Clinical trial NCT02012296
Conditions: Hormone-resistant Prostate Cancer Recurrent Prostate Cancer Stage IV Prostate Cancer
Sponsor: University of Chicago
Start date: 2013-12-13; Completion date: 2020-08-01
Enrollment: 88 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This partially randomized phase I/II trial studies the side effects and best dose of enzalutamide and mifepristone when given together and to see how well they work in treating patients with metastatic hormone resistant prostate cancer. Androgens can cause the growth of prostate cancer cells. Antihormone therapy, such as enzalutamide and mifepristone, may lessen the amount of androgens made by the body. It is not yet known whether enzalutamide is more effective with or without mifepristone in treating patients with prostate cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To establish the safe and pharmacologically active doses of mifepristone and enzalutamide to use in combination. (Phase I) II. To determine if mifepristone in combination with enzalutamide prolongs time to prostate-specific antigen (PSA) progression compared to enzalutamide alone in patients with metastatic castration resistant prostate cancer. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the effect of mifepristone on endocrine biomarkers such as serum cortisol and thyrotropin.

II. To determine the effect of mifepristone on enzalutamide clearance and steady state enzalutamide exposure.

III. To determine if mifepristone affects PSA response rate when added to enzalutamide.

IV. To determine if mifepristone when added to mifepristone prolongs radiographic and clinical progression free survival according to standard working group criteria.

V. To explore the role of glucocorticoid receptor (GR) and androgen receptor (AR) protein expression within circulating tumor cells as a pharmacodynamic biomarker for mifepristone and enzalutamide in castration resistant prostate cancer (CRPC).

VI. To explore the expression of GR and down-stream AR/GR targets in metastatic tumor specimen prior to combination drug administration and at clinical progression.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

PHASE I: Patients receive enzalutamide orally (PO) on days 1-57 and mifepristone PO on days 29-57. Treatment continues in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive enzalutamide PO for 12 weeks per standard of care. Patients are then randomized to 1 of 2 treatment arms.

ARM I: Patients receive enzalutamide PO per standard of care.

ARM II: Patients receive enzalutamide PO and mifepristone PO.

In both arms, treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 1 year.

Arms: arm 1: Patients receive enzalutamide PO per standard of care. arm 2: Patients receive enzalutamide PO and mifepristone PO.
Interventions: intervention 1: enzalutamide intervention 2: mifepristone intervention 3: laboratory biomarker analysis intervention 4: pharmacological study
Intervention descriptions: intervention 1: Given PO intervention 2: Given PO intervention 3: Correlative studies intervention 4: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
 
IRB #:13-0979 
 
Version Date:  07/10/2014  
TITLE: A phase I/II trial of enzalutamide plus the glucocorticoid receptor antagonist 
mifepristone for patients with metastatic castration resistant prostate cancer (CRPC)  
 
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: 
Walter M. Stadler, MD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
 
Peter O’Donnell, MD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
 
David VanderWeele, MD, PhD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
 
Chadi Nabhan, MD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
 
Mark Ratain, MD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
 
Manish Sharma, MD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 


 
 
 
ii
 
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 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
773-702-4135 
 
emartinez1@medicine.bsd.uchicago.edu 
 
Study Coordinator: 
 
Jeff Bozeman 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
773-834-3095 
 
773-702-4889 
 
jbozema1@medicine.bsd.uchicago.edu 
 
 
Data Manager : 
 
Natali Rutiaga 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
773-702-4653 
 
773-702-4889 
Pharmacokinetic Laboratory Coordinator : 
Daniel Bennett 
inventive Health Clinical Lab, Inc. 
301 D. College Road East 
Princeton, NJ 08540 
609-951-0005 
daniel.bennett@inventivhealth.com 
Pathologist for correlative studies: 


 
 
 
iii
 
Gladell Paner 
 
University of Chicago 
 
Department of Pathology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL  60637 
 
 
Independent Research Monitor: 
 
Sumati Murli, PhD 
 
University of Chicago 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL  60637 
 
 
Version # / Version Date: 
Version 07/10/2014 
 
 


 
 
 
iv
SUMMARY 
 
Study design:  This is a phase I/II, open label study of enzalutamide in combination with the 
glucocorticoid receptor (GR) antagonist mifepristone for patients with castration resistant 
prostate cancer (CRPC).  The phase I portion will assess the safety of the two-drug combination 
along with pharmacokinetic (PK) impact of mifepristone on enzalutamide exposure.  Dose 
escalations and de-escalations will be made based on PK and safety to arrive at the randomized 
phase II dose (RP2D).  For the phase II portion, patients who are already on standard of care 
enzalutamide will be randomized to stay on enzalutamide alone or to change to enzalutamide 
plus mifepristone at the RP2D. 
 
Primary objective:  Phase I- To establish the safe and pharmacologically active doses of 
mifepristone and enzalutamide to use in combination. Phase II- to determine if mifepristone 
when added to enzalutamide delays time to PSA progression compared to enzalutamide alone. 
 
Secondary objectives:  (1) To evaluate the effect of mifepristone on endocrine biomarkers such 
as serum cortisol, thyrotropin. (2) To determine the effect of mifepristone on enzalutamide 
clearance and steady state enzalutamide exposure. (3) To determine if mifepristone affects PSA 
response rate when added to enzalutamide. (4) To determine if mifepristone extends time to 
radiographic and clinical progression, according to standard criteria, compared to enzalutamide 
alone. (5) To explore the role of circulating tumor cells, as a pharmacodynamic biomarker for 
mifepristone and enzalutamide in CRPC. (6) To evaluate the baseline and post progression AR 
and GR status within metastatic tumor biopsies. 
 
Key eligibility criteria:  Patients must have histologically confirmed prostate cancer with 
evidence of castration resistance defined as rising PSA or clinical/radiographic progression 
following androgen deprivation. For the phase II portion, patients must be currently on standard 
of care enzalutamide within the first 12 weeks for treatment of CRPC.  Patients must have an 
ECOG performance status of 0-2 and have adequate bone marrow, liver and renal function. 
 
Sample size: For the phase I portion of the study, there are several dose adjustment rules that 
make determination of sample size not possible, however, based on the design, it is estimated 
that 24 patients will enroll in the phase I study.  The phase II portion of the study will randomize 
42 patients/arm for a total of 84 patients in the phase II.  Thus the total estimated accrual for the 
study is 108 patients. 
 
Therapies and route of administration:  Mifepristone and enzalutamide will both be 
administered daily via oral route. 
 
Key study procedures:   
 Imaging examinations including CT scan and bone scans 
 Pharmacokinetic studies on peripheral blood 
 Endocrine biomarker studies from peripheral blood 
 Circulating tumor cell isolation and analysis from peripheral blood 
 Optional tumor biopsy specimen 


 
 
 
v
TABLE OF CONTENTS 
Page 
 
1.0 
BACKGROUND .......................................................................................................................... 87 
1.1 
Castrate Resistant Prostate Cancer (CRPC) ......................................................................... 87 
1.2 
Mechanisms of Castrate Resistant Prostate Cancer Growth ................................................ 87 
1.3 
Enzalutamide: a potent second generation AR antagonist ................................................... 87 
1.4 
Clinical Data with Enzalutamide in Prostate Cancer ........................................................... 98 
1.5 
Enzalutamide Pharmacokinetics .......................................................................................... 98 
1.6 
Glucocorticoid Receptor (GR) Signaling in Prostate Cancer ............................................. 109 
1.7 
Study Rationale: Combined AR/GR blockade in CRPC ................................................. 1110 
1.8 
Mifepristone ..................................................................................................................... 1110 
1.8.1 
Mifepristone clinical pharmacology .....................................................................1211 
1.8.2 
Mifepristone in CRPC .........................................................................................1211 
1.9 
Rationale for and Description of Study Design ............................................................... 1312 
1.10 
Circulating Tumor Cell Evaluation in CRPC ................................................................... 1413 
 
2.0 
OBJECTIVES .......................................................................................................................... 1514 
2.1 
Primary Objective ............................................................................................................ 1514 
2.2 
Secondary Objectives ....................................................................................................... 1514 
 
3.0 
PATIENT SELECTION ......................................................................................................... 1514 
3.1 
Eligibility Criteria ............................................................................................................ 1514 
3.2 
Exclusion Criteria ............................................................................................................ 1615 
3.3 
Inclusion of Minorities ..................................................................................................... 1716 
 
4.0 
REGISTRATION AND DATA COLLECTION/MANAGEMENT ................................... 1716 
4.1 
Registration Process ......................................................................................................... 1716 
4.2 
Treatment Allocation and Randomization Processes ....................................................... 1918 
 
5.0 
STUDY DRUG ADMINISTRATION .................................................................................... 1918 
5.1 
Study Drug administration for each portion is as follows. ............................................... 2019 
      5.1.1        Phase I Study Drug Administration ..........................................................................2019 
5.2 
Dose Limiting Toxicity Definition ................................................................................... 2221 
5.3 
Phase II Study Drug Administration (Figure 4) ............................................................... 2322 
 
6.0 
DURATION OF TREATMENT ............................................................................................ 2322 
 
7.0 
STUDY ASSESSMENTS ........................................................................................................ 2322 
7.1 
Pre-treatment Screening Evaluation ................................................................................. 2322 
7.2 
On Study Visits ................................................................................................................ 2423 
7.2.1 
Pharmacokinetics sampling: .................................................................................2423 
7.3 
Off Study Assessments .................................................................................................... 2625 
 
8.0 
STUDY CALENDAR .............................................................................................................. 2726 
 
9.0 
TREATMENT PLAN .............................................................................................................. 2928 
9.1 
Agent Administration ....................................................................................................... 2928 
9.2 
Management of Castration Related Symptoms: ............................................................... 2928 


 
 
 
vi
9.3 
Dose-ReductionProcedureforAdverseEvent Management .............................................. 2928 
9.4 
Treatment Management of Hypertension ......................................................................... 3130 
9.5 
Treatment-Emergent Edema and Fluid Retention ............................................................ 3231 
9.6 
Management of Hypokalemia .......................................................................................... 3332 
9.7 
ManagementofElevatedLiverFunctionTests .................................................................... 3332 
9.8 
ManagementofAdrenal Insufficiency .............................................................................. 3433 
9.9 
Management of Rash........................................................................................................ 3433 
9.10 
Chemotherapy and Radiotherapy ..................................................................................... 3534 
9.11 
Other Medications ............................................................................................................ 3534 
9.12 
Potential Drug Interactions .............................................................................................. 3534 
 
