Clinical trial NCT01787331
Conditions: Prostate Adenocarcinoma Recurrent Prostate Carcinoma Stage I Prostate Adenocarcinoma AJCC v7 Stage II Prostate Adenocarcinoma AJCC v7 Stage III Prostate Adenocarcinoma AJCC v7
Sponsor: University of California, San Francisco
Start date: 2013-10-29; Completion date: 2018-09-30
Enrollment: 21 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well itraconazole works in treating patients with biochemically relapsed prostate cancer. Itraconazole may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVES:

I. To determine whether the proportion of patients who achieve a \>= 50% decline in serum prostate-specific antigen (PSA) after 12 weeks of protocol therapy with itraconazole dosed at 300 mg orally (PO) twice daily (BID) is superior to a historical control based upon the observed PSA response proportion in prior studies of non-castrating systemic therapy in men with biochemically relapsed hormone sensitive prostate cancer.

SECONDARY OBJECTIVES:

I. To determine the median time to PSA progression from the start of protocol therapy with itraconazole among men with biochemically relapsed prostate cancer.

II. To determine the median time to clinical progression measured from the start of protocol therapy with itraconazole among men with biochemically relapsed prostate cancer.

III. To determine the median metastasis-free survival measured from the start of protocol therapy in patients treated with itraconazole for biochemically relapsed prostate cancer.

IV. To determine the mean percent change from baseline after 12 weeks of protocol therapy compared with pre-treatment in PSA doubling time.

V. To characterize the safety profile of itraconazole in the biochemically relapsed hormone sensitive prostate cancer population, as graded by Common Toxicity Criteria (CTCAE) version 4.03. All adverse events will be tabulated by grade according to the worst grade experienced.

VI. To determine the mean steady-state itraconazole and hydroxy-itraconazole serum levels after 4 weeks of therapy with itraconazole.

Arms: arm 1: Patients receive twice/day 300mg itraconazole (oral)
Interventions: intervention 1: Itraconazole intervention 2: Laboratory Biomarker Analysis intervention 3: Pharmacological Study
Intervention descriptions: intervention 1: Given PO intervention 2: Correlative studies intervention 3: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
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CC# 125513: Hedgehog Inhibition as a Non-Castrating Approach to Hormone 
Sensitive Prostate Cancer: A Phase II Study of Itraconazole in Biochemical Relapse 
 
 
Investigational Agent: Itraconazole 
 
IND: IND Exempt (IND 116597) 
 
 
Protocol Version: 4.0 
 
Version Date: October 8, 2014 
 
 
Principal Investigator: Rahul Aggarwal, M.D., HS Assistant Clinical Professor 
Division of Hematology/Oncology, Department of Medicine 
University of California San Francisco 
1600 Divisadero St. San Francisco, CA94115 
rahul.aggarwal@ucsf.edu 
 
 
 
 
Charles J. Ryan, M.D., 
Professor of Medicine  
Lawrence Fong, M.D., 
Professor in Residence 
Amy Lin, M.D., 
Associate Clinical Professor  
Won Kim, M.D., 
Assistant Clinical Professor 
UCSF Co-Investigators: 
Eric Small, M.D., 
Professor of Medicine and Urology 
Terence Friedlander, M.D., 
Assistant Clinical Professor  
 
 
 
 
 
 
 
Statistician: 
 
Li Zhang, Ph.D, Biostatistics Core 
 
 
 
 
RevisionHistory 
October 8, 2014 
Version 4.0 
November 18, 2013 
Version 3.0 
January 28, 2013 
Version 2.0 
July 16, 2012 
Version 1.0 


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Protocol Signature Page 
 
Protocol No.: 122513 
Version # and Date: 4.0 - October 8, 2014 
 
1.   I agree to follow this protocol version as approved by the UCSF Protocol Review Committee (PRC), 
Committee on Human Research (CHR), and Data Safety Monitoring Committee (DSMC). 
2.   I will conduct the study in accordance with applicable CHR requirements, Federal regulations, and 
state and local laws to maintain the protection of the rights and welfare of study participants. 
3.   I certify that I, and the study staff, have received the requisite training to conduct this research 
protocol. 
4.   I have read and understand the information in the Investigators‟ Brochure (or Manufacturer‟s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in accordance 
with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the Statement of 
Investigator (Form FDA 1572), and with local regulatory requirements. In accordance with the FDA 
Modernization Act, I will ensure the registration of the trial on the www.clinicaltrials.gov website. 
5.   I agree to maintain adequate and accurate records in accordance with CHR policies, Federal, state and 
local laws and regulations. 
 
 
 
UCSF Principal Investigator / Study Chair 
 
 
 
Printed Name 
 
 
 
Signature 
Date 
 
 
 
Principal Investigator 
Site 
 
 
 
Printed Name 
 
 
 
Signature 
Date 


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ABSTRACT 
 
Title 
Hedgehog Inhibition as a Non-Castrating Approach to Hormone Sensitive Prostate Cancer: A 
Phase II Study of Itraconazole in Biochemical Relapse 
Patient 
Population 
Patients with biochemically relapsed hormone sensitive non-metastatic prostate cancer after prior 
definitive local therapy 
Rationale 
for Study 
Preliminary data suggests itraconazole has anti-prostate cancer activity independent of androgen 
synthesis inhibition, thereby potentially avoiding the attendant castration-driven side effects.Its 
antagonistic properties within the Hedgehog signaling pathway and prior extensive safety record 
and demonstrated tolerability as an anti-fungal agent provide additional justification to test this 
agent in a rising PSA, non-metastatic disease setting. 
Favorable results with respect to modulation of serum PSA, along with parallel, exploratory 
findings demonstrating minimal impact on adrenal hormone synthesis, down-regulation of the 
Hedgehog pathway, and acceptable toxicity would form the preliminary basis and justification for 
the further study of itraconazole in biochemically relapsed hormone sensitive prostate cancer. 
Primary 
Objective 
To determine whether the proportion of patients who achieve a ≥ 50% decline in serum PSA after 
12 weeks of protocol therapy with itraconazole dosed at 300 mg BID is superior to a historical 
control based upon the observed PSA response proportion in prior studies of non-castrating 
systemic therapy in men with biochemically relapsed hormone sensitive prostate cancer. 
Secondary 
Objectives 
Clinical Activity 
•   To determine the median time to PSA progression from the start of protocol therapy with 
itraconazole among men with biochemically relapsed prostate cancer. 
•   PSA progression will be defined as follows: (1) If no PSA decline is observed on therapy, PSA 
progression will be defined as an increase in serum PSA > 50% above the baseline PSA, and 
an absolute increase of > 2 ng/mL above baseline, confirmed by repeat measurement at least 
2weeks later (2) If PSA declines on therapy, PSA progression will be defined as an increase in 
serum PSA > 50% above the nadir PSA on therapy, and an absolute increase > 2 ng/mL above 
the nadir, confirmed by repeat measurement at least 2weeks later. 
•   To determine the median time to clinical progression measured from the start of protocol 
therapy with itraconazole among men with biochemically relapsed prostate cancer. Clinical 
progression will be defined as the first occurrence of either the development of metastases or 
initiation of non-protocol therapy. 
•   To determine the median metastasis-free survival measured from the start of protocol therapy 
in patients treated with itraconazole for biochemically relapsed prostate cancer. 
•   To determine the mean percent change from baseline after 12 weeks of protocol therapy 
compared with pre-treatment in PSA doubling time. The pre-treatment PSA doubling time will 
be determined based upon all PSA measurements obtained within 3 months prior to Day 1 of 
protocol therapy, with a minimum of three PSA measurements spaced at least 14 days apart. 
Safety/Pharmacokinetics 
•   To  characterize the  safety profile of  itraconazole in  the  biochemically relapsed  hormone 
sensitive prostate cancer population, as graded by Common Toxicity Criteria (CTCAE) version 
4.03 (14-JUN2010). 
•   To determine the mean steady-state itraconazole and hydroxy-itraconazole serum levels after 4 
weeks of therapy with itraconazole. 
Correlative 
Objectives 
Endocrine Parameters 
•   To determine the mean percent change from baseline in serum androgen levels, including 
serum testosterone, DHEA-S, and androstenedione, after 4 and 12 weeks of protocol therapy 
with itraconazole. 
•  To determine the mean percent change from baseline in additional serum hormone levels, 
including adrenocorticotropic hormone (ACTH), aldosterone, deoxycorticosterone (DOC), 11- 
deoxycortisol, and cortisol after 4 and 12 weeks of protocol therapy with itraconazole. 
•   To determine if there is a  relationship between baseline and/or percent change in serum 
hormone levels and achieving a decline of > 50% in serum PSA after 12 weeks of protocol 
therapy. 


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ABSTRACT 
 
Hedgehog Pathway 
•   To  determine  the  proportion  of  patients  treated  with  itraconazole  who  display  a  down- 
regulation of the Hedgehog pathway, as assessed by measurement of GLI1 mRNA expression 
by qRT-PCR on serial skin biopsies obtained at baseline and after 4 weeks of protocol therapy. 
Down-regulation will be defined as a decline of any magnitude in GLI1 mRNA expression 
after 4 weeks of protocol therapy compared to baseline expression level. 
•   To determine if there is a relationship between down-regulation of the Hedgehog pathway and 
PSA modulation, including proportion of patients achieving a decline of > 50% in serum PSA 
as well as time to PSA progression. 
•   To evaluate archived primary prostate cancer tissue (biopsy or prostatectomy specimen) for 
baseline Hedgehog pathway status, using both qRT-PCR-based mRNA expression analysis and 
protein-based immunohistochemical (IHC) analysis of key Hedgehog pathway components 
(GLI1, PCTH1, SMO) and Sonic hedgehog ligand. 
•   To determine if there is a relationship between mRNA and IHC expression of components in 
the Hedgehog pathway in primary prostate cancer tissue and PSA modulation, including the 
proportion of patients achieving a decline of ≥ 50% in serum PSA as well as time to PSA 
progression. 
Study 
Design 
This is a phase II, single arm study of itraconazole dosed at 300 mg PO BID in patients with 
noncastrate, non-metastatic, biochemically relapsed prostate cancer after prior definitive local 
therapy. Simon‟s two stage minimax design will be followed for accrual and include an interim 
test for lack of efficacy. There is a pre-specified stopping rule for safety after 10 patients have 
been treated for a minimum of 8 weeks of protocol therapy. 
Study Schema: 
Number of 
patients 
40 evaluable patients will be enrolled across three investigational sites 
Duration of 
Therapy 
Patients will continue protocol therapy until PSA progression, development of metastases, 
initiation of non-protocol therapy, unacceptable toxicity, or patient/physician decision, whichever 
comes soonest. 
Duration of 
Follow up 
Follow-Up lasts through patient survival 
Duration of 
study 
The duration from first patient enrolled to analysis of the primary objective is estimated to be 
approximately 18 months. The total study duration including follow up is estimated to be 3 years. 
Study Drug 
Itraconazole: 100 mg capsules administered orally, 300 mg PO BID 


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ABSTRACT 
 
Safety 
Assessments 
Safety  Assessments:  History  and  physical  exam,  toxicity  assessment,  LFTs,  sodium,  and 
potassium level on day 8, week 4, then every 4 weeks thereafter. BUN and creatinine at baseline 
and every 4 weeks thereafter. 
Interim Safety Analysis: Will be performed after 10 patients have completed at least 8 weeks of 
protocol therapy. If 4 or more patients have a grade 3 or higher toxicity during the first 8 weeks of 
protocol therapy (excluding hypokalemia and hypertension) that the study investigator attributes 
as possibly, probably, or definitely related to study drug, further accrual will be halted. Study 
accrual will continue during the period of the interim safety analysis. 
Efficacy 
Endpoints 
• 
Median  time  to  PSA  progression  among  men  with  biochemical  relapse  treated  with 
itraconazole will be estimated. See Section 2 for the definition of PSA progression. 
• 
Median time to clinical progression will be estimated, with clinical progression defined as the 
first  occurrence of  either  development of  overt  metastases or  initiation of  non-protocol 
therapy. The definition of clinical progression excludes PSA-only progression. 
• 
Median  metastasis-free survival  will  be  estimated among  men  with  biochemical relapse 
treated with itraconazole. 
• 
Mean percent change after 12 weeks of protocol therapy compared with pre-treatment in PSA 
doubling time will be determined for those treated with itraconazole. The pre-treatment 
PSADT will be determined based upon all PSA measurements within 3 months prior to Day 1 
of protocol therapy, with a minimum of three PSA values each spaced at least 14 days apart 
(see section 6 of the protocol). 
• 
Median time to PSA progression between patients with and without Hedgehog pathway over- 
activation in archived primary prostate cancer tissue. 
Unique 
Aspects of 
the Study 
This study is the first to evaluate itraconazole and Hedgehog pathway inhibition in hormone 
sensitive biochemically relapsed prostate cancer and will further investigate the impact of 
itraconazole on modulating PSA, dissect its impact on adrenal hormone synthesis, and measure its 
effect on Hedgehog pathway activity in patients with biochemically relapsed prostate cancer. 


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List of Abbreviations 
 
ACTH             adrenocorticotropic hormone 
ADT               androgen deprivation therapy 
ALT                alanine aminotransferase 
AR 
androgen receptor 
AST 
aspartate aminotransferase 
ASTRO 
American Society for Therapeutic Radiation Oncology 
BCR 
biochemical relapse, biochemically relapsed 
BUN 
blood urea nitrogen 
CRPC 
castrate resistant prostate cancer 
CTEP 
Cancer Therapy Evaluation Program 
DES 
diethylstilbestrol 
DHEA-S 
dihydroepiandrostenedione-sulfate 
DOC 
deoxycorticosterone 
EC 
endothelial cell 
ECOG 
Eastern Cooperative Oncology Group 
EMT 
epithelial-to-mesenchymal transition 
FDA 
Food and Drug Administration 
GM-CSF 
granulocyte macrophage- colony stimulating factor 
Hh 
Hedgehog 
HIF 
hypoxia inducible factor 
HIV 
human immunodeficiency virus HUVEC
 
human umbilical vein endothelial cell 
IADT 
intermittent androgen deprivation therapy 
LHRH 
luteinizing hormone releasing hormone 
LLN 
lower limit of normal 
Na-F PET 
Sodium-fluoride positron emission tomography 
NYHA 
New York Heart Association 
PAB 
peripheral androgen blockade 
PCWG 
Prostate Cancer Working Group 
PDAR 
pre-developed assay reagent 
PSA 
prostate specific antigen 
PSADT 
PSA doubling time 
PTCH1 
patchedreceptor 
qRT-PCR 
quantitative reverse transcriptase- polymerase chain reaction 
SHH 
Sonic hedgehog signaling protein 
SMO 
Smoothened 
T 
testosterone 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 


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Table of Contents 
 
 
1.0 
Background....................................................................................................................... 9 
 
1.1 
Rationale for Developing Non-Castrating Therapies for Biochemically Relapsed 
Prostate Cancer ........................................................................................................................ 9 
1.2 
Itraconazole ................................................................................................................ 10 
1.3 
Demonstrating Clinical Activity in Initial Phase II Trials of Non-Hormonal 
Agents for Biochemically Relapsed Disease .............................................................. 17 
1.4 
Overall Study Rationale.............................................................................................. 19 
2.0 
2.0 Hypothesis and Study Objectives ............................................................................. 20 
2.1 
Hypothesis .................................................................................................................. 20 
2.2 
Study Objectives ......................................................................................................... 20 
3.0 
Study Design .................................................................................................................. 22 
 
3.1 
Overall Study Characteristics ..................................................................................... 22 
3.2 
Study Endpoints.......................................................................................................... 23 
3.3 
Study Schema ............................................................................................................. 25 
3.4 
Study Timeline ........................................................................................................... 25 
4.0 
Study Population ............................................................................................................ 25 
 
4.1 
Study Population......................................................................................................... 25 
4.2 
Inclusion Criteria ........................................................................................................ 26 
4.3 
Exclusion Criteria ....................................................................................................... 27 
5.0 
Study Rationale .............................................................................................................. 28 
5.1 
Rationale for the Study Population............................................................................. 28 
5.2 
Rationale for the Study Design and Dose Selection of Itraconazole .......................... 29 
5.3 
Rationale for the Selection of Study Endpoints.......................................................... 30 
6.0 
Study Activities .............................................................................................................. 34 
 
6.1 
Study Schedule ............................................................Error! Bookmark not defined. 
6.2 
Screening Period/Pre-Study Evaluation ..................................................................... 37 
6.3 
Study Treatment ......................................................................................................... 38 
6.4 
Reasons for Treatment Discontinuation ..................................................................... 40 
6.5 
Follow Up ................................................................................................................... 40 
6.6 
Duration of Study ....................................................................................................... 41 
7.0 
Study Drug Information ................................................................................................. 41 
 
7.1 
Itraconazole ................................................................................................................ 41 
8.0 
Dosage Modifications/Toxicity ...................................................................................... 43 
8.1 
Toxicity....................................................................................................................... 43 
8.2 
Dose Modifications for Specific Toxicities ................................................................ 43 
8.3 
Dose Modification for Other Adverse Events ............................................................ 45 
9.0 
Laboratory Assessment and Correlative Studies .............Error! Bookmark not defined. 
 
10.0 
Planned Statistical Methods ........................................................................................... 48 
10.1 Study Design............................................................................................................... 48 
10.2 Determination of Sample Size and Study Power........................................................ 49 
10.3 Accrual........................................................................................................................ 49 


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10.4 Interim Analysis ......................................................................................................... 50 
10.5 Analysis Population .................................................................................................... 50 
10.6 Demographics and Baseline Characteristics............................................................... 50 
10.7 Study Endpoints.......................................................................................................... 51 
11.0 
10.8 Methods for Analysis.................................................................................................. 52 
Reporting and Documentation of Adverse Events ......................................................... 55 
11.1 Definitions of Adverse Events (21 CFR 312.32(a)) ................................................... 55 
11.2 Recording of an Adverse Event .................................................................................. 57 
11.3 Follow-up of Adverse Events ..................................................................................... 58 
11.4 Serious Adverse Events Monitoring ........................................................................... 58 
12.0 
11.5 Serious Adverse Events Expedited Reporting ............................................................ 59 
Study Management ......................................................................................................... 60 
13.0 
References ...................................................................................................................... 65 
 
 
Appendix 1. 
List of Prohibited Medications and Supplements While Patients Are 
Taking Itraconazole ............................................................................................. 68 
 
Appendix 2. 
Potential Drug-Drug Interactions ........................................................................ 69 
 
Appendix 3. 
Skin Biopsy Procedure and Specimen Handling/Shipping Instructions ............. 70 
Appendix 4. 
Data and Safety Monitoring Plan for a Phase 2 Institutional Study.................... 75 


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1.0     Background 
 
An estimated 50,000 men/year in the U.S develop a rising PSA after definitive radical 
prostatectomy and/or radiation therapy for localized disease, a disease state termed biochemical 
relapse (BCR) [1,2].The optimal timing and choice of treatment of men in this disease state is 
unknown and clinical practice varies widely. Salvage prostatectomy and radiation therapy have 
been shown to lead to long-term disease free survival in a minority of patients, especially those 
with a slow PSA doubling time (PSADT), positive surgical margins, and/or lower Gleason grade 
and serum PSA level at the time of initial diagnosis [3]. For patients that are not candidates for 
local salvage therapy, hormonal treatment via androgen deprivation therapy (ADT)is often 
employed  to  control  serum  PSA  and  potentially  delay  the  development  of  symptomatic 
metastatic disease. 
 
1.1      Rationale for Developing Non-Castrating Therapies for Biochemically 
Relapsed Prostate Cancer 
 
Continuous androgen deprivation therapy (ADT), in which serum testosterone is decreased to a 
castrate level (less than 50 ng/dL)using luteinizing hormone releasing hormone (LHRH) agonists 
or antagonists, with or without the addition of an androgen receptor (AR) antagonist (i.e. 
bicalutamide), is a standard and commonly used treatment in BCR. There are no randomized 
data demonstrating an overall survival advantage for early continuous ADT versus deferred 
therapy until the time of progression to metastatic disease. Furthermore, while continuous, long 
term treatment with ADT is effective in terms of decreasing PSA levels, disease progression in 
the setting of castrate levels of testosterone is a near universal event. Additionally, over the past 
decade, there has been a growing appreciation for the significant short term and longer term 
toxicities of continuous ADT, including declining quality of life on treatment and increased risk 
of osteoporosis, diabetes, and potentially cardiovascular mortality with long term treatment. 
 
Given the toxicities of long term, continuous ADT, more contemporary hormonally-based 
treatment strategies utilizing intermittent ADT (IADT) and peripheral androgen blockade 
(PAB)have emerged for men with BCR [4-8].IADT, in which treatment with an LHRH agonist 
or antagonist is given in cycles consisting of “on” and “off” treatment phases, has been shown to 
lead to non-inferior overall survival and potentially improved quality of life in several prior 
phase 3 trials [4-8]. Though seemingly an improvement over continuous ADT with regards to 
preservation of overall quality of life, patients treated with IADT may experience delayed 
testosterone recovery during “off” treatment phases, and the percentage of time spent off 
treatment becomes progressively shorter with successive cycles of treatment, such that many 
patients are still at increased risk of long term metabolic derangements including osteoporosis, 
diabetes, and cardiovascular disease related to ADT[9]. 
 
Given the significant short- and long-term toxicities of castration-based therapy, which can 
impair quality of life and cause significant morbidity in this relatively asymptomatic population 
of men with BCR, there is an unmet medical need for well tolerated non-castrating therapies in 


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this disease setting. Non-castrating therapies may ultimately be used to replace the need for ADT 
in biochemically relapsed disease, delay the initiation of ADT, or potentially lengthen the 
duration of “off” treatment phase as part of an intermittent ADT treatment strategy, 
therebyprolonging the time to development of castrate-resistant disease. 
 
