Conditions: Castration-resistant Prostate Cancer Stage IV Prostate Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 72
Healthy volunteers: no

Brief summary:
This randomized phase II trial studies the best way to give abiraterone acetate in treating patients with castration-resistant prostate cancer. Abiraterone acetate is effective in treating castrate resistant prostate cancer and is taken in the fasting state. However, the body's absorption of abiraterone is increased with food intake. This study will test the whether a lower dose of abiraterone taken with food has a similar effect on prostate specific antigen (PSA) compared to full dose taken fasting.

Detailed description:
PRIMARY OBJECTIVES:

I. To compare the pharmacodynamic effect of reduced dose (250mg daily) abiraterone acetate in the prandial state (250mg-Fed) to the full, standard 1000mg daily dose in the fasting state (1000mg-Fasting) as assessed by change in serum prostate-specific antigen (PSA).

SECONDARY OBJECTIVES:

I. To evaluate the effect of prandial states on plasma levels and the intra-patient pharmacokinetic variability of abiraterone acetate.

II. To evaluate the safety profile of reduced dose abiraterone acetate taken in the prandial state.

III. To evaluate the pharmacodynamic effect of reduced dose abiraterone acetate in the prandial state as assessed by reduction in the extra-gonadal androgen dihydroepiadrosterone sulfate (DHEA-S) and dihydroepiandrostenedione (DHEA).

IV. To evaluate the effect of prandial state on time to disease progression (Working group criteria).

OUTLINE: Patients are randomized to one of two treatment arms.

ARM I: Patients receive abiraterone acetate orally (PO) daily first thing in morning after an overnight fast of at least 8 hours.

ARM II: Patients receive abiraterone acetate PO daily within 30 minutes of a conventional low-fat breakfast.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Both arms will also be treated with prednisone 5mg twice daily.

After completion of study treatment, patients are followed up within 30 days.

Arms:
arm 1: Patients receive abiraterone acetate PO daily first thing in morning after an overnight fast of at least 8 hours. arm 2: Patients receive abiraterone acetate PO daily within 30 minutes of a conventional low-fat breakfast.

Interventions: intervention 1: abiraterone acetate
Intervention descriptions: intervention 1: Given PO

Protocol document:
Prot_SAP_000.pdf: 
 
IRB #:11-0709 
 
Version Date: 06.18.2015 
 
TITLE: A prospective randomized pilot study evaluating the food effect on the 
pharmacokinetics and pharmacodynamics of abiraterone acetate in men with castrate 
resistant prostate cancer 
 
Coordinating Center:  
 
 
University of Chicago  
 
 
*Principal Investigator: 
Russell Szmulewitz, MD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
 
 
 
Chicago, IL 60637 
 
773-702-7609 
 
773-702-3163 
 
rszmulew@medicine.bsd.uchicago.edu  
 
Co-Investigators: 
Mark J. Ratain, MD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
 
Walter M. Stadler, MD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
 
Peter O’Donnell, MD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
 
Olwen Hahn, MD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
 
William Douglas Figg Sr., Pharm.D., M.B.A 
Senior Scientist and Head of the Clinical Pharmacology Program 
and Molecular Pharmacology Section, 
Medical Oncology Branch 
National Cancer Institute 
National Institutes of Health 
Bldg 10/Room 5A01 
9000 Rockville Pike 
 
Bethesda, MD 20892 
 
 
Statistician: 
Theodore Karrison, PhD 
Dept. of Health Studies, MC2007 
5841 S. Maryland Avenue 
Chicago, IL 60637 
tkarrison@health.bsd.uchicago.edu 
 
Responsible Research Nurse: 
Elia Martinez, R.N. 
 
University of Chicago, Department of Medicine 


 
 
 
ii 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
773-702-4135 
 
emartinez1@medicine.bsd.uchicago.edu 
 
Responsible Data Manager/Study Coordinator: 
 
 Jaclyn D. Peterson 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
773-834-1746 
 
773-702-4889 
 
jdpeterson@medicine.bsd.uchicago.edu  
 
Pharmacokinetic Laboratory Coordinator : 
 
Cody Peer 
National Cancer Institute 
National Institutes of Health 
Bldg 10/Room 5A01 
9000 Rockville Pike 
 
Bethesda, MD 20892 
 
Co-Investigator 
 
Maha Hussain, M.D. 
University of Michigan Comprehensive Cancer Center  
Co-Investigator 
Bruce Brockstein, M.D. 
NorthShore Healthcare 
Co-Investigator 
John Godwin, M.D. 
Southern Illinois School of Medicine 
Co-Investigator 
Sreenivasa Nattam, M.D. 
Fort Wayne Oncology/Hematology 
Co-Investigator 
Mark K. Kozloff, M.D. 
Ingalls Cancer Research Center  
Co-Investigator 
Sachdev Thomas, M.D. 
Illinois Cancer Care Peoria 
Co-Investigator 
Tim Kuzel, M.D. 
Northwestern Memorial Hospital 
Co-Investigator 
Bradley Carthon, MD, PhD 
Emory University  
Co-Investigator 
Yong Wei Peng, M.D. 
National University Cancer Institute, Singapore (NCIS) 
 
 
 
 
Protocol Type / Version # / Version Date: Original / Version 1 / 11/15/2011 
 
Version 2 /  12/12/2011 ; Version 3 2/16/12 ; Version 4 2/20/13 
Version 5 8/8/14 ; Version 6 12/28/14 ; Version 7 6/18/2015 
 
 


 
 
 
iii 
SUMMARY 
 
Study Design:  In this open label, two-arm study, patients with castrate resistant prostate cancer 
will be randomized to administer abiraterone acetate 1000mg by mouth daily in the fasting state 
or abiraterone acetate 250mg by mouth daily with a conventional low fat breakfast.  In addition, 
pharmacokinetic samples and standard laboratory studies will be collected. 
 
Eligible Patients:  Patients must have histologically confirmed prostate cancer with evidence of 
castration resistance defined as rising PSA or clinical/radiographic progression following 
androgen deprivation, as well as anti-androgen therapy and anti-androgen withdrawal. Patients 
must have an ECOG performance status of ≤ 2 and have adequate bone marrow, liver and renal 
function. 
 
Primary Objective:  To compare the effect of a lower dose (250mg) of abiraterone acetate in 
the prandial state to the currently recommended higher dose (1000mg) taken in the fasting state, 
with prostate specific antigen (PSA) response rate as a pharmacodynamic marker. 
 
Secondary Objectives:  To evaluate the effect of prandial states on the pharmacokinetic 
properties (TMax, CMax
 
 means and variability), pharmacodynamic properties (change in extra-
gonadal androgen levels), progression-free survival, and safety profile of abiraterone acetate.   


 
 
 
iv 
TABLE OF CONTENTS 
 
Page 
 
SUMMARY
 
 .............................................................................................................................................. iii
 
TABLE OF CONTENTS
 
 ........................................................................................................................ iv
1. 
BACKGROUND
 
 ............................................................................................................................7
1.1. 
Castrate Resistant Prostate Cancer (CRPC)
 
 ...............................................................................7
1.2. 
Mechanisms of Androgen Independent Prostate Cancer Growth ...............................
 
.. . .. .... 6 
1.3. 
Adrenal Androgens in Prostate Cancer
 
 .......................................................................................7
1.4. 
Abiraterone Acetate (CB7630)
8 
...................................................... Error! Bookmark not defined.
1.5. 
Rationale for Using Abiraterone in Prostate Cancer ................................................................
 
.8 
1.6. 
Clinical Data with Abiraterone Acetate.......................................................................................
 
9 
1.7       Clinical Pharmacokinetics with Food ........................................................................................10 
1.8       Adherence to Oral Oncology Medications .................................................................................10 
1.9 
Study Rationale ............................................................................................................................10 
 
 
2. 
OBJECTIVES
 
 ..............................................................................................................................12
2.1. 
Primary Objective
 
 ........................................................................................................................12
2.2. 
Secondary Objectives
 
...................................................................................................................12
 
3. 
PATIENT SELECTION
 
 .............................................................................................................12
3.1. 
Eligibility Criteria
 
 ........................................................................................................................12
3.2. 
Exclusion Criteria
 
 ........................................................................................................................13
3.3. 
Inclusion of Minorities
 
 .................................................................................................................13
 
4. 
REGISTRATION AND DATA COLLECTION/MANAGEMENT
 
 .......................................14
 
5. 
STUDY DRUG ADMINISTRATION
 
 ........................................................................................16
5.1. 
Fasting Patients ........................................................................................................................... 
 
16 
5.2. 
None Fasting Patients
 
 ..................................................................................................................16
 
6. 
DURATION OF TREATMENT ...............................................................................................
 
16 
 
7. 
STUDY ASSESSMENTS ...........................................................................................................
 
16 
7.1. 
Pre-treatment Evaluations..........................................................................................................
 
17 
7.2. 
On Study Visits.............................................................................................................................
 
17 
7.3. 
Off Study Assessments.................................................................................................................
 
19 
7.4. 
Study Calendar.............................................................................................................................19 
 
8. 
TREATMENT PLAN
20 
 .................................................................. Error! Bookmark not defined.
8.1. 
Agent Administration..................................................................................................................
 
20 
8.2. 
Management of Castration Related Symptoms ........................................................................
 
20 


 
 
 
v 
8.3. 
Dose-Reduction Procedure for Adverse Mangement...............................................................
 
21 
8.4. 
Treatment Mangement of Hypertension ...................................................................................
 
21 
8.5. 
Mangement of Hypokalemia.......................................................................................................
 
22 
8.6. 
Management of Evelated Liver Function Tests ........................................................................
 
23 
8.7. 
Mangement
....................................................
 of Non-Mineralocorticoid Based Side Effects 
24 
8.8. 
Concomitant Medication and Treatment ..................................................................................
 
24 
8.9. 
Chemotherapy and Radiotherapy..............................................................................................
 
25 
8.10. Other Medications .......................................................................................................................
 
25 
8.11. Potential Drug Interactions.........................................................................................................
 
25 
 
9. 
SAFETY........................................................................................................................................
 
26 
9.1. 
Adverse Events.............................................................................................................................
 
26 
9.2. 
Serious Adverse Events ...............................................................................................................
 
26 
9.3. 
Serious Adverse Event Reporting...............................................................................................27 
9.4. 
Other Reporting Requirements................................................................................................
 
..28 
9.5. 
Other Safety Considerations.......................................................................................................
 
29 
 
10. 
MEASUREMENT OF EFFECT ................................................................................................
 
29 
10.1. Outcome Measures based on PSA Decline ................................................................................
 
29 
10.2. Radiographic Tumor Response
 
 ..................................................................................................31
10.3. Duration of Response...................................................................................................................
 
30 
10.4. Progression-Free Survival...........................................................................................................
 
30 
 
11. 
STATISTICAL CONSIDERATIONS
 
 .......................................................................................31
11.1. Sample Size/Primary Endpoint ................................................................................................
 
..31 
11.2. Randomization and stratification
 
 ...............................................................................................31
11.3. Analysis of Secondary Endpoints ...............................................................................................
 
31 
11.4. Safety Evaluation and Analysis ................................................................................................
 
..32 
 
 
APPENDIX A 
Performance Status Criteria 
 
 ..................................................................................................................33
 
APPENDIX B 
Sample Data Capture Forms 
 
 .................................................................................................................34
 
APPENDIX C 
Subject’s Study Drug/Meal Diary .........................................................................................................
 
37 
 
APPENDIX D 
Prostate-Specific Antigen Working Group Criteria.............................................................................
 
39 
 
APPENDIX E 
Response Evaluation Criteria in Solid Tumors (RECIST) 
 
 .................................................................40
 


 
 
 
vi 
APPENDIX F 
PHARMAKINETIC SAMPLE SUBMISSION FORM ......................................................................
 
44 
 
APPENDIX G 
MEDICATION ADHERENCE QUESTIONNAIRE 
 
 
 
 
 
        45 
 
 
REFERENCES ........................................................................................................................................
 