10.0 
SAFETY .................................................................................................................................... 3635 
10.1 
Adverse Events ................................................................................................................ 3635 
10.2 
Serious Adverse Events.................................................................................................... 3736 
10.3 
Suspected Adverse Reactions .......................................................................................... 3736 
10.4 
Unexpected Events ........................................................................................................... 3837 
10.5 
Serious Adverse Event Reporting .................................................................................... 3837 
10.6 
Adverse Event Reporting Process .................................................................................... 3938 
10.7 
Adverse Event reporting by the Coordinating Center ...................................................... 4039 
10.8 
Other Safety Considerations ............................................................................................ 4039 
10.8.1 
Laboratory Data ..................................................................................................4039 
10.8.2 
Medication Errors ...............................................................................................4039 
10.8.3 
Follow-Up of Adverse Events ..............................................................................4039 
10.8.4 
Safety Monitoring ...............................................................................................4040 
 
10.8.5     Independent Research Monitor ................................................................................... 41 
11.0 
MEASUREMENT OF EFFECT ............................................................................................ 4142 
 
11.1 
Outcome Measures based on PSA Decline ...................................................................... 4242 
11.2 
Radiographic Tumor Response ........................................................................................ 4242 
11.3 
Duration of Response ....................................................................................................... 4243 
11.4 
Progression-Free Survival ................................................................................................ 4343 
 
12.0 
CORRETALIVE STUDIES .................................................................................................... 4343 
12.1 
Circulating Tumor Cells (CTC) ....................................................................................... 4343 
12.2 
Optional Tumor Biopsies ................................................................................................. 4444 
 
13.0 
STATISTICAL CONSIDERATIONS ................................................................................... 4444 
13.1 
Sample Size/Primary Endpoint ........................................................................................ 4444 
13.2 
Randomization ................................................................................................................. 4545 
13.3 
Analysis of Secondary Endpoints .................................................................................... 4545 
 
APPENDIX A ........................................................................................................................................ 4747 
PERFORMANCE STATUS CRITERIA ......................................................................................... 4747 
 
APPENDIX B ........................................................................................................................................ 4848 
SAMPLE DATA CAPTURE FORMS ............................................................................................ 4848 
 
Appendix C ................................................................................................................................................ 51 
PROSTATE-SPECIFIC ANTIGEN WORKING GROUP CRITERIA49 ............................................ 51 


 
 
 
vii
 
Appendix D ............................................................................................................................................ 5252 
RESPONSE EVALUATION CRITERIA in SOLID TUMORS (RECIST) 45,46 ............................. 5252 
 
Appendix E ............................................................................................................................................ 5656 
PHARMACOKINETIC SAMPLE COLLECTION SCHEME ....................................................... 5656 
 
REFERENCES: .................................................................................................................................... 5757 
 
 
 
 


 
IRB #:13-0979 
 
Version Date:  07/10/2014  
 
 
1.0 
BACKGROUND 
 
1.1 
Castrate Resistant Prostate Cancer (CRPC) 
Although most men are diagnosed with early stage, curable prostate cancer, unfortunately, 
prostate cancer (CaP) 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 
immunotherapy sipuleucel-T, and newer, more potent hormonal therapies abiraterone acetate 
and enzalutamide as the only currently FDA approved therapies shown to improve patient 
survival in the CRPC setting 4,5, 6-9.  
 
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 luteinizing hormone releasing hormone (LHRH) 
agonists.  The mechanism of action is by causing the continuous stimulation of the anterior 
pituitary leading to the inhibition of luteinizing hormone (LH) secretion and ultimately the 
disruption of testicular production of testosterone.  Although ADT has been effective in the 
majority of patients, studies have shown that extra-testicular 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 men10.  
In prostate cancer xenograft models, increased levels of androgen receptor (AR) have been 
observed and appear to be resistant to older antiandrogens such as bicalutamide11. This could 
result in amplified signal output from low levels of circulating adrenal androgens, thus 
suggesting a role for agents that more potently block the AR12.  
 
1.3 
Enzalutamide: a potent second generation AR antagonist 
With the change in fundamental understanding of castration resistant prostate cancer-that AR 
signaling remains a key component of CRPC progression, investigators set out to rationally 
design chemical therapeutics that would potently and specifically bind to and block the AR 
from signaling in CRPC.  Older antiandrogens, such as bicalutamide, have mixed 
agonist/antagonist properties, bind the AR poorly and do not block AR nuclear translocation, 
leaving multiple facets by which these medications can fail to block AR12,13.  Based on the 
crystal structure of the AR, MDV3100 (enzalutamide) was designed to potently bind the AR 
and prevent activation and nuclear localization [Figure 1]13,14.  Early preclinical evaluation 
of enzalutamide showed strong binding of the AR, along with inhibition of nuclear 
localization of the AR upon enzalutamide binding, decreased AR signaling, and preclinical 
CRPC activity14.  This led to rapid clinical development of the compound. 
 


 
 
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1.4 
Clinical Data with Enzalutamide in Prostate Cancer 
Based on the strong preclinical data, enzalutamide quickly moved into a multicenter phase 
I/II trial.  This phase I/II study showed enzalutamide to be well tolerated and to result in AR 
pathway inhibition, as demonstrated by decrease in prostate specific antigen (PSA) levels in 
the majority of patients, independent of prior therapy for metastatic CRPC15.  This trial 
established the maximum tolerated dose of 240mg/day orally.  Most recently, a randomized 
phase III trial of enzalutamide at 160mg/day confirmed its utility in this disease as it 
substantially improved overall survival in patients with progressive CRPC compared to 
placebo9.  Approximately 1200 patients with progressive CRPC were randomized 2:1 to 
enzalutamide versus placebo.  There was significant improvement in patient outcomes with 
enzalutamide.  The hazard ratio for death versus placebo was 0.63 (nearly 40% improvement 
in risk of death).  It also improved progression free survival, time to skeletal event (e.g. bone 
fracture or radiation) and quality of life.  There were few major adverse events, although 
there was more low-grade fatigue, diarrhea an hot flashes compared to placebo and rare 
seizures (0.6% incidence) were identified9.  Based on these results, enzalutamide was FDA 
approved and is now a standard of care for progressive CRPC.  Although clearly and 
improvement upon placebo in CRPC, the median progression free survival remains low at 
8.3 months and overall survival is still limited to less than 1.5 years despite enzalutamide. 
 
1.5 
EnzalutamidePharmacokinetics 
Although enzalutamide is generally well tolerated, the highly potent AR antagonists, 
including enzalutamide are associated with increased risks of seizures, particularly at higher 
plasma concentrations of the drug and may be less effective at lower blood levels15,16. Given 
the concerns of both over- and under-dosing enzalutamide, careful attention to its 
pharmacokinetics (PK)is paramount in designing combination therapy clinical trials with the 
agent. In PK investigations in men with CRPC, enzalutamide was absorbed rapidly after oral 
administration, with the time to maximum plasma concentration (tmax) after a single dose 
typically occurring at 1 hour post-dose.  No major deviations from dose proportionality were 
observed over the dose range 30 mg to 600 mg.  Due to the long terminal half-life 
(approximately 5.8 days), it took approximately 1 month to reach steady state.  With daily 
oral administration, enzalutamide accumulation was observed at steady state with an 8.3-fold 
Figure 1. Molecular structure of MDV3100 and other AR antagonists  


 
 
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Page 10 of 59 
higher exposure (steady state area under the curve, AUC) relative to a single dose.  Based on 
the mean peak to trough ratio, the average difference between the peak (maximum plasma 
concentration, Cmax) and trough (pre-dose plasma concentration, Ctrough) concentrations was 
≤ 25%.  As a result of the low daily fluctuations, plasma profiles at steady state resembled a 
constant infusion.  The Ctrough values in individual patients remained constant beyond day 28 
of chronic therapy, suggesting time linear PK once steady state was achieved.  At steady 
state, plasma concentrations of enzalutamide and the active metabolite, N-desmethyl 
enzalutamide (M2), were approximately the same. Given the limited variability in plasma 
concentration once at steady state, and the linear PK at steady state the Ctrough for the parent 
compound and active metabolite is the appropriate PK parameter to follow with respect to 
potential drug-drug interaction. 
 
In a mass balance and biotransformation study, healthy men received a single oral dose of 
14C enzalutamide 160 mg.  By 77 days post-dose, 85% of the radioactivity was recovered 
including 71% in urine (with only trace amounts of enzalutamide and N-desmethyl 
enzalutamide) and 14% in feces (0.4% of dose as unchanged enzalutamide and 1% as 
N-desmethyl enzalutamide).  In vitro, human CYP2C8 and CYP3A4 are responsible for the 
metabolism of enzalutamide.  Based on in vivo and in vitro data, CYP2C8 is primarily 
responsible for the formation of the active metabolite (N-desmethyl enzalutamide, M2). 
 
In a drug-drug interaction study in healthy male volunteers, a single 160 mg oral dose of 
enzalutamide was administered alone or after multiple oral doses of gemfibrozil (strong 
CYP2C8 inhibitor).  Gemfibrozil increased the composite AUC from time zero to infinity 
(AUC∞) of enzalutamide plus M2 by 2.2-fold with minimal effect on Cmax; therefore, the US 
product label indicates that strong CYP2C8 inhibitors should be avoided if possible as they 
can increase plasma exposure to enzalutamide plus N-desmethyl enzalutamide.  If 
coadministration with a strong CYP2C8 inhibitor is necessary, the dose of enzalutamide 
should be reduced to 80 mg once daily.  If coadministration of the strong CYP2C8 inhibitor 
is discontinued, the enzalutamide dose should be returned to the dose used prior to initiation 
of the strong CYP2C8 inhibitor.  In asecond drug-drug interaction assessment, a single 160 
mg oral dose of enzalutamide was administered alone or after multiple oral doses of 
itraconazole (strong CYP3A4 inhibitor).  Itraconazole increased the composite AUC∞ of 
enzalutamide plus M2 by 1.3-fold with no effect on Cmax
17,18.   For combination drug trials of 
other medications in combination with enzalutamide, consideration of changes in drug 
exposure due to CYP3A4 or CYP2C8 interference is critical. 
 