Various non-castrating agents have been tested in prior phase 2 clinical trials in the bichemically 
relapsed disease setting, including a prostatic acid phosphatase vaccine, GM-CSF, as well as 
other therapies such as imatinib, rosiglitazone,lenalidomide, celecoxib,and superoxide dismutase 
inhibitors including marimastatand ATN-224 [10-16]. In general, the clinical activity of these 
agents has been modest, withless than 5% of patients achievinga decline in serum PSA ≥ 50% 
during protocol therapy with these non-castrating agents. In addition, several of the therapies 
were associated withappreciabletoxicity, including imatinib, which is especially undesirable in 
this population of patients without metastases and low disease burden. There exists a need for 
novel non-hormonal agents with improved biologic activity and better tolerabilityfor use in 
biochemically relapsed disease. 
 
1.2      Itraconazole 
 
Itraconazole, a member of the azole family of anti-fungal antibiotics, has shown intriguing anti- 
cancer  activity  in  pre-clinical  and  clinical  studies,  including  prostate  cancer  [see  further 
discussion below]. Unlike the related compound ketoconazole, which exerts its effects in prostate 
cancer   via   androgen   synthesis   inhibition,   preliminary  data   suggests   that   itraconazole‟s 
mechanism of action in prostate cancer may be independent of androgen synthesis blockade. 
Given the demonstrated biologic activity in prostate cancer with a potentiallynon-castrating 
mechanism of action, as well as its long term safety data and demonstrated tolerability as an anti- 
fungal agent in patients with chronic fungal infections, itraconazole is well-suited for evaluation 
in biochemically relapsed prostate cancer. 
 
1.2.1   Mechanism of Action Distinct From Ketoconazole 
 
The anti-fungal activity of the azole family of antibiotics stems from their ability to inhibit 
fungal wall ergosterol synthesis, via inhibition of the enzyme lanasterol 14α-demethylase [17]. 
As compared with ketoconazole, itraconazole more selectively inhibits fungal wall ergosterol 
synthesis, and spares inhibition of human adrenal hormone synthesis. Consequently, itraconazole 
is not associated with the development of clinically significant adrenal insufficiency, nor is 
concomitant corticosteroid replacement required as it is for ketoconazole [18]. 
 
The results of a prior randomized, non-comparative study of low- (200 mg/day) and high-dose 
(300 mg PO BID) itraconazole in metastatic castrate-resistant prostate cancer (CRPC) provide 
preliminary evidence thatitraconazole has a mechanism of action independent of androgen 
synthesis blockade, distinct from the mechanism of action of ketoconazole [19]. In this trial, 
there was no decrease in serum testosterone (T) or adrenal androgen dihydroepiandrostenedione 
(DHEA) levels in patients treated with either low or high doseitraconazole [see figure 1 below]. 
It is important to note, however, that hormone levels were measured in the context of a medically 


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castrate patient population, with a different hormonal milieu than the proposed study population. 
In contrast to the effects of itraconazole on serum androgen levels in CRPC, a prior randomized 
clinical trial of antiandrogen withdrawal with or without ketoconazole in CRPC, serum levels of 
adrenal androgen hormones DHEA, DHEA-sulfate, and androstenedione decreased by 54%, 
90%,  and  58%  respectively,  and  higher  baseline  levels  of  adrenal  androgen  levels  were 
associated with PSA response to ketoconazole [20, 21]. 
 
Figure 1. Serum Testosterone and DHEA Levels On Itraconazole Therapy In Men With 
Castrate Resistant Prostate Cancer (from Antonarakis E, et al. J of ClinOncol 2011) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2.2   Non-Hormonal Mechanisms of Action of Itraconazole 
 
There are several potential mechanisms of action of itraconazole as an anti-cancer agent that 
have been investigated in prior studies: (1) inhibition of angiogenesis and (2) Hedgehog (Hh) 
pathway suppression. 
 
1.2.2.1   Itraconazole as a Potential Anti-Angiogenesis Agent 
 
In a human umbilical vein endothelial cell (HUVEC) proliferation assay used to screen a library 
of FDA-approved drugs, itraconazole was unexpectedly identified as a potent and selective 
inhibitor of endothelial cell (EC) proliferation [22], only in part via inhibition of the enzyme 
lanosterol 14 alpha-demethylase. Itraconazole inhibited EC proliferation at a potency 40 times 
that of ketoconazole. In another study using a lung cancer xenograft model, treatment with 
itraconazole was shown to increase intra-tumoral levels of hypoxia inducible factor 1 alpha 
(HIF1α) and decrease tumor microvessel density [23]. Whether the mechanism of action of 
itraconazole as a potential anti-neoplastic agent stems from its ability to inhibit angiogenesis 
remains an unresolved question. In the prior clinical trial of itraconazole in metastatic CRPC, 
serum VEGF levels did not consistently decline with treatment, nor were reductions in serum 
VEGF associated with declines in serum PSA on treatment. Furthermore, inhibiting angiogenesis 


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in  non-metastatic  biochemically  relapsed  disease,  in  which  presumed  micrometastases  are 
present, may not be as biologically relevant as other anti-cancer mechanisms of action. 
 
1.2.2.2   Hedgehog Pathway in Prostate Cancer 
 
The hedgehog pathway (see figure 2 below) plays an important role in embryonic development 
and tissue polarity [24]. Secreted Hh molecules bind to the receptor patched (PTCH), thereby 
relieving PTCH-mediated suppression of Smoothened (SMO). SMO thentranslocates to the 
primary cilia, triggering a cascade of intracellular signal transduction events. This results in GLI- 
dependent transcription of various growth factors and signaling molecules, including PTCH and 
GLI1, which act as negative and positive feedback loops respectively. Dysregulation of the Hh 
pathway via somatic mutations has been implicated in the tumorigenesis of various cancer 
subtypes, including basal cell carcinoma of the skin, in which loss-of-function mutations in 
PCTH  and  less  commonly  activating  mutations  in  SMO  lead  to  constitutive  Hh  pathway 
signaling and unrestrained proliferation of basal cells in the skin [25]. 
 
Figure 2. Hedgehog Pathway 
(figure adapted from http://www.thelancetstudent.com/wp-content/uploads/2010/02/fig1.jpg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Preclinical studies in other solid tumors, including prostate and pancreatic adenocarcinoma, 
suggest that aberrant activation of the Hh pathway may promote tumor-stromal interaction and 
the epithelial-to-mesenchymal (EMT) transition, key steps in the progressionto metastatic cancer 
[26]. Re-activation of the Hh pathway, which is quiescent in the normal adult male prostate 
gland, may be an important mechanism in the progressionto metastasesin prostate cancer. 


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In cell lines stably expressing GLI1, Hh pathway activation was shown to promote proliferation 
of prostate cancer cells and malignant transformation of progenitor-like primary cells which 
formeddiffuse visceral metastases in a mouse xenograft model [27]. Administration of 
cyclopamine, a small molecule inhibitor of SMO, inhibits metastasis in this mouse xenograft 
model. The level of E-cadherin, a molecule that maintains epithelial organization and cellular 
attachment, was downregulated in cell lines with forced GLI expression, suggesting that one 
mechanism by which Hhsignaling promotes invasiveness and metastasis is by driving EMT. In 
human prostate cancer, metastatic tissue from 12/12 patients overexpressed PTCH and GLI1 by 
real time RT-PCR analysis; in contrast, only 3/12 localized prostate cancer samples and none of 
the benign prostate tissue samples overexpressed PTCH or GLI1.A separate study reported 
that70% of Gleason grade 8-10 human prostate cancer specimens displayed higher expression 
levels of two Hh pathway target genes, PCTH1 and the hedgehog-interacting protein (HIP) 
compared with only 22% of Gleason grade 3-6 tumors   [28], pointing to a role for the Hh 
pathway in aggressive tumor biology. 
 
 
Thus, inhibition of the Hh pathway may target tumor-stromal interactions and inhibit the EMT, 
thereby delaying microscopic tumor growth and invasion. Biochemically relapsed disease, in 
which  microscopic  disease  is  present  and  potentially  invasive  in  other  tissues,  therefore 
represents a logical disease setting in which to evaluate Hh pathway inhibition. 
 
1.2.2.3   Itraconazole and Hedgehog Pathway Inhibition 
 
Pre-clinical and emerging clinical data suggest that itraconazoleis a potent inhibitor of the 
Hedgehog pathway. In a drug screen study of ~ 2400 FDA-approved or post-phase I drugusing a 
cell line containing a stably integrated GLI1-luciferase reporter which responds to exogenous 
stimulation by Sonic hedgehog signaling protein (SHH), itraconazole was identified as a potent 
inhibitor of the Hh pathway with an IC50  of approximately 800 nM,greater than 10-fold more 
potent than that of ketoconazole (see figure 3 below) [29]. 


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Figure 3.Itraconazole Potently Inhibits Hedgehog Pathway Relative to Other Azoles 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Further experiments in PTCH-null and mutant SMO cell lines indicate that itraconazole inhibits 
the Hh pathway via a mechanism distinct from its effects on sterol biosynthesis by acting as an 
inverse agonist of SMO, thereby preventing its accumulation within the primary cilium. In a 
follow up study using a mouse xenograftmedullablastoma model with constitutively active 
Hhsignaling, itraconazole inhibited the growth of tumor allografts at steady-state serum 
concentrations comparable to those of patients treated with 200-300 mg PO BID on a chronic 
basis for fungal infections (see figure 4 below) [29]. 
 
 
Figure 4.Itraconazole Inhibits In Vivo Growth of a MedulloblastomaXenograft 


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In a recently presented phase II open label study of 19 patients with basal cell carcinoma, 
treatment with itraconazole (dosed at either 200 or 400 mg/day) led to a 23% reduction in 
clinical tumor area and a 65% reduction in Hedgehog activity as assessed by GLI1 mRNA 
expression [30]. In an intriguing correlative study from the previously described phase II trial of 
low- and high-dose itraconazole in patients with CRPC, modulation of Hh pathway activity was 
assessed by serial skin biopsy. Tissue samples were assayed for GLI1 mRNA expression by 
qRT-PCR, using previously validated methods [25]. In this analysis, 33% of patients treated with 
itraconazole 200 mg/day and 68% of patients  treated  with 300 mg PO BID  experienced  a 
decrease inGLI1 expression [31]. Interestingly, GLI1downregulation appeared to be associated 
with an improvement in PSA progression-free survival, the primary endpoint of the study (see 
figure 5 below). 
 
 
Figure  5.  Correlation  of  GLI1Downregulation  with  Outcomes  in  a  Prior  Study  of 
Itraconazole in Castrate Resistant Prostate Cancer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In summary, itraconazole appears to have a distinct mechanism of action from ketoconazole and 
an emerging  role  as  a  non-castrating  prostate  cancer  therapeutic  agent.  The anti-neoplastic 
activity of itraconazole may act via inhibition of the Hedgehog pathway, which is implicated in 
the progression to metastatic prostate cancer. Inhibiting Hh signaling may be especially relevant 
in patients with biochemically relapsed prostate cancer, who havemicrometastases that ultimately 
progress tomacrometastatic diseasein the axial skeleton and other organs. 
 
1.2.3   Clinical Efficacy and Safety of Itraconazole 
 
1.2.3.1   Clinical Efficacy in CRPC 
 
Itraconazole dosed at 300 mg PO BID exhibited promising clinical activity in the phase II, 
randomized, non-comparative trial of low- and high-dose itraconazole (200 mg/day and 300 mg 
BID respectively) in patients with metastatic castrate resistant prostate cancer [19]. In this study, 
the mean age was approximately 72 years old, approximately 30% of patients had prior treatment 


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Phase II - Itraconazole 
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coccidioidomycosis; 28% with cryptococcosis, 12% with aspergillosis), with the majority of 
patients treated with a dose of 400 mg/day, the medication was well tolerated and patients 
received treatment for a median duration of 5 months (range < 1 to 42 months) [32]. As in the 
Antonorakis et al. trial outlined above, gastrointestinal symptoms were among the most common 
adverse events, with 10% of patients experiencing nausea/vomiting, 2% with diarrhea. Elevated 
transaminases occurred in 5% of patients, none with elevations > 3 times the upper limits of 
normal. Toxicity led to discontinuation of itraconazole in 4% of patients. 
 
 
In another study of high dose itraconazole (600 mg/day) delivered for a mean duration of 5.5 
months to 8 patients, none experienced gastrointestinal symptoms attributable to itraconazole 
[33]. No elevations in transaminases were noted. Mild hypokalemia and peripheral edema were 
observed in 3/8 patients, though not in association in hypertension and again without an increase 
in serum aldosterone concentration. Another study of ten patients receiving doses of itraconazole 
ranging from 200-400 mg/day for chronic mycotic infections, serial cosyntropin assays failed to 
detect subclinical adrenal insufficiency in any of the ten patients [22]. In contrast, patients treated 
with ketoconazole at high doses (i.e. 800-1200 mg/day in divided doses) developed clinically 
significant adrenal insufficiency in a prior prospective observational study [34]. 
 
 
Taken together, the clinical efficacy and safety data of itraconazole at a dose of 600 mg/day 
indicates promising clinical benefit in advanced prostate cancer. In a lower tumor burden setting 
such as biochemical relapse, itraconazole may have an even greater impact on disease control 
and/or may be a less toxic alternative to castration therapy.Its long track record of demonstrated 
tolerability  and  safety  as  an  anti-fungal  agent,  even  with  chronic  daily  dosing,  serves  as 
additional justification to explore its potential for clinicalbenefit in this disease setting. 
 
1.3 
Demonstrating Clinical Activityin Initial Phase II Trials of Non- 
Hormonal Agents for Biochemically Relapsed Disease 
 
Developing novel non-castrating therapies for men with biochemical relapse presents several 
unique study design challenges in initial phase I/II trials of newagents tested in this setting. 
Using clinically relevant study endpoints such as time to metastatic disease, time to castrate- 
resistant disease, or overall survival require long term study follow up and large patient numbers 
for  adequate  statistical  power.  Such  endpoints  are  best  utilized  in  larger  phase  II  and 
confirmatory phase III clinical trials. Changes in serum PSA represent the primary means to 
assess the preliminary biologic activity of novel agents tested in phase I/II trials in the 
biochemically relapsed disease setting, yet changes in serum PSA have not been validated as a 
surrogate marker of clinical outcome. Furthermore, the specific choice of PSA-based study 
endpoint has varied in prior trials of non-castrating agents in biochemical relapse. 
 
1.3.1   Decline in Serum PSA 
 
The proportion of patients achieving PSA declines of > 50% is a widely utilized endpoint as a 
means for screening the biologic activity of novel agents in the castrate-resistant disease setting. 


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PCWG2 recommended that phase II trials in the CRPC setting adopt time-to-event variables 
such as progression-free survival based on radiographic/clinical variables rather than declines in 
serum PSA as the primary means of assessing biologic activity in this disease setting. For 
biochemically relapsed disease, however, declines in serum PSA may still have utility as a means 
to determine which agents show anti-cancer activity, as was demonstrated in prior trials of 
imatinib and GM-CSF in biochemically relapsed prostate cancer [12, 15]. Though PSA declines 
are not a validated surrogate marker, a retrospective analysis of hormonal therapy for 
biochemically relapsed hormone sensitive prostate cancer demonstrated that greater declines of 
PSA while on therapy were significantly associated with longer prostate cancer specific survival 
[35]. Preliminary data indicating that a novel therapy leads to substantial PSA declines in a 
significant proportion of patients, along with acceptable safety data, would form the basis for 
larger, placebo-controlled, randomized phase II/III trials with primary efficacy endpoints 
including time to first metastasis or overall survival. Several caveats to the use of PSA decline as 
a study endpoint are the fact that it is not a validated surrogate endpoint for overall survival in 
the CRPC disease setting, certain agents may affect PSA expression without demonstrable anti- 
tumor activity, and conversely, cytostatic agents may have a beneficial effect with respect to 
control of micrometastases without affecting serum PSA. 
 
1.3.2   PSA Progression-Free Survival 
 
Time-to-event variables such as radiographic or PSA progression-free survival have been 
increasingly used as primary endpoints in initial phase II trials of novel agents in the castrate- 
resistant prostate cancer setting, in accordance with updated guidelines from the Prostate Cancer 
Working Group. In the hormone sensitive, biochemically relapsed disease setting there is no 
standardized definition of PSA progression, with PSA Working Group guidelines suggesting the 
definition of PSA progression must be individualized for each study depending upon the 
mechanism of the agent being tested (i.e. hormonal therapy, chemotherapy, immunotherapy, etc.) 
[36].   In a prior phase II study of ATN-224, a novel targeted superoxide dismutase inhibitor, 
progression was defined as an increase in serum PSA over baseline of ≥ 50% (and by > 5 ng/mL) 
[16]. This definition is acknowledged to be arbitrary but does reflect clinical practice with 
intermittent androgen deprivation therapy, in which patient‟s baseline PSA prior to initiation of 
ADT is taken into account when deciding at what PSA level to re-initiate therapy. In contrast, in 
an ongoing phase III trial of ADT +/- docetaxel in the biochemically relapsed disease setting, the 
primary endpoint is progression-free survival, with PSA progression defined as a detectable PSA 
of any level after completion of treatment (NCT00514917). This definition is more appropriate 
for chemohormonal therapy than for non-castrating targeted agents. 
 
Extrapolation from the PCWG2 recommendations for castrate-resistance prostate cancer can be 
applied to the biochemically relapsed disease setting, in which PSA progression is defined by the 
nadir PSA achieved on therapy. According to PCWG2 recommendation, a rise in serum PSA > 
25% and an absolute increase of at least 2 ng/mL above the nadir PSA defines PSA progression 
in  the  castrate-resistant  disease  setting.  Whether  the  same  threshold  is  appropriate  in  the 


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hormone-sensitive biochemically relapsed disease setting is debatable, given the lower burden of 
disease and sensitivity to androgen deprivation in the latter disease state. 
 
At the current time, given the absence of a standard definition of PSA progression in the BCR 
disease setting, choosing a threshold that is consistent with the mechanism of the agent being 
tested, and then uniformly applying the same definition of progression to all patients included in 
the clinical trial or observational study is recommended to avoid potential measurement bias. 
 
1.3.3   Change in PSA Kinetics on Therapy 
 
A   prior   retrospective,   combined   analysis   of   4   clinical   trials   of   non-castrating   agents 
(lenalidomide, marimastat, imatinib, and ATN-224) in biochemically relapsed prostate cancer 
provides preliminary evidence for the potential clinical significance of within-subject changes in 
serum PSA slope during treatment [37]. In this analysis, four factors were predictive of 
metastasis-free survival on multivariate analysis: baseline PSA doubling time, baseline PSA 
slope, on-study change in PSA doubling time, and on-study change in PSA slope. In a landmark 
Kaplan-Meier analysis, median metastasis-free survival was 63.5 months (95% CI 34.6-not 
reached) and 28.9 months (95% CI 13.5-68.0) for men with or without any decrease in PSA 
slope by 6 months of treatment, respectively. These results, however, are retrospective and need 
to be validated in prospective study prior to widespread acceptance of change in PSA slope as an 
alternative endpoint for screening new non-hormonal therapies in patients with biochemical 
relapse. 
 
A prior randomized, placebo-controlled, phase II study of rosiglitazone highlights several of the 
methodological issues with the use of changes in PSADT as the primary study endpoint in 
biochemical relapse [14]. The primary study endpoint was a positive PSA doubling time 
(PSADT) outcome, defined as either a post-treatment PSADT > 150% compared to baseline 
PSADT or a declining PSA on treatment in the absence of development of new metastases. 
Patients were excluded if baseline PSADT was > 24 months. Yet, there was no standardization 
of serum PSA measurement prior to and after study enrollment, both with respect to frequency of 
PSA measurement and potential inter-laboratory variability, thus making within-subject pre- 
treatment and on-treatment calculations of PSADT more difficult to interpret. A second issue 
highlighted by this study is that increases in PSADT can occur even in the absence of treatment, 
due to the inherent variability of PSA measurement over time. In this study, 40% of the men in 
the placebo group experienced an increase in post-treatment PSADT to > 150%, a result that was 
much higher than expected and may have contributed to an overall negative study (38% of 
patients in the rosiglitazone arm had an increase in PSADT > 150%; p = 1). 
 
1.4      Overall Study Rationale 
 
The properties of itraconazole - single agent activity in prostate cancer, a potentially non- 
castrating mechanism of action distinct from ketoconazole, Hedgehog pathway inhibition which 
may block the formation of metastases, and an established safety record at an FDA-approved 
dose level for chronic fungal infections - make it a compelling agent to test in biochemically 


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relapsed prostate cancer. The proposed clinical trial is a single arm phase 2 study of itraconazole 
dosed at 300 mg PO BID in men with biochemically relapsed non-metastatic hormone sensitive 
prostate cancer. The primary endpoint of the study is the proportion of patients achieving ≥ 50% 
PSA decline after 12 weeks of therapy. Secondary endpoints include change in PSA doubling 
time, time to PSA or clinical progression, metastasis-free survival, and toxicity. Correlative 
endpoints will include serum hormone levels and Hedgehog pathway activity. Favorable results 
with   respect   to   modulation   of   serum   PSA,   along   with   parallel,   exploratory   findings 
demonstrating minimal impact on adrenal hormone synthesis, down-regulation of the Hedgehog 
pathway, and acceptable toxicity would form the preliminary basis and justification for the 
further study of itraconazole in biochemically relapsed hormone sensitive prostate cancer. Its use 
in this setting may ultimately either be to delay the need for initiation of ADT or to lengthen the 
duration  of  “off”  treatment  cycles  as  part  of  an  intermittent  ADT  treatment  strategy. 
Furthermore, demonstrating that the anti-prostate cancer activity of itraconazole is not primarily 
related to androgen synthesis inhibition would form the impetus for further study into the 
mechanism of action of itraconazole in prostate cancer. 
 