55 
 
 
 


 
IRB #:11-0709 
 
Version Date: 06.18.2015 
 
 
 
1. BACKGROUND 
 
1.1. Castrate Resistant Prostate Cancer (CRPC) 
Although most men are diagnosed with early stage, curable prostate cancer, unfortunately, 
prostate cancer recurrence is seen in ~40% of patients over time1.   Androgen deprivation therapy 
(ADT) remains the mainstay of treatment and induces a remission in 80 to 90% of patients with 
advanced disease and results in a median progression-free survival of 12 to 33 months, at which 
time an androgen independent phenotype usually emerges. This accounts for the median overall 
survival of 23 to 37 months from the initiation of androgen deprivation.  This transition represents 
an important clinical landmark of an evolving disease that correlates with an increased risk of 
death and morbidity2.   This year ~32,000 men are projected to die from prostate cancer, the vast 
majority of whom will die from metastatic castration resistant disease (mCRPC) with bone 
metastases3.  The effective therapies for progressive CRPC are limited with docetaxel and 
cabazitaxel chemotherapies, the novel immunotherapy sipuleucel-T, and the steroidal enzyme 
inhibitor abiraterone acetate as the only currently FDA approved therapies shown to improve 
patient survival in the CRPC setting 4,5, 6-8
 
.   
1.2. Mechanisms of Castrate Resistant Prostate Cancer Growth 
Androgen deprivation can be achieved surgically with orchiectomy or by pharmacologic means.  
Current approaches to ADT use leutinizing hormone releasing hormone (LHRH) agonists.  The 
mechanism of action is by causing the continuous stimulation of the anterior pituitary leading to 
the inhibition of leutinizing hormone (LH) secretion and ultimately the disruption of testicular 
production of testosterone.  Although AD has been effective in the majority of patients, studies 
have shown that extratesticular sources of testosterone represent an important alternative source of 
androgen stimulation in a significant proportion of prostate cancer patients.  Due to the peripheral 
conversion of adrenal steroids to testosterone, as much as 10% of baseline circulating testosterone 
remains in castrate men9.  In prostate cancer xenograft models, increased levels of androgen 
receptor have been observed and appear to be resistant to antiandrogens10.  This could result in 
amplified signal output from low levels of circulating adrenal androgens, thus suggesting a role 
for agents that target the adrenal androgen synthesis pathway.            
                                                                                                                                                                               
1.3. Adrenal Androgens Production  
If adrenal androgen production is an important cause of relapse after primary hormonal treatment, 
inhibitors of 17a-hydroxylase/C17,20
 
-lyase,  may prove useful as a second-line treatment. The 
adrenal steroid synthesis pathway is shown below in Figure 1.  The CYP17 complex of enzymes, 
(c17-lyase and 17,20 hydroxylase) are the primary enzymes responsible for extra-gonadal, adrenal 
androgen production in that they lead to the production of dihydroepiandrostenedione and 
androstenedione.  As the figure demonstrates, inhibition of CYP17 will lead to a reduction of 
adrenal androgen production (dihydroepiandrostenedione, androstenedione).   


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 8 of 57  
 
 
 
 
Figure 1:  The adrenal steroid synthesis pathway, adapted from Reid et al11. 
 
1.4. Abiraterone Acetate (CB7630) 
Abiraterone Acetate (CP7630) is the 3-acetate and prodrug of CB7598 suitable for oral 
administration.  Abiraterone [CB7598, 17-(3-pyridyl) androsta-5,16-dien-3β-ol] was developed as 
a tight-binding steroidal inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase), with two important 
enzymatic activities in the synthesis of testosterone, based on the observation that nonsteroidal 3-
pyridyl esters had improved selectivity for inhibition of 17α-hydroxylase/C17,20-lyase (12).  
CP7598 is a potent inhibitor with an apparent inhibition constant of 0.5 nM.  The chemical 
nomenclature of CB7630 is 3β-acteoxy-17-(3-pyridyl)androsta-5,16-diene; its empirical formula 
is C26H33NO2
 
.  It has a molecular weight of 381.55.  Once absorbed after oral administration, 
CB7630 is rapidly converted to the active form, CB7598 (Figure 2).  CB7598 was the 
predominant, if not the only form of abiraterone detected in blood both in preclinical studies and 
in previously conducted clinical studies. 
 
Figure 2:  Prodrug abiraterone acetate conversion to abiraterone after absorption. 
 
 
1.5. Clinical Data with Abiraterone Acetate in Prostate Cancer 
To determine if inhibition of 17alpha-hydroxylase/C17,20 lyase could indeed suppress adrenal 
testosterone production in humans as predicted from mechanism of action and animal models, 
three phase I exploratory studies of CB7630 (abiraterone acetate) were conducted in the United 
Kingdom in castrated or non-castrated patients with prostate cancer.  Overall, the results of these 
studies showed that abiraterone acetate was safe and well tolerated, and resulted in a significant 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 9 of 57  
 
PSA response rate12,13.  Based on these preliminary studies, several phase II clinical trials in 
castrate resistant prostate cancer were undertaken and confirmed the impact of abiraterone acetate 
on PSA in both chemotherapy naïve and treated patients14,15. Most recently, the seminal phase III 
study of abiraterone acetate versus placebo in patients with CRPC with previous failure of 
docetaxel based chemotherapy reported a significant improvement in overall survival benefitting 
abiraterone (14.8 vs. 10.9 months, P<0.001)8. Abiraterone acetate is well tolerated with the most 
common toxicities being those of mineralocorticoid excess, including hypertension, edema, and 
hypokalemia, with no adverse event in either arm of the phase III study seen in >2% of patients..  
Abiraterone with prednisone is also effective in the chemotherapy naïve population, where it was 
proven superior to prednisone alone16 Based on these studies, abiraterone acetate at 1000mg daily 
dose in the fasting state, along with 5mg twice-daily prednisone was approved by the Food and 
Drug Administration (FDA) for use in patients with metastatic CRPC after failure of docetaxel 
chemotherapy17. It is now a standard of care in this patient population. 
 
1.6 Clinical Pharmacokinetics 
Blood specimens from phase I studies were analyzed for CB7598 (abiraterone). The 
pharmacokinetic parameters all show considerable variability between patients and are presented 
in Table 1. The mean Tmax was 2.70 hours (+ SD 2.71) with a mean elimination half-life of 27.6 
hours (+ SD 20.2). A range of up to 10-fold in AUC was seen for a given dose. The level of inter-
patient variability made analysis of dose-dependent pharmacokinetic relationships difficult. 
Further investigation is required in clinical trials, especially with administering abiraterone with 
food.  
 
1.7 Clinical Pharmacokinetics with Food 
While oral drugs are generally easier for patients, they are much more complex from a 
pharmacokinetic perspective.  In particular, one needs to be concerned regarding low and/or 
variable bioavailability, drug-food interactions, and a greater potential for drug-drug 
interactions18. 
 
Food can alter pharmacokinetics of a drug and subsequently have clinically significant 
consequences.  Various mechanisms have been proposed as a means by which food can alter 
pharmacokinetics of a drug.  These include:  delayed gastric emptying, increased biliary flow, 
changes in gastrointestinal pH, increased splanchnic blood flow, or change in luminal metabolism 
of a drug.  Generally, food effects on pharmacokinetics have the highest impact when the drug is 
administered shortly after a meal.  It is also known that calorie and fat contents of meals would 
have significant implications on the bioavailability of a drug as different types of meals are likely 
to have varying impacts on gastrointestinal physiology in relation to a drug disposition18,19. 
 
A significant food effect on pharmacokinetic profiles of orally administered anticancer agents and 
their metabolites have been observed with existing oral anticancer agents.  As an example, high fat 
meals have been shown to significantly increase Lapatinib’s bioavailability and systemic 
exposure20.  However, this significant effect on pharmacokinetics of lapatinib was not 
appropriately addressed in its registration trial and in the subsequent FDA label21.  Consequently, 
the efforts to optimize the drug efficacy and safety by taking advantage of this knowledge have 
been delayed:  a study of lower dose of lapatinib with food for example.  This missed opportunity 
is the result of inadequately addressing critical pharmacokinetics issues early on in the drug 
development process before undertaking large phase III trials22.   
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 10 of 57  
 
1.7.1 Abiraterone pharmacokinetics with food 
The effect of food on abiraterone administration has been tested previously in two phase I 
studies.   In a UK study, patients who received abiraterone at 1000mg or 2000mg were 
randomly assigned to receive single dose abiraterone five days apart either after an overnight 
fast or with a high-fat meal prior to continuous dosing.  Pharmacokinetic samples were 
obtained and showed that when administered with a high-fat meal, abiraterone drug exposure 
was increased by 4.4-fold (P = 0.049).  There was no significant increase in Cmax
13
, but 
absorption was significantly extended after food .  Similarly, in a phase I study conducted in 
the US, the effect of food with abiraterone was examined after single dose administration 
either in the fasting state or with a high calorie breakfast in four escalating dose cohorts (250, 
500, 750, and 1000mg).  The small number of patients per cohort and the high degree of inter-
patient variability limited further interpretation.  However, the authors did find that abiraterone 
exposures appeared to be higher in fed patients, suggestive of a food effect23.  Currently, the 
FDA label for abiraterone states that though there is food effect seen with this drug, 
abiraterone is recommended only to be taken on an empty stomach17.  Further rationale for 
performing a food effect study with abiraterone is warranted because the pharmacokinetics of 
this drug has not been examined with continuous dosing, nor have the pharmacodynamic 
effects of lower dose with food been assessed in comparison to standard dosing. 
 
1.8 Adherence to Oral Oncology Medications 
Over the last decade oral anticancer medications (OAMs), including abiraterone acetate, represent 
a major shift in the management of cancer patients from directly observed intravenous therapy to 
self-administered oral chronic therapy24.  Adherence, broadly defined by the International Society 
for Pharmacoeconomics and Outcome Research as “the degree of conformity to the 
recommendations about day-to-day treatment by the provider with respect to the timing, dosage, 
and frequency” has been a factor for decades in many other chronic diseases, and is now 
becoming relevant in oncology25,26.  Physicians are poor at recognizing nonadherence and 
techniques to quantify adherence are imperfect27.  Much of the literature in this area has focused 
on adjuvant treatment of breast cancer as well as chronic myelogenous leukemia (CML) and one 
representative study showed that only 47% of breast cancer patients took adjuvant hormonal 
therapy for the full duration at the optimal schedule and early discontinuation and nonadherence 
was associated with increased mortality28,29.  In CML nonadherence was seen in over 30% and 
adversely affected event free survival30,31.  Many factors can be an obstacle to adherence, 
including the complexity of the regimen and dietary restrictions24.  This study will explore 
adherence to abiraterone acetate in men with CRPC to determine if lower-dose abiraterone taken 
with food will lead to increased self-reported adherence.     
1.9 Study Rationale 
The current FDA labeling for abiraterone mandates the drug be taken fasting, which is 
complicated for patients and often difficult for patients to comply with.  There are data to support 
increased absorption of abiraterone when taken with food.  We therefore hypothesize that lower-
dose abiraterone taken with food will have a similar effect on CRPC as full-dose taken fasting.  
We will use serum PSA as a pharmacodynamic marker of abiraterone effect. 
Table1:  Summary of Pharmacokinetic Data for Abiraterone Acetate Measured as Abiraterone 
in Plasma12 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 11 of 57  
 
 
 Details of patients:
 
 
 
 
PT 17-20: single dose in non-castrate males 
 
PT 1-16: single dose study in castrate males 
 
 
 
 
PT 21-26:  multi-dose study in non-castrate males 
Abbreviations:  NE – non evaluated due to problems with assay; ND – non-detectable, plasma 
concentrations below the permit estimation of the pharmacokinetic behavior or drug; AUC – area 
under the concentration time curve; Cmax – maximum concentration; Tmax – time to maximum 
concentration, T1/2α – initial half-life; T1/2β – terminal half-life; Kabs
 
 – absorption rate constant. 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 12 of 57  
 
2. OBJECTIVES 
2.1. Primary Objective 
• 
The primary objective of the study is to compare the pharmacodynamic effect of reduced 
dose (250mg daily) abiraterone acetate in the prandial state (250mg-Fed) to the full, 
standard 1000mg daily dose in the fasting state (1000mg-Fasting) as assessed by change in 
serum PSA. 
2.2. Secondary Objectives 
• 
To evaluate the effect of prandial states on plasma levels and the intra-patient 
pharmacokinetic variability of abiraterone acetate 
• 
To evaluate the safety profile of reduced dose abiraterone acetate taken in the prandial 
state. 
• 
To evaluate the pharmacodynamic effect of reduced dose abiraterone acetate in the 
prandial state as assessed by reduction in the extra-gonadal androgen 
dihydroepiadrosterone sulfate (DHEA-S) and dihydroepiandrostenedione (DHEA).    
• 
To evaluate the effect of prandial state on time to disease progression (Working group 
criteria32). 
• 
To assess and describe medication adherence to abiraterone acetate for both dosing 
schedules 
 
3. PATIENT SELECTION 
 
3.1. Eligibility Criteria 
 
3.1.1. 
Histologically or cytologically confirmed prostate cancer with progressive disease 
defined as either: 
 
− 
2 or more new lesions on bone scan 
− 
Progressive disease on CT/MRI according to RECIST 1.1 criteria
or 
33 
− 
Rising PSA: PSA evidence for progressive prostate cancer consists of a minimum PSA 
level of at least 2 ng/ml, which has subsequently risen on at least 2 successive 
occasions, at least 2 weeks apart. 
or 
3.1.2. 
Evidence of castration resistance defined as disease progression despite a testosterone 
level <50ng/dL (or surgical castration)  
 
3.1.3. 
Any prior therapy for castrate disease is acceptable except prior abiraterone, which is 
excluded.  A minimum washout of 28 days for any other anticancer therapy prior to 
first dose of study drug is required. 
 