1.6 
Glucocorticoid Receptor (GR) Signaling in Prostate Cancer 
There have been multiple mechanisms involving AR biology that have been proposed to 
explain progression of CRPC which include AR splice variants, AR mutations that do not 
require ligand or are sensitive to non-androgen ligands, and ligand-independent AR 
activation19-23.  In addition, alternative signaling pathways inversely linked to AR signaling 
may also contribute to CRPC progression in the setting of potent AR inhibition24.  
Classically, single agent corticosteroids (ligand for the glucocorticoid receptor) have been 
shown to have modest activity in CRPC25,26.  However, these studies were conducted in the 
setting of intact AR signaling.  The central hypothesis underlying this clinical trial is that the 
glucocorticoid receptor (GR) can compensate for AR signaling to enable CaP cell survival in 
the context of potent AR pathway blockade.  Several lines of evidence support our central 
hypothesis.For example, GR and AR are in the same nuclear hormone receptor family and in 


 
 
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fact share target DNA sequence binding homology27,28.  Additionally, the AR has been 
shown to bind DNA elements associated putative GR regulated genes, including pro-cell 
survival genes such as serum-glucocorticoid regulated kinase 1 (SKG1)27,29,30.  However, 
their functional overlap physiologically is less clear. In fact, despite homology in structure 
and target DNA sequence, the GR and AR often have adversarial effects in normal 
physiology (e.g. in skeletal muscle with AR activation being anabolic, while GR activation 
is catabolic), and they may negatively regulate each other27.  The role of the glucocorticoid 
receptor in prostate cancer is equally complex.  Although in primary prostate cancer 
specimens, the expression of the GR is relatively low, a recent examinations of prostate 
cancer samples from patients, published by the principal investigator (PI) and others, 
demonstrated that in the setting of hormonal therapy targeting androgen signaling, 
expression of the GR increases significantly31-33.   This suggests that the GR expression 
increases to compensate for diminished AR activity in prostate cancer treated with hormonal 
therapies. 
 
Preclinical evidence also supports a role for the GR in CRPC progression.  In commonly 
utilized prostate cancer cells for preclinical exploration, the expression at baseline is variable 
and its function within these lines is unclear as the data are limited. Recently, preclinical in 
vitro and in vivo data has been presented that demonstrates that in the context of AR 
antagonism with enzalutamide, or after surgical castration of an immunocompromised 
mouse harboring a human prostate cancer xenograft, GR expression and/or nuclear 
localization, indicating activation, increases.  Furthermore, GR activation with 
dexamethasone, a synthetic glucocorticoid receptor agonist, can rescue AR transcription 
activity of multiple pro-survival target gene, such as SGK1, in the setting of enzalutamide34. 
 
1.7 
Study Rationale: Combined AR/GR blockade in CRPC 
Further clarifying a potential compensatory role of GR signaling in CRPC in the context of 
AR inhibition, preclinical work, in vitro and in vivo, supports that GR expression and 
activation blunt the therapeutic efficacy of AR targeted therapy leading to CRPC progression 
[Szmulewitz lab, under review Molecular Endocrinology].  In multiple AR expressing CaP 
cell lines, GR activation confers relative protection from enzalutamide associated cell death. 
Mifepristone, a potent GR antagonist [see sections 1.8-1.9], was able to mitigate these 
effects, and potentiated the effects of MDV3100 on CaP cell survival34.  Furthermore, CRPC 
progression in vivo was delayed when GR was modulated in combination with androgen 
targeted therapy.  In CRPC xenografts engineered to have diminished GR expression, or 
treated with mifepristone,CRPC progression was impaired compared to control [Szmulewitz 
lab, under review Molecular Endocrinology].  Finally, within the phase III AFFIRM 
enzalutamide study, it has now been reported that patients who were taking GR agonist 
corticosteroids within the enzalutamide arm of the study had poorer survival and diminished 
benefit of enzalutamide than those not taking glucocorticoids35. In sum, these data provide a 
strong rationale for combining enzalutamide AR antagonism with a GR antagonist in CRPC. 
 
1.8 
Mifepristone 
Mifepristone is a synthetically synthesized hormone receptor modulator derived from the 
naturally occurring material estrone. Mifepristone is a progesterone and glucocorticoid 
receptor (GR) antagonist currently FDA approved for emergency contraception and 
Cushing’s disease.  It is also know to be a potent inhibitor of the GR36.  While a single dose 
of mifepristone 200 mg combined with misoprostol is needed to terminate pregnancy, 


 
 
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potentially higher doses are required for potent anti-GR effects37.  Mifepristone is now FDA 
approved for the indication of Cushing’s disease at daily doses ranging 300mg-1200mg 
(Korlym, Corcept).  It is also being studied in patients without Cushing’s disease for 
indications including hypercholesterolemia, weight gain, Alzheimer’s and psychosis, and has 
been well tolerated at multiple different doses including ranging from 200-600mg daily38-40.  
With daily dosing, the most common side effects considered related to study drug include 
headache, dizziness, nausea/vomiting, constipation, fatigue, abdominal cramping, rash, and 
depression.  In the study of Alzheimer’s patients who were treated for 16-weeks with 
300mg/day there were 4 severe adverse events (SAE’s) in the 41 patients on the mifepristone 
arm 2 of which were considered potentially related to the study drug (rash/nausea/decreased 
appetite, seizure).  Hypokalemia, likely due to mineralocorticoid excess, was observed more 
frequently in the mifepristone arm of the study then placebo, however there were no high 
grade hypokalemia events and no clinically serious consequences noted40.  The other adverse 
event related to mechanism of action (GR antagonism) is adrenal insufficiency.  As of 2013 
investigator brochure, with over 1400 subjects enrolled, only 7 cases of adrenal insufficiency 
have been documented, all in the studies for Cushing’s disease.  They were mild and treated 
with supplemental corticosteroids.  Although a macular-papular rash with mifepristone is 
common, it is also typically mild and treated with topical agents, and does not typically recur 
or escalate with retreatment.  Severe rash syndromes and/or adrenal crisis have not been 
observed40. 
 
1.8.1 
Mifepristone clinical pharmacology 
Mifepristone has an approximate 40% bioavailability when taken orally at 100mg and ~70% 
when taken at lower doses.  The Tmax is 1-2 hours.  It is highly protein bound.  Cytochrome 
P450 3A4 (CYP3A4) is the major enzyme involved in the metabolism of mifepristone 
leading to ~90% of elimination through the biliary system into the feces (10% eliminated in 
the urine).  It is metabolized into six metabolites with an approximate half-life of the parent 
compound ranging 24-50 hours.  In volunteer multiple dose studies, approximately 2 weeks 
is required for elimination of 90% of maximum concentration.  Multiple-dose administration 
results in a plateau of trough concentrations in mifepristone at between 5 and 7 days.  No 
dose adjustments are needed for mild-moderate hepatic impairment or renal impairment.  
The fed state increases plasma concentrations of mifepristone (however there is not a large 
effect of high fat diets) and mifepristone is to be taken with meals.  Mifepristone is an 
inhibitor of CYP2A6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4, however it also induces 
CYP3A4 enzyme expression. 
 
1.8.2 
Mifepristone in CRPC 
Mifepristone as a single agent has been tested in CRPC, with the hypothesis that it would act 
as an AR inhibitor (given structural similarities between the AR and GR and potential effects 
of co-regulatory molecules).  In this small single agent study, although mifepristone was 
well tolerated with no significant adverse events at 200mg/day, there were no reported 
responses as measured by decrease in PSA.  However, it was noted that mifepristone led to a 
significant increase in detectable androgen levels41.  This may explain the potential 
occasional palliative benefits seen in CRPC treated with glucocorticoids.  In addition to anti-
inflammatory effects on bone pain, exogenous glucocorticoids likely decrease androgen 
levels42.  Blockade of AR signaling with a potent AR antagonist such as enzalutamide will 
obviate any effect on systemic androgen levels.   
 


 
 
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1.9 
Rationale for and Description of Study Design 
We hypothesize that activated GR compensates for diminished AR signaling in CRPC 
treated with the potent AR inhibitor enzalutamide, thereby facilitating cancer cell survival 
and clinical castrate resistant progression. The safe co-administration of the GR antagonist 
mifepristone with enzalutamide is expected to block this pathway and improve patient 
outcomes.  To adequately test the hypothesis will require several steps-1) Define the effect 
of mifepristone on enzalutamide exposure.2) Ensure that enzalutamide and mifepristone can 
be given together, daily in patients with CRPC, at pharmacologically active doses. 3) 
Evaluate if mifepristone, when added to enzalutamide, prolongs its efficacy in CRPC. 
 
As will be detailed below, the clinical trial centers on a two-part study schematic [Schema-
Figure 2].  Mifepristone, being an inhibitor of CYP2C8 and CYP3A4, the two primary 
enzymes responsible for enzalutamide metabolism may have the potential to increase plasma 
exposure to enzalutamide active moieties.  Furthermore, although the two drugs are very 
well tolerated alone, with little overlapping toxicity profiles, the combination of 
enzalutamide and mifepristone may have unanticipated toxicity. Thus the clinical trial will 
begin with a phase I study to define the effect of mifepristone on enzalutamide metabolism 
and determine safety of the combination.  For the phase I study, subjects will be treated with 
enzalutamide at standard dose of 160mg/day orally for 28days to achieve steady state. After 
which, combination dosing with mifepristone will begin.  The lead in of enzalutamide alone 
will allow the drug to achieve steady state plasma concentrations.  Plasma levels of 
enzalutamide and M2 metabolite will be measured at this time point to determine a subject’s 
baseline steady-state Ctrough.   As mifepristone inhibits both CYP2C8 and CYP3A4, after the 
single agent lead in, study subjects will enter the combination portion of the study, starting at 
300mg/day mifepristone along with 40mg/day (1/4 dose) enzalutamide as in Figure 2.  40mg 
of mifepristone (1/4 standard 160mg/day dose) was chosen as a conservative estimate of the 
dose that will provide safe and pharmacologically active exposure to the enzalutamide active 
moieties without risking unsafe high plasma concentrations.  The dose of enzalutamide to be 
used in the phase I/II trial will be informed by the results of the phase PK studies imbedded 
in this trial, and may need to be modified to achieve appropriate steady state concentrations 
of enzalutamide active moieties.  In addition to PK studies, the phase I study will measure 
changes in endocrine biomarkers to assess systemic effects of mifepristone on the GR.   
 
The phase II portion of the trial is a randomized study of enzalutamide alone versus the 
combination of enzalutamide plus mifepristone [Figure 2].  It will utilize pharmacodynamic 
(PD) endocrine biomarkers to support the underlying hypothesis that under the pressure of 
potent AR blockade the GR may drive prostate cancer cell survival. Time to PSA 
progression will be utilized as a PD biomarker of GR antagonism within CRPC tumors as 
activation of both the GR and the AR can drive PSA expression in prostate cancer28,34.  
Subjects will be enrolled in the phase II trial who are currently on standard of care single-
agent enzalutamideand have stable disease or better after 12 weeks of enzalutamide to allow 
for adaptive upregulation of GR signaling,which is proposed to enrich the patient population.  
In addition, the 12-week randomization is optimally timed to exclude patients with disease 
that is entirely refractory to further endocrine manipulation (“androgen independent” 
disease).  
 
