Clinical trial NCT03827473
Conditions: Castration-Sensitive Prostate Carcinoma Metastatic Prostatic Adenocarcinoma Stage IV Prostate Cancer Stage IVA Prostate Cancer Stage IVB Prostate Cancer
Sponsor: University of Utah
Start date: 2019-02-08; Completion date: 2019-07-31
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase II trial studies how well docetaxel or abiraterone acetate work when combined with androgen deprivation therapy (ADT) in treating patients with hormone sensitive prostate cancer that has spread to other parts of the body. Drugs used in chemotherapy, such as docetaxel and abiraterone acetate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Antihormone therapy, such as ADT may lessen the amount of androgen made by the body. It is not yet known whether docetaxel or abiraterone acetate work better when combined with ADT in treating patients with hormone sensitive prostate cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the impact of abiraterone acetate (abiraterone) and docetaxel on total quality of life between screening and month 12 of the study.

SECONDARY OBJECTIVES:

I. To assess prostate specific androgen (PSA) response rates across the entire population and compared between groups.

II. To assess impact of abiraterone and docetaxel on additional quality of life measurements and quality of life trends throughout the duration of the study.

III. To assess the potential clinical efficacy between treatment groups.

Arms: arm 1: Participants receive androgen deprivation therapy (ADT) per standard of care and docetaxel IV over 1 hour on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. arm 2: Participants receive androgen deprivation therapy (ADT) per standard of care, abiraterone acetate PO daily, and prednisone PO twice daily. Treatment continues in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Abiraterone Acetate intervention 2: Antiandrogen Therapy intervention 3: Docetaxel intervention 4: Prednisone intervention 5: Quality-of-Life Assessment intervention 6: Questionnaire Administration
Intervention descriptions: intervention 1: Given PO intervention 2: Given per standard of care intervention 3: Given IV intervention 4: Given PO intervention 5: Ancillary studies intervention 6: Ancillary studies

Protocol documents:
Prot_SAP_000.pdf: 
Short Title: ACADEMIC: ADT + Docetaxel vs ADT + Abiraterone 
Version Date:  13MAR2019 
Principal Investigator: Benjamin Maughan, MD, PharmD 
 
ACADEMIC: A Randomized Phase II Clinical Trial of ADT 
Combined with Abiraterone or Docetaxel in Metastatic Hormone 
Sensitive Prostate Cancer 
HCI-18-GU-11/Trial ID: HCI115099 
Coordinating Center 
Huntsman Cancer Institute 
Principal Investigator 
 
 
 
 
 
 
Co-Investigators 
 
Benjamin L. Maughan MD, PharmD  
Huntsman Cancer Institute 
University of Utah 
2000 Circle of Hope 
Salt Lake City, Utah 84112 
Email: benjamin.maughan@hci.utah.edu  
 
Abhishek Tripathi MD 
Stephenson Cancer Center 
Oklahoma State University 
 
Mehmet Bilen MD 
Winship Cancer Institute 
Emory University 
Statistician(s) 
Ken Boucher, PhD 
Huntsman Cancer Institute - University of Utah 
2000 Circle of Hope Room 1710 
Email: Ken.Boucher@hci.utah.edu  
Medical Monitor 
TBD 
Coordinating Center Site 
Contact 
Please contact your assigned Clinical Site Monitor and 
the Clinical Trials Compliance Office 
2000 Circle of Hope 
Salt Lake City, UT 84112 
compliance@hci.utah.edu  
Commercial agents 
Abiraterone Acetate (Zytiga, Yonsa, or generic), 
Docetaxel (Taxotere) 
IND Number 
N/A 
NCT Number (CT.gov) 
NCT03827473 
Historical Protocol Version Dates 
Version 1: 09OCT2018 
Version 2: 13MAR2019 