• Any other radiotherapy or radionuclide require 28-day washout prior to first 
dose of study drug. 
• Denosumab or zoledronic acid are allowed. 
 
3.1.4. 
ECOG performance status ≤ 2 (Appendix A). 
 
3.1.5. 
Patients must have normal hepatic function as defined below: 
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 13 of 57  
 
− 
Total bilirubin  
 
 
 
 
 
<1.5 x the upper limit of normal 
− 
AST(SGOT)/ALT(SGPT)  
     
 <2.5 X institutional upper limit of normal 
 
3.1.6. 
Ability to understand and the willingness to sign a written informed consent document. 
 
3.2. Exclusion Criteria 
 
3.2.1. 
Therapy with other hormonal therapy, including any dose of megestrol acetate 
(Megace), finasteride (Proscar), dutasteride (Avodart), or any herbal product known to 
decrease PSA levels (e.g., saw palmetto and PC-SPES), or any systemic corticosteroid 
(other than prednisone ≤10mg/day) within 4 weeks prior to first dose of study drug. 
 
3.2.2. 
Therapy with supplements or complementary is excluded with the following 
exceptions.  All other supplements must be discontinued prior to initiation of study 
drug. 
 
- 
Conventional multivitamin supplements 
 
- 
Selenium 
 
- 
Lycopene 
 
- 
Soy supplements 
 
3.2.3. 
Inability to swallow capsules or known gastrointestinal malabsorption. 
 
3.2.4. 
History of other malignancies, with the exception of adequately treated non-melanoma 
skin cancer or adequately treated superficial bladder cancer or other solid tumors 
curatively treated with no evidence of disease for > 5 years from enrollment. 
 
3.2.5. 
Blood pressure that is not controlled despite > 2 oral agents (SBP >160 and DBP >90 
documented during the screening period with no subsequent blood pressure readings 
<160/100) 
 
3.2.6. 
Serum K+ < 3.5 mmoL/L. Patients with a K+ < 3.5 mmoL/L are required to have a 
documented subsequent K+ >3.5 prior to enrollment to be eligible.  
 
3.2.7. 
Serious intercurrent infections or non-malignant medical illnesses that are uncontrolled 
 
3.2.8. 
Active psychiatric illness/social situations that would limit compliance with protocol 
requirements. 
 
3.2.9. 
NYHA class II, NYHA class III, or IV congestive heart failure  (any symptomatic 
heart failure). 
 
3.2.10. Concurrent therapy with strong inhibitors or inducers of CYP3A4 (See Section 8.12 
below for list of strong inhibitor or inducers) due to concerning possible drug-drug 
interactions with abiraterone. 
 
3.3. Inclusion of Minorities 
 
Men of all races and ethnic groups are eligible for the trial.   


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 14 of 57  
 
 
4. REGISTRATION AND DATA COLLECTION/MANAGEMENT 
 
4.1. Registration Process 
Prior to registration, potential patients must have documented ability and willingness to procure 
standard commercially available abiraterone (Zytiga®).  Prior authorization assistance for 
commercially available abiraterone is available through the manufacturer:  
• www.centocoraccessone.com/assets/zytiga/PEF.pdf  
The University of Chicago Comprehensive Cancer Center maintains a secure, password protected, 
and regularly backed up commercial clinical trials database called “Velos.” Patients on the trial will 
be entered into the Velos database centrally at the University of Chicago by the study coordinator.  
Data will be entered by the study coordinator and stored within the database using the patient-study 
number as well as a unique identifier generated by Velos.  
 
 
Jaclyn D. Peterson 
Study Coordinator: 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
773-834-1746 
 
773-702-4889 
 
 
 
 
phaseIICRA@medicine.bsd.uchicago.edu 
 
 
Eligible patients will be entered on study centrally at the University of Chicago by the Study 
Coordinator. Forms are available to UC Phase II Consortium Affiliates on the University of Chicago 
Cancer Research Center website.   
• http://cancer.uchicago.edu  
• Click on the Intranet (top right corner). 
• Enter your site specific user name and password 
• Click on Phase II Website 
• Click on Forms 
 
For non-UC Consortium affiliates, forms will be provided by request from the study coordinator. 
 
The following baseline clinical variables will be collected and stored in the database using data entry 
forms all available in the Velos database (Appendix B): 
 
• Demographics 
• Age 
• Race 
• Performance status 
• Primary tumor data 
• Diagnosis date 
• Baseline staging 
• Baseline PSA  


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 15 of 57  
 
• Gleason grade  
• Primary tumor treatment 
• Systemic therapy administered 
• Date of androgen ablation start 
• Dates of anti-androgen therapy, and withdrawal 
• Dates and types of other systemic therapy 
• Dates and types of systemic radiotherapy 
• Sites of metastatic disease 
 
Patients can be registered only after the initial IRB approval for the participating site has been 
forwarded to the Coordinating Center, University of Chicago.  
 
All patients must be registered with the University of Chicago Study Coordinator. The following 
documents should be completed by the research nurse or data manager and faxed to (773) 702-4889 or 
emailed to the study coordinator at:  PhaseIICRA@medicine.bsd.uchicago.edu a minimum of 48 hours 
prior to expected study med start date: 
 
• Provider of information 
• Treating Physician (NCI investigator number) 
• Patient name and hospital ID number 
• Patient's zip code of residence 
• Date & copy of signed informed consent 
• Race, gender, date of birth of patient 
• Diagnosis and date of initial diagnosis 
• Complete Phase II Consortium Affiliate Clinical Trial Patient Registration Form 
• Source documentation for eligibility and pre-study procedures 
• Prior authorization and documentation of abiraterone availability 
    
The research nurse or data manager at the participating site will then call the study coordinator to 
confirm all selection criteria listed in Section 3.   
To complete the registration process, the UCMC Coordinator will: 
 
• Assign a patient study number 
• Register the patient on the study 
• Fax or e-mail the patient study number to the participating site 
• Fax or e-mail, within 28 hours of completed registration, the assigned treatment arm 
• Call the research nurse or data manager at the participating site and verbally confirm registration. 
 
4.2. Randomization process 
All patients with will be randomized to 250mg-Fed versus 1000mg-Fasting after successful 
registration by the Study Coordinator.  Patients will be randomized by the University of Chicago 
Cancer Clinical Trials Office (CCTO), in cooperation with the Biostatistics Core Facility of the 
UCCRC.  Patients will remain on their allocated treatment arm throughout the duration of study 
therapy with no crossover while on study.  Participating sites will be notified by the coordinator 
within 48-hours of registered patient’s open label, randomized treatment group assignment. 
Following registration, patients should begin treatment within 14 days.  Issues that would cause a 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 16 of 57  
 
delay in treatment initiation (e.g. delay in procurement of commercially available abiraterone) should 
be discussed with the Principal Investigator.   
 
5. STUDY DRUG ADMINISTRATION 
5.1 Treatment will be administered on an outpatient basis continuously.  Study drug is 
commercially available and will be procured by the patient through their pharmacy.  A 
specialty pharmacy may be needed.  As noted above (Section 4.1), prior authorization and 
documentation of abiraterone availability is necessary prior to registration.   
 
5.2 Therapy will consist of: 
5.2.1 For fasting patients:  abiraterone acetate 1000mg per day (in the form of four 250mg 
tablets), plus prednisone 5 mg po bid.  The abiraterone will be taken first thing in the 
morning after an overnight fast of a minimum 8 hours.  It will be taken at least 2 hours 
prior to any food intake. 
5.2.2 For fed patients (not fasting):  abiraterone acetate 250mg per day (in the form of one 
250mg tablet), plus prednisone 5mg po bid.  The abiraterone will be taken either 
concomitantly or within 30 minutes of a conventional low-fat breakfast.  The nature of 
the breakfast is at the discretion of the patient, however, high fat food items (foods 
with 250 or more calories from fat-e.g. sausage, bacon, etc.) should not be consumed 
with abiraterone.  
5.2.3 All patients will be treated with prednisone 5mg twice daily obtained through their 
standard pharmacy.  
 
6. DURATION OF TREATMENT 
Therapy with abiraterone acetate will continue until one of the following events occurs. 
1. Progression of disease according to 2008 PSAWG-2 criteria34 is met (Appendix D, E).  
Note-PSA progression (or response) will not be assessed until the patients’ first 12-week 
disease assessment visit . 
2. Unacceptable toxicity is encountered. 
3. Patient withdraws consent 
4. Patient is withdrawn from study at the discretion of the investigator 
Note that if the patient discontinues abiraterone therapy, he should continue to be followed for 
PSA levels unless he has withdrawn consent for further follow-up. 
 
7. STUDY ASSESSMENTS 
These assessments are summarized in the study calendar below. 
 
7.1. Pre-treatment Evaluation 
Eligible patients who have signed informed consent and have had eligibility confirmed will be 
seen in the outpatient clinic within four weeks of starting the study.  They will undergo a history 
and physical examination, have ECOG performance status, concomitant medications, and baseline 
toxicity documented at this visit.  In addition, to confirm eligibility, the patient will have standard 
of care screening labs drawn within four weeks of initiating therapy.  These include:  CBC (white 
blood cell count, hemoglobin, platelet count, white blood cell differential) and serum chemistries 
(sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, calcium, 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 17 of 57  
 
alanine aminotransferase, aspartate aminotransferase, total bilirubin, total protein, alkaline 
phophatase, and albumin), serum testosterone and DHEA-S (Quest diagnositics).   
 
Disease burden evaluation with a bone scan, abdominal/pelvis imaging (CT or MRI), and CT 
chest (when clinically indicated) must be obtained within 30 days of study entry 
 
7.2 On Study Visits 
On study visit will occur weekly for two weeks, at week 4 and then monthly. After patients have 
been on the study for more than 12 months, on-study visit intervals may be changed from monthly 
to every 12 weeks at the discretion of the treating investigator.  The blood draw at day 8 will be 
limited to steady state PK samples.  The draw on day 15 will be limited to serum chemistries for 
toxicity assessment. 
For the monthly visits, including day 1, the following full set of blood tests will need to be 
obtained:  CBC, serum chemistries, LDH, PSA.  Other monthly assessments including ECOG 
status, concomitant medications etc. to be collected are outlined in the study calendar.  Note: 
monthly visits can occur ±3 days of scheduled visit.  
Disease assessment with imaging (as in pre-study evaluation) will be repeated every 12 weeks 
while on study.  A testosterone and DHEA-S level (Quest) will also be obtained at each 3 month 
visits (month 4, 7, 10, etc.).  
 
  
7.2.1 
Plasma and serum will be collected at the day 1 visit and month 2 visit and stored to assay 
for pertinent endocrine labs (e.g. Androstenedione, and DHEA) using a highly sensitive 
diagnostic assay in the future.  For these samples, approximately 7-10 ml of blood will be 
collected into one sodium EDTA (lavender top-for plasma) vacutainer tube and one serum 
separator tube (red-grey speckled, SST- for serum).  Tubes will be centrifuged (2500 rpm, 
20 min, 4ºC) and plasma/serum immediately separated and transferred as two aliquots into 
storage cryotubes.  The plasma samples will be labeled with patient’s initial and ID number, 
UC protocol number, initials of phlebotomist, and sample ID (e.g. baseline, month 2).  
Samples will be transported to the BioFluids Core Facility (Room AB201, Scientific 
Director, Dr. Michael Maitland) to be stored at –80ºC.   
Adrenal androgen sampling: 
Frozen plamsa samples from participating institutions will be shipped on dry ice to the 
University of Chicago in Styrofoam container to the Study Coordinator who will log and 
transport the samples to the UC BioFluids Facility for storage: 
 
 
 
Jaclyn Peterson 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
jdpeterson@medicine.bsd.uchicago.edu 
 
 
 
7.2.2 
All abiraterone acetate and abiraterone PK assays will be conducted within the 
Pharmacology Laboratory at the National Cancer Institute within the National Institutes of 
Heath (Laboratory Director Dr. William Douglas Figg Sr., Pharm. D) by solid phase 
extraction after plasma acidification and quantified using a calibration curve.  Samples will 
Pharmacokinetics sampling: 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 18 of 57  
 
be analyzed using LC/MS/MS with electrospray ionization35. Stored frozen samples (see 
7.2.1.1) will be sent to the Figg laboratory for batch processing at the following address:  
 
 
 
Cody Peer 
Center for Cancer Research 
National Cancer Institute 
National Institute of Health 
Bldg 10/Room 5A01 
Bethesda, MD 20892 
 
Blood samples will be collected according to the following schedule for PK studies (steady state Cmax, 
Tmax
1. Day 1, time zero: before ingestion of fist abiraterone. 
): 
2. Day 8, time zero:  before ingestion of abiraterone.  
3. Day 8, 2h: two hours post ingestion of abiraterone. 
4. Day 8, 3h: three hours post ingestion of abiraterone. 
5. Day 8, 4h: four hours post ingestion of abiraterone. 
6. Month 2, time zero: before ingestion of abiraterone dose 
7. Month 2, 2h: two hours post ingestion of abiraterone. 
8. Month 3, time zero: before ingestion of abiraterone dose 
9. Month 3, 2h: two hours post ingestion of abiraterone. 
10. Month 4, time zero: before ingestion of abiraterone dose 
11. Month 4, 2h: two hours post ingestion of abiraterone. 
 