 Figure 2. Trial Schema 


 
 
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1.10 
Circulating Tumor Cell Evaluation in CRPC 
When combining therapies, and therefore potentially introducing additive toxicity, utilization 
of PD biomarkers will enrich our ability to define the population most likely to benefit from 
such a combination while also ensuring on-target efficacy. As will be done in this trial of 
hormonal therapies, interrogation of the endocrine system may define PD markers of target 
inhibition.  However, procurement of bio-specimens representative of a patient’s disease at 
the time of disease progression is a key component to personalizing cancer therapy.  
Metastatic prostate cancer is particularly challenging as patients routinely metastasize to the 
bones, a secondary site that is painful to biopsy and unfortunately low relative yield43. A 
potential source of metastatic prostate cancer specimens is cancer cells in the peripheral 
blood circulation (circulating tumor cells, CTCs). This trial will explore a CTC interrogation 
platform that will examine intracellular AR expression. While multiple technologies exist for 
the enumeration of CTCs, very few allow interrogation of cancer biology critical for 
utilizing CTCs as a therapy specific predictive biomarker. Furthermore, little attention has 
been paid to the analytic development of these assays, which is critical in the development of 
any CTC isolation platform. This trial will be essential in clinical validation of a new multi-
step technique (see section 12.1 below) that allows for the evaluation of therapeutic target 
expression within CTCs in real time. State of the art flow cytometry with embedded digital 
microscopy and recently developed fluorescently conjugated primary antibodies allows the 
interrogation of intracellular AR and GR simultaneously. The novel multi-marker 
interrogation methodologies will allow for preliminary studies validating AR/GR status 
within CTCs as a predictive therapeutic biomarker for targeted therapies. This trial will 


 
 
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analyze the reproducibility and variability of these measures. 
 
2.0 
OBJECTIVES 
2.1 
Primary Objective 
 Phase I: To establish the safe and pharmacologically active doses of mifepristone and 
enzalutamide to use in combination. 
 
 Phase II: To determine if mifepristone in combination with enzalutamide prolongs 
time to PSA progression compared to enzalutamide alone in patients with metastatic 
castration resistant prostate cancer 
 
2.2 
Secondary Objectives 
 To evaluate the effect of mifepristone on endocrine biomarkers such as serum 
cortisol and thyrotropin.  
 
 To determine the effect of mifepristone on enzalutamide clearance and steady state 
enzalutamide exposure.  
 
 To determine if mifepristone affects PSA response rate when added to enzalutamide.  
 
 To determine if mifepristone when added to mifepristone prolongs radiographic and 
clinical progression free survival according to standard working group criteria44. 
 
 To explore the role of GR and AR protein expression within circulating tumor cells 
as a pharmacodynamic biomarker for mifepristone and enzalutamide in CRPC. 
 
 To explore the expression of GR and down-stream AR/GR targets in metastatic 
tumor specimen prior to combination drug administration and at clinical progression. 
 
3.0 
PATIENT SELECTION 
3.1 
Eligibility Criteria 
 
1. Histologically or cytologically confirmed prostate cancer 
 
2. Evidence of castrate testosterone level <50ng/dL (or surgical castration) 
 
3. For Phase I portion of the study: Evidence of disease progression: 
 2 or more new lesions on bone scan or 
 Progressive disease on CT/MRI according to RECIST 1.1 criteria45or 
 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. 
 
4. For Phase II portion of the study:  


 
 
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 Subjects must be on enzalutamide for metastatic CRPC and within the first 12 weeks 
of enzalutamide at 160mg/day 
 Record of subject’s enzalutamide start date and baseline PSA (within 28 days of 
starting) before starting enzalutamide available 
 
5. Subjects must have documented clinically stable disease or better during the screening 
period of the study (see Section 7.1) as defined by all of the following (for Phase II 
portion of the study): 
 PSA ≤1.25 times the PSA at start of enzalutamide 
 Lack of radiographic progression as defined by RECIST 1.1 and Prostate Cancer 
Working Group Criteria44-46 
 Clinically stable as confirmed by treating physician 
 
6. Any prior therapy for castrate disease is acceptable except prior specific CYP17 
antagonists (e.g. abiraterone acetate, orteronel) or prior second generation AR 
antagonists (e.g. enzalutamide or ARN509) which are excluded other than enzalutamide 
as specified for phase II portion.  A minimum washout of 28 days for any other 
anticancer therapy prior to first dose of study drug is required (only applicable for phase 
I). 
 
7. Any other radiotherapy or radionuclide require 28-day washout prior to first dose of 
study drug. 
 
8. Denosumab or zoledronic acid are allowed. 
 
9. ECOG performance status ≤ 2 (Appendix A). 
 
10. Patients must have normal hepatic function as defined below: 
 
 Total bilirubin 
 
 
 
<1.5 x the upper limit of normal 
 AST(SGOT)/ALT(SGPT) 
 
<2.5 X institutional upper limit of normal 
 
11. Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
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 within 2 
weeks prior to first dose of study drug. 
 
2. Inability to swallow capsules or known gastrointestinal malabsorption. 
 
3. History of other malignancies, with the exception of: adequately treated non-melanoma 
skin cancer, adequately treated superficial bladder cancer, stage 1 or 2 solid tumor 


 
 
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malignancies who are without evidence of disease, or other solid tumors curatively 
treated with no evidence of disease for > 5 years from enrollment. 
 
4. 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). 
 
5. History of seizure disorder or active use of anticonvulsants.  
 
6. QTc on EKG >450 msec 
 
7. Serious intercurrent infections or non-malignant medical illnesses that are uncontrolled. 
 
8. Active psychiatric illness/social situations that would limit compliance with protocol 
requirements. 
 
9. NYHA class II, NYHA class III, or IV congestive heart failure  (any symptomatic heart 
failure). 
 
10. Concurrent therapy with strong inhibitors or inducers of CYP3A4 or CYP2C8 (See 
Section 9.12below for list of strong inhibitor or inducers) due to concerning possible 
drug-drug interactions 
 
3.3 
Inclusion of Minorities 
 
Men of all races and ethnic groups are eligible for the trial.   
 
4.0 
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 enzalutamide (Xtandi®).  Prior authorization 
assistance for commercially available enzalutamide is available through the manufacturer: 
 
http://www.astellasaccess.com/home/pat/xtandi/ 
 
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.  
 
Study Coordinator: 
 
Jeff Bozeman 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 


 
 
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5841 S. Maryland Ave. MC2115 
 
773-834-3095 
 
773-702-4889 
 
jbozema1@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 Personalized Cancer Care Consortium 
(PCCC) Affiliates on the University of Chicago Cancer Research Center website.   
http://cancer.uchicago.edu/trials/pccc/index.shtml 
Click on the Log in to access 
Enter your site specific user name and password 
 
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  
 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 


 
 
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 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 enzalutamideavailability 
 
The research nurse or data manager at the participating site will then call the study 
coordinator to confirm all selection criteria listed in Section 3.0.   
 
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 dose 
(for phase I portion) or treatment arm (for phase II portion) 
 Call the research nurse or data manager at the participating site and verbally confirm 
registration. 
 
4.2 
Treatment Allocation and RandomizationProcesses 
For the phase I portion of the study, based on the dosing schema described below, study 
subjects will be assigned the applicable doses of mifepristone and enzalutamide.  The dose 
level will be included in the registration information provided by the study coordinator as in 
Section 4.2 above. 
 
For the phase II portion of the study, eligible registered subjects will be randomized to either 
continue standard dose enzalutamide at 160mg/day orally or to the enzalutamide and 
mifepristone at the Recommended Phase II Dose (See Section 5.3).  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. 
 
5.0 
STUDY DRUG ADMINISTRATION 
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 enzalutamide availability is necessary prior to registration.   
 
Mifepristone will be provided by Corcept Therapeutics and shipped to the University of 
Chicago for use on site and distribution to participating institutions upon patient registration 
and treatment allocation.  The mifepristone will be provided as 300mg tablets, 30 
tablets/bottle.  Appropriate number of bottles will be dispersed by the investigator to the 
patient depending on the treatment dose allocation.  Each bottle provided to the subjects will 
be labeled with the protocol number, dosing and storage instructions, and expiration 


 
 
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date.  The contents of the label will be in accordance with applicable regulatory 
requirements.   
 
The mifepristone may be requested by the Principal Investigator (or their authorized 
designees) at the University of Chicago. Corcept will only ship the agent directly to the 
University of Chicago. Other sites who require study agent should submit a completed 
Clinical Drug Request Forms to the University of Chicago Investigational Drug Service by 
fax (773) 834-7461. Orders received on Fridays will not be shipped until the following 
business day.  
 
For questions about drug orders, transfers, returns, or accountability call (773) 834-7466 
Monday through Friday between 8:00 am and 4:30 pm (CST) or email 
IDS.PHARMACY@uchospitals.edu anytime.  
 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all  
 
As noted in Figure 2 Trial Schema, this clinical trial consists of two parts:  
 
 Phase I portion, in which the doses of enzalutamide and mifepristone will be adjusted 
based on safety and pharmacokinetics to reach the Recommended Phase II Dose 
(RP2D) 
 
 Phase II randomized study of mifepristone and enzalutamide at RP2D versus 
enzalutamide alone 
 
5.1 
Study Drug administration for each portion is as follows. 
5.1.1 
Phase I Study Drug Administration 
 The eligible subjects will begin standard of care dosing of enzalutamide at 160mg/day.   
 
 Beginning day 29, subjects will enter phase I combination drug portion of the study 
beginning at mifepristone dose 0 and at enzalutamide dose A (40mg/day). Dose levels 
are defined in Table 1. 
 