2.0     Hypothesis and Study Objectives 
 
2.1      Hypothesis 
 
A significantly greater proportion of patients treated withitraconazole will achieve at least a 50% 
decline from baseline in serum PSA after 12 weeks of therapy, as compared to a historical 
control based upon the PSA response proportion observed in prior phase II clinical trials of other 
non-castrating therapiesin men with biochemically relapsed hormone sensitive prostate cancer. 
Favorable results with respect to PSA modulation, along with parallel findings demonstrating 
acceptable toxicity, potent Hedgehog pathway inhibition, and absence of significant impact on 
serum hormone levels,would form the basis for the further study of itraconazoleas a potentially 
viable non-castrating treatment option for men with biochemically relapsed prostate cancer. 
 
2.2      Study Objectives 
 
2.2.1   Primary Objective 
 
To determine whether the proportion of patients who achieve a ≥ 50% decline in serum PSA 
after 12 weeks of protocol therapy with itraconazole dosed at 300 mg PO BID is superior to a 
historical control based upon the observed PSA response proportion in prior studies of non- 
castrating systemic therapy in men with biochemically relapsed hormone sensitive prostate 
cancer. 


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2.2.2   Secondary Objectives 
 
Clinical Activity 
• To determine the median time to PSA progression from the start of protocol therapy with 
itraconazole among men with biochemically relapsed prostate cancer. 
PSA progression will be defined as follows: (1) If no PSA decline is observed on therapy, 
PSA progression will be defined as an increase in serum PSA > 50% above the baseline 
PSA, and an absolute increase of > 2 ng/mL above baseline, confirmed by repeat 
measurement at least 2weeks later (2) If PSA declines on therapy, PSA progression will be 
defined as an increase in serum PSA > 50% above the nadir PSA on therapy, and an 
absolute increase > 2 ng/mL above the nadir, confirmed by repeat measurement at least 
2weeks later. 
• To determine the median time to clinical progression measured from the start of protocol 
therapy with itraconazole among men with biochemically relapsed prostate cancer. Clinical 
progression will be defined as the first occurrence of either the development of metastases 
or initiation of non-protocol therapy, and will exclude PSA-only progression. 
• To determine the median metastasis-free survival measured from the start of protocol 
therapy in patients treated with itraconazole for biochemically relapsed prostate cancer. 
• To determine the mean percent change from baseline after 12 weeks of protocol therapy 
compared with pre-treatment in PSA doubling time. The pre-treatment PSA doubling time 
will be determined based upon all PSA measurements obtained within 3 months prior to 
Day 1 of protocol therapy, with a minimum of three PSA measurements spaced at least 14 
days apart. 
 
 
Safety/Pharmacokinetics 
• To characterize the safety profile of itraconazole in the biochemically relapsed hormone 
sensitive prostate cancer population, as graded by Common Toxicity Criteria (CTCAE) 
version 4.03 (14-JUN-2010). 
• To determine the mean steady-state itraconazole and hydroxy-itraconazole serum levels 
after 4 weeks of therapy with itraconazole. 
 
2.2.3   Correlative Objectives 
 
Endocrine Parameters 
• To determine the mean percent change from baseline in serum androgen levels, including 
serum  testosterone,  DHEA-S,  and  androstenedione,  after  4  and  12  weeks  of  protocol 
therapy with itraconazole. 
• To determine the mean percent change from baseline in additional serum hormone levels, 
including adrenocorticotropic hormone (ACTH), aldosterone, deoxycorticosterone (DOC), 
11-deoxycortisol, and cortisol after 4 and 12 weeks of protocol therapy with itraconazole. 


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• To determine if there is a relationship between baseline and/or percent change in serum 
hormone levels and achieving a decline of ≥ 50% in serum PSA after 12 weeks of protocol 
therapy. 
 
 
Hedgehog Pathway: 
• To determine the proportion of patients treated with itraconazole who display a down- 
regulation of the Hedgehog pathway, as assessed by measurement of GLI1 mRNA 
expression by qRT-PCR on serial skin biopsies obtained at baseline and after 4 weeks of 
protocol therapy. Down-regulation will be defined as a decline of any magnitude in GLI1 
mRNA expression after 4 weeks of protocol therapy compared to baseline expression level. 
• To determine if there is a relationship between down-regulation of the Hedgehog pathway 
and PSA modulation, including proportion of patients achieving a decline of ≥ 50% in 
serum PSA as well as time to PSA progression. 
• To evaluate archived primary prostate cancer tissue (biopsy or prostatectomy specimen) for 
baseline Hedgehog pathway status, using both qRT-PCR-based mRNA expression analysis 
and protein-based immunohistochemical (IHC) analysis of key Hh pathway components 
(GLI1, PCTH1, SMO) and Sonic hedgehog ligand. 
• To determine if there is a relationship between mRNA and ICH expression of components 
in the Hedgehog pathway in primary prostate cancer tissue and PSA modulation on 
itraconazole therapy, including the proportion of patients achieving a decline of ≥ 50% in 
serum PSA as well as time to PSA progression. 
 
3.0     Study Design 
 
3.1      Overall Study Characteristics 
 
This is a phase II, single arm study of itraconazole dosed at 300 mg PO BID in patients with non- 
castrate, non-metastatic, biochemically relapsed prostate cancer after prior definitive local 
therapy. Simon‟s two stage minimax design will be followed for accrual and include an interim 
test for lack of efficacy (see Sections 10.2 and 10.4). There is a pre-specified stopping rule for 
safety after 10 patients have been treated for a minimum of 8 weeks of protocol therapy (see 
Section 10.4).  Patients will remain on protocol therapy until the first occurrence of any of the 
following: PSA progression, as defined in Section 2, development of metastasis, unacceptable 
toxicity, initiation of non-protocol therapy, or patient/physician withdrawal from study. Patients 
will remain on study until development of metastasis, initiation of non-protocol therapy, or 
patient/physician withdrawal from study, whichever occurs soonest. The total study duration 
including follow up is expected to be 3 years from the date of first patient enrolled onto study. 


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3.2      Study Endpoints 
 
3.2.1   Primary Endpoint 
 
The proportion of patients with biochemically relapsed disease after prior definitive local therapy 
who achieve a ≥ 50% decline from baseline in serum PSA after 12 weeks of therapy with 
itraconazole, confirmed by repeat measurement at least 2 weeks later, will be calculated. 
 
3.2.2   Secondary Endpoints 
 
Clinical Activity 
 
• Median  time  to  PSA  progression  among  men  with  biochemical  relapse  treated  with 
itraconazole will be estimated. See Section 2 for the definition of PSA progression. 
 
• Median time to clinical progression will be estimated, with clinical progression defined as 
the first occurrence of either development of overt metastases or initiation of non-protocol 
therapy. The definition of clinical progression excludes PSA-only progression. 
 
• Median metastasis-free survival will be estimated among men with biochemical relapse 
treated with itraconazole. 
 
• Mean percent change after 12 weeks of protocol therapy compared with pre-treatment in 
PSA doubling time will be determined for those treated with itraconazole. The pre- 
treatment PSADT will be determined based upon all PSA measurements within 3 months 
prior to Day 1 of protocol therapy, with a minimum of three PSA values each spaced at 
least 14 days apart (see Section 6.2.1). 
 
Safety/Pharmacokinetics 
 
• Maximum  grade  toxicities  observed  during  treatment  with  itraconazole,  as  graded  by 
CTCAE version 4.03. 
 
• Mean steady-state trough level of serum itraconazole and its active metabolite, hydroxy- 
itraconazole, after 4 weeks of therapy with itraconazole. 
 
3.2.3   Correlative Endpoints 
 
Endocrine Parameters 
 
• Mean   percent   change   from   baseline   in   serum   androgen   levels,   including   serum 
testosterone, DHEA-S, and androstenedione, after 4 and 12 weeks of protocol therapy. 
 
• Mean percent change from baseline in additional serum hormone levels, including ACTH, 
aldosterone, deoxycorticosterone (DOC), 11-deoxycortisol, and cortisol after 4 and 12 
weeks of protocol therapy. 
 
• Mean  baseline  and  mean  percent  change  in  serum  hormone  levels  among  patients 
achieving ≥ 50% decline from baseline in serum PSA after 12 weeks of itraconazole 
therapy and among those not achieving this decline. 


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Hedgehog  Pathway  (assessed  by  serial  skin  biopsies  on  protocol  therapy  and  analysis  of 
archived primary prostate cancer tissue including prior biopsy or prostatectomy specimen) 
 
• Proportion  of  patients  who  display  a  down-regulation  of  the  Hedgehog  pathway,  as 
assessed by measurement of GLI1 mRNA expression by RT-PCR on serial skin biopsies 
obtained at baseline and after 4 weeks of protocol therapy with itraconazole. Down- 
regulation will be defined as a decline of any magnitude in GLI1 mRNA expression after 4 
weeks of protocol therapy compared to baseline expression level. 
 
• Proportion of patients with and without at least a 50% decline from baseline after 12 weeks 
of protocol therapy in PSA exhibiting a down-regulation of the Hedgehog pathway. 
 
• Median time to PSA progression between patients with and without down-regulation of the 
Hedgehog pathway on itraconazole therapy. 
 
• Proportion of patients with and without at least 50% decline from baseline after 12 weeks 
of protocol therapy in PSA exhibiting over-activation of Hedgehog pathway components as 
assessed by immunohistochemical (IHC) and mRNA expression analysis of primary 
prostate cancer tissue (prior biopsy or prostatectomy specimen). Patients will be 
dichotomized (immunohistochemical staining 0 to 1+ vs. 2 to 3+ staining intensity; mRNA 
expression above and below median) for the purposes of analysis of the Hedgehog pathway 
in primary prostate cancer tissue. 
 
• Median time to PSA progression between patients with and without Hedgehog pathway 
over-activation in archived primary prostate cancer tissue. 


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3.3   Study Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.4      Study Timeline 
 
3.4.1   Primary Completion: 
 
The study will reach primary completion approximately 18 months from the date the first patient 
is enrolled. 
 
3.4.2   Study Completion: 
 
The total study duration including follow up is estimated to be 3 years. 
 
4.0     Study Population 
 
4.1      Study Population 
 
40 evaluable patients with biochemically relapsed hormone sensitive non-metastatic prostate 
cancer after prior definitive local therapy will be enrolled onto this study across three 
investigational sites, including the University of California San Francisco, Dana-Farber Cancer 
Institute,  and  theSidney Kimmel Comprehensive  Cancer Center at  Johns  Hopkins  Hospital. 


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5. 
No evidence of metastatic disease on imaging by whole body bone scan (technetium-99 or 
Na-F PET bone scan) and cross-sectional imaging of the abdomen/pelvis (CT or MRI) 
within 6 weeks of Day 1 of protocol therapy 
6. 
Prior androgen deprivation therapy (ADT) with LHRH agonist and/or antagonist allowed 
for either (neo)adjuvant treatment with local therapy or for biochemical relapse 
7. 
Last effective dose of LHRH agonist/antagonist “expired” > 3 months prior to study entry. 
8. 
For  example,  a  patient  receiving  LHRH  agonist  injection  every  3  months  would  be 
eligible provided their last injection was > 6 months prior to Day 1 of protocol therapy. A 
patient receiving LHRH agonist injections every 4 months will be eligible provided last 
injection was >7 months prior to Day 1 of protocol therapy. 
9. 
Serum testosterone level: 
• If no prior androgen deprivation therapy: 
- A single measurement greater than 150 ng/dL within 3 months of day 1 of 
protocol therapy 
• If prior androgen deprivation therapy (either in adjuvant or biochemical relapse 
setting): 
The two most recent measurements of serum testosterone prior to Day 1 of protocol 
therapy must fulfill the following criteria:  
- Both measurements are greater than 150 ng/dL. 
- The two measurements are spaced at least 14 days apart. 
- Both must be measured within 3 months of Day 1 of protocol therapy. 
- There must not be an increase of > 50 ng/dL between these two successive 
measurements. 
10.  PSA doubling time (PSADT) ≤ 15 months, calculated based upon all serum PSA 
measurements obtained within 3 months prior to Day 1 of protocol therapy, witha 
minimum of three PSA measurements spaced at least 14 days apart (see section 6). PSA 
values obtained when serum testosterone was known to be less than 150 ng/dL, prior to 
local therapy, or within three months of last dose of LHRH agonist/antagonist or 
antiandrogen will be excluded from the calculation of the PSADT.PSADT calculation to 
be carried out using the following website: 
http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx 
 
11.  Total bilirubin less than 1.5 times upper limit of normal (ULN), or less than 3 times ULN 
at study entry in a patient with documented Gilbert‟s disease. 
12.  ALT and AST levels less than 1.5 times ULN at study entry 
13.  Serum potassium greater than 3.5 mmol/L without oral supplementation 
14.  No history of uncontrolled hypertension (blood pressure > 160/100 mm Hg despite anti- 
hypertensive medication) 
15.  ECOG performance status of 0 or 1 
16.  Estimated life expectancy greater than 5 years 
17.  Age greater than or equal to 18 years at time of study entry 
18.  Ability to sign written informed consent 


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19.  Ability to swallow study drug whole as a capsule 
20.  Primary prostate cancer tissue available for analysis is not required for inclusion onto this 
study but is strongly encouraged. 
21. Patients who have partners of childbearing potential must be willing to use a method of 
birth control with adequate barrier protection as determined to be acceptable by the 
principal investigator and sponsor during the study and for 1 week after last study drug 
administration.  
 
4.3 
Exclusion Criteria 
 
1. 
Castrate-resistant disease, as evidenced by either: 
• Rising PSA on 2 consecutive measurements at least 2 weeks apart with concurrent 
documented serum testosterone < 50 ng/dL at the time of PSA measurement, or 
• Rising PSA on 2 consecutive measurements at least 2 weeks apart measured within 3 
months after last LHRH agonist/antagonist injection 
1. 
Prior bilateral orchiectomy 
2. 
Congestive heart failure of NYHA class III or higher severity at study entry 
3. 
History of chronic active hepatitis 
4. 
Grade 2 or higher peripheral neuropathy at the time of study entry 
5. 
Use of 5-alpha reductase antagonist (i.e. finasteride, dutasteride) or antiandrogen (i.e. 
flutamide, bicalutamide) within 6 weeks of Day 1 of protocol therapy 
6. 
Use of systemic steroids at an equivalent dose of prednisone 5 mg/day or higher within 6 
weeks of Day 1 of protocol therapy 
7. 
Use of medications or herbal supplements which are known to potentially lower serum 
PSA within 6 weeks of Day 1 of protocol therapy (see appendix 1 for list of medications) 
8. 
Use of other medications that may potentially interact with itraconazole within 1 week of 
study entry (see appendix 2 for list of medications) 
9. 
Use of other investigational agents within 6 weeks of Day 1 of protocol therapy 
10.  Prior pathology consistent with small cell carcinoma or prostate cancer with 
predominantly neuroendocrine differentiation 
 
 
5.0     Study Rationale 
 
5.1      Rationale for the Study Population 
 
Patients with biochemically relapsed, non-castrate, non-metastatic prostate adenocarcinoma after 
prior definitive local therapy will be enrolled onto this study. Both patients without prior ADT 
for biochemical relapse, or those on the “off” phase of a cycle of intermittent ADT will be 
allowed to enroll on the current study. Though allowing prior ADT for BCR may add 
heterogeneity with respect to expected disease outcomeswithin the study population, the primary 
objective  of  the  current  study is  to  investigate  whether  or  not  itraconazole  has  significant 
biologic activity in this disease setting, as reflected by decline in serum PSA after 12 weeks of 
therapy. Prior ADT for BCR is not hypothesized to significantly decrease the chance of detecting 


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PSA decline on itraconazole therapy, though it is acknowledged that prior studies of intermittent 
ADT  have  shown  that  nadir  PSA  tends  to  be  higher  and  “off”  phase  length  shorter  with 
successive cycles of intermittent ADT [9]. Furthermore, the role for non-hormonal agents in 
BCR may eventually fit within the framework of an intermittent ADT strategy, to lengthen the 
period “off” therapy. As such, including patients with prior ADT for BCR in the current study 
reflects this potential future application of these agents. 
 
Patients with up to 15 months baseline PSADT can be enrolled onto the current study. Prior 
studies have shown that pre-treatment PSADT is an independent prognostic factor in the BCR 
disease setting, and patients with a progressively shorter PSADT have an increasing risk of 
distant metastases and prostate-cancer specific mortality [38, 39]. Patients with a slow PSA 
doubling time > 15 months may be more suited to observation alone or local salvage therapies, 
and as such will be excluded from the current clinical trial. 
 
The minimum PSA required for study entry varies depending on the modality of prior treatment, 
in keeping with guidelines set forth by the PSA Working Group [36]. In patients with prior 
radiation therapy (external beam or brachytherapy), the minimum PSA required for study entry is 
nadir PSA after RT + 2.0 ng/mL, consistent with ASTRO guidelines to define biochemical 
recurrence [40]. For patients with prior radical prostatectomy, definition of BCR varies by 
institution, but in general is usually defined as a PSA > 0.4 using a sensitive assay. A minimum 
PSA of 1.0 ng/mL is chosen for this study to allow for a more accurate determination of baseline 


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PSADT. For patients with prior ADT for biochemically relapsed disease, as outlined in section 1 
of the protocol, there is no standard and commonly accepted definition of PSA progression. In 
prior clinical trials of intermittent ADT, widely varying PSA thresholds have been used as a 
“trigger” to re-initiate therapy,  ranging from 2-20 ng/mL in  absolute  value or 25-100% of 
baseline or nadir PSA. The minimum PSA after prior ADT for BCR utilized in the current study 
(4.0 ng/mL or  > 2 ng/mL above nadir PSA on prior ADT, whichever is higher) is acknowledged 
to be arbitrary but reflects current clinical practice and prior clinical trials of intermittent ADT, in 
which the second and subsequent cycles of ADT are often initiated upon reaching a pre-specified 
absolute PSA level that ranges from 2-20 ng/mL. 
 
Patients with a history of prior androgen deprivation therapy will be required to have a stable 
serum testosterone level, as defined by the absence of an increase of more than 50 ng/dLbetween 
consecutive measurementsusing thetwo most recent measurements prior to the initiation of 
protocol therapy. A rising serum testosterone level may drive the rise in PSA during the period 
of testosterone recovery, which would then confound efforts to interpret pre-treatment vs. on- 
treatment changes in PSA doubling time and PSA kinetics, one of the secondary endpoints of the 
current study. Without attempting to exclude patients in the testosterone recovery phase, a 
lengthening of the PSA doubling time on therapy may be reflective of a plateau in testosterone 
recovery rather than a biologic effect of the therapeutic agent being tested. 
 
5.2      Rationale for the Study Design and Dose Selection of Itraconazole 
 
5.2.1   Rationale for the Study Design 
 
The current study is a single arm, phase II trial ofitraconazole in patients with biochemically 
relapsed disease. The primary aim of the study is to assess biological activity of itraconazole at 
dose of300 mg PO BID as evidenced by decline in serum PSA ≥ 50% from baseline after 12 
weeks of protocol therapy. Estimates of historical control PSA response proportions can be fairly 
accurately estimated based upon the numerous prior studies of non-castrating agents in 
biochemically relapsed prostate cancer, including the recently published trial of the superoxide 
dismutase inhibitor ATN-224 [10-16]. In these studies, the biologic activity was modest, with the 
proportion of patients achieving > 50% decline in serum PSA on therapy usually 5% or less. 
Preliminary evidence demonstrating substantial modulation of serum PSA with itraconazole, 
along with acceptable toxicity and minimal impact on the adrenal hormone synthetic pathway, 
would potentially demonstrate that itraconazole is a viable non-castrating treatment alternative 
for patients with biochemical relapse and may additionally form the basis for further study of 
itraconazole in a larger placebo-controlled, randomized phase II/III trial, with adequate statistical 
power to detect a difference in clinically relevant efficacy endpoints such as time to first 
metastasis. 
 
Interim analyses with pre-specified stopping rules for safety andlack of efficacy will be carried 
out after 10 patients have been treated for a minimum of 8 weeks and 30 patients for a minimum 
of  12  weeks,  respectively  (see  Section  10).  Study  accrual  will  continue  during  the  two 


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plannedinterim analyses, which we feel is acceptable due to the previously well-documented 
safety profile of itraconazole, continuous safety data monitoring, the relatively asymptomatic 
nature of the biochemically relapsed non-castrate patient population, and the previously utilized 
single stage study designs of other non-castrating therapies in the biochemically relapse disease 
setting. 
 
5.2.2   Rationale for Dose Selection of Itraconazole 
 
Itraconazole is FDA-approved at doses ranging from 100 mg/day to 300 mg PO BID for chronic 
treatment of invasive fungal infections. High-dose itraconazole (300 mg PO BID) has 
demonstrated  acceptable  safety  and  tolerability  in  immunosuppressed  patients  with  chronic 
fungal infections, as well as in a prior phase II trial in patients with CRPC [19], and thus has 
acceptable prior safety data to justify dosing at 300 mg PO BID in the current study. The 
protocol contains pre-specified dose reductions for anticipated toxicities (see Section 8) and a 
stopping rule for safety after the first 10 patients have been treated for a minimum of 8 weeks 
(see Section 10). 
 