7.2.1.1 
Blood samples for pharmacokinetic analysis will be processed in the follow manner:  
Approximately 7 ml of blood will be collected into sodium heparinized (green top) vacutainer.  
Green top tubes will be centrifuged (2500 rpm, 20 min, 4ºC) and plasma immediately separated 
and transferred as two aliquots into storage cryotubes.  The plasma samples will be labeled with 
patient’s initial and ID number, UC protocol number, initials of phlebotomist, sample ID (i.e. 
baseline, 0.5 hrs, etc) and actual time and date of blood collection. Actual blood sampling times 
will be noted for each patient in the attached flow sheet (pharmacology referral form, appendix F).  
Any delays or problems will be carefully noted under comments along with the initials of the 
phlebotomist. Samples will be transported to the BioFluids Core Facility (Room AB201, 
Scientific Director, Dr. Michael Maitland) to be stored at –80ºC.  For all PK sampling, the time of 
blood collection will be recorded on the specimen collection sheet as well as tube label by the 
phlebotomist.   
Collection and Handling of Specimen(s) 
PK samples from participating institutions other then the University of Chicago will be collected 
and processed according to the same methods and stored at the participating institutions at –80ºC 
for batched shipment.  Cryotubes for plasma storage will be provided by the University of 
Chicago as will blank labels.  Frozen PK samples will be shipped on dry ice to the University of 
Chicago in a styrofoam container (not supplied by UC) to the Study Coordinator. Samples can be 
batch shipped to the University of Chicago at quarterly intervals. 
 
7.2.3 
For those patients still on study at 60 days, a questionnaire addressing issues of adherence to 
abiraterone acetate will be administered either in person or over the phone (Appendix G).  
Medication adherence questionnaire: 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 19 of 57  
 
7.3 Off Study Assessments 
Patients will be followed with these assessments until taken off study.  Upon study 
discontinuation, subjects will undergo a complete evaluation with a history and physical 
examination, ECOG performance status, concomitant medications, and baseline toxicity 
documented at this visit.  The subject will also have standard laboratory studies collected at this 
visit (CBC, serum chemistries, LDH, PSA, testosterone, adrenal androgen studies), and have 
radiologic tumor assessments performed, unless already performed within four weeks of being 
taken off study.  Study participant refusal or inability to undergo these evaluations should be 
noted.  This visit should be done on the day patients are taken off study medication but may be 
completed within 30 days of coming off treatment.  At the time of study completion for any 
reason, patients will once again be asked to partake in a questionnaire (Appendix G).  If a patient 
completed the questionnaire less than 30 days prior as part of their on-study visit, they will not be 
asked to participate. 
7.4 Study Calendar 
 
 
Pre-
treatment 
Day 1 
& 
Monthlyj 
±3 Days 
Month 1, 
Day 8 
Month 1,  
Day 15 
Every 
3 Months 
(Month 4, 7, 
10…) 
 
Off study visit
k 
Procedures 
 
 
 
 
 
 
Informed Consent
a 
X 
 
 
 
 
 
Medical History, 
including 
demographics 
 
X 
 
X 
 
 
 
 
Physical exam, 
including height (only 
at screening) and 
weight 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
Vital Signs 
b 
X 
X 
X 
X 
 
X 
ECOG performance 
status 
 
X 
 
X 
 
 
 
X 
 
 
X 
Concomitant 
medications 
 
X 
 
X 
 
 
 
X 
 
 
X 
Concurrent Anti 
Cancer Therapies
c 
 
 
X 
 
 
 
 
X 
Medication Compliance 
Questionnaire  
 
 
X 
 
 
 
 
X 
Adverse Events 
 
X 
 
X 
 
X 
Laboratory 
Assessments 
 
 
 
 
 
 
CBC with platelets & 
differential counts 
 
X 
 
Xl 
 
X 
 
X 
 
 
X 
Serum chemistry and 
electrolytes
d 
 
X 
 
Xl 
 
X 
 
X 
 
 
X 
AST, ALT, total 
bilirubin, alk. phos. 
 
X 
 
X 
 
 
 
 
PSA 
 
X 
 
 
 
X 
Testosterone, DHEA-S 
X 
 
 
 
X 
X 
Adrenal Androgen 
Levels
e 
 
 
X 
 
 
 
 
X 
LDH 
 
X 
 
 
 
 
PK sample 
 
Xf 
X 
 
 
 
Tumor Assessments
g 
 
 
 
 
 
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 20 of 57  
 
Bone scanh 
X 
 
 
 
X 
X 
CT or MRI of the 
abdomen/pelvis 
 
X 
 
 
 
 
X 
 
X 
CT chesti 
X 
 
 
 
X 
X 
 
a Written informed consent must be obtained before any screening assessments are performed (it can 
be no more than 28 days prior to starting beginning study medication). 
b Includes blood pressure, pulse, respiratory rate, and body temperature. 
 
c Other than LHRH agonists that are required to maintain castrate levels of testosterone, anti-cancer therapies are 
excluded during this study. These include chemotherapy, radiotherapy, immunotherapy, ketoconazole, 
diethylstilbesterol,  PC-SPES, and other experimental anticancer medications, such as herbal preparations. 
d Serum chemistry includes BUN, creatinine, ALT, AST, glucose, alkaline phosphatase, total bilirubin, 
electrolytes (K+, Cl-, Na+,CO2, Ca+). Serum AST/ALT should be measured at a minimum day 1 each month.  Current FDA 
guidance suggests every two weeks for first 12 weeks. More frequent AST/ALT monitoring, especially during the first 12 weeks on 
study is thus at the investigator discretion 
e Day 1, Month 2 visits and end of study visit only-  Androstenedione, DHEA 
f PK samples will be obtained at the Month 2, Month 3, Month 4 visits in addition to Month 1, Day 1, 8 visits 
g Imaging will be evaluated at screening and for clinical benefit every 12 weeks (3 cycles) of treatment 
h  Isolated new lesions on bone scan at the 12-week scan will be confirmed with a repeat bone scan at 6 weeks to rule out 
bone scan flair. 
l Obtain if clinically warranted. 
j +/- 3 days. 
k End of study visit – within 30 days of the last abiraterone dose. Tumor assessment not necessary if done within 
preceding 30 days. 
l These test will be performed at your monthly doctor visits. In addition, during the first month on the study, subjects will have 
these tests performed during two extra weekly visits (after 1 week and after 2 weeks of taking the study drug). After patients 
have been on the study for more than 12 months, on-study visit intervals may be changed from monthly to every 12 weeks 
at the discretion of the treating investigator. 
m Questionnaire will only be performed at day 60 (month 3 day 1) and at the end of the study 
 
8. TREATMENT PLAN 
8.1. Agent Administration for patients in the US and Other Participating Countries 
Treatment for all patients will be administered on an outpatient basis as per Section 5.   
 
The patients on study will procure the abiraterone as stated above through their standard outpatient 
pharmacy, but will not take any doses of therapy until instructed to do so, and until after 
randomization.   
 
For patients participating outside of the US, 250mg tablets of abiraterone acetate will be dispensed in 
accordance with their site’s standard practice.  Regardless of location, all subjects are required to 
complete a daily medication log (Appendix C) to document appropriate medication adherence.  
 
Patients randomized to the 250mg fed state arm will have 90 extra 250mg tablets at the end of each 28 
day cycle.  Study drug administration calendars will be filled out by the patient while on study.  The 
patients’ pill bottles will be brought to each study visit for pill counting by the research nurse to 
validate the calendars.  
 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient's malignancy with the exception of patients who are 
chemically castrated who should continue to receive their LHRH agonist while on this clinical trial.  
Medications for bone health (e.g. zoledronic acid or denosumab) should likewise be continued 
(Section 3.1.5). 
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 21 of 57  
 
8.2. Management of Castration Related Symptoms: 
Treatment with androgens, estrogens, and progestin to control hot flushes is not allowed.  However, 
selective serotonin re-uptake inhibitors (SSRIs) are permitted for the management of hot flashes. 
 
8.3. Dose-Reduction Procedure for Adverse Event Management 
In the event where  dose-reduction  is  used  for  AE  management,  2  dose  reductions  are 
allowed according to the following table.   The maximum time a patient’s study medication may be 
held due to toxicity is 14 days.  After which, the patient must be discontinued from study 
participation. 
Dosing Cohort 
Starting Dose 
Dose level -1 
Dose level -2 
Fasting State 
1000mg daily 
750mg daily 
500mg daily 
Fed State 
250mg daily 
250mg every 
other day 
250mg every 
third day 
8.4. Treatment Management of Hypertension 
Hypertension may develop while on abiraterone due to excess mineralocorticoid activity arising 
from a compensatory increase in deoxycorticosterone as a result of the inhibition of the 17"-
hydroxylase at an earlier point in the steroid synthesis pathway. Because of this, hypertension 
occurring secondary to abiraterone may be most effectively prevented through the concurrent 
administration of corticosteroids, which are given to all patients concomitant with abiraterone 
therapy. Further treatment of hypertension is not restricted; however consideration should be 
given to the use of eplerenone which is capable of inhibiting mineralocorticoid induced 
hypertension. The following table provides a recommended algorithm for treatment-emergent 
hypertension management. Decisions to hold or decrease the dose of study treatment must be based 
on blood pressure (BP) readings confirmed with a second measurement at least 5 minutes after the 
first measurement.  
 
If toxicity occurs, hold study treatment, adjust or add medications to mitigate the toxicity.  When 
resolved to <Grade 1, resume study treatment with first dose level reduction. 
BP Measurements – Systolic/Diastolic 
Treatment/Dose Modification 
> 140 mm Hg (systolic) and <160 mm Hg 
OR 
> 90 mm Hg (diastolic) and < 105 mm Hg 
OR 
 
• 
Add new or additional antihypertensive 
medications or increase dose of existing 
medications. 
• 
Maintain dose of study treatment. 
≥ 160 mm Hg (systolic) 
OR 
≥ 105 mm Hg (diastolic) 
 
• 
Hold study treatment. 
• 
Add new or additional anti-
hypertensive medications or increase dose of 
existing medications. 
• 
Monitor subject closely for hypotension 
(if on anti-hypertensive medications) until 
study treatment is restarted. 
• 
Resume treatment at same dose level 
when BP falls to < 140/90 mm Hg. 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 22 of 57  
 
If toxicity recurs at the first dose level reduction, hold study treatment, adjust or add medications to 
mitigate the toxicity.  When resolved to <Grade 1, resume study treatment with the second dose level 
reduction. 
8.5. Treatment-Emergent Edema and Fluid Retention 
Fluid retention can be managed with aldosterone antagonists such as eplerenone and other diuretics as 
needed.  Serum potassium level should be monitored closely. 
 
Symptoms 
Treatment/Dose Modification 
• Pedal Edema 
• Management per investigator.  No study 
treatment dose reduction 
• Anasarca and/or pulmonary edema 
requiring supplemental oxygen 
• Hold study treatment.  Adjust or add 
medications to mitigate the toxicity and/or 
consider specific mineralocorticoid 
receptor blocker, eplerenone.  When 
toxicity resolves to <Grade 1, resume 
study treatment at full dose. 
• Recurrence of anasarca and/or pulmonary 
edema requiring oxygen. 
• Hold study treatment. Adjust or add 
medications to mitigate the toxicity.  
When toxicity resolves to <Grade 1, 
resume study treatment at first dose level 
reduction (for fasting patients, 3 tablets or 
750 mg of abiraterone, 250mg every other 
day for fed state patients). 
• Recurrence of anasarca and/or pulmonary 
edema requiring oxygen at first dose level 
reduction 
• Hold study treatment. Adjust or add 
medications to mitigate the toxicity.  
When toxicity resolves to <Grade 1, 
resume study treatment at second dose 
level reduction (for fasting patients, 2 
tablets or 500 mg of abiraterone; 250mg 
every third day for fed state patients) 
• Recurrence of toxicity despite optimal 
medical management and with two dose 
level reductions 
• Discontinue study treatment.  
 