Short Title: ACADEMIC: ADT + Docetaxel vs ADT + Abiraterone  
Version Date: 13MAR2019 
Page 2 of 52 
TABLE OF CONTENTS 
Page 
LIST OF ABBREVIATION ........................................................................................................... 4 
PROTOCOL SIGNATURE ......................................................................................................... 7 
STUDY SUMMARY...................................................................................................................... 8 
SCHEMA ...................................................................................................................................... 10 
1 
OBJECTIVES ....................................................................................................................... 11 
1.1 
Primary Objective .......................................................... Error! Bookmark not defined. 
1.2 
Secondary Objectives.................................................................................................... 11 
1.3 
Exploratory Objectives ................................................................................................. 11 
2 
BACKGROUND .................................................................................................................. 12 
2.1 
Hypothesis..................................................................................................................... 12 
3 
DRUG INFORMATION ...................................................................................................... 13 
3.1 
Androgen Deprivation Therapy .................................................................................... 13 
3.2 
Docetaxel (Taxotere) .................................................................................................... 13 
3.3 
Abiraterone Acetate (Abiraterone) ............................................................................... 15 
4 
STUDY DESIGN.................................................................................................................. 19 
4.1 
Description .................................................................................................................... 19 
4.2 
Number of Patients ....................................................................................................... 19 
4.3 
Number of Study Centers.............................................................................................. 19 
4.4 
Study Duration .............................................................................................................. 19 
5 
ELIGIBILITY CRITERIA.................................................................................................... 20 
5.1 
Inclusion Criteria .......................................................................................................... 20 
5.2 
Exclusion Criteria ......................................................................................................... 21 
5.3 
Recruitment Strategies .................................................................................................. 23 
6 
RANDOMIZATION............................................................................................................. 23 
7 
TREATMENT PLAN ........................................................................................................... 23 
7.1 
Administration Schedule ............................................................................................... 23 
7.2 
Docetaxel ...................................................................................................................... 23 
7.3 
Zytiga (Abiraterone) ..................................................................................................... 24 
7.4 
Concomitant Medications and Therapies...................................................................... 24 
7.5 
Duration of Therapy ...................................................................................................... 25 
8 
TOXICITIES AND DOSEAGE MODIFICATION ............................................................. 26 
8.1 
Dose Modifications and Guidelines for Adverse Event Management.......................... 26 
8.2 
Supportive Care ............................................................................................................ 26 
8.3 
Contraception ................................................................................................................ 26 
9 
STUDY CALENDAR .......................................................................................................... 28 
10 
STUDY PROCEDURES .................................................................................................. 30 
10.1 
Screening Evaluations ................................................................................................... 30 
10.2 
On Treatment Evaluations ............................................................................................ 30 
10.2.2 
At the time of Progression, if prior to M18 visit....................................................... 31 
11 
CRITERIA FOR EVALUATION AND ENDPOINT ...................................................... 31 
11.1 
Safety ............................................................................................................................ 31 
11.2 
Efficacy ......................................................................................................................... 31 
12 
STATISTICAL CONSIDERATIONS.............................................................................. 32 


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12.1 
Primary Objective and Endpoint ................................................................................... 32 
12.2 
Statistical Hypothesis .................................................................................................... 32 
12.3 
Secondary Objective and Endpoint ............................................................................... 32 
12.4 
Sample Size Determination........................................................................................... 32 
12.5 
Statistical Methods ........................................................................................................ 32 
13 
REGISTRATION GUIDELINES ..................................................................................... 33 
14 
DATA SUBMISSION SCHEDULE ................................................................................ 33 
15 
SPECIAL INSTRUCTIONS ............................................................................................ 34 
15.1 
Correlative Studies ........................................................................................................ 34 
16 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................ 35 
16.1 
Informed consent .......................................................................................................... 35 
16.2 
Institutional Review ...................................................................................................... 35 
16.3 
SAE Reporting Requirements ....................................................................................... 38 
16.4 
Reporting of Pregnancy ................................................................................................ 38 
16.5 
Protocol Amendments ................................................................................................... 38 
16.6 
Protocol Deviations ....................................................................................................... 38 
16.7 
FDA Annual Reporting ................................................................................................. 39 
16.8 
Clinical Trials Data Bank.............................................................................................. 39 
16.9 
Record Keeping ............................................................................................................ 39 
17 
BIBLIOGRAPHY ............................................................................................................. 40 
Appendix A: FACIT Administration Guidelines .......................................................................... 42 
Appendix B: FACT-P ................................................................................................................... 43 
Appendix C: FACT/GOG – NTX ................................................................................................. 46 
Appendix E: ECOG/KPS Conversion Table ................................................................................ 48 
Appendix F: Overall Treatment Utility Form ............................................................................... 49 
Appendix G: Was It Worth It Questionnaire ................................................................................ 50 
Appendix H: End of Study Evaluation Form ................................................................................ 51 
 