From an efficacy and pharmacodynamic standpoint, the optimal dose of itraconazole in prostate 
cancer is not yet well-characterized. However, based on the prior randomized phase II study of 
low- and high-dose itraconazole (200 mg/day and 300 mg PO BID respectively) in metastatic 
castrate resistant prostate cancer, low-dose itraconazole appeared to have only minimal biologic 
activity and down-regulated GLI1 expression in only one third of patients (see Section 1). In 
contrast, the high-dose study arm demonstrated significant biologic activity and down-regulated 
GLI1 expression in approximately two-thirds of patients. Thus, the dose of 300 mg PO BID will 
be chosen for further study in the current trial. 
 
5.3      Rationale for the Selection of Study Endpoints 
 
5.3.1   Primary Endpoint 
 
The primary endpoint of this trial will be the proportion of patients who achieve a≥ 50% decline 
in serum PSAafter 12 weeks of protocol therapy, which can serve as a marker of biological 
activity of itraconazole in biochemically relapsed hormone sensitive prostate cancer. Although 
decline in serum PSA has not been prospectively validated as a surrogate marker for clinical 
outcomes in this disease setting, a prior retrospective analysis identified PSA decline on therapy 
as an independent predictor of prostate-cancer mortality in patients with biochemically relapsed 
prostate cancer treated with androgen deprivation therapy [35].In addition, PSA decline was 
chosen as the primary endpoint in several prior trials of non-hormonal agents with varying 
mechanisms of actionin this disease setting, including studies investigatingthe small molecule 
tyrosine kinase inhibitorimatinib and immune-modulating therapy with GM-CSF [12, 15]. 
Furthermore, PSA decline on therapy as a primary endpoint may be less prone to inter-patient 
variability than other endpoints involving PSA modulation such as time to PSA progression or 
change in PSA doubling time, as has been observed in prior trials of non-hormonal therapies in 
biochemical relapse [14]. 


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Favorable   results   with   respect   to   decline   in   PSA,   along   with   acceptable   safety   and 
endocrinologic data, would form the basis for further study of itraconazole in biochemically 
relapsed disease, with the larger subsequent studies adequately designed (with sufficient power) 
for primary efficacy endpoints of clinical relevance, including time to first metastasis and overall 
survival. 
 
5.3.2   Secondary Endpoints 
 
A number of additional endpoints will be evaluated to assess the overall impact of itraconazole 
on PSA kinetics, clinical outcome, safety, and pharmacokinetics. 
 
5.3.2.1    PSA Kinetics 
 
Mean Change From Baseline inPSADT 
The mean change from baseline in PSADT after 12 weeks of protocol therapy will be measured 
for patients treated with itraconazole. A prior retrospective analysis of four non-hormonal agents 
tested in the biochemically relapsed setting identified change in the pre-treatment vs. on- 
treatment natural log PSA slope as an independent prognostic factor with respect to development 
of metastatic disease [37]. Novel agents tested in BCR may have clinical benefit without causing 
PSA decline but by slowing the rate of PSA rise instead, especially for agents with a cytostatic 
effect on tumor cells. It is not known if itraconazole has either cytocidal or cytostatic activity (or 
neither) in biochemically relapsed prostate cancer, and thus measuring both declines in PSA and 
changes in PSA kinetics is warranted. 
 
Time to PSA Progression 
The PCWG2 has suggested that duration of clinical activity is a key intermediate endpoint in 
initial phase II trials of agents conducted in the BCR disease population [36]. Indeed, in an 
exploratory analysis of a trial of IADT in BCR patients, Yu and colleagues demonstrated that in 
patients who completed the first cycle of IADT, a shorter duration of the first “off treatment” 
interval was associated with a shorter time to developing castrate resistant prostate cancer and 
shorter overall survival [41]. In the proposed trial, the median time to PSA progression on 
itraconazole therapy will be evaluated. The definition of PSA progression, as outlined in Section 
2 (> 50% and >2 ng/mL above nadir (or above baseline if no PSA decline), is acknowledged to 
be arbitrary but does reflect PCWG2 guidelines for PSA progression in the castrate-resistant 
disease setting. 
 
Given the heterogeneity of the study populations in prior studies of non-hormonal agents 
evaluated in BCR, as well as the variable definition of PSA progression used in prior clinical 
trials, using historical data to generate accurate estimates of median time to PSA progression is 
problematic. The analysis in the current study is exploratory in nature, aimed at generating 
preliminary estimates of the impact of itraconazole on the time to PSA progression. 
 
5.3.2.2    Clinical Outcome 
 
The median time to clinical progression, as defined by the first occurrence of either initiation of 
non-protocol  therapy  (including  initiation  or  resumption  of  ADT)  or  development  of  overt 


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metastatic disease, as well as the median metastasis-free survival, will be determined for patients 
treated  with  itraconazole.  As  was  the  case  for  time  to  PSA  progression,  this  analysis  is 
exploratory in nature, and the aim is to generate preliminary estimates of time to disease 
progression to potentially aid in the planning of future study of itraconazole in biochemically 
relapsed prostate cancer. Serial radiographic scans will not be mandated by the study, as this 
does not reflect standard clinical practice (see Section 6). Scans will be required at baseline, at 
the time of PSA progression, and as clinically indicated for signs/symptoms on history and 
physical exam. If itraconazole is further evaluated in a definitive, placebo-controlled phase II/III 
trial in BCR, periodic scans would need to be mandated to ensure balanced evaluations per 
treatment arm. 
 
5.3.2.3    Pharmacokinetics 
 
The mean steady-state serum concentration ofitraconazole and hydroxyl-itraconazole, its major 
active metabolite, will be measured after 4 weeks of protocol therapy. Prior studies have 
demonstrated variability in the oral bioavailability of the oral capsule formulation, dependent 
mostly upon the degree of gastric acidity (lower pH enhances oral absorption) at the time of 
ingestion. In an exploratory analysis of low- and high-dose itraconazole in CRPC, higher steady- 
state serum concentrations of itraconazole and hydroxyl-itraconazole were associated with a 
higher likelihood of being free of PSA progression at 24 weeks and displaying greater percentage 
PSA decline on therapy [31]. A similar analysis will be carried out in the current study. 
 
5.3.3   Correlative Endpoints 
 
5.3.3.1    Endocrine Parameters 
 
The mean change from baseline in serum androgen levels, including testosterone, DHEA-S, and 
androstenedione after 12 weeks of therapy with itraconazole will be determined to investigate 
further the mechanism of action of itraconazole in prostate cancer. Prior study in CRPC provided 
preliminary evidence that itraconazole, unlike the related azole compound ketoconazole, has a 
mechanism of action distinct from androgen synthesis inhibition [19], albeit in a castrate patient 
population. Demonstrating in the current study, with a non-castrate patient population,that 
itraconazoletherapy concurrently does not significantly impact serum androgen levels yet 
modulates serum PSA will lend further support to the hypothesis that itraconazole has a 
mechanism of action distinct from ketoconazoleand androgen synthesis inhibition. The main 
limitations of this particular analysis is that serum hormone levels may not reflect intra-tumoral 
androgen concentrations, and that this patient population is non-castrate with a different systemic 
hormonal milieu than the previous study in CRPC. 
 
In the prior clinical trial of itraconazole in CRPC, there were several patients with a constellation 
of adverse events including hypokalemia, hypertension, and peripheral edema [19]. This 
constellation of symptoms has also occasionally been observed in prior studies of high dose 
itraconazole in patients with chronic fungal infections, and raises the possibility of induced 
mineralocorticoid excess. Serum aldosterone levels were measured in the prior study of 
itraconazole in CRPC (and were not elevated on therapy); however upstream compounds within 


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the adrenal synthetic pathway with mineralocorticoid activity, including deoxycorticosterone 
(DOC) and 11-deoxycortisol were not measured. A more comprehensive panel of adrenal and 
pituitary hormones, including ACTH, DOC, aldosterone, and 11-deoxycortisol, will be measured 
on a serial basis in the current study and the mean change from baseline will be determined. 
 
Evaluation for a relationship between baseline and percent change in serum hormone levels with 
PSA modulation will be evaluated in the current study. Prior studies of ketoconazole and 
abiraterone in metastatic CRPC demonstrated a relationship between higher baseline levels of 
adrenal androgen levels with clinical response [21, 42], and a prior trial of estrogenic compounds 
(DES and the herbal supplement PC-SPES) in CRPC demonstrated that a declinein adrenal 
androgen DHEA-S was related to a decline in serum PSA on therapy [43]. Whether the same 
relationships apply to itraconazole, which is hypothesized to have a mainly non-hormonal 
mechanism of action, and whether the same relationships between serum hormone levels and 
clinical response apply to the biochemically relapsed disease setting as it does in CRPC, will be 
evaluated in the current study. 
 
5.3.3.2    Hedgehog Pathway 
 
The impact of itraconazole on Hedgehog pathway activity will be assessed by serial skin biopsies 
obtained at baseline and after 4 weeks of therapy. Hedgehog pathway activity will be assessed by 
quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of GLI1mRNA 
transcripts in the skin biopsy specimens. GLI1 is a downstream transcription factor upregulated 
by activation of the Hh pathway that functions in a positive feedback loop. This method for 
analysis of Hh pathway activity has been previously validated in a study of the small molecule 
SMO inhibitor GDC-0449 in basal cell carcinoma of the skin [25]. In patients with CRPC treated 
with itraconazole, down-regulation of GLI1 expression was shown to be associated with a longer 
PSA progression- free survival [31]. 
 
In  an  exploratory  fashion,  for  patients  with  prior  archived  primary  prostate  cancer  tissue 
available, the relationship between mRNA andimmunohistochemical expression of components 
involved in the Hh pathway, including Sonic hedgehog ligand, PCTH1, GLI1, and SMO, and 
PSA modulation on subsequent itraconazole therapy will be determined. Such an analysis may 
eventually lead to the development of a predictive biomarker for itraconazole, which would 
require prospective validation in larger placebo controlled trials. 
 
 
In summary, the proposed trial will evaluate the effects ofitraconazole in patients with non- 
metastatic biochemically relapsed prostate cancer with a variety of biologically relevant 
endpoints. Favorable results with respect to PSA modulation, along with acceptable toxicity and 
lack of adverse impact on endocrine parameters, along with demonstration of Hedgehog pathway 
down-regulation, would demonstrate itraconazole as a viable non-castrating treatment strategy in 
this disease setting, and may help to form the justification for a larger placebo-controlled clinical 
trial of itraconazole in BCR, with primary endpoints potentially including time to metastatic 
disease and overall survival. 


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6.0 
Study Activities 
 
6.1 
Study Schedule 
 
 
 
 
 
Pre-Study 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 and 
beyond 
 
 
 
 
 
End of Study 
 
 
Procedure 
Screening 
Day 1 
Day 8 
(+/- 3 days) 
Day 1 
(+/- 7 days) 
Day 1 
(+/- 7 days) 
Day 1 
(+/- 7 days) 
Day 1 
(+/- 7 days) 
PSA or 
Clinical 
Progression 
Informed Consent a 
X 
Within 3 months of Cycle Day 1 
PSA b 
X c 
X 
X 
X 
X 
X 
X 
Serum Testosteroned 
X e 
X 
X 
X 
Within 6 weeks of Cycle Day 1 
Whole body bone scan + CT 
or MRI of and/pelvis f 
X 
X g 
Skin biopsy (optional) h 
X 
X 
Within 28 days (4 weeks) of Cycle Day 1 
Demographics 
X 
History / Physical 
X 
X 
X 
X 
X 
X 
X 
Height/Weight 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
 
Toxicity Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff and platelets 
X 
X 
 
BUN / Creatinine 
X 
X 
 
ALT, AST, AlkP, total 
bilirubin 
X 
X 
X 
X 
X 
X 
Other serum hormones d 
X 
X 
X 
X 


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6.1 
Study Schedule 
 
 
Pre-Study 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 and 
beyond 
 
 
End of Study 
 
Procedure 
Screening 
Day 1 
Day 8 
(+/- 3 days) 
Day 1 
(+/- 7 days) 
Day 1 
(+/- 7 days) 
Day 1 
(+/- 7 days) 
Day 1 
(+/- 7 days) 
PSA or 
Clinical 
Progression 
Plasma/serum for banking 
(optional)i 
X 
X 
X 
X 
PBMCs for banking 
(optional)i 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
Serum sodium and potassium 
X 
X 
X 
X 
X 
X 
Archived primary prostate 
cancer tissue (optional) j 
X 
Itraconazole dispensedk 
X 
X 
X 
X 
X 
After Cycle 1 
Trough itraconazole& [OH]- 
itraconazole serum levelsl 
X 
a 
Informed Consent prior to any Screening procedures 
b 
Measured in same laboratory at each time point during study (if possible). 
c 
All serum PSA measurements within 3 months prior to Day 1 of protocol therapy will be included for the calculation of baselin e PSA doubling time, with a minimum of three values each 
spaced at least 14 days apart. 
d 
Serum hormone levels should be collected between 8:00 am and 12:00pm if possible; will be shipped to UCSF and banked for later analyses; includes testosterone, cortisol, aldosterone, 
deoxycorticosterone, 11-deoxycortisol, adrenocorticotropic hormone (ACTH), dihydroepiandrostenedione-sulfate (DHEA-S), and androstenedione (see Appendix 3, section IV for 
processing, storage, and shipping instructions). 
e 
For serum testosterone measurement, if the patient does not have a history of ADT, a single measurement > 150 ng/dL within 3 months prior to Day 1 of protocol therapy will be required for 
study entry. For patients with any prior history of ADT, the two most recent serum testosterone measurements prior to Day 1 o f protocol therapy must fulfill the following requirements: 
-  Both measurements > 150 ng/dL 
-  Both measurements obtained within 3 months prior to day 1 of protocol therapy 
-  Measurements must be spaced at least 14 days apart 
-  There must not be an increase of > 50 ng/dL between the two consecutive measurements 
f 
IV contrast with CT or MRI per individual investigator discretion. Whole body bone scan may consist of either technetium-99 labeled scan or sodium-fluoride PET bone scan. 
g 
May be omitted if completed within the past 30 days. 
h 
3 mm punch biopsy non-scalp skin containing hair follicles 
i 
Collection of PBMCs at baseline and serum/plasma at baseline, cycle 2 day 1, cycle 4 day 1, and at disease progression is optional. Blood will be shipped to UCSF and stored within 
HDFCCC Tissue Bank. See appendix 3, section IV for processing and shipping instructions). 


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6.1 
Study Schedule 
 
 
Pre-Study 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 and 
beyond 
 
 
End of Study 
 
Procedure 
Screening 
Day 1 
Day 8 
(+/- 3 days) 
Day 1 
(+/- 7 days) 
Day 1 
(+/- 7 days) 
Day 1 
(+/- 7 days) 
Day 1 
(+/- 7 days) 
PSA or 
Clinical 
Progression 
j 
Archived formalin-fixed paraffin embedded prostate biopsy or prostatectomy specimen (optional) 
k 
Itraconazole to be taken as three (100 mg) capsules twice daily with food (6 capsules total per day; 168 capsules dispensed every 4 weeks during study visits) 
l 
Hold am dose of itraconazole 
 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, AlkP = alkaline phosphatase, PBMC = peripheral blood mononuclear cells 


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37
 
 
6.2      Screening Period/Pre-Study Evaluation 
 
All  patients  must  sign  a  written  informed  consent  form  before  study  specific  screening 
procedures are performed. Screening procedures to evaluate patient eligibility will be conducted 
as per the schedule outlined below. If the patient meets eligibility and screening requirements he 
will return to the site for the day 1 visit and drug dispensation. 
 
6.2.1   Establish baseline PSA doubling time and serum testosterone levelfor 
eligibility determination 
(within 3 months prior to day 1 of protocol therapy) 
 
• Estimation of baseline PSA doubling time 
• Calculated based upon all serum PSA measurements obtained within 3 months prior 
to day 1 of protocol therapy, with a minimum of three PSA measurements each 
spaced at least 14 days apart. 
• PSA values obtained when serum testosterone was known to be less than 150 ng/dL, 
prior to local therapy, or within three months of last dose of LHRH agonist/antagonist 
or antiandrogen will be excluded from the calculation of the PSA doubling time. 
• Measurement of all PSA values included in determination of PSA doubling time 
recommended to be performed in the same laboratory 
• Actual calculation of the PSA doubling time can be obtained from the following 
online calculator:  http://nomograms.mskcc.org/Prostate/PsaDoublingTime.aspx 
• Patients eligible if PSA doubling time is less than or equal to 15 months. 
 
 
• Serum testosterone level 
• If no prior androgen deprivation therapy: 
- A single measurement greater than 150 ng/dL within 3 months of day 1 of 
protocol therapy 
• If prior androgen deprivation therapy (either in adjuvant or biochemical relapse 
setting): 
The two most recent measurements of serum testosterone prior to study entry must 
fulfill the following criteria: 
- Both measurements greater than 150 ng/dL, 
- The two measurements are spaced at least 14 days apart 
- Both must be measured within 3 months of day 1 of protocol therapy 
- There must not be an increase of > 50 ng/dL between these two successive 
measurements 
 
6.2.2   Clinical (within 28 days of day 1 of protocol therapy) 
 
• Complete history and physical examination 
• Baseline demographics 


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• Height and weight 
• ECOG Performance Status 
• Adverse Event Assessment 
 
6.2.3   Laboratory (within 28 days of day 1 of protocol therapy) 
 
• Complete blood count including differential and platelet count 
• Total bilirubin, alkaline phosphatase, AST, ALT, BUN, creatinine, sodium, potassium 
• Serum testosterone, androstenedione, DHEA-S, cortisol, aldosterone, 
deoxycortiocosterone, 11-deoxycortisol, and ACTH levels 
• Plasma/serum and PBMCs for banking (Optional) 
 
6.2.4   Radiographic Studies and Procedures (within 6 weeks of day 1 of protocol 
therapy) 
 
The following will only be conducted if the patient is otherwise eligible for the study as per the 
laboratory/clinical parameters outlined above and has given written, informed consent. 
 
• Radionuclide bone scan(either technetium-99 or Na-F radiolabel) 
• Cross-sectional imaging of the abdomen and pelvis (CT or MRI). Use of IV contrast per 
individual investigator discretion. 
• Skin biopsy (if additional consent is obtained).  
 
6.3      Study Treatment 
 
Patients will commence protocol therapy on Day 1 of study treatment. Patients will continue 
protocol therapy and remain on study until PSA progression (see Section 2 for definition), 
development of metastases, initiation of non-protocol therapy, unacceptable toxicity, or 
patient/physician withdrawal from the study, whichever occurs soonest. The study timeline is 
defined as Day 1 = first day of study treatment initiation. Subsequent study time points will be 
defined  based  on  study  calendar,  irrespective  of  subsequent  dose  delays/interruptions  (see 
Section 8 for discussion of dose delays due to toxicity). 
 
6.3.1   Day 1 of Study Treatment 
 
Patients will return to study site for a history and physical exam including weight, adverse event 
and con meds assessment, ECOG, measurement of serum PSA, and dispensing of study drug. 
The starting dose of itraconazole will be 300 mg PO BID, taken as 3 (100 mg) capsules twice 
daily with meals. 
 
6.3.2   Dose Modifications 
 
Both dose interruptions and dose reductions will be permitted for toxicity, as outlined in Section 
8. 


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6.3.3   Concomitant Medications 
 
Concomitant medications will be recorded at each monthly clinic visit. No concomitant use of 
any anti-neoplastic therapy will be permitted. 
This will include: 
 
• Surgery 
• Radiation therapy 
• Other secondary hormonal therapies including antiandrogens, 5-alpha reductase inhibitors 
(i.e. Finasteride, dutasteride), megestrol acetate 
• Immunotherapy 
• Chemotherapy 
• Or other investigational agents 
 
Nutritional supplements containing saw palmetto, pomegranate extract, or pomegranate juiceare 
also specifically prohibited. See Appendix 1 for a full list of medications and substances that are 
prohibited while taking itraconazole. 
 
Patients may not currently be taking drugs that significantly interact with CYP3A4. A list of 
medications and substances with the potential to interact with itraconazoleare provided in 
Appendix 2. Patients taking digoxin should have serum digoxin levels monitored frequently; 
patients on warfarin should have INR levels measured regularly. 
 
Because of the potential for drug-drug interaction, the electronic case report form (eCRF) must 
capture the concurrent use of all other drugs, over-the-counter medications, or alternative 
therapies. 
 
6.3.4   Safety Assessment 
 
Patients will be assessed for adverse events at Day 1 (for baseline) and Day 8, week 4, and every 
4 weeks thereafterwhile receiving protocol therapy. Adverse events will be graded according to 
CTCAE version 4.03 (available at  http://ctep.cancer.gov).  Adverse events will be assessed by 
the individual investigator as definitely, probably, possibly, unlikely, or not related to study drug. 
Laboratory measurement is outlined below in Section 6.3.5. Additional laboratory measurements 
are at the discretion of the treating physician. 
 
6.3.5   Laboratory/Radiographic Assessment 
 
The frequency and schedule of laboratory and radiographic assessment is outlined above in the 
study schedule. Serum PSA will be measured on a monthly basis while patients are receiving 
protocol therapy. A whole body bone scan (either Na-F PET or technetium-99 bone scan), along 
with cross-sectional imaging of the abdomen/pelvis (CT or MRI) will be obtained at baseline and 
at the time of PSA or clinical progression, whichever occurs first. 


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Liver function tests and serum sodium and potassium levels will be measured pre-study, on day 8 
+/- 3 days, day 28 +/- 7 days, then every 4 weeks +/- 7 days thereafter. BUN/serum creatinine 
will be measured pre-study and every 4 weeks +/- 7 days. 
 