 After the first 6 patients are evaluated at this dose level, subsequent patients will be 
enrolled and dosed similarly (after 28 day standard dose lead in) with dose of 
enzalutamide and mifepristone to be determined based on the following dose 
escalation/de-escalation rules. 
5.1.1.1 Phase I Dose Level Determination 
Mifepristone and enzalutamide dose levels (Table 1) will be adjusted by dose cohorts 
according to the following rules, which are illustrated in the algorithm below (Figure 3).  
Each cohort will enroll a minimum of six patients, beginning with dose level 0A, with 
additional patients added or doses adjusted as described in the algorithm by following rules 
1-4 in order to take into account dose limiting toxicity (DLT) rate and the change in steady-
state (Ctrough) enzalutamide levels (ř,  Figure 3).  As noted above, it is estimated that 
mifepristone at both 300mg and 600mg will increase enzalutamide exposure by 
approximately 4-fold, with no significant difference in CYP inhibition based on mifepristone 


 
 
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dose.  Thus, the initial dose level for enzalutamide, to ensure safety is ¼ the standard dose of 
160mg/day.  As noted in the Figure 3 rules, if enzalutamide plasma levels are lower then 
expected, the enzalutamide dose will be increased for the next cohort (e.g. from A to A’), 
whereas if higher then anticipated, the dose will be decreased (e.g. from A to B). 
Mifepristone dose will be escalated or decreased based on tolerability (DLT rate-see 
proceeding section).  The recommended Phase II dose (RP2D) will be the highest 
mifepristone dose in combination with enzalutamide such that <33% (4/12) experience 
DLT and ř <1.5. Although we anticipate that a 12 patient cohort will be sufficient to 
estimate effect of mifepristone on enzalutamide clearance and that the intra-patient 
comparison will account for variability within each patient in baseline enzalutamide 
clearance characteristics, it is possible that the variability in affect of mifepristone on 
enzalutamide metabolism will be larger then anticipated.  In this case, dose cohorts will be 
expanded in a protocol amendment to better characterize PK interactions. 
 
Table 1. Dose levels 
Mifepristone 
Enzalutamide 
Level 
Dose 
Level 
Dose 
‐1 
300 mg/every other 
day 
A’ 
80 mg/day 
0 
300 mg/day 
A 
40 mg/ day 
1 
600 mg/day 
B 
40 mg every other day 
 
 
C 
40 mg every 3rd day 
 
 
 
[Rest of Page Intentionally Left Blank for Formatting Purposes] 


 
 
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Figure 3. Phase I schema and dose escalation/de-escalation algorithm 
 
 
ri = ratio of trough drug concentration after 28 days concurrent dosing divided by trough drug 
concentration after 28 days enzalutamide alone dosing for an individual patient 
   = [Ctrough Enzalutamide + Ctrough M2 metabolite] day 57 /[Ctrough Enzalutamide + Ctrough M2 metabolite] 
day 29 
 ř = average of ri for all patients within a dose cohort (i.e., mean of 6 or 12 patients) 
 
5.2 
Dose Limiting Toxicity Definition 
A grade 3 or 4 toxicity (CTCAE 4.0, http://evs.nci.nih.gov/ftp1/CTCAE/About.html) that is 
potentially related to the therapy will be classified as a dose limiting toxicity (DLT). There will 
be a 28day DLT monitoring period (after combination treatment) during the phase I study in 
which safety will be examined prior to dose escalation from 300mg to 600mg.  A 28 day DLT 
period was chosen as the majority of dose limiting toxicities seen with enzalutamide, including 
rare seizures were seen in this period in previous phase I/II studies were seen within 6 weeks of 
beginning enzalutamide and patients will be on enzalutamide for 28 days prior to combination 
dosing already15. The DLT period begins at day 29, upon the onset of concurrent mifepristone 
and enzalutamide drug daily administration, and ends at day 57, fourweeks later. 
 


 
 
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5.3 
Phase II Study Drug Administration (Figure 4) 
 Eligible subjects will be enrolled and registered within the first 12 weeks of standard of 
care enzalutamide 160mg/day for CRPC and randomized to one of the following two 
arms: 
o Arm 1: Enzalutamide 160mg/day standard dose 
 
o Arm 2: Enzalutamide + Mifepristone at RP2D 
 
 Subjects will begin randomized study treatment after 12 weeks of standard of care 
enzalutamide lead-in.  Treatment on study may start up to 14 weeks after initial 
enzalutamide (+2 week grace period). 
 
 
6.0 
DURATION OF TREATMENT 
Therapy with enzalutamide or enzalutamide/mifepristone will continue until one of the 
following events occurs. 
1. Progression of disease according to 2008 PSAWG-2 criteria47 is met (Appendix C, 
D).  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 
 
7.0 
STUDY ASSESSMENTS 
These assessments are summarized in the study calendar below. 
 
7.1 
Pre-treatment Screening Evaluation 
Eligible patients who have signed informed consent and have had eligibility confirmed will 
be seen in the outpatient clinic within two 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, alanine aminotransferase, aspartate aminotransferase, 
total bilirubin, total protein, alkaline phophatase, and albumin), LDH, serum testosterone and 
Figure 4: Phase II Enrollment and Study Treatment meline 
12 Week Eligibility Period 
Day 1 Standard 
enzalutamide 
12‐14 weeks: 
Start of Study Drug 
28 Day Screening 
Period 
Q12 weeks: 
On‐study Disease 
Assessments 


 
 
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PSA.  A whole blood sample for circulating tumor cell correlative study will be performed 
during the screening period and processed as described in Section 12.1.  An optional pre-
study tumor biopsy will be obtained during screening period (see section 12.2).  Subjects 
will have an EKG to insure normal QTc prior to enrolling. 
 
Disease burden evaluation with a nuclear medicine bone scan (or Fluoride PET), 
abdominal/pelvis imaging (CT or MRI), and CT chest (when clinically indicated) must be 
obtained within 30 days of study entry.  Study entry date is defined as day of first on-study 
treatment as detailed in Section 5.1-5.3. 
 
7.2 
On Study Visits 
On study visit will every 2 weeks through 8 weeks on study, then monthly.  The frequency 
of visits early in the trial is to ensure adequate patient safety while on study.   
 
For study visits, including day 1, the following full set of blood tests will need to be 
obtained:  CBC, serum chemistries, LDH, PSA.  In addition, as mifepristone can affect the 
hypothalamic-adrenal gland axis and to monitor for endocrine related adverse events, serum 
cortisol cortisol and thyrotropin will be assessed at day 1 and at the subsequent two monthly 
(day 29, 57) study visits.  A second whole blood sample for circulating tumor cell correlative 
study will be performed on first day of study drug as described in Section 12.1.  Other 
monthly assessments including ECOG status, concomitant medications etc. to be collected 
are outlined in the study calendar.  To asses for potential QTc prolongation with the 
combination of study agents, a second EKG will be obtained after both medications at steady 
state. 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, starting at first day of concomitant daily study drug administration.  
 
7.2.1 
Pharmacokinetics sampling: 
Plasma samples to determine enzalutamide and M2 metabolite levels within the serum of 
patients on study will be collected and sent to Medivation Inc. for pharmacokinetic (PK) 
analysis.  Patients should withhold enzalutamide administration prior to visits with PK 
sampling and should take enzalutamide after the PK sample is collected.  The pre-dose PK 
sample should be taken immediately before enzalutamide administration.  The PK sample 
should be collected even if patient did not withhold enzalutamide. 
 
For the phase I study, the following samples will be collected for PK modeling before 
enzalutamide, mifepristone dose for each day.  Samples will be taken weekly starting at day 
29 for the next four weeks. 
 
1. Day 29 
2. Day 36 
3. Day 43  
4. Day 50  
5. Day 57 (4 weeks after start of phase I daily concomitant dosing) 
 
For patients in the Phase II portion of the study, PK’s will be collected on day 1 of on-study 
period (steady-state enzalutamide alone) and after 4 weeks on study.   
 


 
 
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All samples will be shipped to: 
 
 
Darla Tyrrel, Sample Receiving 
inVentive Health Clinical Lab, Inc. 
301A College Road East 
Princton, NJ 08540 
Phone:  (609) 951-0005 
Fax:  (609) 951-0080 
Email:  Dtyrrel@inventrivhealth.com 
 
 
7.2.1.1 Collection and Handling of PK Specimen(s) 
Blood samples for pharmacokinetic analysis will be processed in the follow manner:   
 
Completely fill a 2-mL lavender-top, K2EDTA blood collection tube.  Mix 
immediately by gently inverting the tube at least 8 to 10 times to ensure 
thorough mixing of the anticoagulant. 
 
 
Document the actual time and date of collection on the PK Collection Form 
(Appendix E). 
 
 
Immediately after collection, place the blood sample on ice, in a refrigerator 
(2°C to 8°C), or in an equivalent cooling device until centrifugation for 
preparation of plasma.  Within 30 minutes of blood collection, centrifuge the 
blood samples in a refrigerated centrifuge (~4°C) at approximately 2000 x g for 
10 minutes. 
 
 
Use a new polyethylene disposable pipette to divide the plasma into two pre-
labeled screw-cap 2mL polypropylene cryovial plasma storage tubes (i.e., 
Primary PK Sample and Backup PK Sample).  Ensure equal amounts 
(approximately 0.5 mL) are transferred to each aliquot tube.  If the supernatant is 
limited (approximately 0.5 mL or lower), it should be transferred entirely to the 
Primary PK sample tube.  
 
 
Immediately place the PK Samples upright in a sample storage cryobox and 
transfer them to a -80°C or a –20°C freezer.  
 
The plasma samples will be labeled with patient’s initial and ID number, UC protocol 
number, initials of phlebotomist, sample ID (i.e. Day 29, Day 50, etc) and date of blood 
collection. Actual blood sampling times will be noted for each patient in the attached 
flow sheet (pharmacology referral form, appendix E).  Any delays or problems will be 
carefully noted under comments along with the initials of the phlebotomist.  
 
PK samples obtained of the UC 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.   
 
PK samples from participating institutions other than the University of Chicago will be 
collected and processed according to the same methods and stored at the participating 


 
 
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institutions at –80ºC (or -20ºC if -80ºC not available, provided it is not a “self-
defrosting” model due to variability in temperature for these models) for shipment.  
Cryotubes for plasma storage will be provided by the University of Chicago as will blank 
labels.  Frozen PK samples will be shipped to Dr. Gibbonsin a styrofoam container (not 
supplied by UC).  Samples will be batched and shipped together with each dose level 
cohort (Phase I) or quarterly (for phase II).  
 
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 toxicity documented 
at this visit.  The subject will also have standard laboratory studies collected at this visit 
(CBC, serum chemistries, LDH, PSA, testosterone), 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.  A third CTC sample will be obtained.  In addition, a 
second optional pre-study tumor biopsy will be obtained at time of disease progression for 
those coming off study for progression. 
 