 
8.5 Management of Hypokalemia 
Hypokalemia may occur in patients treated with abiraterone acetate therapy due to 
mineralocorticoid excess. Initial management of hypokalemia should include oral K+ 
supplementation as well as the addition of eplerenone, as appropriate. 
 
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 23 of 57  
 
 
 
 
Serum K+ 
Hypo-
kalemia 
Grade 
 
Action 
Further Action and/or 
Maintenance 
 
< 3.5mM 
- 
3.0mM 
•  
•  
Grade 1 
Initiate oral 
K+ 
Supplements 
Titrate K+ dose to maintain serum 
K+ ≥3.5mM  ≤5.0mM (Maintenance of 
pts at ≥4.0mM is recommended); 
weekly laboratory studies until K+ 
≥3.5mM  ≤5.0mM.  
< 3.0mM 
– 
2.5mM 
•  
•  
Grade 3 
Withhold study 
treatment and 
initiate IV K+ 
and cardiac 
monitoring 
Restart abiraterone at dose level -1; 
Titrate K+ dose to maintain serum 
K+ ≥3.5mM  ≤5.0mM; weekly 
laboratory studies until K+ 
≥3.5mM  ≤5.0mM.  
 
< 2.5mM 
 
Grade 4 
Withhold study 
treatment and 
initiate IV K+ 
and cardiac 
monitoring 
Call study PI prior to re- initiating 
study treatment. 
 
8.6 Management of Elevated Liver Function Tests 
• If Grade 1 increases in AST, ALT or bilirubin occur (e.g. increase in AST or ALT from 
ULN to 2.5X ULN; increase in total bilirubin from ULN to 1.5X ULN):  The frequency 
of liver function test monitoring should be increased per Investigator discretion, if the 
Investigator judges that the laboratory abnormalities are potentially related to study 
medication. No study treatment dose reduction is required. 
• If Grade 2 increases in AST, ALT or bilirubin occur (e.g. increase in AST or ALT to 
>2.5-5X ULN; increase in total bilirubin from >1.5-3X ULN):  The frequency of liver 
function test monitoring should be increased to ≥once a week, if the Investigator judges 
that the laboratory abnormalities are potentially related to study medication. No study 
treatment dose reduction is required. 
• If Grade 3 or higher increases in AST, ALT, or bilirubin occur (e.g. increase in AST or 
ALT to >5X ULN; increase in total bilirubin to >3X ULN), hold study medication and 
all other concomitant medications that are potentially hepatotoxic.  Frequent laboratory 
evaluations (at least once weekly) should be conducted until the liver function tests 
return to baseline value or Grade 1.  
If study treatment resumption is considered for subjects who have experienced Grade 
3 increases in AST, ALT, or bilirubin, resume study treatment with the first dose level 
reduction (Section 8.8 below) when Grade 3 toxicities resolve to Grade 1 or 
baseline. 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 24 of 57  
 
 
If Grade 3 or higher increases in AST, ALT, or bilirubin recur after the first dose 
reduction hold study medication and all other concomitant medications that are 
potentially hepatotoxic.  Frequent laboratory evaluations should be conducted (at 
minimum weekly) until the liver function tests return to baseline value or Grade 1. Liver 
enzyme measurements should be made immediately, regardless of when the next study 
visit or monitoring interval is scheduled. 
 
If study treatment resumption is considered for patients who have experienced Grade 3 
increases in AST, ALT, or bilirubin with the first dose reduction, resume study 
treatment with the second dose level reduction when AST, ALT, or bilirubin returns to 
baseline value or Grade 1. 
 
If Grade 4 increases in AST, ALT, or bilirubin occur (e.g. increase in AST or ALT to 
>20X ULN; increase in total bilirubin to >10X ULN), patients must discontinue study 
treatment immediately and will not be re-challenged. They should be followed until 
resolution of abnormal liver function tests. 
 
8.7 
Management of Non-Mineralocorticoid Based Side Effects 
• If  Grade  1-2  toxicities,  give  supportive  care  per  institutional  guidelines.  No 
study treatment dose reduction. 
 
• If Grade 3 or higher toxicities including headache (interferes with ADL), nausea 
(TPN, IVF), vomiting (>6 episodes/24hrs, TPN or IVF), diarrhea (IVF, 
hospitalization, hemodynamic collapse), or any other toxicity judged to be related 
to study treatment is observed where the patient’s safety is jeopardized, hold study 
treatment. 
 
• When toxicity resolves to ≤ Grade 1, resume study treatment at full dose. 
 
• If toxicity recurs, hold study treatment, and adjust or add medications to 
mitigate the toxicity.  When resolved to ≤ Grade 1, resume study treatment with 
the first dose level reduction. 
• If toxicity recurs, hold study treatment, and adjust or add medications to 
mitigate the toxicity. When resolve to ≤ Grade 1, resume study treatment with 
the second dose level. 
• If toxicity   recurs despite   aggressive   medical   management   and  two  dose  
level reductions, discontinue study treatment. 
 
 
8.8 Concomitant Medication and Treatment 
If the subject must use a concomitant medication during the study, it is the responsibility of the 
investigator to ensure that details regarding the medication are recorded.  
 
8.9 Chemotherapy and Radiotherapy 
If possible, alternative anticancer treatment should not be initiated until PD has been observed by 
standard guidelines and study treatment has been discontinued. If a subject requires additional 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 25 of 57  
 
systemic anticancer treatment, study treatment must be discontinued. Local intervention (e.g. 
nephrostomy tube placement, TURP) is discouraged unless medically unavoidable. Subjects receiving 
local intervention are allowed to continue to receive study treatment at the investigator’s discretion. 
 
8.10 Other Medications 
Anti-emetics and anti-diarrheal medications should not be administered prophylactically prior to the 
first dose of study drug. After the first dose of study drug, at the discretion of the investigator and 
after the onset of symptoms, treatment (or prophylaxis) with anti-emetic and anti-diarrheal 
medications may be undertaken per standard clinical practice. 
 
Pain medications administered as dictated by standard practice are acceptable while the subject is 
enrolled in the study.  Colony stimulating factors (e.g. granulocyte colony-stimulating factors) 
administered as dictated by standard practice are acceptable while the subject is enrolled in the study. 
However, colony stimulating factors should not be administered prophylactically before the first dose 
of study treatment. Erythropoietin should not be used based on a recent report of increased risk of 
tumor recurrence/progression associated with erythropoietin36. 
 
No concurrent investigational agents will be permitted. 
 
8.11 Potential Drug Interactions 
Potent inhibition  of  P450  CYPs  2D6  and  1A2  by  abiraterone   acetate  was observed  in in 
vitro preclinical  studies. Moderate inhibition of P450 CYPs 2C9, 2C19, and 3A4 was also 
observed.   However, investigators should keep in mind the possibility that  abiraterone  acetate  
may  interact  with  concomitant medications,  particularly  those that are metabolized  or 
activated by P450 CYPs 2D6 and 1A2 and, less likely, P450 CYPs 2C9, 2C19, and 3A4.  
 
Abiraterone is a substrate of CYP3A4, in vitro. The effects of strong CYP3A4 inhibitors or inducers 
on the pharmacokinetics of abiraterone have not been evaluated in vivo. Strong inhibitors and inducers 
of CYP3A4 should be avoided or used with caution. The following table should be used as a reference 
(from http://www.fda.gov/drugs/). 
 
 
Strong: Prohibited 
Moderate: Used with caution 
CYP3A4 inducers 
Avasimibe, carbamazepine, phenytoin, 
rifampin, St. John’s wort 
 
Bosentan, efavirenz, etravirine, 
modafinil, nafcillin 
 
CYP3A4 inhibitors 
Boceprevir, clarithromycin, conivaptan, 
grapefruit juice, indinavir, itraconazole, 
ketoconazole, lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, 
posaconazole, 
ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole 
 
Amprenavir, aprepitant, 
atazanavir, ciprofloxacin, 
darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, 
fosamprenavir,verapamil 
 
 
Although no known interaction with warfarin is known, given its narrow therapeutic window, it 
should be used with caution due to potential drug-drug interaction.   
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 26 of 57  
 
Additional information with regards to drug-drug interactions is available online through the 
manufacturer (http://www.zytiga.com/hcp/druginteractions) and on the FDA prescribing information.   
• http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202379lbl.pdf. 
 
9. SAFETY 
 
9.1. Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation of a 
subject who has been enrolled in a clinical study and who may have been administered an 
investigational product, regardless of whether or not the event is assessed as related to the study drug 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an investigational 
product, regardless of whether or not the event is assessed as related to the investigational product. 
Abnormal laboratory values, ECG findings, or vital signs that are considered clinically significant by 
the investigator, and pre-existing medical conditions that worsen during a study, should be recorded 
as AEs. 
 
For the purpose of data collection, all AEs that occur after initiation of study drug through 30 days 
after last dose of study treatment (or until a subject is determined to be a screening failure) are to be 
recorded by the investigational site. This requirement includes AEs from unscheduled as well as 
scheduled visits. 
 
Assessment of toxicities and adverse events will be graded according to the Common Toxicity 
Criteria (CTC), version 4.03:  
 
• 
V4.03 (CTCAE): publish date June 14, 2010:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  
 
9.2.  Serious Adverse Events 
The serious adverse event (SAE) definition and reporting requirements are in accordance with the 
International Conference of Harmonisation (ICH) Guideline for Clinical Safety Data Management, 
Definitions and Standards for Expedited Reporting, Topic E2A. 
 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in death. 
2. Is immediately life-threatening (i.e. in the opinion of the investigator, the AE places the 
subject at immediate risk of death; it does not include a reaction that, had it occurred in a 
more severe form, might have caused death). 
3. Requires inpatient hospitalization or results in prolongation of an existing hospitalization. 
4. Results in persistent or significant disability or incapacity. 
• Note:  The term “disability” refers to events that result in a substantial disruption of a 
subject’s ability to conduct normal life function. 
5. Is a congenital anomaly or birth defect. 
6. Is an important medical event (IME) 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 27 of 57  
 
• Note:  The term “important medical event” refers to an event that, based upon 
appropriate medical judgment, may not be immediately life-threatening or result in 
death or hospitalization, but may jeopardize the subject or require intervention to 
prevent one of the other serious outcomes listed under the definition of Serious 
Adverse Event.  Examples of IMEs include:  intensive treatment in an emergency room 
or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization; or development of product dependency or product abuse. 
 
9.3. Serious Adverse Event Reporting  
This study will be using MedWatch for SAE reporting.  
 
MedWatch forms and information:  http://www.fda.gov/medwatch/getforms.htm 
 
The minimum information required for SAE reporting includes identity of investigator, site number, 
patient number, an event description, SAE term(s), onset date, the reason why the event is considered 
to be serious (ie the seriousness criteria) and the investigator’s assessment of the relationship of the 
event to study treatment. Additional SAE information including medications or other therapeutic 
measures used to treat the event, action taken with the study treatment due to the event, and the 
outcome/resolution of the event will be recorded on the SAE form.  
 
In all cases, the investigator should continue to monitor the clinical situation and report all material 
facts relating to the progression or outcome of the SAE.  
 