Serum itraconazole and hydroxy-itraconazole levels will be measured at the day 28 (+/- 7 days) 
study visit. Hormone levels (outlined above in the study schedule) will be measured at baseline, 
day 28 (+/- 7 days), and week 12 (+/- 7 days) of protocol therapy. 
 
6.3.6   Skin Biopsy 
 
For  patients  who  sign  additional  consent  form,  a  3  mm  punch  biopsy  of  non-scalp  skin 
containing hair follicles (will be obtained at baseline (within 6 weeks of Day 1 of protocol 
therapy) and day 28 +/- 7 days of protocol therapy.  Serial skin biopsies are an optional part of 
this study. 
 
6.4      Reasons for Treatment Discontinuation 
 
Patients will discontinue protocol therapy and betreated per individual investigator discretion at 
the first occurrence of any of the following: 
• PSA progression 
• Development of overt metastases 
• Patient or treating physician decision 
• Unacceptable toxicity 
• Non-protocol therapy 
 
 
Patients who discontinue therapy due to development of metastases detected on radiographic 
tests, initiation of non-protocol therapy, or patient/physician decision will be removed from study 
at the time of protocol therapy discontinuation. 
 
 
Patients who discontinue protocol therapy due to PSA progression or unacceptable toxicity will 
remain on study in follow up phase (see next section) until clinical progression. 
 
6.5      Follow Up 
 
Patients will have a safety follow up visit 30 days after the last dose of study drug.  
 
If patients discontinue protocol therapy due to PSA progression or unacceptable toxicity, they 
will be followed until the time of initiation of non-protocol therapy, development of metastases, 
or patient/physician withdrawal from study, whichever occurs soonest, at which point they will 
be taken off study. 
 
 
During the follow up phase, the frequency of clinical/laboratory/radiographic assessment will 
beper individual investigator discretion. 


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41
 
6.6      Duration of Study 
 
The total duration of the study including follow up is expected to be approximately 3 years from 
the date the first patient is enrolled onto study. 
 
7.0     Study Drug Information 
 
7.1      Itraconazole 
 
Drug Substance:Itraconazole is an almost white to slightly yellow powder. 
 
Chemical Name:(±)-cis-4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3- 
dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1- 
methylpropyl)-3H-1,2,4-triazol-3-one 
 
Molecular Formula: C35H38Cl2N8O4 
 
Molecular Weight:   705.64 
 
Formulation:Itraconazole is available as pink and blue capsules containing 100 mg of 
itraconazole in a pellet formulation. Each capsule contains 100 mg of itraconazole as well as: 
sugar  spheres  (NF),  hydroxypropylmethylcellulose,  gelatin,  polyethylene  glycol,  titanium 
dioxide, FD&C Blue No. 1, FD&C Blue No. 2, D&C Red No. 22 and D&C Red No. 28. The 
pKa of itraconazole is 3.7 with a melting range of 165-169 degrees Celsius.It is highly 
hydrophobic and lipophilic, with a log partition coefficient of 5.66 in the n-octanol/aqueous 
buffer solution of pH=8.1. Itraconazole is very poorly soluble in water (<1 μg/mL) and in diluted 
acidic solutions (<5 μg/mL). 
 
 
Route of Administration:Itraconazole 100 mg capsules are administered orally. Absorption of 
itraconazole is impaired when the gastric pH is increased. Capsules should be taken after a meal. 
If a patient is taking a concurrent proton pump inhibitor or H2-antagonist, it is advisable that 
itraconazole be taken in conjunction with an acidic beverage such as a cola product or orange 
juice to increase absorption. Grapefruit juice is not recommended due the potential drug 
interaction with itraconazole. 
 
Pharmacokinetics: 
Absorption:Better absorbed with food and lower gastric pH. 
Distribution: Vd  (average): 796 ± 185 L or 10 L/kg; highly lipophilic and tissue concentrations 
are higher than plasma concentrations. The highest concentrations: adipose, omentum, 
endometrium, cervical and vaginal mucus, and skin/nails. Aqueous fluids (eg, CSF and urine) 
contain negligible amounts. 
Protein binding, plasma: 99.8%; metabolite hydroxy-itraconazole: 99.5% 
Metabolism: Extensively hepatic via CYP3A4 into >30 metabolites including hydroxy- 
itraconazole (major metabolite); appears to have in vitro antifungal activity. Main metabolic 
pathway is oxidation; may undergo saturation metabolism with multiple dosing. 


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Bioavailability: Variable, ~30-40%% (capsule). 
Half-life elimination: Oral: Single dose: ~21 hours, steady state: 64 hours; Cirrhosis (single 
dose): 37 hours (range 20-54 hours) 
Time to peak, plasma: 3-5 hours 
Excretion: Urine (<0.03% active drug, 40% as inactive metabolites); feces (~3% to 18%) 
 
Storage and Handling:Itraconazole capsules are supplied in HDPE bottles of 30. They should 
be stored at room temperature (15-30 degrees Celsius) and protected from light and moisture. 
 
Dose: 300 mg PO BID. Three 100 mg capsules taken twice daily with food (6 capsules per day 
in total). 
 
Possible Anticipated Adverse Events:The most frequently reported adverse events in prior 
clinical trials of itraconazole were gastrointestinal in nature, including diarrhea, nausea and/or 
vomiting, anorexia, or abdominal pain. Other potential adverse events include peripheral edema, 
hypertension, hypokalemia, fatigue, and elevated liver enzymes. Rare but serious and potentially 
life  threatening  adverse  events  include  adrenal  insufficiency,  allergic  reactions  including 
Stevens-Johnson syndrome, congestive heart failure, and liver failure. Itraconazole may also 
potentially interact with a number of other medications and herbal supplements, so a careful 
review of the concurrent medications is warranted during therapy (see Appendix 2 for list of 
potential interacting medications to avoid while on itraconazole therapy). 
 
Dispensing of Drug: A 28 day supply of study drug will be provided to patients at each study 
visit every 4 weeks. 
 
Inventory and Control: The itraconazoleused for this study must be maintained under adequate 
security and stored in the pharmacy at the study site until dispensing or their return to the UCSF 
Helen Diller Family Comprehensive Cancer Center investigational pharmacy. Investigators may 
not supply study medication to any person not enrolled in this study or to any person not named 
as a sub-investigator. 
 
In addition, the investigator must maintain an accurate, running inventory of all drug supplies 
received and dispensed during conduct of the study. At the completion of the study, a copy of the 
final inventory will be supplied to the UCSF Helen Diller Family Comprehensive Cancer Center 
investigational pharmacy. The original will be retained by the investigator in the study files. 
 
Return of Clinical Supplies: Upon completion or termination of the study, all used and unused 
original study drug bottles, whether empty or containing study drug, will be returned to the 
UCSF Helen Diller Family Comprehensive Cancer Center investigational pharmacy. Return 
shipments must provide proof of delivery, and will be accompanied by the Drug Accountability 
Form and a memo noting the number of bottles and quantity of study drug being returned. 


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8.0     Dosage Modifications/Toxicity 
 
8.1      Toxicity 
 
Toxicities and Adverse Events will be assessed during each monthly clinic visit using the NCI 
CTCAEversion 4.03.  Since CTEP has standardized the CTC, the NCI does not require the 
inclusion of the CTCAE within this protocol document.   However, all appropriate treatment 
areas will have access to a copy of the CTCAEversion 4.03. A copy can be downloaded from the 
CTEP home page:  http://ctep.cancer.gov 
 
Dose re-escalation after prior dose reduction due to toxicity will not be permitted. 
 
8.2      Dose Modifications for Specific Toxicities 
 
8.2.1   Management of Hypokalemia 
 
Every patient that experiences Grade 1 hypokalemia (serum potassium < 3.5 mM or below lower 
limit of normal range, but ≥ 3.0 mM) will require oral potassium supplementation, and will be 
monitored bi-weekly until serum potassium is between 3.5 to 5.0 for ≥ 4 weeks. The frequency 
of testing after supplementation is at Investigator discretion. The dose of potassium supplement 
must be titrated to maintain serum potassium at ≥ 3.5mM but ≤ 5.0 mM. If any patient 
experiences Grade 3 hypokalemia (serum potassium levels < 3.0 mM but ≥ 2.5 mM) study 
treatment will be held, and the patient will be given intravenous and/or oral potassium 
replacement. If hypokalemia resolves and potassium level remains > 3.5 mM on a stable oral 
dose for a period > 1 week, itraconazole may be restarted at 200 mg/day per discretion of study 
investigator. If hypokalemia recurs to grade 3 or higher, itraconazole will be permanently 
discontinued. If any patient experiences Grade 4 hypokalemia (< 2.5 mM), itraconazole will be 
permanently discontinued and the patient will be hospitalized for IV potassium supplementation 
and cardiac monitoring. Any treatment delay greater than 4 weeks will result in permanent 
discontinuation of the study drug. 
 
 
 
Serum Potassium 
Grade of 
Hypokalemia 
Action 
Further Action/Maintenance 
< 3.8 mM – 3.0 mM 
1/2 
Initiate oral K+ supplementation 
and increase frequency of K+ lab 
monitoring to bi-weekly 
Titrate oral K+ dose to maintain 
concentration 3.5 – 5.0 mM 
 
< 3.0 – 2.5 mM 
3 
Hold itraconazole; 
initiatestanding oral 
supplementation +/- temporary IV 
supplementation 
If K+ > 3.5 mMfor > 1 week, re- 
initiate itraconazole at 200 
mg/day per investigator discretion 
 
< 2.5 mM 
4 
Permanently discontinue 
itraconazole; hospitalize for IV 
supplementation and cardiac 
monitoring 
Permanently discontinue 
itraconazole 


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8.2.2   Management of Elevated Liver Function Tests 
 
If Grade 1 increases in AST, ALT, or total bilirubin occur (AST or ALT > ULN – 3.0 x ULN or 
bilirubin > ULN – 1.5 x ULN), the frequency of LFT monitoring will be increased to bi-weekly 
but dose reduction and/or delay will not be mandated. If Grade 2 increases in AST, ALT or total 
bilirubin occur (AST or ALT > 3.0 – 5.0 x ULN or bilirubin > 1.5 – 3.0 x ULN, itraconazole will 
be held until the LFT abnormality improves to Grade 1 or lower, at which point the study drug 
will be restarted at 400 mg/day. If a grade 2 increase in AST, ALT, or bilirubin recurs, 
itraconazole will be held until improved to Grade 1 or lower in severity, and then restarted at 200 
mg/day. If Grade 3 increases in AST, ALT, or bilirubin occur (AST or ALT > 5.0 – 20.0 x ULN 
or bilirubin > 3.0 – 10.0 x ULN, itraconazole will be held until the LFT abnormality improves to 
Grade 1 or lower, at which point study drug may be restarted at 200 mg/day per individual 
investigator discretion. If a grade 3 increase in AST, ALT, or bilirubin recurs, itraconazole will 
be  permanently  discontinued.  If  a  grade  4  increase  in  AST,  ALT,  or  bilirubin  occurs, 
itraconazole will be permanently discontinued. Any treatment delay greater than 4 weeks will 
result in permanent discontinuation of itraconazole. 
 
 
 
AST or ALT 
Bilirubin 
Grade of LFT 
Abnormality 
Action 
Further 
Action/Maintenance 
>ULN – 3X ULN 
> ULN – 1.5 X ULN 
1 
Increase frequency of LFT 
monitoring to bi-weekly 
None 
> 3.0 – 5.0 X ULN 
> 1.5 – 3.0 X ULN 
2 
Hold itraconazole; increase 
frequency of LFT monitoring to 
weekly 
If improves to Grade 1 or lower, 
re-initiate at 400 mg/day. If 
recurrent grade 2 AE, hold until 
Grade 1 or lower, then re-start at 
200 mg/day. 
> 5.0 – 20.0 X ULN 
> 3.0 – 10.0 X ULN 
3 
Hold itraconazole; increase 
frequency of LFT monitoring to 
weekly 
If improves to Grade 1 or lower, 
re-initiate at 200 mg/day per 
investigator discretion. If 
recurrent grade 3 AE, perman- 
ently discontinue itraconazole. 
> 20.0 X ULN 
> 10.0 X ULN 
4 
Permanently discontinue 
itraconazole 
N/A 
 
 
8.2.3   Management of Hypertension 
 
For  grade  1-2  hypertension,  management  will  be  per  study  investigator  discretion  and 
institutional guidelines. Treatment with eplerenone should be avoided due to the potential drug 
interaction with itraconazole. Spironolactone should likewise be avoided due to the potential to 
contribute to prostate cancer progression. No dose reduction or interruption will be mandated for 
grade 1 or 2 hypertension. For grade 3 hypertension, itraconazole will be held until hypertension 
is grade ≤ 1 in severity, at which point itraconazole will be restarted at 400 mg/day. BP will be 


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monitored  at  investigator‟s  discretion.If  there  is  a  recurrence  of  grade  3 
hypertension,itraconazole will be held until grade ≤ 1 in severity, and then restarted at 200 
mg/day. If there is a second recurrence of grade 3 hypertension, itraconazole will be permanently 
discontinued. If grade 4 hypertension occurs during study treatment, itraconazole will be 
permanently discontinued. If there is a greater than 4 week delay in treatment, itraconazole will 
be permanently discontinued. 
 
8.3      Dose Modification for Other Adverse Events 
 
For adverse events of grade 1 in severity, treatment will be per institutional guidelines, and no 
dose interruption will be mandated. For adverse events of grade 2 in severity that the study 
investigator deems as possibly, probably or definitely related to study drug, treatment will be 
interrupted until the adverse event resolves to grade ≤ 1 in severity, at which point itraconazole 
will be re-started at a reduced dose of 400 mg/day. If a patient experiences a recurrent adverse 
event of grade 2 in severity, itraconazole will be held until the adverse event resolves to grade 
≤ 1 in severity, at which point itraconazole will be re-started at 200 mg/day. 
 
Treatment will be interrupted for grade 3 adverse events that study investigator attributed as 
possibly, probably, or definitely related to study medication. Treatment will be held until the 
adverse event resolves to grade ≤ 1 in severity, at which point therapy will be re-instituted at a 
reduced dose of 200 mg/day. If the adverse event recurs to grade 2 in severity, treatment will be 
held until the adverse event resolves to grade ≤ 1 in severity, at which point therapy will be re- 
instituted at 200 mg/day per individual investigator discretion. If the adverse event recurs to 
grade 3 or higher in severity, treatment will be permanently discontinued. Treatment will be 
permanently discontinued and patients will not be re-challenged for any grade 4 adverse events 
occurring while receiving protocol therapy. 
 
If there is a greater than 4 week delay in treatment, protocol therapy will be permanently 
discontinued. 
 
Grade of 
Other AE 
Action 
Further Action/Maintenance 
1 
•   Treatment per institutional guidelines 
•   No dose interruption will be mandated 
None 
2 
•   Treatment interrupted until the adverse 
event resolves to grade ≤ 1 in severity 
•   @ ≤ 1 in severity, re-start itraconazole at 
reduced dose of 400 mg/day 
•   If recurrent grade 2 AE, hold itraconazole 
until resolves to grade ≤ 1 in severity 
•   @ ≤ 1 in severity, re-start itraconazole at 
reduced dose of 400 mg/day 
3 
•   Treatment interrupted and held until 
resolves to grade ≤ 1 in severity 
•   @ ≤ 1 in severity, re-start itraconazole at 
reduced dose of 200 mg/day 
•   If recurrent grade 2 AE, hold itraconazole 
until resolves to grade ≤ 1 in severity 
•   @ ≤ 1 in severity, re-start itraconazole at 
reduced dose of 200 mg/day 
•   If the AE recurs to grade 3 or higher in 
severity, permanently discontinue treatment 


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Grade of 
Other AE 
Action 
Further Action/Maintenance 
4 
Treatment permanently discontinued and 
patients will not be re-challenged 
N/A 
 
 
Dose re-escalation after prior dose reduction due to toxicity will not be permitted. 
 
9.0     Laboratory Assessment and Correlative Studies 
 
9.1      Serum Hormone Levels 
 
Serum hormone levels will be measured at baseline, week 4, week 12, and at the time of PSA or 
clinical progression for patients enrolled onto this study.Serum hormone levels should be drawn 
between 8:00 am and 12:00pm, please see table below for all collection parameters.Peripheral 
blood for serum hormone levels will be processed and stored using procedures outlined below 
and in appendix 3 section IV.The blood will be shipped to UCSF (see appendix 3 section IV) and 
subsequently analyzed at UCSFaccording to the methods outlined below. 
 
 
Time of 
Day 
Method 
Volume 
Container 
Processing 
Testosterone 
Any 
LC/MS/MS 2 mL 
Red Top 
Separate serum and 
freeze at -20 degrees C 
Androstenedione 
AM* 
LC/MS/MS 2 mL 
Red Top 
Separate serum and 
freeze at -20 degrees C 
DHEA-S 
Any 
RIA after 
hydrolysis 
1 mL 
Gold Top 
Separate serum and 
freeze at -20 degrees C 
ACTH 
AM 
CLIA 
3 mL 
Lavender Top 
(pre-chilled); 
deliver on ice to 
laboratory 
Separate serum and 
freeze plasma in plastic 
tube at -20 degrees C 
Cortisol 
AM 
CLIA 
1 mL 
Gold Top 
Separate serum and 
freeze at -20 degrees C 
Aldosterone 
AM 
LC/MS/MS 2 mL 
Red Top 
Separate serum and 
freeze at -20 degrees C 
11-Deoxycortisol 
AM 
RIA 
2 mL 
Gold Top 
Separate serum and 
freeze at -20 degrees C 


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Time of 
Day 
Method 
Volume 
Container 
Processing 
Deoxycorticosterone 
AM 
RIA 
2 mL 
Gold Top 
Separate serum and 
freeze at -20 degrees C 
* Between 8:00 am and 12:00pm* Between 8:00 am and 12:00pm 
DHEA-S = dihydroepiandrostenedione-sulfate; LC = liquid chromatography; MS = mass spectroscopy; RIA = 
radioimmunoassay; CLIA = chemiluminescent immunoassay 
 
9.2      Hedgehog Pathway Assessment BymRNA Expression Analysis 
 
Because Hedgehog signaling is present in skin and hair follicles, GLI1 mRNA expression (a 
marker  of  Hedgehog  pathway  activation)  will  be  analyzed  using  3-millimeter  skin  punch- 
biopsies from hair-containing non-scalp skin (e.g. upper back or arms) obtained at baseline and 
after 4 weeks on study, using previously described and validated methodology [25].The skin 
sample should be placed immediately into a 5 mL Tissue Protect Tube containing RNAlater 
solution, and care must be taken to ensure that the skin sample is fully submerged in RNAlater. 
Samples should then be frozen at -20 degrees Celsius or colder until the time of RNA extraction. 
Additionally, mRNA expression analysis of archived, formalin-fixed paraffin embedded primary 
prostate cancer tissue will be performed when tissue is available. Please see Appendix 3 for 
details regarding the skin biopsy procedure as well as specimen handling/shipping instructions. 
GLI1mRNA expression levels in tissue samples will be analyzed using the RT2 Profiler Custom 
PCR Array protocol (SABiosciences, Qiagen).  RNA will be extracted from tissue samples using 
RNeasy Fibrous Tissue kit (Qiagen). The RT2  PCR Array First Strand kit (SuperArray 
Bioscience), will be used to synthesize cDNA. Quantitative PCR will be performed using RT2 
Real-Time SYBR Green PCR Master Mix (SABiosciences, Qiagen), in an ICycler PCR System 
(Bio-Rad  Laboratories),  according  to  the  manufacturer's  protocol.  The  housekeeper  gene 
GAPDH will be used, as the expression level of this gene has been previously shown to not 
change with itraconazole therapy using a housekeeper array (Cat#: PHAS-000, SABiosciences, 
Qiagen). Cycling threshold (Ct) values for GLI1and GAPDH from each experiment will be 
analyzed using the SABiosciences software and fold change of GLI1expression, normalized to 
GAPDH, will be derived for each sample. 
 
Patients will be dichotomized for the purposes of statistical analysis. The full statistical analytic 
plan for GLI1 expression datais described in Section 10. 
 
9.3      Immunohistochemical Analysis of the Hedgehog Pathway in Primary 
Prostate Cancer Tissue 
 
Availability of archived primary prostate cancer tissue (either prior biopsy or prostatectomy 
specimen) is recommended but not required for study entry. The goal is to obtain archival 
primary prostate cancer tissue from 50% of the patients enrolled onto study. Representative 


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formalin 
fixed 
and 
paraffin 
embedded 
tissue 
sections 
will 
be 
used 
for 
thisimmunohistochemicalanalysis (see Appendix 3 for shipping instructions).Tissue sections will 
be deparaffinized, followed by rehydration with decreased concentrations of ethanol, and 
immersed in 3% H2O2 (in distilled H2O) for 10 minutes. Following antigen retrieval in citrate 
buffer, the tissue sections will be incubated with normal goat serum to block non-specific 
antibody binding (20 min at room temperature). The sections will then be incubated with primary 
antibotides (at 1:200 dilution) at 37 degrees C in humid chambers for 2 hours. After washing 
with PBS three times, the sections will be incubated with biotinylated secondary antibody (goal 
anti-rabbit IgG or monkey anti-goal IgG) and streptavidin conjugated to horseradish peroxidase 
for 20 min at 37 degrees C, followed by PBS wash. Hematoxylin will be used for counter- 
staining. Negative controls will be performed in all cases by omitting the first antibodies.Specific 
antibodies to Sonic hedgehog ligand, SMO, GLI1, and PTCH1(Cat. No. 9024 for Sonic hedgehog 
ligand, Cat. No. 6149 for PTCH1, Cat. No. 166685 for SMO, and Cat. No. 20291 for GLI1, Santa 
Cruz  Biotechnology  Inc.,  Santa  Cruz,  CA)  will  be  utilized.  The  intensity  of 
immunohistochemical  staining  will  be  scored  by  pathology  reviewers  blinded  to  clinical 
outcomes on a scale from 0, 1+, 2+, and 3+. Patients will be dichotomized for the purposes of 
statistical analysis (0 and 1+ staining vs. 2-3+; see Section 10). 
 