 
 
 
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IRB #:13-0979 
 
Version Date:  07/10/2014  
 
8.0 
STUDY CALENDAR 
 
 
 
 
Screening
m 
Day1, 15, 29, 43, 57 
then Monthlyg 
Every 
3Monthsg 
(beginning at start of 
concomitant dosing) 
Offstudy visitj 
Procedures 
 
 
 
 
Informed Consenta 
X 
 
 
 
Medical History, 
including demographics 
X 
 
 
 
Physical exam, including height 
(only at screening) and weight 
X 
X 
X 
X 
Vital Signsb 
X 
X 
X 
X 
ECOG performance status 
X 
X 
X 
X 
Concomitant 
medications 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
EKG 
X 
Xl 
 
 
Laboratory 
Assessments 
 
 
 
 
CBC with platelets & 
Differential counts 
X 
X 
X 
X 
Serum chemistry and 
electrolytesc 
X 
X 
X 
X 
LDH 
X 
X 
X 
X 
PSA 
X 
X 
X 
X 
Testosterone 
X 
 
X 
X 
Hypothalamic-pituitary labs 
 
Xk 
 
 
PK sample-per Sec. 7.2.1 
 
Xh 
 
 
TumorAssessmentsd 
 
 
 
 
Bonescan/F18 PETe 
X 
 
X 
X 
CT or MRI of the abdomen/pelvis 
X 
 
X 
X 
CT chestf 
X 
 
X 
X 
Correlative Studies 
 
 
 
 
Circulating tumor cell 
(CTC) collection 
X 
Xi 
 
X 
Tumor biopsies (optional) 
X 
 
 
X 
 
a. 
Written informed consent must be obtained before any study-specific 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. 
Serum chemistry includes BUN, creatinine, ALT, AST, glucose, alkaline phosphatase, total bilirubin, electrolytes 
(K+, Cl-, Na+,CO2, Ca+).  
d. Imaging will be evaluated at screening and for clinical benefit every 12 weeks (3 cycles) of treatment, beginning at 
start of concomitant drug dosing (day 29 for phase I, day 1 for phase II). 
e. 
Isolated new lesions on bone scan at the first12-week scan will be confirmed with a repeat bone scan at 6 weeks to 
rule out bone scan flair. 
f. 
Obtain if clinically warranted. 
g. +/- 3 days.  
h. PK assessments per Section 7.2.1(day 29, 43, 57 then monthly) 
i. 
Whole blood for CTC assessment will be collected on Day 1 of study drug administration.   
j. 
End of study visit – within 30 days of the last enzalutamide dose. Tumor assessment not necessary if done within 
preceding 30 days. 
k. Serum TSH and AM cortisol will be measured at day 1, 29, 57 


 
 
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l. 
EKG to assess QTcon study will be obtained Day 57 for Phase I, Day 29 for Phase II 
m. In calculating days of tests and measurements, the day a test or measurement is done is considered day 0.  Therefore, 
if a test is done on a Monday, the Monday 4 weeks later would be considered day 28.  Eligible patients will be seen 
in the outpatient clinic within two weeks of starting the study to have history and physical examination, ECOG 
performance status, concomitant medications, and baseline toxicity documented.  To confirm eligibility, the patient 
will have standard of care screening labs drawn within four weeks of initiating therapy.   
 


 
IRB #:13-0979 
 
Version Date:  07/10/2014  
 
 
 
9.0 
TREATMENT PLAN 
9.1 
Agent Administration 
Treatment will be administered on an outpatient basis as per Section 5.0, Figure 2.  The 
patients on study will procure the enzalutamide as stated above through their standard 
outpatient pharmacy, but will not take any doses of therapy until instructed to do so, and at 
doses specified by study nurse and investigator. 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/antagonist while on this clinical trial.  Medications for bone health (e.g. zoledronic 
acid or denosumab) should likewise be continued (Section 3.1). 
 
9.2 
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. 
 
9.3 
Dose-Reduction Procedure for Adverse Event Management 
In the event where dose-reduction is used for AE management, dose reductions are 
allowed according to table 2 below, however given the study design, the starting dose for 
a subject may vary. For mifepristone the dose reduction algorithm is downward from level 
11’0-1; for enzalutamide dose reductions follow A’ABC depending on 
subjects starting dose.  The maximum time a patient’s study medication may be held due to 
toxicity is 28 days.  After which, the patient must be discontinued from study participation.  
A dose delay of 14 days or more will mandate a dose reduction.   
 
All grade 3 or 4 toxicity (CTCAE 4.0, http://evs.nci.nih.gov/ftp1/CTCAE/About.html) that 
are potentially related to the therapy, unless specifically addressed below, should necessitate 
holding offending study drug, which can be reintroduced according to the instructions listed 
below.  Holding or reducing dose otherwise (unless specifically addressed below) is at the 
discretion of the investigator. 
 
 If Grade 1-2 toxicities, give supportive care per institutional guidelines. No study 
treatment dose reduction. 
 
 If Grade3 or higher toxicities including headache (interferes with ADL), nausea 
(TPN, IVF), vomiting (>6episodes/24hrs,TP Nor 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. 
 


 
 
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 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 ≤ Grade1, 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 ≤  Grade1, resume study treatment with these dose 
level. 
 
 If toxicity recurs despite   aggressive  medical   management, and two dose level 
reductions, discontinue study treatment. 
 
Several of the potential adverse events for this study are side effects common to both 
mifepristone and enzalutamide, such as diarrhea, anhedonia, nausea and fatigue.  Given the 
established efficacy of enzalutamide for patients with CRPC, if dose delays or adjustments 
necessary for non-specific adverse events, it is recommended that the mifepristone be 
delayed/reduced first, and if no improvement in adverse event with adjustment of 
mifepristone, enzalutamide then be delayed/reduced. 
 
Table 2. Dose reduction levels 
Mifepristone 
Enzalutamide 
Level 
Dose/Day 
Level 
Dose 
‐1 
Will be removed 
from study for 
toxicity 
A’ 
80 mg/day 
0 
300 mg/ every other 
day 
A 
40 mg/ day 
1’ 
300/600 alternating 
every other day 
B 
40 mg every other day 
1 
600 mg/day 
C 
40 mg every 3rd day 
 
 
 
 
 
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9.4 
Treatment Management of Hypertension 
Hypertension may develop while on mifepristone due to excess mineralocorticoid activity 
due to treatment dependent increase in ACTH. Because of this, hypertension occurring 
secondary to mifepristone may be most effectively prevented through the concurrent 
administration 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. 
 
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. 
 
 
 
 
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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 mifepristone. 
• 
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. 


 
 
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9.5 
Treatment-Emergent Edema and Fluid Retention 
Fluid retention can similarly 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 mifepristone.  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 mifepristone treatment. Adjust or 
add medications to mitigate the 
toxicity.  When toxicity resolves to 
<Grade 1, resume study treatment at 
first dose level reduction. 
 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  
 Recurrence of toxicity despite optimal 
medical management and with two 
dose level reductions 
 Discontinue study treatment.  
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.6 
Management of Hypokalemia 
Hypokalemia may occur in patients treated with mifepristone due to mineralocorticoid excess 
and potentially.  Initial management of hypokalemia should include oral K+ supplementation 
as well as the addition of eplerenone, as appropriate. 
 
Serum K+ 
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 
mifepristone and 
initiate IV K+ and 
cardiac monitoring
Restart mifepristone 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 
mifepristone and 
initiate IV K+ and 
cardiac monitoring
Call study PI prior to re- initiating study 
treatment. 
 
9.7 
ManagementofElevatedLiverFunctionTests 
Although elevated liver function studies are an uncommon adverse event for both 
enzalutamide and mifepristone, given the hepatic metabolism of both drugs, potential for 
increased toxicity is noted. 
• IfGrade1increasesinAST,AL Torbilirubin occur(e.g. increase in AST or ALT from 
ULN to 2.5 XULN; increase into talbilirubin from ULN to 1.5 XULN): 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>2.5-5XULN; increase into talbilirubin from > 1.5-3 XULN): 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 Grade3 or higher increases in AST, ALT, o rbilirubin occur (e.g. increase in AST 
or ALT to>5 XULN; increase in total bilirubin to > 3 XULN), hold mifepristone and 


 
 
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enzalutamide 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.When liver function studies 
do normalize, first reintroduce enzalutamide at one dose reduction.  If after 2 
weeks of single agent enzalutamide, AST/ALT are still grade 1 or better, 
mifepristone may be introduced at one dose level reduction.  
 
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 Grade1. 
Liver enzyme measurements should be made immediately, regardless of when the 
next study visitor 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 as above 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 >10 XULN), patients must discontinue 
study treatment immediately and will not be re-challenged. They should be followed 
until resolution of abnormal liver function tests. 
 
9.8 
ManagementofAdrenal Insufficiency 
Administration of mifepristone, particularly with long-term dosing, carries a risk of inducing 
adrenal insufficiency by virtue of blockade of the glucocorticoid receptor.  Of note, signs and 
symptoms of adrenal insufficiency may occur with normal or high cortisol level given the 
blockade of the GR rather than primary insufficiency of the adrenal gland.  Unlike primary 
adrenal insufficiency, adrenal insufficiency that may be seen with mifepristone is not 
anticipated to be associated with hyperkalemia given the maintenance, and potential 
increase, in mineralocorticoid activity in the setting of GR blockade.  Throughout the 
Corcept mifepristone program of over 1200 subjects, there have only been three cases of 
adrenal insufficiency documented as adverse events40.  However, the symptoms of adrenal 
insufficiency can be vague and include fatigue, hypoglycemia, anorexia, constipation, nausea 
and hypotension, particularly orthostatic hypotension.  Should a constellation of these 
symptoms occur in a subject, no change is necessary other then supportive care for grade 1 
and 2 adrenal insufficiency.  For grade 3 adrenal insufficiency, for example severe symptoms 
requiring hospitalization, mifepristone should be held and hydrocortisone initiated for 
adrenal replacement. 
 
9.9 
Management of Rash 
Mifepristone is associated with macular-papular eruptive rash on the upper torso, trunk that 
can extend to extremities and face.  It is a relatively frequent adverse event noted with 
mifepristone (~30%).  It typically occurs within the first two weeks of drug exposure, is 
typically mild (grade 1-2) and associated with pruritis.  It should be treated with topical 
antihistimines ± topical corticosteroids.  It is typically self-limited.  Should a subject 


 
 
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experience severe rash that does not improve with topical agents, mifepristone can be held, 
which in most instances leads to resolution.  Rechallange of full dose mifepristone should be 
initiated upon resolution of the rash.  Severe (grade 4) rash such as Stevens-Johnson 
syndrome or Toxic Epidermal Necrolysis has not been observed with mifepristone. 
 
9.10 
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 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. 
 
9.11 
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 erythropoietin48. 
 
No concurrent investigational agents will be permitted. 
 