When reporting serious adverse events, the following additional points should be noted: 
• 
When the diagnosis of an SAE is known or suspected, the investigator should report the diagnosis 
or syndrome as the primary SAE term, rather than as signs or symptoms. Signs and symptoms 
may then be described in the event description.  
• 
Death should not be reported as an SAE, but as an outcome of a specific SAE, unless the event 
preceding the death is unknown. In the exceptional case where the events leading to death are 
unknown, then Death may be used as an event term and should be reported as “death, cause 
unknown”. If an autopsy was performed, the autopsy report should be provided.  
• 
While most hospitalizations necessitate reporting of an SAE, some hospitalizations do not require 
SAE reporting, as follows:  
• 
Elective or previously scheduled surgery, e.g., a previously scheduled ventral hernia repair. 
• 
Procedures for pre-existing conditions that have not worsened after initiation of treatment. 
• 
Pre-specified study hospitalizations for observation. 
• 
Events that result in hospital stays of less than 24 hours and that do not require admission, eg, an 
emergency room visit for hematuria that results in a diagnosis of cystitis and discharge to home 
on oral antibiotics. 
• 
SAEs must, however, be reported for any surgical or procedural complication resulting in 
prolongation
• 
All serious unexpected adverse drug reactions (unexpected related SAEs) must be reported to the 
FDA by the investigator as required by 21 CFR 312.32 (See Section 9.4.2 below). 
 of the hospitalization. 
• These reports are to be filed utilizing the Form FDA 3500A (MedWatch Form). 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 28 of 57  
 
 
9.4. Other Reporting Requirements 
 
9.4.1. 
All serious adverse events and protocol deviations must also be reported to the University of 
Chicago Comprehensive Cancer Center (UCCCC) Cancer Clinical Trials Office (CCTO) via 
email at 
University of Chicago Comprehensive Cancer Center 
qaccto@bsd.uchicago.edu and copied to the study nurse and PI.  Events will be reported 
to the University of Chicago Institutional Review Board (UCIRB) in accordance with their 
current policies. The Research Nurse or other designated individual should report the 
SAE/deviation to the UCCCC Quality Assurance (QA) Coordinator by the end of the business 
day when s/he becomes aware of the event.  Events occurring after business hours will be 
reported to the CCTO by 12pm (noon) the next business day.  Each event report must indicate 
where the event meets the IRB’s Unanticipated Problem reporting criteria. 
When appropriate, the IRB’s Unanticipated Problem electronic submission form must be 
completed by the research nurse or other designated individual and submitted by the investigator 
via the IRB’s electronic submission system within the IRB’s designated reporting 
timeframes.  Details of the IRB’s current policy can be found on their website at: 
http://bsdirb.bsd.uchicago.edu/forms-guidelines/up.html 
 
9.4.2. 
Any Serious Adverse Event (SAE) will be reported to the local institution’s IRB and the 
University of Chicago Comprehensive Cancer Center (UCCCC) Cancer Clinical Trials Office 
(CCTO) as specified below.  UCCCC will circulate all SAE's to the participating centers. 
Reporting Requirements for Participating Sites 
 
Any adverse event falling under the definition of Serious will be reported immediately to 
the Study Chairman who, in turn, must notify the UCCCC IRB per IRB policy. 
Symptoms related to progressive disease such as severe bone pain will not be reported as 
toxicity or as Serious Adverse Events. 
 
Multi-center sites participating in the study will notify the UCCCC CCTO via phone at 773-
702-5928 and email at qaccto@bsd.uchicago.edu of all serious adverse events within 24 
hours of knowledge of the event. The UCCCC clinical research staff will immediately 
notify the principal investigator (PI) or his designee of the SAE. The participating 
institutions will submit the SAE to their own IRB. The participating institution must 
forward a copy of the report filed with their local IRB to UCCCC within 5 calendar days. 
After the UCCCC clinical research staff receives and processes the initial SAE report from 
the participating institution, it will be forwarded to the PI or his designee for review and 
signature. 
 
9.5. Other Safety Considerations 
9.5.1. 
All laboratory data obtained during the course of the study should be reviewed. Any abnormal 
value that leads to a change in subject management (e.g., dose reduction or delay, requirement 
for additional medication or monitoring) or is considered to be of clinical significance by the 
investigator should be reported as an adverse event or serious adverse event as appropriate, 
Laboratory Data 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 29 of 57  
 
unless this value is consistent with the patient’s present disease state or is consistent with values 
obtained prior to entry into the study. 
9.5.2. 
Any medication error that results in an adverse event, even if it does not meet the definition of 
serious, requires reporting to the UCCCC CCTO as above.  
Medication Errors 
 
9.5.3. 
Any SAE or AE assessed as possibly related that led to treatment discontinuation (including 
clinically significant abnormal laboratory values that meet these criteria) and is ongoing 30 days 
after last dose of study treatment must be followed until either resolution of the event or 
determination by the investigator that the event has become stable or irreversible. This follow-up 
guidance also applies to possibly-related serious adverse events that occur greater than 30 days 
after last dose of study treatment. The status of all other continuing adverse events will be 
documented as of 30 days after last dose of study treatment. 
Follow-Up of Adverse Events 
 
9.5.4 
According to University of Chicago Cancer Center Guidelines, this protocol will be classified as 
moderate risk.  Data and Safety Monitoring (DSM) will occur at the weekly University of 
Chicago Genitourinary Oncology DSM meeting.  At each meeting, the study will be reviewed 
for safety and progress toward completion.  Toxicities and adverse events will also be reviewed 
and a DSM form will be completed at each meeting.  Twenty percent of research charts will be 
audited annually for protocol compliance items including eligibility, completion of procedures, 
administration of treatment, reporting of toxicities, documentation of response, follow-up, data-
collection, record keeping, and the collection of correlative studies. 
Safety Monitoring 
 
10. MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of this trial, patients with measurable disease will be 
assessed by standard criteria33,37(Appendix D, E).  For the purposes of this study, patients should be 
re-evaluated every 12 weeks.   
 
10.1. Outcome Measures based on PSA Decline 
The following parameters will be recorded after the initial 12 weeks of therapy and at 12-week 
intervals thereafter.  
• 
PSA decline will be measured according to PSAWG-2 (2008) criteria. 
• 
PSA changes from baseline will be calculated for all patients. 
• 
Time to progression (TTP) based on revised PSA Working Group-2 criteria (2008 
version).  
• 
PSA progression free survival: PSA measurements will be taken at screening (baseline) 
and subsequently at time points as indicated in the schedule of visits. Any unscheduled 
PSA measurement will be utilized in the periodic assessment of PSA progression.  
• 
The maximal decline in PSA for each patient will be recorded for each patient. 
• 
The date of the maximal PSA decline (nadir date) will be recorded for each patient, as will 
the duration from the start of therapy to the nadir PSA.  
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 30 of 57  
 
10.2.  Radiographic Tumor Response 
Change in measurable disease, when applicable, will be determined according to RECIST 1.1 and 
PSAWG-2 criteria (Appendix E)33,37,38.  For the purposes of this study, imaging will be repeated 
according to the study calendar (Section 5.5) every 12 weeks unless otherwise indicated clinically. 
 
Lymph nodes37: To be considered pathologically enlarged and measurable, a lymph node must be at 
least 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be not 
greater than 5 mm). Lymph nodes that are at least 10 mm but less than 15 mm in short axis may be 
pathologic and can be considered non-measurable/non-target lesions (that are not measured). At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
Bone lesions
38
:  Bone lesions are by definition non-measurable.  If bone lesions are identified on MRI 
that have soft tissue components that are identifiable and accurately measurable the bi-dimensional 
measurements of these lesions will be recorded as soft tissue measurable disease.  Of note, 
progression based on bone scan will be assessed according to PSAWG-2 criteria .  Isolated new 
lesions on bone scan at the 12-week scan will be confirmed with a repeat bone scan at 6 weeks to rule 
out bone scan flair.  If no new lesions are seen at the 6-week confirmation, it will be considered flair.  
All subsequent bone scans will follow standard criteria with regards to progression (two new lesions 
necessary for progression). 
 
10.3. Duration of Response 
The duration of overall response is measured from the time measurement criteria are met for complete 
or partial response until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded since the treatment 
started). 
 
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded since the treatment started, including the 
baseline measurements.  
 
10.4. Progression-Free Survival 
Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of 
progression (by either PSA or RECIST) or death, whichever occurs first.   
 
11. STATISTICAL CONSIDERATIONS 
 
11.1. Sample Size/Primary Endpoint 
The primary endpoint of the study is change in PSA level from baseline to 12 weeks (analyzed on a 
log scale).  The benchmark data for our power calculations are taken from the phase II open label 
abiraterone trial by Danila and colleagues15 and the much larger, randomized phase III abiraterone vs. 
placebo trial conducted by de Bono et al8, which used the standard, high-dose fasting regimen.  In 
Danila et al, which allowed prior ketoconazole exposure, 21 of 58 patients (36%) exhibited a 50% or 
greater decline in PSA.  Among 797 patients randomized to abiraterone in the de Bono study, 29% 
had a confirmed PSA response.  Pooling these data (weighted by sample size) yields an historical 
29.5% PSA response rate.   
 
We will conduct a randomized, phase II, non-inferiority trial, using a non-inferiority margin of 15%.  


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 31 of 57  
 
Specifically, letting pL denote the true response rate for the low-dose fed regimen and pH the response 
rate for the high-dose fasting treatment, we will test H0: pL-pH= -0.15 vs. HA:  pL-pH > -0.15.  
However to reduce sample size requirements we will analyze change in PSA measured on a 
continuous scale.  Assuming the log ratio of the 12-week to baseline PSA levels, i.e., log 
(PSA12/PSA0
 -0.525- (-1.035) = 0.51 SD difference in means.  Letting µ
), is approximately normally distributed, a 30% vs. 15% rate difference maps into a 
1 and µ2 denote the respective true means, 
we have H0:  µ1 - µ2 > 0.51 SD vs. HA:  µ1 - µ2 
 
< 0.51SD.  Assuming the PSA response rates are truly 
equivalent, a total sample size of 72 patients (36) per treatment arm, will provide 80% power for the 
non-inferiority test, using a one-sided alpha level of 0.10.   A significant number of patient dropouts is 
unexpected before the 12-week endpoint.  However, if there is a dropout rate seen that will impact the 
statistical power, the sample size will be increased accordingly to compensate for unevaluable 
patients. 
An interim futility analysis will be performed midway through the trial.  If the observed difference in 
means exceeds 0.75SD (i.e., if the low-dose regimen is performing more than 0.75SD worse than the 
high-dose treatment on the log ratio scale), the trial will be terminated and the low-dose regimen will 
be considered inferior.  This criterion will reduce the power only very slightly below 80%.  
 
11.2. Randomization and stratification 
Randomization to either the fasting or fed state treatment groups will be done through Dr. Karrison 
and colleagues in the biostatistics core at the University of Chicago in a 1:1 fashion.  The only 
stratification factor will be prior history of high dose ketoconazole treatment for CRPC given the 
potential variability in PSA response rate based on this factor.  Upon documented and confirmed 
eligibility, the patient will be enrolled and randomized. 
 
11.3. Analysis of Secondary Endpoints 
The stratified log-rank will be used to compare the two treatment arms with respect to progression-
free survival (PFS) adjusting on the stratification factor (prior ketoconazole treatment).  PFS is 
defined above.  For patients without disease progression at the time of analysis, PFS will be censored 
at the time of the patient’s last tumor assessment. The Kaplan-Meier approach will be used to estimate 
PFS distribution and the proportional hazards model will be used to assess the importance of treatment 
arm in predicting PFS. 
The pharmacokinetic data will be obtained from steady states PK samples from day 8 and the three 
subsequent visits.  (Section 7.2.).  The steady state Cmax and Tmax will be imputed by Kehua Wu 
within the PK laboratory at the University of Chicago and summarized using standard descriptive 
methods (means, standard deviations, medians and ranges).  We will compare mean plasma levels 
between the two treatment arms using a two-sample t test.  Our sample size of 36 patients per group 
will provide 80% power to detect a 0.66 standard deviation (SD) difference in the means.  We will 
compare interpatient (between patient) and intrapatient (within one patient) steady state abiraterone 
and abiraterone acetate Cmax 
To assess the pharmacodynamic effects of dosing arm on adrenal androgen production (DHEA, 
DHEA-S), descriptive statistics will be employed to note the maximal percentage change from 
baseline, as well as the mean, median, and range of percentage change within each dosing group.  
Group comparisons will be performed using two-sample t tests or nonparametric, Wilcoxon 
rank-sum tests.   
variability between the two treatment groups using Levene’s test.  The 
variability will also be summarized by calculating the coefficient of variation (SD/mean x 100) for 
each group.   


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 32 of 57  
 
 
To assess degree of adherence, medication diaries will be examined and a questionnaire will be 
administered up to two times throughout the study (Appendix G).  Questions were derived from 
previously validated instruments of adherence in various other medical settings with an addition of 
several new questions (ASK-12, BMQ-Specific, Basel Assessment of Adherence Scale, VAS scale of 
adherence, Morisky Adherence Scale).  A composite index of nonadherence using multiple scales will 
be determined and the two sample t-test will be used to compare the low-dose and standard dose 
abiraterone groups.  Baseline to follow-up comparisons will be done using the paired t-test or its 
nonparametric analog (Wilcoxon signed rank test).  Associations between adherence and other 
variables such as socioeconomic status and beliefs about abiraterone will be determined by the 
Pearson product moment correlation coefficient. 
 
 
11.4 Safety Evaluation and Analysis 
Safety analysis will be conducted on the full analysis set. All AEs occurring on study will be listed by 
subject in a data listing. The type of adverse events (AEs), severity, and incidence rates will be 
presented in all treated subjects.  Comparison of the frequency of adverse events (for example, 
percentage of patients with worst toxicity grade 2 or higher) will be conducted using chisquare or 
Fisher exact tests.   
 
