 


Study Number – 122014-038 
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36 
Drug Class 
Contraindicated 
Not Recommended Use with Caution 
Comments 
concentrations of 
dihydropyridines. 
Edema has been 
reported in patients 
concomitantly 
receiving itraconazole 
and dihydropyridine 
calcium channel 
blockers. 
Dihydropyridines:  
Cardiovascular 
Drugs, 
Miscellaneous 
ranolazine 
aliskiren 
 
The potential increase 
in plasma 
concentrations of 
ranolazine when 
coadministered with 
itraconazole may 
increase the risk of 
serious cardiovascular 
events including QTc 
prolongation. 
Ranolazine:  
Diuretics 
eplerenone 
 
 
The potential increase 
in plasma 
concentrations of 
eplerenone when 
coadministered with 
itraconazole may 
increase the risk of 
hyperkalemia and 
hypotension. 
Eplerenone:  
Gastrointestinal 
Drugs 
cisapride 
 
aprepitant 
The potential increase 
in plasma 
concentrations of 
cisapride when 
coadministered with 
itraconazole may 
increase the risk of 
serious cardiovascular 
events including QTc 
prolongation. 
Cisapride:  
Immunosuppressants  
everolimus, 
temsirolimus 
budesonide, ciclesonide, 
cyclosporine, 
dexamethasone, 
fluticasone, 
methylprednisolone, 
rapamycin (also known 
as sirolimus), tacrolimus 
 
Lipid Regulating 
Drugs 
lovastatin, 
simvastatin 
 
atorvastatin 
The potential increase 
in plasma 
concentrations of 
atorvastatin, lovastatin, 
and simvastatin when 
coadministered with 
itraconazole may 


Study Number – 122014-038 
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37 
Drug Class 
Contraindicated 
Not Recommended Use with Caution 
Comments 
increase the risk of 
skeletal muscle 
toxicity, including 
rhabdomyolysis. 
Respiratory Drugs 
 
salmeterol 
 
 
Urological Drugs 
 
vardenafil 
fesoterodine. sildenafil, 
solifenacin, tadalafil, 
tolterodine 
 
Other 
colchicine, in 
subjects with renal 
or hepatic 
impairment 
colchicine 
cinacalcet, tolvaptan 
The potential increase 
in plasma 
concentrations of 
colchicine when 
coadministered with 
itraconazole may 
increase the risk of 
potentially fatal 
adverse events. 
Colchicine: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Number – 122014-038 
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38 
 
 
Appendix B: Biospecimen collection and processing:  
  
Tumor specimens will be obtained from archived samples of the pre-treatment core-needle biopsy and 
core(s) obtained from the resected specimen at the time of surgery.  To account for intratumoral 
heterogeneity, we will employ image guidance for pre- and post-treatment tissue sampling, thereby 
obtaining tissue from similar sites within the tumor.  Specimens will be divided, with half to be (1) flash 
frozen in liquid nitrogen (for qPCR for Hh pathway components), and half designated to be (2) fixed in 4% 
paraformaldehyde (for RNAScope for Hh pathway components and IHC for angiogenic markers).   
 
Blood samples will be collected in the Simmons Cancer Center laboratory.  Plasma samples with EDTA 
will be collected at specified time-points.  Samples will be centrifuged at 1,100 × g (relative centrifugal 
force) for 15 min at 4°C for separation of plasma and mononuclear cell layers. Plasma will be stored at 
−70°C. Before analysis, samples will be thawed overnight at 4°C and centrifuged at 1,500 × g to remove 
debris.  PK time points have been selected to provide sufficient PK data but also to fit within hours of 
operation of this facility, thereby avoiding the need to admit subjects to our inpatient unit.   
 
Skin biopsies will be performed by trained study personnel according to previously-described methods. 
(69)  A 4-mm punch biopsy will be performed with a single suture placed after the procedure.  Lidocaine 
will be used to numb the patient skin and antibiotic ointment will be applied to the suture site. The 
specimen will be flash frozen for RNA procurement (PCR). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Study Number – 122014-038 
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39 
 
 
Appendix C: Pill Diary 
 
Itraconazole pill diary 
 
 
Dosing instructions: Take itraconazole with a meal. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AM
PM
AM
PM
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Time                
hh:mm
Number of pills 
taken
Day
Date             
MM/DD/YYYY


Study Number – 122014-038 
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40 
 
 
 
Appendix D: ECOG performance status scale: 
 (From Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 
5:649-655, 1982) 
 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light house work, 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair 
5 
Dead