9.12 
Potential Drug Interactions 
As noted above, mifepristone is an inhibitor of both CYP3A4 and is also metabolized by 
CYP3A4.  Similarly, enzalutamide is metabolized by CYP3A4 and CYP2C8.  Strong 
inhibitors and inducers of CYP3A4 and CYP2C8 should be avoided.  In addition substrates 
of CYP3A4 or CYP 2C8/9 should be used with caution and at the lowest dose available.  
The following table should be used as a reference (from http://www.fda.gov/drugs/).Given 
the prevalence of CYP3A4 metabolism, all concomitant medications should be 
evaluated for potential drug-drug interaction. 
 
 
 
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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 
 
CYP 3A4 substrates Avoid if possible/use at lowest dose: 
Alprazolam, erythromycin, felodipine, 
amlodipine, verapamil, fentanyl, 
lovastatin, nifedipine, simvastatin,  
 
CYP2C8/9 inducers 
 
Rifampin, carbamazepine 
CYP2C8/9 
inhibitors 
Gemfibrozil 
Amiodorone, fluconazole, 
miconazole 
CYP 2C8/9 
substrates 
Avoid if possible/use at lowest dose: 
Warfarin, rosiglitazone, celecoxib, 
ibuprofen, losartan, naproxen, 
sulfamethoxazole,  
 
 
Although warfarin is not excluded, it should be used with caution and close monitoring of INR.   
 
Additional information with regards to drug-drug interactions is available on the FDA 
prescribing information for enzalutamide and mifepristone.   
 
 Enzalutamide: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203415lbl.pdf 
 
 Mifepristone:  
http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202107s000lbl.pdf 
 
10.0 
SAFETY 
10.1 
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. 


 
 
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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 
 
10.2 
 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) 
 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. 
 
10.3 
Suspected Adverse Reactions 
An adverse event (AE) is considered to be a suspected adverse reaction if there evidence to 
suggest a causal relationship to the study agent.  This may include a single occurrence of an 
event strongly associated with drug exposure (e.g. Stevens-Johnson Syndrome), one or more 
occurrence of an event otherwise uncommon is the study population, or an aggregate analysis of 
specific events occurring at greater frequency than expected from historical controls. 


 
 
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10.4 
Unexpected Events 
Unexpected events are those not listed at the observed specificity or severity in the protocol, 
consent, investigator brochure, and/or FDA-approved package.  This includes adverse events 
listed in the protocol or consent as occurring within the class of drugs or otherwise expected 
from the drug’s pharmacological properties but which have not been previously observed 
with this investigational agent. 
 
10.5 
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. 


 
 
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 SAEs must, however, be reported for any surgical or procedural complication 
resulting in prolongation of the hospitalization. 
 Symptoms related to progressive diseases uc has severe bone pain will not be 
reported as toxicity or as Serious Adverse Events. 
 ALL SAEs, whether or not they are considered related to the study agent MUST be 
reported to the IND Holder (Rita Nanda, MD) and to the University of Chicago 
Comprehensive Cancer Center (UCCCC).  Refer to Section10.6 for reporting 
guidelines.  
 All serious unexpected adverse drug reactions (see definitions in Section 10.3 and 
10.4) must be reported to the FDA by the investigator as required by 21 CFR 312.32 
(See Section 10.6 below for reporting processes). 
o These reports are to be filed utilizing the Form FDA 3500A (MedWatch 
Form). 
 
10.6 
Adverse Event Reporting Process 
All SAEs and protocol deviations must be reported to the University of Chicago 
Comprehensive Cancer Center (UCCCC) Cancer Clinical Trials Office (CCTO).  The 
responsible Research Nurse or other designated individual should report the SAE/deviation 
to the CCTO 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.  Reports should be made using the eVelos database ‘Serious Event 
Report’ Form.Each event report must indicate whether the event meets the IRB’s 
Unanticipated Problem reporting criteria.  Notification of each reported event to the Study 
Chair and IND Holder will occur.   
 
When appropriate, the UC 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. 
 
For events occurring at a non-UC site (e.g. participating site): 
 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.   
 Each SAE should be reported to the local IRB of record in accordance with their 
current policies  
 These events should also be reported to the UC IRB if the event meets current 
reporting requirements.   
 
For all Unexpected and Serious Adverse Drug Reactions (i.e. unexpected SAEs that are 
related to the study agent (mifepristone), in addition to the required reporting to the 
UCCCC via Velos, the responsible Research Nurse or other designated individual at the 
treating site should: 
 Provide a more complete written report using the FDA MedWatch 3500A form.     
 The completed form should be sent to the CCTO at qaccto@bsd.uchicago.edu, 


 
 
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within the specified timelines below regardless of whether all information 
regarding the event is available.   
 If applicable, a follow-up report should be provided to the CCTO if additional 
information on the event becomes available.   
 
Participating sites should not forward any adverse event reports directly to the FDA.  The 
CCTO will report all events to the FDA as per the current FDA guidelines.   
 
Fatal or Life-threatening Events: within 4 calendar days from treating investigator 
knowledge of the event 
 
All Other Reportable Events: within10 calendar days of treating investigator knowledge 
of the event 
 
10.7 
Adverse Event reporting by the Coordinating Center 
The designated UCCCC Regulatory Manager will notify all participating sites of all 
unexpected and serious adverse reactions that occur on this clinical trial and which are 
reported to the FDA and/or UC Institutional Review Board (IRB).  When reported to the 
FDA, a copy of the completed Form 3500A (MedWatch) will be provided to the 
responsible Regulatory Manager by the CCTO IND Coordinator for distribution to all 
participating sites. 
 
10.8 
Other Safety Considerations 
10.8.1 
Laboratory Data 
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, unless this value is consistent with the patient’s present 
disease state or is consistent with values obtained prior to entry into the study. 
10.8.2 
Medication Errors 
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. 
 
10.8.3 
Follow-Up of Adverse Events 
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. 
 
10.8.4 
Safety Monitoring 
According to University of Chicago Cancer Center Guidelines, this protocol will be 


 
 
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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 of participating subjects at other sites will also be reviewed 
at the University of Chicago DSM, however safety will also be monitored locally per each 
institutions guidelines.  During the phase 1 portion of the study, there will be weekly 
teleconferences between participating centers to review subject safety and study progress.  
For the phase II portion, there will be a similar monthly teleconference. 
 
10.8.5 
Independent Safety Monitor 
       Dr. Sumati Murli, PhD, Director for Clinical Research Operations in the University of        
Chicago Comprehensive Cancer Center, will serve as the Independent Research Monitor (IRM) 
for this study as stipulated by DOD Directive 3216.02.  The principle role of the IRM within the 
context of this study will be to oversee study conduct specifically with respect to safety.  Given 
the phase I/II nature of the study, and the potential for dose adjustments based on both 
pharmacokinetics and safety, the IRM will have direct oversight with respect to assessment of 
patient safety, independent of the research team.  In the case of serious adverse events or subject 
deaths that she feels meet the criteria to be classified as unanticipated problems, her independent 
report in the form of a memo will be promptly submitted to the DOD (USAMRMC ORP HRPO) 
and University of Chicago IRB along with the report of the event.  In addition to attending 
weekly data safety monitoring meetings, she will participate in the regular teleconferences once 
more than one site is participating in the trial.  In the event that she is not able to attend the data 
safety monitoring meeting in person, she will review the data safety monitoring minutes from 
that meeting.  Specifically, she will review all unanticipated problems involving risk to subjects 
or others, serious adverse events and all subject deaths associated with the protocol and provide 
an unbiased written report of the event should she feel it qualifies as an unanticipated 
problem.  For those events qualifying as unanticipated problems, the IRM will comment on the 
outcomes of the event or problem and, in case of a serious adverse event or death, she will 
comment on the relationship to participation in the study.  The IRM will indicate whether she 
concurs with the details of the unanticipated problem report provided by the principal 
investigator.  Reports for events determined by either the investigator or research monitor to be 
possibly or definitely related to participation and reports of events resulting in death will be 
promptly forwarded to the USAMRMC ORP HRPO and the University of Chicago IRB.  The 
IRM has the authority to stop this research protocol in progress in parallel with the submission 
of a UP to the University of Chicago IRB, remove individual human subjects from this research 
protocol, and take whatever steps are necessary to protect the safety and well-being of human 
subjects participating in this protocol until the University of Chicago IRB assesses the UP and 
the IRM's report and determines appropriate next steps. 
   
 
11.0 
MEASUREMENT OF EFFECT 
Patients with measurable disease will be assessed by standard criteria45,46(Appendix C, D).  
For the purposes of this study, patients should be re-evaluated every 12 weeks.   
 


 
 
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11.1 
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 and response will be measured according to PSAWG-2 (2008) criteria. 
 
PSA changes from baseline will be calculated for all patients and reported as a 
waterfall plot. 
 
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.  
 
11.2 
 Radiographic Tumor Response 
Change in measurable disease, when applicable, will be determined according to RECIST 
1.1 and PSAWG-2 criteria (Appendix E)45,46,49.  For the purposes of this study, imaging will 
be repeated according to the study calendar (Section 8.0) every 12 weeks unless otherwise 
indicated clinically. 
 
Lymph nodes46: 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:  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 
criteria49.  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). 
 
11.3 
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). 


 
 
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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.  
 
11.4 
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.   
 
12.0 
CORRETALIVE STUDIES 
12.1 
Circulating Tumor Cells (CTC) 
Circulating Tumor Cell isolation and characterization 
CTC are emerging potential source of tumor tissue for therapeutic biomarker interrogation.  
At present, there is no standard procedure for extracting and evaluating CTC beyond 
enumeration.  This study will utilize methodologies developed in the PI’s laboratory50 for 
further biomarker validation. 
 
For evaluation of CTC, 15mL of whole blood will be collected in two (7.5mL each) BD CPT 
vacutainers which will be provided.  For this exploratory endpoint, samples will only be 
collected for University of Chicago study subjects. Samples will processed within 60minutes 
of sample acquisition. 
 
CPT tubes will be centrifuged at 1500g for 20minutes at room temperature.  Following 
centrifugation, the uppermost plasma layer will be removed and saved for correlative 
studies.  Mononuclear cell layer will be then transferred from both tubes into one new 15ml 
conical tube.  Phosphate buffered saline (PBS) will be added to a total volume of 15ml.  The 
cells will be centrifuged at 450g for 5 minutes at room temperature. The supernatant will be 
discarded and the washed mononuclear cells will be resuspended in 10ml of PBS for further 
processing.  
 