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 33 of 57  
 
 
APPENDIX A 
 
Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 34 of 57  
 
APPENDIX B 
 
Sample Data Capture Forms 
 
 
 
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 35 of 57  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 36 of 57  
 
 
Treatment History 
 
 
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 37 of 57  
 
APPENDIX C 
SUBJECT’S STUDY DRUG/MEAL DIARY 
 
 
Subject Name  
 (initials acceptable) 
Subject Study ID   
 
 
MEDICATION & FOOD DIARY 
INSTRUCTIONS TO THE SUBJECT : 
1. 
Complete one form for each month of drug administration. 
2. 
You will take Abiraterone Acetate capsules once daily.  You should take the capsules at approximately the same 
time each morning as instructed by your doctor. 
 
Dose (circled by your nurse/MD): Take one (1) 250 mg capsule or (4) 1000mg 
 
3. 
Record the date, the number of capsules that you took, and when you took them. 
     4.     Record the date, time of your meal (starting time and finishing time), and content of meal. 
     5.     Please bring this form and your bottles of Abiraterone Acetate capsules when you return each appointment. 
 
If you are in the Fasting arm: Following an overnight fast of at least 8hours, you should take the study drug Abiraterone 
Acetate with 240 mL (8 fluid ounces) of water first thing in the morning.  No food is allowed for at least 2 hours after you 
ingest the study drug. You may drink water as desired. Please record your first meal after taking your medication. 
If you are in the Fed arm: Following an overnight fast of at least 8 hours, you should take the study drug with breakfast 
(or within 30 minutes). The abiraterone should be administered with 240 mL (8 fluid ounces) of water.   
Day 
 
Date 
# of Pills 
Taken 
Time Pills 
Taken 
Time of 
Meal 
Content of meal 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 38 of 57  
 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
Subject’s signature:    
 
 
Physician’s Office will complete 
this section: 
1. Date subject started protocol drug administration 
2. Date subject was removed from study 
3. Subject’s planned total daily dose 
4. Total number of capsules taken this month 
5. Physician/Nurse/Data Manager’s Signature


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 39 of 57  
 
Appendix D 
 
PROSTATE-SPECIFIC ANTIGEN WORKING GROUP CRITERIA38 
 
Progressive Disease after Androgen Deprivation Eligibility Criteria: 
 
PSA evidence for progressive prostate cancer consists of a PSA level of at least 5 ng/ml which 
has risen on at least 2 successive occasions, at least 2 weeks apart. If the confirmatory PSA (#3 
below) value is less (i.e., #3b) than the screening PSA (#2) value, then an additional test for 
rising PSA (#4) will be required to document progression. 
 
Procedures for Assessing PSA Progression Post Study Treatment 
PSA measurements will be taken on a monthly basis.  PSA increases and decreases will be 
tracked in order to assess disease response.  
PSA partial response is defined by at least a 50% decline from screening (baseline) PSA value.  
The declined must be confirmed by a second PSA value obtained 4 or more weeks later.   
PSA progressive disease may be defined in both patients who have not shown a decrease in 
their PSA and those who have.  For patients who have not shown a decrease, progressive 
disease is defined as an increase of 25% over the screening (baseline) PSA value and an 
increase in the absolute-value PSA level by at least 5ng/mL.  This increase should be 
confirmed by a second value.   
For those patients whose PSA have decreased but has not reached response criteria, 
progressive disease is defined as 25% increase over the nadir PSA value provided that the 
increase is at least 5ng/mL and is confirmed. 
 
Duration of PSA Response  
Duration of PSA Response is measured from the time when the PSA value first declines by at 
least 50% of the screening (baseline) and that was eventually confirmed by a second value.  It 
is calculated until the time at which there is an increase of 50% of PSA nadir, provided the 
absolute increase is at least 5 ng/mL. The increase must be confirmed by a second consecutive 
measurement that is at least 50% above the nadir. 
If the PSA never shows a 50% increase over the nadir value, then the patient will be censored 
at the last PSA measurement. 
 
Time to Disease Progression 
For patients who have achieved a ≥ 50% decrease from the screening (baseline) PSA, 
assessment of time to disease progression is when the PSA has increased 50% above the nadir 
and at a minimum of 5ng/mL.   For patients without a PSA decrease of this magnitude or 
without a decrease, the time for progression is calculated at the time a 25% increase from 
screening (baseline) PSA has been achieved.  
 
 
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 40 of 57  
 
Appendix E 
 
RESPONSE EVALUATION CRITERIA in SOLID TUMORS (RECIST) 33,37 
 
Eligibility 
• Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint.  
 
Measurable disease - the presence of at least one measurable lesion. If the measurable disease is 
restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
 
Measurable lesions (non-lymph nodes) - lesions that can be accurately measured in at least one 
dimension with longest diameter ≥20 mm using conventional techniques or ≥10 mm with spiral 
CT scan. 
 
Lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be 
at least 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be not greater than 5 mm). Lymph nodes that are at least 10 mm but less than 15 mm in short axis 
may be pathologic and can be considered non-measurable/non-target lesions (that are not 
measured). At baseline and in follow-up, only the short axis will be measured and followed. 
 
 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 mm 
with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, and also abdominal masses that are not confirmed and followed by 
imaging techniques; and. 
 
• All measurements should be taken and recorded in metric notation, using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.  
• The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up.  
• Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Methods of Measurement  
• CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm.  This applies to tumors of the chest, 
abdomen and pelvis. Head and neck tumors and those of extremities usually require 
specific protocols. 
• Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 41 of 57  
 
• When the primary endpoint of the study is objective response evaluation, ultrasound (US) 
should not be used to measure tumor lesions. It is, however, a possible alternative to 
clinical measurements of superficial palpable lymph nodes, subcutaneous lesions and 
thyroid nodules. US might also be useful to confirm the complete disappearance of 
superficial lesions usually assessed by clinical examination. 
• The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet 
been fully and widely validated. Their uses in this specific context require sophisticated 
equipment and a high level of expertise that may only be available in some centers. 
Therefore, the utilization of such techniques for objective tumor response should be 
restricted to validation purposes in specialized centers. However, such techniques can be 
useful in confirming complete pathological response when biopsies are obtained. 
• Cytology and histology can be used to differentiate between PR and CR in rare cases 
(e.g., after treatment to differentiate between residual benign lesions and residual 
malignant lesions in tumor types such as germ cell tumors). 
 
Baseline documentation of “Target” and “Non-Target” lesions 
• All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded 
and measured at baseline.  
• Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  
• A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor. 
• All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up.  


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 42 of 57  
 
Response Evaluation:  Evaluation of target lesions 
 
* Complete Response (CR): 
Disappearance of all target lesions 
* Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target 
lesions, taking as reference the baseline sum LD 
* Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 
since the treatment started or the appearance of one or more 
new lesions 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started 
 
Evaluation of non-target lesions 
* Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level 
* Incomplete Response/ Stable 
Disease (SD):  
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits 
* Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions (1)  
(1) Although a clear progression of “non target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression status 
should be confirmed later on by the review panel (or study chair). 
 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). In general, the patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria  
 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
• Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as 
having “symptomatic deterioration”. Every effort should be made to document the 
objective progression even after discontinuation of treatment.  


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 43 of 57  
 
• In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status. 
 
Confirmation 
• The main goal of confirmation of objective response is to avoid overestimating the 
response rate observed.  In cases where confirmation of response is not feasible, it should 
be made clear when reporting the outcome of such studies that the responses are not 
confirmed. 
• To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed no less than 4 weeks after the criteria for 
response are first met. Longer intervals as determined by the study protocol may also be 
appropriate.  
 
In the case of SD, follow-up measurements must have met the SD criteria at least once after study 
entry at a minimum interval (in general, not less than 6-8 weeks) that is defined in the study 
protocol  
 
 
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 44 of 57  
 
Appendix F 
 
PHARMACOKINETIC SAMPLE COLLECTION SCHEME 
UC PROTOCOL# 11-0709 
 
A randomized phase II study evaluating the food effect on the pharmacokinetics and 
pharmacodynamics of abiraterone acetate in men with castrate resistant prostate cancer 
 
SAMPLES TO BE COLLECTED AT:  
Day 1, Day 8, Month 2, Month 3, Month 4 
 
PATIENT NAME:  
 
 
PATIENT ID: 
 
DATE: 
 
 
 
DOSING TIME: 
 
 
 
No 
SampleID 
 
Date of 
Sample 
Draw 
Actual 
Clock Time 
Calculated 
Clock Time 
(with respect 
to dose) 
Initials 
of 
Sample 
Collector 
Comments 
1 
Pre-dose, 
Day 1 
 
 
 
 
 
2 
Pre-dose,  
Day 8 
 
 
 
 
 
3 
2 hours Post 
dose, Day 8 
 
 
 
 
 
4 
3 hours Post 
dose, Day 8 
 
 
 
 
 
5 
4 hours Post 
dose, Day 8 
 
 
 
 
 
6 
Pre-dose, 
Month 2  
 
 
 
 
 
7 
2 hours Post 
dose, Month 2 
 
 
 
 
 
8 
Pre-dose, 
Month 3   
 
 
 
 
 
9 
2 hours Post 
dose, Month 3 
 
 
 
 
 
10 
Pre-dose, 
Month 4   
 
 
 
 
 
11 
2 hours Post 
dose, Month 4 
 
 
 
 
 
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 45 of 57  
 
 
Appendix G 
Subject Questionnaire 
Principle Investigator: Russell Szmulewitz, MD 
 
Adherence Interview of CRPC Patients on Abiraterone Phase II Trial 
 
 
Patient Name:                                                                      
 
Date: ___________ 
ID    Number (Medical Record Number ): ____________________                                                      
Treatment Arm: ______________________________ 
 
 
 
Hello my name is __________.  I am from the University of Chicago and I work with some of the 
doctors and other health care workers involved in the Abiraterone Acetate trial in which you are 
participating.  
 
May I please talk with you for a few moments? I would like to talk with you about your adherence 
to abiraterone acetate as mentioned in the consent form for the trial. The information gained from talking 
with you will help us to better care for and talk with cancer patients like yourself in the future. I know this 
may be a very difficult time for you, but I would like to ask if it would be all right to talk with you now for 
about 20 to 30 minutes. In answering my questions, you would be participating in a research study that 
we hope will help to improve the care of cancer patients. There are no benefits to you by participating in 
the study. There are no physical risks to you by participating in this study. The only risk is that it might be 
slightly uncomfortable to talk about your illness. Your participation is completely voluntary and you can 
withdraw at any time. Any answers you might give would be kept entirely confidential and would not affect 
your care in any way.  If you do not wish to talk with me, I would certainly understand and respect your 
decision.  
 
I want to emphasize that the questions that I will ask are entirely confidential and you should not think that 
the answers you provide will impact the care your doctor or clinical team provide for you or your 
participation in the clinical trial that you are enrolled in.  We are asking these questions in order to help 
understand how we can take care of other patients in the future. 
 
 
Would it be an inconvenience if we talk? 
 
 
Accepts                
 
 
 
 
Declines_______ 
 
 
   Reason: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Revised 2.4.12 
Adherence to Abiraterone Acetate Questionnaire 
 
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 46 of 57  
 
 
Patient Name  
 
 
 
Date 
 
Section One: Demographic information 
To start off, I would like to ask you a few questions about yourself: 
 
1. What is your age in years? 
 
2. Interviewer: Is the respondent male or female? 
 
3. Which of the following best describes you?  Are you… (interviewer: read responses out 
loud) 
a. Asian or pacific islander 
b. Black or African American 
c. Latino, Hispanic or of Spanish origin or descent 
d. Native American or Alaskan native 
e. White 
f. Some other race, specify 
 
4. What is the last grade or year that you completed in school? (interviewer: read responses 
out loud) 
a. Some high school 
b. High school or graduate school 
c. Some college 
d. College graduate 
e. Some post graduate 
f. Postgraduate or professional degree 
g. Other, specify 
 
5. Which of the following best describes your employment status prior to your illness?  
Were you employed…(interviewer: read responses out loud) 
a. Full-time 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 47 of 57  
 
b. Part-time 
c. Retired 
d. Not employed 
 
6. How much are you working now? 
a. Full-time 
b. Part-time 
c. Not working/retired/on disability 
 
7. Which category best describes your combined family income in the last year (before 
taxes) (interviewer: read responses out loud) 
a. less than $5,000 
b. $5,001-$19,999 
c. $20,000-$39,999 
d. $40,000-$59,999 
e. $60,000-$79,999 
f. greater than $80,000 
g. don’t know 
h. refused 
 
8. How would you rate your current health status?  Would you say that your health 
is…(interviewer: read responses out loud)  
a. Excellent 
b. Very good 
c. Good 
d. Fair 
e. Poor 
 
9. What is your marital status 
a. Married 
b. Divorced/Separated 
c. Widowed 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 48 of 57  
 
d. Single 
 
Section two: Adherence 
I would like to now ask you a few questions about you taking your abiraterone acetate. We would 
be surprised if people took 100% of their medications.   This information is confidential, but if 
you let me know that you have some difficulty with taking your medications, I will ask your 
permission to let your treatment team know so they can better assist you.  If you do not wish me 
to discuss this with your team I will not.  
 