9.4      Serum Drug Levels 
 
The plasma trough concentrations of itraconazole and hydroxyitraconazole will be assessed by a 
validated liquid chromatography-mass spectrometry assay developed by the Analytical 
Pharmacology Core Laboratory at Johns Hopkins University. Trough levels will be drawn after 4 
weeks of protocol therapy, collected before the morning dose of itraconazole. Patients should 
hold their morning dose until the collection is completed. 
 
Patients will have about 5 ml of blood collected into tubes containing K2-EDTA as an 
anticoagulant (lavender top). Following extraction, blood will be immediately placed on ice or 
refrigerated until processed. The actual day and time of collection will be recorded. Plasma will 
be separated from whole blood as soon as possible following extraction. This will be done by 
centrifuging whole blood at 1000 x g for 10 minutes at 4°C. Plasma will then be transferred to a 
screw-cap polypropylene cryotube for determination of itraconazole and hydroxyitraconazole 
concentrations. The polypropylene tube will be labeled with patient‟s initials, study number, day, 
time, and protocol day and then frozen at –70°C until the time of analysis (see appendix 3 for 
additional information regarding processing and shipping instructions). 
 
10.0  Planned Statistical Methods 
 
10.1   Study Design 
 
This is a phase II, single arm study of itraconazole dosed at 300 mg BID in patients with non- 
castrate, non-metastatic, biochemically relapsed prostate cancer after prior definitive local 
therapy. Simon‟s two stage minimax design will be followed for accrual and include an interim 
test for lack of efficacy (see Sections 10.2 and 10.4). There is a pre-specified stopping rule for 


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safety after 10 patients have been treated for a minimum of 8 weeks of protocol therapy (see 
Section 10.4).  Patients will remain on protocol therapy until the first occurrence of any of the 
following: PSA progression, as defined in Section 2, development of metastasis, unacceptable 
toxicity, initiation of non-protocol therapy, or patient/physician withdrawal from study. Patients 
will remain on study until development of metastasis, initiation of non-protocol therapy, or 
patient/physician withdrawal from study, whichever occurs soonest. The total study duration 
including follow up is expected to be 3 years from the date of first patient enrolled onto study. 
 
10.2   Determination of Sample Size and Study Power 
 
This is a single arm phase II study to test the hypothesis for an improvement in the proportion of 
patients achieving a PSA decline of at least 50% from baseline with itraconazole therapy. The 
null hypothesis is that 10% of patients treated with itraconazole will achieve a > 50% decline in 
serum PSA after 12 weeks of protocol therapy. This response proportion is based upon the 
overall PSA response proportions observed in prior clinical trials of non-castrating agents in 
biochemically relapsed prostate cancer, which demonstrated modest activity with 0-10% of 
patients achieving a ≥ 50% PSA decline on therapy [10-16]. A response proportion of 10% or 
less in the current study would indicate minimal disease activity and would not justify further 
testing of itraconazole in this disease setting. The alternative hypothesis is that 25% of patients 
treated with itraconazole will achieve a ≥ 50% decline in serum PSA after 12 weeks of protocol 
therapy, a clinically meaningful result that would represent promising biologic activity of a novel 
potentially non-castrating agent tested in the biochemically relapsed disease setting. The sample 
size is based upon the primary study endpoint and will follow a two stage design for accrual 
following Simon‟s two-stage minimax approach.  Twenty-two patients will be accrued at the first 
stage. If more than two patients achieve a PSA decline of at least 50% within 12 weeks of 
starting protocol therapy, accrual will continue to the second stage and an additional 18 patients 
will be entered. If at least 8 of the 40 patients entered on study achieve a PSA decline of at least 
50%, then the null hypothesis will be rejected in favor of the alternative. This test with a total 
evaluable accrual of 40 patients has a power of 80% and a directional level of significance of 
0.05. The probability of stopping accrual at the first stage is 0.62 if the null hypothesis is true. A 
drop-out rate for reasons not due to treatment or disease progression of 5% prior to the cut-off 
point for the primary analysis is assumed for a total study accrual of 42 patients. 
 
10.3   Accrual 
 
A total of 40 evaluable patients will be enrolled across three investigational sites.The estimated 
enrollment rate across the three sites is 3 patients per month, leading to anticipated enrollment 
duration of approximately 14 months. The duration from first patient enrolled to primary analysis 
is approximately 18 months, and the total study duration including follow upis expected to be 3 
years. 


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10.4   Interim Analysis 
 
There will be an interim analysis for safetyafter 10 patients have received a minimum of 8 weeks 
of protocol therapy. Study accrual will continue during the interim safety analysis. 
 
If, after 8 weeks of protocol therapy, four or more out of ten patients have a grade 3 or higher 
adverse event that the study investigator deems as possibly, probably, or definitely related to 
study drug (excluding hypokalemia or hypertension), the study will close to further accrual. 
 
An interim analysis for lack of efficacy will be performed after completion of the first stage of 
accrual of 22 patients. Study accrual will not stop for this analysis,consistent with the study 
design of prior non-hormonal therapies in biochemically relapsed prostate cancer, the majority of 
which were single stage phase II studies without pre-specified stopping rules for lack of efficacy 
despite observed PSA response proportions of less than 5%. 
 
10.5   Analysis Population 
 
The primary efficacy analysis will include all patients who have at least one PSA follow-up 
measurement. In addition, if a patient comes off study prior to obtaining one PSA follow-up 
measurement for disease progression or toxicity, they will be included in the analysis of PSA 
response as a treatment failure. All patients who receive at least one dose of study drug will be 
included in the analysis of safety. 
 
10.6   Demographics and Baseline Characteristics 
 
Demographic variables will include age, race, ethnicity, height, and weight. Baseline 
characteristics will include the following: 
 
• Number of years since diagnosis of prostate cancer 
• Gleason grade/clinical stage/pathologic stage (if prior prostatectomy)/PSA at the time of 
diagnosis 
• Type and timing of local therapy (surgery and/or radiation) for prostate cancer 
• Nadir PSA after definitive local therapy and time to nadir PSA 
• Time from definitive local therapy to PSA progression (as defined by first PSA ≥ 0.2 
ng/mL in patients with prior radical prostatectomy with or without adjuvant radiation 
therapy; first PSA rise of 2.0 ng/mL or more above the nadir in patients with prior primary 
definitive radiation therapy) 
• Time interval from biochemical relapse to study entry 
• PSA doubling timeat the time of study entry 
• Use of prior ADT, nadir PSA on ADT, duration of ADT, time interval from last dose of 
ADT and study enrollment, and indication (i.e. adjuvant or in biochemical relapse) (if 
applicable) 
• Use of prior antiandrogen therapy, time interval since prior therapy to study enrollment, 
and indication (if applicable) 


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10.7   Study Endpoints 
 
10.7.1 Primary Endpoint 
 
The proportion of patients with biochemically relapsed disease after prior definitive local therapy 
who achieve a ≥ 50% decline from baseline in serum PSA after 12 weeks of therapy with 
itraconazole, confirmed by repeat measurement at least 2 weeks later, will be calculated. 
 
10.7.2 Secondary Endpoints 
 
A) Clinical Activity: 
 
• Median  time  to  PSA  progression  among  men  with  biochemical  relapse  treated  with 
itraconazole will be estimated. See Section 2 for the definition of PSA progression. 
• Median time to clinical progression will be estimated, with clinical progression defined as 
the first occurrence of either development of overt metastases or initiation of non-protocol 
therapy. The definition of clinical progression excludes PSA-only progression. 
• Median metastasis-free survival will be estimated among men with biochemical relapse 
treated with itraconazole. 
• Mean percent change after 12 weeks of protocol therapy compared with pre-treatment in 
PSA doubling time will be determined for those treated with itraconazole. The pre- 
treatment PSADT will be determined based upon all PSA measurements within 3 months 
prior to Day 1 of protocol therapy, with a minimum of three PSA values each spaced at 
least 14 days apart (see Section 6.2.1). 
B) Safety/Pharmacokinetics: 
 
• Maximum  grade  toxicities  observed  during  treatment  with  itraconazole,  as  graded  by 
CTCAE version 4.03. 
 
• Mean steady-state trough level of serum itraconazole and its active metabolite, hydroxy- 
itraconazole, after 4 weeks of therapy with itraconazole. 
 
10.7.3 Correlative Endpoints 
 
A) Endocrine Parameters: 
 
• Mean   percent   change   from   baseline   in   serum   androgen   levels,   including   serum 
testosterone, DHEA-S, and androstenedione, after 4 and 12 weeks of protocol therapy. 
• Mean percent change from baseline in additional serum hormone levels, including ACTH, 
aldosterone, deoxycorticosterone (DOC), 11-deoxycortisol, and cortisol after 4 and 12 
weeks of protocol therapy. 
• Mean  baseline  and  mean  percent  change  in  serum  hormone  levels  among  patients 
achieving ≥ 50% decline from baseline in serum PSA after 12 weeks of itraconazole 
therapy and among those not achieving this decline. 


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B) Hedgehog Pathway (assessed by serial skin biopsies on protocol therapy and analysis of 
archived primary prostate cancer tissue including prior biopsy or prostatectomy specimen): 
 
• Proportion  of patients  who display a down-regulation  of the Hedgehog pathway,  as 
assessed by measurement of GLI1 mRNA expression by RT-PCR on serial skin biopsies 
obtained at baseline and after 4 weeks of protocol therapy with itraconazole. Down- 
regulation will be defined as a decline of any magnitude in GLI1 mRNA expression after 
4 weeks of protocol therapy compared to baseline expression level. 
 
• Proportion of patients with and without at least a 50% decline from baseline after 12 
weeks  of  protocol  therapy  in  PSA  exhibiting  a  down-regulation  of  the  Hedgehog 
pathway. 
• Median time to PSA progression between patients with and without down-regulation of 
the Hedgehog pathway on itraconazole therapy as assessed by serial skin biopsy. 
• Proportion of patients with and without at least 50% decline from baseline after 12 weeks 
of protocol therapy in PSA exhibiting over-activation of Hedgehog pathway components 
as assessed by immunohistochemical (IHC) and mRNA expression analysis of primary 
prostate cancer tissue (prior biopsy or prostatectomy specimen). Patients will be 
dichotomized  (immunohistochemical  staining 0  to 1+ vs.  2 to  3+ staining intensity; 
mRNA  expression  above  and  below  median)  for  the  purposes  of  analysis  of  the 
Hedgehog pathway in primary prostate cancer tissue. 
• Median time to PSA progression between patients with and without Hedgehog pathway 
over-activation in archived primary prostate cancer tissue. 
 
10.8   Methods for Analysis 
 
10.8.1 Analytic Plan for the Primary Objective 
 
The primary objective will be evaluated following the decision rules for Simon‟s minimax 2 
stage design as defined above (Section 10.2). The proportion of patients who achieve a ≥ 50% 
decline in serum PSA compared to baseline after 12 weeks of protocol therapy, confirmed by 
repeat measurement at least two weeks later, will be calculated.Patients with at least one PSA 
follow-up measurement who discontinue protocol therapy prior to 12 weeks due to any reason 
will be counted as failures for analysis of the primary objective. In addition, patients who 
discontinue protocol therapy due to disease progression or toxicity prior to obtaining one PSA 
follow-up measurement will be counted as failures for analysis of the primary objective. Patients 
who withdraw from the study for other reasons prior to one PSA follow-up measurement will be 
excluded in the analysis of the primary objective. The null hypothesis is that 10% of patients will 
achieve a ≥ 50% decline in serum PSA after 12 weeks of protocol therapy, with an alternative 
hypothesis  that  25%  of  patients  will  achieve  such  a  decline  in  serum  PSA.  If  accrual  is 
completed and at least 8 patients achieve a ≥ 50% decline in serum PSA from their baseline 
measurement then the null hypothesis will be rejected based upon a test with 80% power and a 


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directional level of significance of 5%. The results will be summarized by the proportion of 
patients who achieve a ≥ 50% decline in serum PSA along with a 95% confidence interval. 
 
10.8.2 Analytic Plan for the Secondary Objectives 
 
Clinical Activity 
 
The probability distribution of the time to PSA progression will be estimated using the Kaplan- 
Meier product limit method measured from the start of protocol therapy. The results will be 
summarized by the estimated median with 95% confidence intervals. PSA progression will be 
defined as follows: (1) If no PSA decline is observed on therapy, PSA progression will be 
defined as an increase in serum PSA > 50% above the baseline PSA, and an absolute increase of 
> 2ng/mL above baseline, confirmed by repeat measurement at least 2weeks later (2) If PSA 
declines on therapy, PSA progression will be defined as an increase in serum PSA > 50% above 
the nadir PSA on therapy, and an absolute increase > 2ng/mL above the nadir, confirmed by 
repeat measurement at least 2weeks later. Durations will be measured from Day 1 of study 
treatment to the first date of PSA progression. Patients who discontinue study therapy prior to 
PSA progression due to unacceptable toxicity, patient/physician withdrawal, initiation of non- 
protocol therapy, or development of metastases will be censored at the time of last PSA 
measurement prior to the event. 
 
 
The probability distribution of the time to clinical progression and time to first metastasis will be 
estimated using the Kaplan-Meier product limit method measured from the time of start of 
protocol therapy. The results will be summarized by the estimated median with 95% confidence 
intervals. Clinical progression will be defined as the first occurrence of either development of 
metastasis detected by radiographic scans or initiation of non-protocol therapy, whichever occurs 
soonest. PSA-only progression will not be counted as clinical progression. If a patient withdraws 
from study, discontinues therapy due to unacceptable toxicity, or is lost to follow up prior to 
clinical progression, he will be censored at the date of the last recorded study visit. Additionally, 
for the analysis of time to first metastasis, if a patient initiates non-protocol therapy prior to 
development of metastatic disease, he will be censored at the start date of non-protocol therapy. 
 
 
The mean percent changein PSA doubling time after 12 weeks of protocol therapy from pre- 
treatment PSA doubling timewill be calculated. Calculation of baseline PSA doubling time will 
be based upon all PSA measurements obtained within 3 months prior to Day 1 of protocol 
therapy, with a minimum of threePSA values spaced at least 14 days apart(see  Section6). The 
PSA doubling time both pre- and on-treatment will be estimated using the relationship of natural 
log (Ln) 2 divided by the slope of lnPSA versus time. Descriptive statistics will be presented to 
summarize the PSA doubling time at baseline and after 12 weeks of protocol therapy as well as 
the change between time points. Pearson‟s correlation will be used to estimate the relationship 
between pre-treatment PSA doubling time and percent change in PSA doubling time after 12 
weeks of protocol therapy. In an exploratory fashion, the mean percent change in PSA doubling 
time after 12 weeks of protocol therapy from pre-treatment PSA doubling time will be calculated 


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for the subsets  of patients  with  and  without  a decline in  serum  PSA on  therapy.  Either a 
dependent t statistic or the Wilcoxon matched pairs test will be performed for the subset of 
patients without a PSA decline to describe any change in PSA doubling time from pretreatment 
and for the full study cohort. 
 
Safety and Pharmacokinetics: 
 
All patients who receive at least one dose of study drug will be analyzed for safety. Safety 
endpoints including vital signs, adverse events, and clinical laboratory parameters will be 
summarized using descriptive statistics. All adverse events will be tabulated by grade according 
to CTCAE version 4.03, according to the worst grade experienced. 
 
Descriptive statistics including the mean, standard deviation, and range of steady-state trough 
serum levels of itraconazole and its active metabolite hydroxy-itraconazole will be determined. 
 
10.8.3 Analytic Plan for the Correlative Objectives 
 
Endocrine Parameters 
 
Serum hormone levels, including testosterone,androstenedione, DHEA-S, cortisol, aldosterone, 
11-deoxycortisol, ACTH, and deoxycorticosterone, will be measured at baseline, at week 4, 
week 12, and at the time of PSA or clinical progression. To summarize the outcome, descriptive 
statistics including the mean percent change from baseline in serum hormone levels at 4 and 12 
weeks will be presented with a standard deviation and Pearson‟s correlation will be used to 
estimate the relationship between the baseline hormone level and percent change in hormone 
level after 4 and 12 weeks of treatment. Analysis of variance (ANOVA) methods for mixed 
models allowing for variable number of follow-up measurementswith linear contrasts will be 
used to evaluate the change in serum hormone levels after 4 and 12 weeks of protocol therapy. It 
is hypothesized that approximately 15% of patients treated with protocol therapy will achieve a 
PSA decline ≥ 50%. Depending upon the observed frequency, the ANOVA model will include a 
factor to test for the effect of PSA decline on change in serum hormone levels. Otherwise, 
analyses will compare the baseline and percent change in serum hormone levels at 4 and 12 
weeks between patients achieving a PSA decline ≥ 50% or not using a two group t statistic. For 
these exploratory analyses, graphic presentations will also be used to explore the overall pattern 
of change in serum hormone levels between those with and without a PSA decline. 
 
Hedgehog Pathway 
 
The quantitative expression of GLI1, a downstream product of the Hedgehog signal transduction 
pathway, will be measured by quantitative RT-PCR from serial skin biopsies obtained at baseline 
and after 4 weeks of therapy. The fold change in expression level after 4 weeks of protocol 
therapy will be calculated for each patient. Descriptive statistics will be used to summarize the 
proportion of patients with down-regulation of GLI1 expression after 4 weeks of treatment with 
itraconazole. Down-regulation will be defined as any magnitude of decrease in GLI1 mRNA 
expression after 4 weeks of protocol therapy compared to baseline expression level. The patient 


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cohort will be dichotomized by whether there is up- or down-regulation of GLI1 expression. 
Fisher‟s exact test will be used to test for an association between down-regulation of GLI1 
expression and PSA decline≥ 50% on protocol therapy.The probability distributions for each 
GLI1 expressionsubset (as defined above)of the time to PSA progression will be estimated using 
the Kaplan-Meier product limit method. The results will be summarized by the estimated median 
with 95% confidence intervals. An exploratory analysis using the log-rank test will be used to 
test  for  differences  in  the  distributions  between  patients  with  down-regulation  of  GLI1 
expression vs. those without GLI1 down-regulation on therapy. 
 
The  quantitative  expression  of  GLI1  will  also  be  measured  by  quantitative  RT-PCR  from 
archived primary prostate cancer tissue. The patient cohort will be dichotomized by expression 
level of GLI1 (above vs. below the median). Fisher‟s exact test will be used to test for an 
association between GLI1 expression in primary prostate cancer tissue and PSA decline ≥ 50% 
on itraconazole therapy. The probability distributions for each GLI1 expression subset of the 
time to PSA progression will be estimated using the Kaplan-Meier product limit method. The 
results will be summarized by the estimated median with 95% confidence intervals. An 
exploratory analysis using the log-rank test will be performed to test for differences in the 
distributions between patients with GLI1 expression above vs. below the median from primary 
prostate cancer tissue specimens. 
 
Immunohistochemical  analysis  of  primary  prostate  cancer  tissue  for  protein  expression  of 
PCTH1, GLI1, SMO, as well as Sonic hedgehog ligand will be carried out for patients with 
evaluable tissue. It is estimated that approximately 50% of patients will have tissue available for 
analysis. Immunohistochemical expression will be graded as 0, 1+, 2+, and 3+ staining intensity 
by independent, blinded pathologic assessment. For each protein, the patient cohort will be 
dichotomized based on intensity of IHC staining (0 and 1+ vs. 2+-3+). Fisher‟s exact test will be 
used to test for an association between IHC expression and PSA decline > 50% on protocol 
therapy. The probability distibutions for each expression subset of the time to PSA progression 
will be estimated using the Kaplan-Meier product limit method. The results will be summarized 
by the estimated median with 95% confidence intervals. 
 
No adjustment for multiple comparisons will be made for the analysis of the secondary and 
correlative objectives. 
 
11.0  Reporting and Documentation of Adverse Events 
 
11.1   Definitions of Adverse Events (21 CFR 312.32(a)) 
 
Adverse Event 
 
Adverse event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not considered drug related. 


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An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended  sign  (e.g.,  an  abnormal  laboratory  finding),  symptom,  or  disease  temporally 
associated with the use of a drug, without any judgment about causality. An adverse event can 
arise from any use of the drug (e.g., off-label use, use in combination with another drug) and 
from any route of administration, formulation, or dose, including an overdose. 
 
Adverse reaction 
 
An adverse reaction means any adverse event caused by a drug.  Adverse reactions are a subset 
of all suspected adverse reactions for which there is reason to conclude that the drug caused the 
event. 
 
Suspected adverse reaction 
 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. For the purposes of IND safety reporting, „reasonable 
possibility‟ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any adverse event caused by a drug. 
 
Unexpected 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the investigator brochure or package insert(s) or, is not listed at the specificity or severity that 
has been observed; or, if an investigator brochure is not required or available, is not consistent 
with the risk information described in the general investigational plan or elsewhere in the current 
application. 
 
"Unexpected," as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation. 
 