Once mononuclear cell fraction isolated, prostate cancer cells will be identified and further 
characterized using flow cytometry cell sorting (FACS) and analysis.  Pellet of cells will be 
resuspended in cell separation buffer (PBS with 2mM EDTA, 0.5% serum albumin), FcR 
blocking buffer (Miltenyi), EpCAM (to bind epithelial cells) and CD45 (to bind white blood 
cells) primary antibodies conjugated to specific fluorescent markers.  Cells will then by 
analyzed in conjunction with the flow cytometry core facility gating for the EpCAM 
positive, CD45 negative population.  The cells will be characterized using multiplex 
flourescent immunocytochemistry with fluorescently conjugated antibodies to the AR, GR 
(Cell Signaling) along with DAPI nuclear staining.  
 
Cells will be FACS sorted onto charged glass chamber slides, and then fixed with 3% 
formalin and stained with ICC antibodies for multiplex fluorescence. The slides will be 
imaged using the Leica SP2 laser confocal microscope.  Alternatively, depending on FACS 
machine availability, the Image Stream flow cytometer may be used to analyze fixed and 
stained cells.  Captured images will be analyzed for fluorescence intensity and digitally 
scored using ImageJ software.  Positive and negative control cells stained concomitantly will 
also be digitally analyzed and will provide the reference for staining intensity analysis. In 


 
 
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addition to staining intensity, intra-cellular localization will be described for CTC for each 
marker. Immunofluorescence will be assessed in conjunction with Dr. Paner in the 
Pathology Department, University of Chicago. 
 
12.2 
Optional Tumor Biopsies 
Studies have shown that GR expression increases in response to androgen pathway 
inhibition in prostate cancer32.  The GR expression in CRPC is unknown.  To better 
understand the potential compensatory role of the GR in CRPC progression, to explore the 
role of baseline intra-tumoral GR expression as a predictive biomarker for GR inhibition 
with mifepristone, and to query other resistance pathway mechanisms, subjects will be asked 
to contribute an optional tumor core needle biopsy (under CT guidance if necessary).  An 
optional biopsy will be obtained both during the screening period and at the off study visit 
(Section 7.0above) if possible.  While the exact number of specimens obtained depends on 
the size of the target, the difficulty of the procedure, and risk of complications, the goal is to 
obtain between 2-3 samples for analysis.  A full standard operating procedure (SOP) for 
biopsy acquisition and handling will be provided to study sites.  The primary sample will be 
fixed in paraformaldehyde, decalcified (if needed) and embedded in formalin.  Samples will 
be processed for immunohistochemistry (IHC) and assessed for standard pathologic 
parameters (with H&E staining), AR and GR staining.  These pathology parameters will be 
assessed in conjunction with Dr. Paner in the Pathology Department, University of Chicago.  
If a second core biopsy is obtained, it will be embedded in Tissue TekTM OCT and frozen at -
80°C for future molecular analysis of AR pathway resistance. 
 
13.0 
STATISTICAL CONSIDERATIONS 
13.1 
Sample Size/Primary Endpoint 
Within the phase I portion of the study, steady-state Ctrough for Enzalutamide and the active 
metabolite will be determined for each patient and means and standard deviations calculated.  
As described above, the mean of the ratio of Ctrough for Enzalutamide and the active 
metabolite will be calculated for each dosing cohort, and mean value will be used for dos 
adjustment determinations.  Standard deviation and range of the Ctrough and ratio will also be 
calucalated and reported.   
 
The randomized phase II study, will be conducted with appropriate sample size to power 
primary endpoint- to determine if mifepristone in combination with enzalutamide prolongs 
time to PSA progression compared to enzalutamide alone in patients with metastatic 
castration resistant prostate cancer. The primary statistical consideration will be PSA 
progression-free survival (PFS) post randomization, defined as the time to PSA progression 
or death, whichever comes first.  PSA progression will be defined as a PSA (confirmed 2 
weeks later) that is ≥1.25 times (25% increase) the PSA at randomization (week 12). We 
assume the median time to PSA progression in the control (enzalutamide alone) arm will be 
6 months post randomization.  The rationale for this assumption is as follows.  In the phase 
III enzalutamide (AFFIRM) trial13, ~10% of treated patients had PSA progression prior to 12 
weeks.  The PSA progression-free rate was ~42% at 9 months, which would correspond to a 
6-month rate, conditional on no event at 12 weeks, of 0.42/0.9=0.47. Thus our enrichment 
strategy should lead to a patient population with a median PFS of 6 months (24 weeks) in the 
control arm post randomization.  In order to detect a hazard ratio (HR) of 0.60, which 
corresponds to an increase in the median from 24 to 40 weeks, with 80% power, a sample 


 
 
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size of 84 patients (42/arm) is required, using a one-sided test at the α=0.10 significance 
level.  This assumes a two-year accrual period and a subsequent one-year follow-up period.  
Kaplan-Meier41 curves will be generated and the two treatment arms compared using a 
logrank test.  Median time to event in each group will be estimated along with 90% 
confidence intervals using the method of Brookmeyer and Crowley42.  Cox43 proportional 
hazards regression models will be fit to assess and adjust for the effects of baseline 
covariates.  Overall survival and radiographic progression-free survival will be analyzed 
similarly.  The relative PSA change within each arm will also be reported using a waterfall 
plot according to working group recommendations for phase II studies in CRPC, as a 
secondary endpoint44. Adverse events will be summarized by grade and type and compared 
between groups using chi-square or Fisher’s exact tests.   
 
For the secondary endocrine PD endpoint, we will compare endocrine PD marker differences 
between the enzalutamide alone versus the Enzalutamide + Mif treatment arms.  In previous 
placebo controlled trials of Mif, serum cortisol levels reliably doubled from a baseline of 
approximately 15 μg/dL to >30 μg/dL after treatment with mifepristone38,39.  Based on the 
reported interquartile ranges, and assuming normality of the distribution, the coefficient of 
variation is estimated at 50%.  An interim futility analysis will be conducted after half (35) 
of the expected 70 PSA events are observed.  At this stage we will conduct an interim 
analysis of the difference in cortisol levels; a lack of biomarker effect would provide 
justification for closing the trial.  Thus, assuming a true mean for the control arm of 15 and 
standard deviation of 7.5 on day 29 post randomization, our sample size will provide 90% 
power to detect a difference of 15 vs. 22 μg/dL between the two treatment arms, based on t-
test at a two-sided alpha level of 0.05.  This calculation allows for a 15% missing data rate 
prior to day 29 post randomization. The other endocrine laboratories collected at day 29, will 
be similarly compared between treatment groups.   
 
In addition, if at the interim analysis the conditional power for the primary PSA endpoint is 
<25%, we will consider terminating the trial for futility.  This stopping rule will provide 
minimal power loss (<3%)44. 
 
13.2 
Randomization 
Upon documented and confirmed eligibility, the patient will be enrolled and randomized.  
Randomization for phase II portions of the study will be done through Dr. Karrison and 
colleagues in the biostatistics core at the University of Chicago in a 1:1 fashion.  There will 
be no specific stratification as the 12-week standard of care enzalutamide lead in for the 
phase II study we hypothesize will add homogeneity to the population.  As only patients 
with stable disease or better at 12 weeks are randomized any affect of prior therapy, etc. on 
the study population will be mitigated.   
 
13.3 
Analysis of Secondary Endpoints 
The stratified log-rank will be used to compare the two treatment arms with respect to 
progression-free survival (PFS).  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. 
 


 
 
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The pharmacokinetic data will be obtained from PK samples described above (Section 
7.2.1.).These PK parameters will be summarized using standard descriptive methods (means, 
standard deviations, medians and ranges).  
 
The primary objective of the exploratory CTC aim is to assess intra- and inter-patient 
variability in AR and GR expression within CTCs from patients with progressive CRPC. 
The second objective of this aim is to explore the correlation between baseline AR and GR 
expression and PSA progression-free survival in patients treated with enzalutamide ± 
mifepristone. The median/range, mean/standard deviation of expression (relative 
fluorescence) for AR and GR will be summarized for each patient (intra-patient variability) 
and for the entire population (inter-patient variability). The components of variability will be 
estimated using analysis of variance.   In addition percent nuclear/cytoplasmic/both cellular 
localization will be calculated for both receptors.  Finally, Cox regression models for time to 
PSA progression will be fit using the expression of AR and GR as covariates incorporating 
treatment-by-marker interaction terms to determine whether they have prognostic and/or 
predictive value. Based on prior studies in this patient population ~50-60% of patients 
enrolled will have CTCs isolated and available for imaging.  The percentage of patients with 
CTC’s following 12 weeks of enzalutamide is unknown, but likely lower, and thus we will 
assume 30% will have evaluable CTC’s at the time of randomization.  This should provide 
~25 patients (.3x82) for analyses.  
 
12.4 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.   
 
 


 
 
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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. 
 


 
 
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APPENDIX B 
 
Sample Data Capture Forms 
 
 
 
 


 
 
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Treatment History 
 
 
 
 


 
 
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Appendix C 
 
PROSTATE-SPECIFIC ANTIGEN WORKING GROUP CRITERIA49 
 
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.  
 
 
 


 
 
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Appendix D 
RESPONSE EVALUATION CRITERIA in SOLID TUMORS (RECIST) 45,46 
 
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. 


 
 
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 Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  
 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.  


 
 
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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 


 
 
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document the objective progression even after discontinuation of treatment.  
 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  
 
 
 


 
 
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Appendix E 
PHARMACOKINETIC SAMPLE COLLECTION SCHEME 
 
A phase I/II trial of enzalutamide plus the glucocorticoid receptor antagonist mifepristone 
for patients with metastatic castration resistant prostate cancer (CRPC) 
 
ENZALUTAMIDE PREDOSE PK SAMPLES TO BE COLLECTED AT:  
 
Phase I: Day 29 (day 1 of concomitant dosing), Day 36, Day 43, Day 50, Day 57 
Phase II: Day 1, Day 29 (month 2) 
 
All PK samples prior to that day’s enzalutamide administration 
 
PATIENT NAME:  
 
 
 
 
PATIENT ID: 
 
DATE: 
 
 
 
 
No SampleID 
 
Date of 
Sample 
Draw 
Actual 
Clock 
Time 
Calculated 
Clock Time 
(with 
respect to 
dose) 
Initials 
of 
Sample 
Collector 
Comments 
Phase I 
1 
Pre-dose,  
Day 29 
 
 
 
 
 
2 
Day 36 
 
 
 
 
 
3 
Day 43 
 
 
 
 
 
4 
Day 50 
 
 
 
 
 
5 
Day 57 
 
 
 
 
 
PHASE II 
1 
Pre-dose, 
Day 1 
 
 
 
 
 
2 
Pre-dose, 
Day 29 
 
 
 
 
 
 
 


 
 
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