 
10. Do you ever forget to take your abiraterone? 
a. Yes 
b. No 
 
11. Have you skipped several doses in a row of your abiraterone? 
a. Yes 
b. No 
 
12. Have you lowered or raised the prescribed amount of your abiraterone on your own? 
a. Yes 
b. No 
 
13. Do you recall talking your abiraterone more than 2 hours earlier or later than the 
prescribed dosing time?  
a. Yes 
b. No 
 
14. When you feel better do you sometimes stop taking your abiraterone? 
a. Yes 
b. No 
 
15. I run out of my abiraterone because I don’t get refills on time. 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 49 of 57  
 
a. Strongly agree 
b. Agree 
c. Neither agree nor disagree 
d. Disagree 
e. Strongly disagree 
 
16. Have you skipped or stopped abiraterone because you didn’t think it was working? 
a. In the last week 
b. In the last two weeks 
c. In the last month 
d. In the last 3 months 
e. Never 
 
17. Have you skipped or stopped taking abiraterone because it made you feel bad? 
a. In the last week 
b. In the last two weeks 
c. In the last month 
d. In the last 3 months 
e. Never 
 
18. Have you skipped, stopped, not refilled, or taken less abiraterone because of cost? 
a. In the last week 
b. In the last two weeks 
c. In the last month 
d. In the last 3 months 
e. Never 
 
19. How much do you have to pay out-of-pocket for your abiraterone monthly? 
$____________________________ 
 
20. Have you not had abiraterone with you when it was time to take it? 
a. In the last week 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 50 of 57  
 
b. In the last two weeks 
c. In the last month 
d. In the last 3 months 
e. Never 
 
Section three: Beliefs 
I would like to now ask you about your personal views about abiraterone prescribed for you as 
well as your prostate cancer.  These are statements that other people have made about their 
medicines. Please indicate the extent to which you agree or disagree with each one of the 
following statements.  You will be asked if STRONGLY AGREE, AGREE, UNCERTAIN, 
DISAGREE, OR STRONGLY DISAGREE.   There are no right or wrong answers.  We are 
interested in your personal views.  
 
21. My health, at present, depends on my abiraterone. 
a. Strongly agree 
b. Agree 
c. Uncertain 
d. Disagree 
e. Strongly disagree 
 
22. Having to take abiraterone worries me. 
a. Strongly agree 
b. Agree 
c. Uncertain 
d. Disagree 
e. Strongly disagree 
 
23. My life would be impossible without my abiraterone. 
a. Strongly agree 
b. Agree 
c. Uncertain 
d. Disagree 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 51 of 57  
 
e. Strongly disagree 
 
24. Without my abiraterone I would be very ill. 
a. Strongly agree 
b. Agree 
c. Uncertain 
d. Disagree 
e. Strongly disagree 
 
25. I sometimes worry about long-term effects of my abiraterone. 
a. Strongly agree 
b. Agree 
c. Uncertain 
d. Disagree 
e. Strongly disagree 
 
26. My abiraterone is a mystery to me. 
a. Strongly agree 
b. Agree 
c. Uncertain 
d. Disagree 
e. Strongly disagree 
 
27. My health in the future will depend on my abiraterone. 
a. Strongly agree 
b. Agree 
c. Uncertain 
d. Disagree 
e. Strongly disagree 
 
28. My abiraterone disrupts my life. 
a. Strongly agree 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 52 of 57  
 
b. Agree 
c. Uncertain 
d. Disagree 
e. Strongly disagree 
 
29. I sometimes worry about becoming too dependent on my abiraterone. 
a. Strongly agree 
b. Agree 
c. Uncertain 
d. Disagree 
e. Strongly disagree 
 
30. My abiraterone protects me from becoming worse. 
a. Strongly agree 
b. Agree 
c. Uncertain 
d. Disagree 
e. Strongly disagree 
 
31. Do you believe that the abiraterone you are taking is chemotherapy? 
a. Yes 
b. No 
 
32. If you are taking other medicines, do you believe that the abiraterone you are taking is 
more, less or as important as the other medicines you are taking? 
a. More 
b. Less 
c. As important 
d. I do not take other medications 
 
33. Do you believe that your prostate cancer is a chronic disease like diabetes, heart disease 
or high cholesterol is for some people? 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 53 of 57  
 
a. Yes 
b. No 
 
Section four: Communication and Barriers 
Now, I would like to ask you a few more final questions about communication. 
 
34. Have you received counseling about how and when to take your abiraterone? 
a. Yes 
b. No 
 
35. If you received counseling, whom did you speak with? 
a. Physician 
b. Nurse 
c. Pharmacist 
d. Someone else 
 
36. I have someone I can call with questions about my abiraterone 
a. Strongly agree 
b. Agree 
c. Neither agree nor disagree 
d. Disagree 
e. Strongly disagree 
 
37. How satisfied are you with the communication you have had with your team about issues 
surrounding taking your abiraterone? 
a. Strongly satisfied 
b. Satisfied 
c. Neither satisfied or dissatisfied 
d. Dissatisfied 
e. Strongly Dissatisfied 
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 54 of 57  
 
38. We would be surprised if people took 100% of their medications.  Below 0% means you 
have taken no abiraterone this past month, 50% means you have taken half of your 
abiraterone this past month and 100% means you have taken every single dose this past 
month.  What percent of your abiraterone did you take? 
 
 
 
 
    
0% 
10 
20 
30 
40 
50% 
60 
70 
80 
90 
100% 
 
Is there anything else that you would like to share with me about taking your abiraterone? If not, 
I would like to thank you again for your time and information shared with me during this 
interview.  Your feedback has been extremely important in trying to improve the care of future 
cancer patients.   
 
 
 
 
 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 55 of 57  
 
REFERENCES: 
 
1. 
Ward JF, Moul JW. Rising prostate-specific antigen after primary prostate cancer 
therapy. Nat Clin Pract Urol. Apr 2005;2(4):174-182. 
2. 
Scher H, Heller G. Clinical states in prostate cancer: toward a dynamic model of disease 
progression. Urology. 2000;55(3):323-327. 
3. 
Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. Sep-Oct 
2010;60(5):277-300. 
4. 
Tannock I, de Wit R, Berry W, et al. Docetaxel plus prednisone or mitoxantrone plus 
prednisone for advanced prostate cancer. New England Journal of Medicine. 
2004;351(15):1502. 
5. 
Petrylak D, Tangen C, Hussain M, et al. Docetaxel and estramustine compared with 
mitoxantrone and prednisone for advanced refractory prostate cancer. New England 
Journal of Medicine. 2004;351(15):1513. 
6. 
Epstein J. 2010 Annual Oncology Meeting–Genitourinary Malignancies. 
7. 
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-
resistant prostate cancer. N Engl J Med. Jul 29 2010;363(5):411-422. 
8. 
de Bono JS, Logothetis CJ, Molina A, et al. Abiraterone and increased survival in 
metastatic prostate cancer. N Engl J Med. May 26 2011;364(21):1995-2005. 
9. 
Hellerstedt BA, Pienta KJ. The current state of hormonal therapy for prostate cancer. CA 
Cancer J Clin. May-Jun 2002;52(3):154-179. 
10. 
Chen CD, Welsbie DS, Tran C, et al. Molecular determinants of resistance to 
antiandrogen therapy. Nat Med. Jan 2004;10(1):33-39. 
11. 
Reid AH, Attard G, Barrie E, de Bono JS. CYP17 inhibition as a hormonal strategy for 
prostate cancer. Nat Clin Pract Urol. Nov 2008;5(11):610-620. 
12. 
Steinkamp MP, O'Mahony OA, Brogley M, et al. Treatment-dependent androgen 
receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. 
Cancer Res. May 15 2009;69(10):4434-4442. 
13. 
Attard G, Reid AH, Yap TA, et al. Phase I clinical trial of a selective inhibitor of CYP17, 
abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains 
hormone driven. J Clin Oncol. Oct 1 2008;26(28):4563-4571. 
14. 
Ryan CJ, Shah SK, Efstathiou E, et al. Phase II Study of Abiraterone Acetate in 
Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer Displaying Bone 
Flare Discordant With Serologic Response. Clin Cancer Res. Jun 1 2011. 
15. 
Danila DC, Morris MJ, de Bono JS, et al. Phase II multicenter study of abiraterone 
acetate plus prednisone therapy in patients with docetaxel-treated castration-resistant 
prostate cancer. J Clin Oncol. Mar 20 2010;28(9):1496-1501. 
16. 
Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without 
previous chemotherapy. N Engl J Med. Jan 10 2013;368(2):138-148. 
17. 
Biotech CO. ZYTIGA label. 
18. 
Singh BN, Malhotra BK. Effects of food on the clinical pharmacokinetics of anticancer 
agents: underlying mechanisms and implications for oral chemotherapy. Clin 
Pharmacokinet. 2004;43(15):1127-1156. 
19. 
FDA. Food-effect bioavailability and fed  bioequivalence studies2002. 
20. 
Koch KM, Reddy NJ, Cohen RB, et al. Effects of food on the relative bioavailability of 
lapatinib in cancer patients. J Clin Oncol. Mar 10 2009;27(8):1191-1196. 
21. 
GlaxoSmithKline. TYKERB label.  http://us.gsk.com/products/assets/us_tykerb.pdf. 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 56 of 57  
 
22. 
Ratain MJ, Cohen EE. The value meal: how to save $1,700 per month or more on 
lapatinib. J Clin Oncol. Aug 10 2007;25(23):3397-3398. 
23. 
Ryan CJ, Smith MR, Fong L, et al. Phase I clinical trial of the CYP17 inhibitor 
abiraterone acetate demonstrating clinical activity in patients with castration-resistant 
prostate cancer who received prior ketoconazole therapy. J Clin Oncol. Mar 20 
2010;28(9):1481-1488. 
24. 
Gebbia V, Bellavia G, Ferrau F, Valerio MR. Adherence, compliance and persistence to 
oral antineoplastic therapy: a review focused on chemotherapeutic and biologic agents. 
Expert Opin Drug Saf. Dec 13 2011. 
25. 
Ruddy K, Mayer E, Partridge A. Patient adherence and persistence with oral anticancer 
treatment. CA Cancer J Clin. Jan-Feb 2009;59(1):56-66. 
26. 
Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology 
and definitions. Value Health. Jan-Feb 2008;11(1):44-47. 
27. 
Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. Aug 4 
2005;353(5):487-497. 
28. 
Hershman DL, Kushi LH, Shao T, et al. Early discontinuation and nonadherence to 
adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin 
Oncol. Sep 20 2010;28(27):4120-4128. 
29. 
Hershman DL, Shao T, Kushi LH, et al. Early discontinuation and non-adherence to 
adjuvant hormonal therapy are associated with increased mortality in women with breast 
cancer. Breast Cancer Res Treat. Apr 2011;126(2):529-537. 
30. 
Ganesan P, Sagar TG, Dubashi B, et al. Nonadherence to imatinib adversely affects event 
free survival in chronic phase chronic myeloid leukemia. Am J Hematol. Jun 
2011;86(6):471-474. 
31. 
Noens L, van Lierde MA, De Bock R, et al. Prevalence, determinants, and outcomes of 
nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the 
ADAGIO study. Blood. May 28 2009;113(22):5401-5411. 
32. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients 
with progressive prostate cancer and castrate levels of testosterone: recommendations of 
the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. Mar 1 
2008;26(7):1148-1159. 
33. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. Jan 2009;45(2):228-247. 
34. 
Sobel RE, Sadar MD. Cell lines used in prostate cancer research: a compendium of old 
and new lines--part 2. J Urol. Feb 2005;173(2):360-372. 
35. 
Martins V, Asad Y, Wilsher N, Raynaud F. A validated liquid chromatographic-tandem 
mass spectroscopy method for the quantification of abiraterone acetate and abiraterone in 
human plasma. J Chromatogr B Analyt Technol Biomed Life Sci. Nov 7 2006;843(2):262-
267. 
36. 
Wright JR, Ung YC, Julian JA, et al. Randomized, double-blind, placebo-controlled trial 
of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol. 
Mar 20 2007;25(9):1027-1032. 
37. 
Schwartz LH, Bogaerts J, Ford R, et al. Evaluation of lymph nodes with RECIST 1.1. 
Eur J Cancer. Jan 2009;45(2):261-267. 
38. 
Scher HI, Halabi S, Tannock I, et al. Design and End Points of Clinical Trials for Patients 
With Progressive Prostate Cancer and Castrate Levels of Testosterone: 
Recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 


 
 
University of Chicago  
Comprehensive Cancer Center 
 
Page 57 of 57  
 
March 1, 2008 2008;26(7):1148-1159.