Adverse events that would be anticipated to occur as part of the disease process are considered 
unexpected for the purposes of reporting because they would not be listed in the investigator 
brochure.   For example, a certain number of non-acute deaths in a cancer trial would be 
anticipated as an outcome of the underlying disease, but such deaths would generally not be 
listed as a suspected adverse reaction in the investigator brochure. 
 
Some adverse events are listed in the investigator brochure as occurring with the same class of 
drugs, or as anticipated from the pharmacological properties of the drug, even though they have 
not  been  observed  with  the  drug  under  investigation.  Such  events  would  be  considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the ACE 
inhibitor class and angioedema would be described in the investigator brochure as a class effect, 


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the first case of angioedema observed with the drug under investigation should be considered 
unexpected for reporting purposes. 
 
Serious 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: 
 
• Death 
• a life-threatening adverse event 
 
• inpatient hospitalization or prolongation of existing hospitalization 
• a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function 
• a congenital anomaly/birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
Life-threatening 
 
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of 
death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death. 
 
11.2   Recording of an Adverse Event 
 
All adverse events will be entered into OnCore®, UCSF‟s Clinical Trial Management System, 
whether or not the event is believed to be associated with use of the investigational drug.  Data 
about these events and their severity will be recorded using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) (V4.0), when applicable, on the appropriate case report 
forms (CRFs).  The Investigator will assign attribution of the possible association of the event 
with use of the investigational drug, and this information will be entered into OnCore using the 
classification system listed below: 


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Relationship 
Attribution 
Description 
 
Unrelated to 
investigational 
agent/intervention1 
 
Related to 
investigational 
agent/intervention1 
Unrelated 
The AE is clearly NOT related to the intervention 
 
Unlikely 
The AE is doubtfully related to the intervention 
 
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention 
 
 
Signs or symptoms reported as adverse events will be graded and recorded by the Investigator 
according to the CTCAE.  When specific adverse events are not listed in the CTCAE they are to 
be graded by the Investigator as none, mild, moderate or severe according to the following 
grades and definitions: 
 
Grade 0:          No AE (or within normal limits). 
 
Grade 1:          Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 
Grade 2:          Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL). 
 
Grade 3:          Severe    or    medically    significant    but    not    immediately    life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL. 
 
Grade 4: 
Life-threatening consequences; urgent intervention indicated. 
Grade 5: 
Death related to AE. 
 
11.3   Follow-up of Adverse Events 
 
All adverse events must be followed with appropriate medical management until resolved.  For 
selected adverse events for which administration of the investigational drug was stopped, a re- 
challenge of the subject with the investigational drug may be conducted if considered both safe 
and ethical by the Investigator. 
 
11.4   Serious Adverse Events Monitoring 
 
All serious adverse events, whether or not unexpected, and whether or not considered to be 
associated with the use of the study drug, will be entered into OnCore®, as noted above. 
 
The Principal Investigator will assess each Serious Adverse Event (SAE) and determine 
reportability requirements to the Data and Safety Monitoring Committee (DSMC), UCSF‟s 
Committee on Human Research (CHR), and, when the study is conducted under an 
Investigational Drug Application (IND), to the Food and Drug Administration. 


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All serious adverse events entered into OnCore® will be reviewed by the Site Committee on a 
weekly basis.  The Site Committee will review and discuss at each weekly meeting the selected 
toxicity, the toxicity grade, and the attribution of relationship of the SAE to the administration of 
the study drug(s). 
 
In addition, all serious adverse events entered into OnCore® will be reviewed and monitored by 
the Data and Safety Monitoring Committee on a monthly basis and prior to dose escalation.  At 
the time of dose escalation, a written report will be submitted to the DSMC Chair outlining the 
cohorts, dose, AEs and SAE reports, and any Dose Limiting Toxicities observed, in accordance 
with the protocol.  The report will be reviewed and approved by the DSMC Chair (or designee) 
prior to dose escalation. 
 
11.5   Serious Adverse Events Expedited Reporting 
 
Reporting to the Data and Safety Monitoring Committee (DSMC) 
 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study drug(s) or 
to a study procedure, the Investigator or his/her designee must notify the DSMC Chair within 24 
hours of knowledge of the event.  The contact may be by phone or e-mail. 
 
Reporting to the Committee on Human Research (CHR) 
 
The Investigator must report SAEs meeting the CHR definition of “Unanticipated Problem” (UP) 
within 10 working days of his/her awareness of the event. 
 
Specific  instructions  on  SAE  reporting  may  be  found  at  the  UCSF  CHR  website  at: 
http://www.research.ucsf.edu/chr/Guide/Adverse_Events_Guidelines.asp 
 
Expedited Reporting to the IND 
 
If the study is being conducted under an Investigational Drug Application, the Sponsor- 
Investigator  is  responsible  for  determining  whether  or  not  the  SAE  meets  the  criteria  for 
expedited reporting in accordance with Federal Regulations (21 CFR §312.32). 
 
The Investigator must report in an IND safety report any suspected adverse reaction that is both 
serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets all three 
definitions: 
 
• Suspected adverse reaction 
 
• Serious 
• Unexpected 
 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report. 


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The timeframe for submitting an IND safety report to FDA is no later than 15 calendar days 
after the Investigator determines that the suspected adverse reaction qualifies for reporting (21 
CFR 312.32(c)(1)). 
 
Any unexpected fatal or life-threatening suspected adverse reaction must be reported to FDA no 
later than 7 calendar days after the Investigator‟s initial receipt of the information (21 CFR 
312.32(c)(2)). 
 
Any relevant additional information that pertains to a previously submitted IND safety report 
must be submitted to FDA as a Follow Up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
 
 
For additional information and guidance on IND Safety Reports, please refer to the FDA 
Guidance for Industry:  Safety Reporting Requirements for INDs. 
 
12.0  Study Management 
 
Pre-study Documentation 
 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all 
applicable regulatory requirements. 
 
 
Prior to implementing this protocol at UCSF HDFCCC, the protocol, informed consent form, 
HIPAA authorization and any other information pertaining to participants must be approved by 
the UCSF Committee on Human Research (CHR). Prior to implementing this protocol at the 
participating sites, approval for the UCSF CHR approved protocol must be obtained from the 
participating site‟s IRB. 
 
 
The following documents must be provided to UCSF HDFCCC before the participating site can 
be initiated and begin enrolling participants: 
• Participating Site IRB approval(s) for the protocol, appendices, informed consent form and 
HIPAA authorization 
• Participating Site IRB approved consent form 
• Participating Site IRB membership list 
• Participating Site IRB‟s Federal Wide Assurance number and OHRP Registration number 
• Curriculum vitae and medical license for each investigator and consenting professional 
• Documentation of Human Subject Research Certification training for investigators and key 
staff members at the Participating Site 
• Participating site laboratory certifications and normals 


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Upon receipt of the required documents, UCSF HDFCCC will formally contact the site and grant 
permission to proceed with enrollment (a detailed listing of the documents required from 
participating sites is provided in Appendix 4). 
 
 
The clinical investigation will not begin until either FDA has determined that the study under the 
Investigational Drug Application (IND) is allowed to proceed or the Investigator has received a 
letter from FDA stating that the study is exempt from IND requirements. 
 
 
The Investigator must comply with the applicable regulations in Title 21 of the Code of Federal 
Regulations (21 CFR) Parts §50, §54, and §312, GCP/ICH guidelines, and all applicable 
regulatory  requirements.    The  IRB  must  comply  with  the  regulations  in  21  CFR  56  and 
applicable regulatory requirements. 
 
Institutional Review Board Approval 
 
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the Committee on Human Research (UCSF‟s IRB).   Prior to obtaining CHR 
approval, the protocol must be approved by the Helen Diller Family Comprehensive Cancer 
Center Protocol Review Committee (PRC).   The initial protocol and all protocol amendments 
must be approved by the IRB prior to implementation. 
 
Informed Consent 
All participants must be provided a consent form describing the study with sufficient information 
for participants to make an informed decision regarding their participation.   Participants must 
sign the IRB-approved informed consent form prior to participation in any study specific 
procedure.  The participant must receive a copy of the signed and dated consent document.  The 
original signed copy of the consent document must be retained in the medical record or research 
file. 
 
Changes in the Protocol 
 
Once the protocol has been approved by the UCSF Committee on Human Research (CHR), any 
changes to the protocol must be documented in the form of an amendment.   The amendment 
must be signed by the Investigator and approved by PRC and the CHR prior to implementation. 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to CHR approval.  In this circumstance, however, the 
Investigator must then notify the CHR in writing within five (5) working days after 
implementation. 
 
Handling and Documentation of Clinical Supplies 
 
The Investigator shall maintain complete records showing the receipt, dispensation, return, or 
other disposition of all investigational drugs.  The date, quantity and batch or code number of the 


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drug, and the identification of patients to whom study drug has been dispensed by patient number 
and initials will be included. 
 
 
The Investigator shall not make the investigational drug available to any individuals other than to 
qualified study patients.  Furthermore, the Investigator will not allow the investigational drug to 
be used in any manner other than that specified in this protocol. 
 
Case Report Forms (CRFs) 
 
The Principal Investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document treatment outcomes for data analysis.   All 
study data will be entered into OnCore®, UCSF‟s Clinical Trial Management System (CTMS) 
via standardized CRFs in accordance with the CTMS study calendar, using single data entry with 
a secure access account.  The Clinical Research Coordinator (CRC) will complete the CRFs as 
soon as possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs. 
 
 
The information collected on CRFs shall be identical to that appearing in original source 
documents.   Source documents will be found in the patient‟s medical records maintained by 
UCSF personnel.  All source documentation should be kept in separate research folders for each 
patient. 
 
 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  Each CRF must be reviewed 
for accuracy by the Investigator, corrected as necessary, and then approved.  Alternatively, the 
Investigator may sign individual, printed CRFs.  These signatures attest that the information 
contained on the CRFs is true and accurate. 
 
 
All source documentation and CTMS data will be available for review/monitoring by the Data 
and Safety Monitoring Committee (DSMC) and regulatory agencies. 
 
 
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  At 
study completion, when the database has been declared to be complete and accurate, the database 
will be locked.  Any changes to the database after that time can only be made by joint written 
agreement among the Principal Investigator, the Trial Statistician, and the Protocol Project 
Manager. 
 
Oversight and Monitoring Plan 
 
The Helen Diller Family Comprehensive Cancer Center Data and Safety Monitoring Committee 
(DSMC) will be the monitoring entity for this study.  The DSMC will monitor the study in 
accordance with the NCI-approved Data and Safety Monitoring Plan (DSMP).   The Data and 


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Safety Monitoring Plan for Multicenter Institutional Study (Phase 2 or 3) is described in 
Appendix 4. The DSMC will audit study-related activities to ensure that the study is conducted 
in accordance with the protocol, local standard operating procedures, FDA regulations, and Good 
Clinical Practice (GCP).  In addition, the DSMC will regularly review serious adverse events and 
protocol deviations associated with the research to ensure the protection of human subjects. 
Results of the DSMC audit will be communicated to the IRB and the appropriate regulatory 
authorities at the time of continuing review, or in an expedited fashion, as applicable. 
 
Retention of Records 
 
The Investigator will retain a copy of all study documents in accordance with FDA regulations: 
•    for  a  minimum  of  two  years  following  the  date  a  marketing  application  (New  Drug 
Application or NDA) is approved for the drug for the proposed clinical indication; or 
 
• if no marketing application is filed, or if the marketing application has been filed but is not 
approved by the FDA, then for a minimum of two years following the release date of the 
final report; or 
 
The  Investigator  agrees  to  maintain  a  complete  and  current  record  of  all  documentation 
associated with the study.  All of the documents shall be kept together.  Each should be available 
for ready review.  These study documents will include the: 
• protocol 
• protocol amendments, when applicable 
• signed FDA Form 1572 
• 
Investigator‟s current curriculum vitae 
• documentation of CHR approvals for the protocol, amendments, informed consents and 
advertisements used to recruit patients 
• Investigator's Brochure(s) 
• site visit log 
• correspondence (all “to” and “from” correspondence) 
• drug accountability records, drug shipment forms, and drug disposal records 
• case report forms and informed consent documents for individual patients 
• final report for the study if available. 
 
13.0  Protection of Human Subjects 
 
Protection from Unnecessary Harm 
 
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the CHR mechanism and the process of informed consent. The 
CHR reviews all proposed studies involving human experimentation and ensures that the 
subject‟s rights and welfare are protected and that the potential benefits and/or the importance of 
the knowledge to be gained outweigh the risks to the individual. The CHR also reviews the 


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informed consent document associated with each study in order to ensure that the consent 
document accurately and clearly communicates the nature of the research to be done and its 
associated risks and benefits. 
 
Protection of Privacy 
 
Patients will be informed of the extent to which their confidential health information generated 
from this study may be used for research purposes. Following this discussion, they will be asked 
to sign the HIPAA form and informed consent documents. The original signed document will 
become part of the patient‟s medical records, and each patient will receive a copy of the signed 
document. The use and disclosure of protected health information will be limited to the 
individuals described in the informed consent document. 


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a Cancer and Leukemia Group B study. Clin Cancer Research 2007; 13(7):2030-2037. 
22. Chong CR, Xu J, Lu J, Bhat S, Sullivan Jr. DJ, and Liu JO. Inhibition of angiogenesis by the 
antifungal drug itraconazole. ACS Chemical Biology 2007; 2(4): 263-270. 
23. Aftab BT, Dobromilskaya I, Liu JO, and Rudin CM. Itraconazoleinhibits angiogenesis and 
tumor growth in non-small cell lung cancer. Cancer Research 2011; 71(21): 6764-72. 
24. Taipale J and Beachy PA. The Hedgehog and Wnt signaling pathways in cancer. Nature 
2001; 411:349-354. 
25. Von Hoff DD, LoRusso PM, Rudin CM, et al. Inhibition of the Hedgehog pathway in 
advanced basal-cell carcinoma. New Engl J of Med 2009; 361:1164-1172. 
26. Low JA and de Sauvage FJ. Clinical experience with Hedgehog pathway inhibitors. J 
ClinOncol 2010; 28(36):5321-5326. 
27. Karhadkar SS, Bova SG, Abdallah N, et al. Hedgehog signaling in prostate regeneration, 
neoplasia and metastasis. Nature 2004; 431:707-712. 
28. Sheng T, Li C, Zhang X, et al. Activation of the Hedgehog pathway in advanced prostate 
cancer. Molecular Cancer 2004;3:29. 
29. Kim J, Tang JY, Gong R, et al. Itraconazole, a commonly used antifungal that inhibits 
Hedgehog pathway activity and cancer growth. Cancer Cell 2010; 17:388-399. 
30. Kim D, Kim J, Spaunhurst K, et al. An open-label, exploratory phase II study of oral 
itraconazole for the treatment of basal cell carcinoma. Abstract # LB-223. AACR Annual 
Meeting April 2012; Chicago, IL, USA. 
31. Antonarakis ES, Heath EI, Smith DC, et al. A randomized phase 2 study of two doses of 
itraconazole in men with metastatic castration-resistant prostate cancer (mCRPC). Abstract # 
LB-224. AACR Annual Meeting April 2012; Chicago, IL, USA. 
32. Tucker RM, Haq Y, Denning DW, and Stevens DA. Adverse events associated with 
itraconazole in 189 patients on chronic therapy. Journal of Antimicrobial Chemotherapy 
1990; 26:561-566. 
33. Sharkey PK, Rinaldi MG, Dunn JF, Hardin TC, Fetchick RJ, and Graybill JR. High-dose 
itraconazole in the treatment of severe mycoses. Antimicrobial Agents and Chemotherapy 
1991; 35(4):707-713. 
34. Pont A, Graybill JR, Craven PC, et al. High-dose ketoconazole therapy and adrenal and 
testicular function in humans. Archives of Internal Medicine 1984; 144:2150-2153. 


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35. Stewart AJ, Scher HI, Chen MH, et al. Prostate-specific antigen nadir and cancer-specific 
mortality following hormonal therapy for prostate-specific antigen failure. J ClinOncol 2005; 
23(27):6556-6560. 
36. Scher HI, Eisenberger M, D‟Amico AV, et al. Eligibility and outcomes reporting guidelines 
for clinical trials for patients in the state of a rising prostate-specific antigen: 
recommendations from the Prostate-Specific Antigen Working Group. J ClinOncol 2004; 
22(3):537-556. 
37. Antonarakis ES, Zahurak ML, Lin J, et al. Changes in PSA kinetics predict metastasis-free 
survival in men with PSA-recurrent prostate cancer treated with nonhormonal agents. Cancer 
2012;118:1533-1542. 
38. D‟Amico AV, Moul J, Carroll PR, et al. Prostate specific antigen doubling time as a 
surrogate end point for prostate cancer specific mortality following radical prostatectomy or 
radiation therapy. J Urol 2005; 172(5): S42-S47. 
39. Zelefsky MJ, Ben-Porat L, Scher HI, et al. Outcome predictors for the increasing PSA state 
after definitive external-beam radiotherapy for prostate cancer. J ClinOncol, 2005; 23(4):826- 
831. 
40. Roach M 3rd, Hanks G, Thames H Jr, et al. Defining biochemical failure following 
radiotherapy with or without hormonal therapy in men with clinically localized prostate 
cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J 
RadiatOncolBiol Phys. 2006; 65(4):965-74. 
41. Yu EY, Gulati R, Telesca D, et al. Duration of first off-treatment interval is prognostic for 
time to castration resistance and death in men with biochemical relapse of prostate cancer 
treated on a prospective trial of intermittent androgen deprivation. J ClinOncol 2010; 
28(16):2668-2673. 
42. Ryan C, Li J, Kheoh T, et al. Baseline serum adrenal androgens are prognostic and predictive 
of overall survival (OS) in patients (pts) with metastatic castrate-resistant prostate cancer 
(mCRPC): Results of the COU-AA-301 phase 3 randomized trial. Abstract # LB-434. AACR 
Annual Meeting 2012; Chicago, IL, USA. 
43. Aggarwal R, Weinberg V, Small EJ, Oh W, Rushakoff R, and Ryan CJ. The mechanism of 
action of estrogen in castration-resistant prostate cancer: clues from hormone levels. Clinical 
Genitourinary Cancer 2009; 7(3):E71-E76. 


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Appendix 1. 
List of Prohibited Medications and Supplements While 
Patients Are Taking Itraconazole 
 
Abiraterone acetate 
Amiodarone 
Astemizole 
Atorvastatin 
Bicalutamide 
Chemotherapy 
Cisapride 
Cyproterone acetate 
Diethylstilbesterol 
Degarelix 
Dofetilide 
Dutasteride 
Enzalutamide (MDV3100) 
Eplerenone 
Ergot alkaloids 
Estrogens  
Felodipine 
Finasteride 
Fluconazole 
Flutamide 
GM-CSF 
Goserelin 
Ketoconazole  
Levomethadyl 
Leuprolide acetate 
Lovastatin 
Megestrol  
Methadone 
Midazolam 
Milk thistle 
Nilutamide 
Nisoldipine 
Other investigational agents 
PC-SPES Pimozide 
Pomegranate extract 
Pomegranate juice 
Progesterones 
Quinidine 
Radiation therapy 
Saw palmetto 
Simvastatin 
Sipuleucel-T 
Spironolactone 
Steroids at an equivalent dose of prednisone 5 mg per day or higher 


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Terfenadine 
Triazolam 


Phase II- ltraconazole 
 
 
70
Phase  11    Studv of ltraconalole  in Biochemical Relapse 
 
 
 
 
Appendix 2. Potential Drug-Drug Interactions 
 
 
 
CYP3A4 Iuductrs (drug,s that decrease the bioavailability of itraconazole) 
 I.Aminoglutethimide 
2.Barbiturates 
3.Carbamazepine 
.Efavirenz 
5.Glucocorticoids 
6.Modafinil 
7. Nafcillin 
8. Nevirapine 
9. Oxcarbaze.pine 
10. Phenobarbital 
II.Phenytoin 
12. Pioglitazone 
13.Rifabutin 
14.Rifampin 
15.StJohn's wort 
16.Troglitazoue 
 
 
CYP3A4 Inhibitors Cdrues that increase the bioavailability of itraconazole) 
 
I. Amiodarone * 
2. Aprepitant 
3.Cimetidine 
4.Clarithromycin 
5.Diltiazem 
6.Erythromycin 
7.Fluconazole 
8.Fluvoxantine 
9. Grapefruit juice 
10. Indinavir 
II.Isoniazid 
12. Ketoconazole 
13. Mibefradil 
14. Nefazodone 
IS. Nelfinavir 
16. Nortloxacin 
17.Ritonavir 
18.Saquinavir 
19.Telithromycin 
20.Troleandomycin 
21. Veraparnil 
22.Voriconazole 
 
CYP3A4 Substrates (drug,s whose bioavailability may increase with itraconazole use) 
 
I. Alprazolam 
2. Amiodarone * 
3. Amlodipine 
4. Aripiprazole 
5. Astemizole • 
6. Atorvastatin • 
7.Buspirone 
8.CWorpbenirantine 
9.Cilostazol 
I 0.Cisapride • 
II. Clarithromycin 
12.Cyclosporine 
13.Diazepam 
14.Digoxin 
15.Diltiazem 
16.Disopyrarnide 
17.Dofetilide • 
18.Ergot alkaloids * 
19. Erythromycin 
20. Felodipine 
21. Fentanyl 
22. Glucocorticoids 
23. Haloperidol 
24. In1atinib 
25. Indinavir 
26. Levacetylmetl:adol • 
27. Lovastatin • 
28. Methadone 
29. Midazolam * 
30. Mirtazapine 
31. Nateglinide 
32. Nifedipine 
33. Nisoldipine 
34. Nitrendipine 
35. Oral hypoglycernics 
36. Pimozide • 
37.Quinidine • 
38.Quinine 
39.Ritonavir 
40.Saquinavir 
41. Sildenafil 
42.Simvastatin • 
43.Sirolinms 
44.Tacrolimus 
45.Tamoxifen 
46.Telithromycin 
47.Terfenadine • 
48.Trazodone 
49.Triazolam * 
50.Veraparnil 
51. Vinca alkaloids 
52.Warfarin 
 
• These drugs are absolutely contraindicated in patients taking concurrent itraconazole. The 
remainder maybe used with caution. 


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Appendix 3.    Skin Biopsy Procedure and Specimen Handling 
Shipping Instructions for Serum and Tissue Specimens 
 
There  are  three  categories  of  specimens  for  this  trial  which  will  be  shipped  to  a  central 
processing site: skin biopsies, archived primary prostate cancer tissue (radical prostatectomy or 
biopsy specimens), and peripheral blood collected for serum drug levels. Serum hormone levels 
will be analyzed locally at each participating institution. 
 
I.  Skin Biopsy Procedure, Processing, and Shipping Instructions 
 
For patients enrolled at UCSF, the skin biopsies will occur at the Helen Diller Family 
Comprehensive Cancer Center. Skin biopsies will be obtained twice for each patient who signs 
additional consent to participate in this correlative study: (1) pre-study (within 6 weeks of Day 1 
of protocol therapy) and (2) at 28 days (+/- 7 days) of protocol therapy. 
 
 
Specimen Requirements: A 3 mm skin punch biopsy (to the level of the subcutaneous tissue) 
should be obtained from an area of non-scalp skin with hairs and/or hair follicles. The upper 
back and arms are the preferred biopsy sites. Subsequent biopsies should be taken from the same 
general  area  of  the  body.  Skin  biopsies  should  be  performed  according  to  standard  local 
protocols. One example is the following: the biopsy site should be cleaned and prepped using 
sterile technique, and anesthetized with 1-2% lidocaine with epinephrine. The biopsy should be 
performed using a sterile 3 mm punch biopsy tool. The biopsy site may be closed with steri- 
strips, or with one or two sutures, and a sterile dressing may be applied. The skin biopsy sample 
should be placed immediately into a 5 ml Tissue Protect Tube containing RNAlater solution 
(Ambion, catalog # AM7023). Care must be taken to ensure that the skin sample is fully 
submerged in RNAlater. RNAse Zap spray should not be used on gloves or the work surface 
during skin biopsy collection. 
 
 
Processing Instructions: The sample should be kept at 4°C overnight (for ≥ 12 hours) so that 
RNAlater can seep into the tissue. The sample should then be frozen at –20°C or colder until the 
time of transport, and should be shipped to the analyzing lab on dry ice (see below). The sample 
is stable for 5 days at room temperature, for one month at 4°C, and for one year at –20°C. Once 
received by the analyzing lab, the sample should be stored at –20°C or colder until the time of 
RNA extraction. 
 
 
Comments: The date and time of collection should be recorded on the Biomarkers Worksheet. 
Tissue Protect Tubes should be labeled with patients‟ initials, identification number, biopsy site, 
date, time, study number, and protocol day. 
 
 
Shipping Instructions: Skin GLI1mRNA analysis will be performed at Johns Hopkins in the 
research laboratory of SushantKachhap, PhD, under the direction of David M. Berman, MD, 


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PhD. Skin biopsies arriving from outside institutions should be shipped on dry ice (a minimum 
of 5 kg) using overnight shipping to Kai Pollard in the Specimen Accessioning Core (SAC) 
laboratory at Johns Hopkins, at the address below. Overnight shipments should occur on Monday 
through Thursday, except when the following day is a holiday. A fax or call should be placed to 
the SAC laboratory prior to shipment, providing the shipment tracking information. 
 
Kai Pollard 
Specimen Accessioning Core (SAC) 
Johns Hopkins Hospital 
Attn: Itraconazole Study Samples 
417 North Caroline Street, Room 305 
Baltimore, MD 21231 
Phone: (410) 502-3672 or (410) 502-0586 
Pager: (410) 283-2148 
Fax: (410) 614-2688 
Email:  mkai1@jhmi.edu 
 
II. Archived Primary Prostate Cancer Specimens 
Availability of archived primary prostate cancer tissue (prior biopsy or prostatectomy specimens) 
is not a requirement for study entry but is encouraged. Archived primary prostate cancer tissue 
will be sent to Dr. Christopher Sweeney at the Dana-Farber Cancer Institute for mRNA 
expression and immunohistochemical analysis as outlined in Section 9. (Tissue specimens will 
be returned to submitting site.) 
 
Shipping Address: 
Dana-Farber Cancer Institute 
Attn: Dr. Edward Stack 
450 Brookline Avenue, JF-215 
Boston, MA, 02215 
Phone: 617-582-7536 
Fax: 617-582-8750 
 
 
III.  Processing and Shipping of Serum Drug Levels 
Patients will have about 5 ml of blood collected into tubes containing K2-EDTA as an 
anticoagulant (lavender top). Following extraction, blood will be immediately placed on ice or 
refrigerated until processed. The actual day and time of collection will be recorded. Plasma will 
be separated from whole blood as soon as possible following extraction. This will be done by 
centrifuging whole blood at 1000 x g for 10 minutes at 4°C. Plasma will then be transferred to a 
screw-cap polypropylene cryotube for determination of itraconazole and hydroxyitraconazole 
concentrations. The polypropylene tube will be labeled with patient‟s initials, study number, day, 
time, and protocol day and then frozen at –70°C until the time of analysis. 


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Pharmacokinetic studies will be performed in the Analytical Pharmacology Core Laboratory at 
Johns Hopkins, under the direction of Michelle Rudek, PharmD, PhD. 
 
 
Michelle A. Rudek, PharmD, PhD 
Analytical Pharmacology Core Laboratory 
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 
1650 Orleans Street, CRB1 - Room 184 
Baltimore, MD 21231 
Phone: (410) 955-1129 or (410) 502-7192 
Fax: (410) 502-0895 
Email:  mrudek2@jhmi.edu 
 
Samples arriving from outside institutions should be shipped on dry ice (a minimum of 5 kg) 
using overnight shipping to Kai Pollard in the Specimen Accessioning Core (SAC) laboratory at 
Johns Hopkins, at the address below. Overnight shipments should occur on Monday through 
Thursday, except when the following day is a holiday. A fax or call should be placed to the SAC 
laboratory prior to shipment, providing the shipment tracking information. 
 
Kai Pollard 
Specimen Accessioning Core (SAC) 
Johns Hopkins Hospital 
Attn: Itraconazole Study Samples 
417 North Caroline Street, Room 305 
Baltimore, MD 21231 
Phone: (410) 502-3672 or (410) 502-0586 
Pager: (410) 283-2148 
Fax: (410) 614-2688 
Email:  mkai1@jhmi.edu 
 
 
IV.  Processing and Shipping of Serum Hormone Levels 
 
 
Peripheral 
blood 
for 
measurement 
of 
serum 
testosterone, 
cortisol, 
aldosterone, 
deoxycorticosterone, 
11-deoxycortisol, 
adrenocorticotropic 
hormone 
(ACTH), 
dihydroepiandrostenedione-sulfate (DHEA-S), and androstenedionewill be collected at each site 
according to the instructions outlined below, and shipped to UCSF for analysis. Specimens 
should be shipped within 1 month of date of collection. 
 
 
Peripheral blood collection for banking of peripheral blood mononuclear cells, plasma, and 
serum is optional. Specimens will be banked at UCSF-HDFCCC Tissue Bank. 
 
 
A.        Patient Confidentiality 


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Prior to the date of collection of each sample to be shipped to UCSF, the local CRC should 
notify the lead center CRC that specimen is to be collected at the patient‟s next visit.  The lead 
center CRC will then assign unique specimen log numbers to be written on the specimen vials; 
this will ensure patient confidentiality. 
 
 
The UCSF-HDFCCC Tissue Bank will serve as a repository for banking human samples. 
Specimen and data registries will be kept by the UCSF-HDFCCC. This registry will have a 
coordinated database to protect patient confidentiality and safety. The samples will receive a 
patient-insensitive identifier and the link to patient identity will be kept in a locked file with 
access only by the director of the Tissue Bank. Other investigators will have access to the 
samples only through established Tissue Core procedures. That is, investigators must submit a 
written request to use the stored samples as part of a CHR-approved protocol that is reviewed by 
the Tissue Core committee. This review limits the testing that can be done on these samples. 
Patients have the right at any time to request that all remaining samples be destroyed. The patient 
or relatives may be contacted about future, additional research on stored samples, if necessary. 
Additional written consent will be required if additional samples are to be taken. 
 
 
B.        Serum Hormones 
 
 
At baseline, cycle 2 day 1, cycle 4 day 1, and at disease progression, nine mL of whole blood 
will be collected in two red top tubes (no gel) and centrifuged at 3000 rpm for 10 minutes. The 
serum will be decanted into three 2mL polypropylene screw cap (leak-proof) vials that have been 
properly labeled with the unique specimen log numbers provided and stored at -80°C until 
shipment to UCSF. 
 
 
At baseline, cycle 2 day 1, cycle 4 day 1, and at disease progression, twelve mL of whole blood 
will be collected in two gold top tubes and centrifuged at 3000 rpm for 10 minutes. The serum 
will be decanted into four 2mL polypropylene screw cap (leak-proof) vials that have been 
properly labeled with the unique specimen log numbers provided and stored at -80°C until 
shipment to UCSF. 
 
 
At baseline, cycle 2 day 1, cycle 4 day 1, and at disease progression, three mL of whole blood 
will be collected in a pre-chilled lavender top tube at centrifuged at 3000 rpm for 10 minutes. 
The plasma will be decanted into one 2mL polypropylene screw cap (leak-proof) vial that has 
been properly labeled with the unique specimen log numbers provided and stored at -80°C until 
shipment to UCSF. 
 
 
 
C.        Banking of Peripheral BloodMonononuclear Cells, Plasma, and Serum (Optional) 
 
 
At baseline, on cycle 2 day 1, cycle 4 day 1, and disease progression, twenty mL of whole blood 
will be collected in one yellow-top serum separator tube and one lavender top tube (plasma) and 


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centrifuged at 3000 rpm for 10 minutes. The serum and plasma will be decanted into two 2mL 
polypropylene screw cap (leak-proof) vials (four total vials) that have been properly labeled 
with the unique specimen log numbers provided and stored at –80°C until shipment to UCSF. 
 
 
At baseline, twelve mL of whole blood in 2 plastic EDTA tubes will also collected and freshly 
frozen at -80°C until shipment to UCSF. 
 
 
IV.      Shipping Instructions 
 
 
Specimen may be batch-shipped on dry ice to the lead center (UCSF-HDFCCC) by overnight 
delivery Mondays-Thursdays.   The local coordinator should notify the lead center coordinator 
prior to specimen shipment. 
 
 
V.   Local Storage and Confidentiality 
 
 
Samples will be cataloged individually in password protected tissue database. Patient identifiers 
will be removed from this database and substituted with study ID numbers. Annotations for 
individual tissue/blood samples will be made for processing. 


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Appendix 4. Multicenter Institutional Studies 
 
4.1 
Data and Safety Monitoring Plan for Multicenter Institutional Study 
(Phase 2 or 3 Institutional Study) 
 
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety for 
all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study 
includes: 
 
• Review of subject data 
• Review of suspected adverse reactions considered “serious” 
• Monthly monitoring (depending on study accrual) 
• Minimum of a yearly regulatory audit 
 
Monitoring and Reporting Guidelines 
 
All institutional Phase 2 or 3 therapeutic studies are designated with a moderate risk assessment. 
The data is monitored every six months, with twenty percent of the subjects monitored (or at 
least three subjects if the calculated value is less than three). 
 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial. The UCSF 
Coordinating Center will also coordinate quarterly conference calls with the participating sites to 
communicate the review of adverse events, safety data, and other study matters. 
 
The Principal Investigator at the UCSF Coordinating Center will hold the role of Study Chair. 
The Study Chair is responsible for the overall conduct of the study and for monitoring its safety 
and progress at all participating sites. The Study Chair will conduct continuous review of data 
and subject safety and discuss each subject‟s treatment at monthly UCSF Site Committee 
meetings. The discussions are documented in the UCSF Site Committee meeting minutes. 
Multicenter communication 
The UCSF Coordinating Center provides administration, data management, and organizational 
support for the participating sites in the conduct of a multicenter clinical trial.  The UCSF 
Coordinating Center will also coordinate, at minimum, monthly conference calls with the 
participating sites at the completion of each cohort or more frequently as needed to discuss risk 
assessment.  The following issues will be discussed as appropriate: 
• Enrollment information 
• Adverse events (i.e. new adverse events and updates on unresolved adverse events and 
new safety information) 
• Protocol violations 
• Other issues affecting the conduct of the study 
 
Adverse events reporting to the DSMC will include reports from both the UCSF Coordinating 
Center, as well as the participating sites.  The DSMC will be responsible for monitoring all data 
entered in OnCore® at the UCSF Coordinating Center and the participating sites.  The data (i.e. 
copies of source documents) from the participating sites will be sent electronically or faxed over 
to the UCSF Coordinating Center prior to the monitoring visits in order for the DSMC to monitor 
the participating site‟s compliance with the protocol, patient safety, and to verify data entry. 


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Adverse Event Review and Monitoring 
 
Adverse Event Monitoring 
 
All Grade 3-5 Adverse Events, whether or not unexpected, and whether or not considered to be 
associated with the use of study drug, will be entered into OnCore®, UCSF‟s Clinical Trial 
Management System. 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly basis at the 
UCSF Site Committee meetings. All clinically significant adverse events must be reported to the 
UCSF Coordinating Center by the participating sites within 10 business days of becoming aware 
of the event or during the next scheduled quarterly conference call, whichever is sooner. The 
UCSF Site Committee will review and discuss the selected toxicity, the toxicity grade, and the 
attribution of relationship of the adverse event to the administration of the study drug(s) from the 
UCSF Coordinating Center and the participating sites. 
 
In addition, all suspected adverse reactions considered “serious” must be entered in OnCore® 
and reported to the UCSF Coordinating Center within 1 business day. The suspected adverse 
reactions considered “serious” will be reviewed and monitored by the Data and Safety 
Monitoring Committee on an ongoing basis and discussed at the DSMC meeting, which take 
place every six (6) weeks. 
 
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and is determined to be related either to the investigational 
drug or any research related procedure, the Study Chair at the UCSF Coordinating Center or the 
assigned designee must be notified within 1 business day from the participating site(s) and the 
Study Chair must then notify the DSMC Chair or qualified alternate within 1 business day of this 
notification. The contact may be by phone or e-mail. 
 
Increase in Adverse Event Rates 
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported in the 
Investigator Brochure or package insert), the Study Chair at the UCSF Coordinating Center is 
responsible for notifying the DSMC at the time the increased rate is identified.  The report will 
indicate if the incidence of adverse events observed in the study is above the range stated in the 
Investigator Brochure or package insert. 
 
If at any time the Study Chair stops enrollment or stops the study due to safety issues, the DSMC 
Chair and DSMC Manager must be notified within 1 business day via e-mail.  The DSMC must 
receive a formal letter within 10 business days and the CHR must be notified. 
 
Data and Safety Monitoring Committee Contacts: 
 
DSMC 
Chair: 
Alan Venook, MD 
DSMC Monitors 
Phone: 
Email: 
Address: 
415-353-2745 
venook@cc.ucsf.edu 
Box 1705 
UCSF 
San Francisco, CA 94115 
Box 1297 
UCSF Helen Diller Family 
Comprehensive Cancer Center 
San Francisco, CA 94115 
 
 
 
 
 
 
*  DSMP approved by NCI 09/February2012 


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4.2 
UCSF Policy/Procedure for Required Regulatory Documents for a UCSF 
Multicenter Investigator-Initiated Oncology Clinical Trials with an 
Investigator held Investigational New Drug (IND) 
 
Purpose 
This policy defines the required Regulatory Documents for Single Site and Multicenter 
Investigator Initiated Oncology Clinical Trials at the Helen Diller Family Comprehensive Cancer 
Center (HDFCCC) where the Principal Investigator (PI) holds the IND. 
 
Background 
The International Conference on Harmonization (ICH) Good Clinical Practices (GCP) 
Guidelines define Essential Regulatory Documents as those documents which individually and 
collectively permit evaluation of the conduct of a trial and the quality of data produced. These 
documents serve to demonstrate compliance with standards of GCP and with all applicable 
regulatory requirements. Filing essential documents in a timely manner can greatly assist in the 
successful management of a clinical trial. 
 
The Regulatory Documents will consist of electronic files in both iMedRIS and OnCore®, as 
well as paper files in the Regulatory Binders for both the Coordinating Site and the Participating 
Site(s) in the HDFCCC Investigator Initiated Oncology Clinical Trials. 
 
Procedures 
 
1.   HDFCCC Essential Regulatory Documents 
 
Documents Filed in iMedRIS: 
 
• CHR approvals for initial submission of application, all modifications, and continuing 
annual renewals 
• Current and prior approved protocol versions with signed protocol signature page(s) 
• Committee for Human Research (CHR) approval letters and Informed Consent Form(s) 
(ICF) 
• Current and prior versions of the Investigator Brochure (IB). 
• Serious Adverse Event Reporting 
• Protocol Violations and Single Patient Exception (SPE) Reports to CHR with supporting 
fax documentation 
 
Documents Filed in OnCore®: 
 
• Package Insert (if the study drug is commercial) or Investigator Brochure 
• Protocol Review Committee (PRC) approved protocols, protocol amendments and 
Summary of Changes (SOC) 
• Patient handouts 
• Screening/enrollment log 
• Data and Safety Monitoring Committee (DSMC) monitoring reports 
• OnCore® Case Report Form (CRF) completion manual 


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Documents Filed in Regulatory Binder: 
• Completed Food and Drug Administration (FDA) 1572 document with Principal 
Investigator‟s signature 
• For all Principal Investigators and Sub-Investigators listed on the FDA 1572, will need 
Financial Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) 
Licenses, and Staff Training Documents (i.e. Collaborative Institute Training Initiative 
(CITI), etc.) 
• Site Initiation Visit (SIV) minutes and correspondence with participating site(s). 
• As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center 
• Serious Adverse Event (SAE) reports to CHR and sponsor. 
• MedWatch reporting to FDA and sponsor 
• Delegation of Authority Form 
• Drug Destruction Standard Operating Procedure (SOP) 
• For all laboratories listed on the FDA 1572, will need CLIA certifications, CAP 
certifications, lab licenses, CVs of Lab Directors, and laboratory reference ranges 
 
2.   Additional Essential Documents for Multicenter Trials for the Coordinating Center (filed 
in Regulatory Binder or OnCore) 
• Institutional Review Board (IRB) approval letters, IRB roster, Informed Consent Form 
(ICF), and Health Insurance Portability and Accountability Act (HIPAA) Consent Form for 
the Participating Site(s) 
• For all Principal Investigators and Sub-Investigators listed on the 1572 at the Participating 
Site(s) – Financial Disclosure Forms, CVs, MD Licenses, and Staff Training documents 
(i.e. Collaborative Institute Training Initiative (CITI), etc.) (for Investigational New Drug 
Application 
• Site Initiation Visit (SIV) minutes and correspondence with Participating Site(s). 
• As applicable, approvals for Biosafety Committee, Radiation Committee, and Infusion 
Center for the Participating Site(s) 
• Protocol Violations and Single Patient Exception (SPE) reports to IRB with supporting fax 
documentation for Participating Site(s) 
• Drug Destruction Standard Operating Procedure (SOP) for the Participating Site(s) 
• Data and Safety Monitoring Committee (DSMC) monitoring reports for the Participating 
Site(s) 
• For all laboratories listed on FDA 1572, will need CLIA certifications, CAP certifications, 
lab licenses, CVs of Lab Directors, and laboratory reference ranges for the Participating 
Site(s) 
• Copy of the Data and Safety Monitoring Plan (DSMP) Monitoring Plan for all participating 
site(s) in Multicenter studies or Contract Research Organization (CRO) Monitoring Plan (if 
an outside CRO is used for the study) 
• Serious Adverse Event (SAE) forms submitted to both the IRB and the sponsor for the 
Participating Site(s) 
 
 
 
27 April 2012 


P h a s e    I I    S t u d y    o f    I t r a c o n a z o l e    i n    B i o c h e m i c a l    R e l a p s e 
Phase II - Itraconazole 
 
 
80
 
4.3 
Required Regulatory Documents for Sub-sites Participating in a UCSF 
Investigator Initiated Multicenter Trial (Checklist) 
 
Directions: 
 
1) Fax the documents listed below to the UCSF Coordinating center at 415-514-6955 or 
 
2) Scan the documents and upload to OnCore® and create a Note to File for the on-site 
Regulatory binder to indicate where these documents may be found 
 
1572 
PI and Sub investigators: 
CV and Medical license 
Financial disclosure form 
NIH or CITI human subject protection training certification 
Laboratories 
 
CLIA and CAP 
CV of Lab Director and Lab Licenses 
Laboratory reference ranges 
 
Local Institutional Review Board 
 
IRB Approval letter 
Reviewed/Approved documents 
• Protocol version date: 
  
 
• Informed consent version date:    
 
• Investigator Brochure version date:    
 
• HIPAA 
Current IRB Roster 
 
Other 
 
Delegation of Authority Log 
• Include NIH or CITI human subject protection training certificates or GCP training 
certification 
Pharmacy 
• Drug destruction SOP and Policy 
Protocol signature page 
Executed sub contract 
 
 
 
27.apr.2012