 


Short Title: ACADEMIC: ADT + Docetaxel vs ADT + Abiraterone  
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LIST OF ABBREVIATION 
Abbreviation or Term1 
Definition/Explanation 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ANOVA 
Analysis of variance 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
β-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BLQ 
Below limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
Ca++ 
Calcium 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
Cl- 
Chloride 
CLcr 
Creatinine clearance 
Cmax 
Maximum observed concentration 
Cmin 
Trough observed concentration 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CV 
Coefficient of variation 
CYP 
Cytochrome P450 
D/C 
Discontinue 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
DLT 
Dose Limiting Toxicity 
ECG 
Electrocardiogram 
Eg 
Exempli gratia (for example) 
FACS 
Fluorescence Activated Cell Sorting  
FDA 
Food and Drug Administration 


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Abbreviation or Term1 
Definition/Explanation 
FDG-PET 
Fluorodeoxyglucose (FDG)-positron emission tomography (PET) 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
GLP 
Good laboratory practice  
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCO3- 
Bicarbonate 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
hr 
Hour or hours 
IC50 
Half maximal inhibitory concentration 
i.e. 
Id est (that is) 
IEC 
Independent ethics committee 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional review board 
IU 
International unit 
IV 
Intravenous, intravenously 
LDH 
Lactate dehydrogenase 
LHRH 
Luteinizing hormone releasing hormone 
LLQ 
Lower limit of quantitation 
MedRA 
Medical Dictionary for Drug Regulatory Activities 
MRI 
Magnetic resonance imaging 
MRSD 
Maximum recommended starting dose 
MTD 
Maximum tolerated dose  
NOAEL 
No-observed-adverse-effect level 
NOEL 
No-observed-effect-level 
PD 
Pharmacodynamic(s) 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PO 
Per os (administered by mouth) 
PR 
Partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QC 
Quality control 
RBC 
Red blood cell 


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Abbreviation or Term1 
Definition/Explanation 
QD 
Once daily 
QTc 
QT interval corrected  
QTcF 
QT interval corrected using Frederichia equation 
SAE 
Serious adverse event 
SD 
Standard deviation or stable disease 
T1/2 
Terminal elimination half-life 
T3 
Triiodothyronine 
T4 
Thyroxine 
Tmax 
Time of maximum observed concentration 
TID 
Three times daily 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
ULQ 
Upper limit of quantitation 
UV 
Ultraviolet 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
WONCBP 
Women of nonchildbearing potential 
1 All of these abbreviations may or may not be used in protocol.  
 


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PROTOCOL SIGNATURE 
I confirm that I have read this protocol, and I will conduct the study as outlined herein and 
according to the ethical principles stated in the latest version of the Declaration of Helsinki, the 
applicable ICH guidelines for good clinical practice, and the applicable laws and regulations of the 
federal government. I will promptly submit the protocol to the IRB for review and approval. Once 
the protocol has been approved by the IRB, I understand that any modifications made during the 
study must first be approved by the IRB prior to implementation except when such modification 
is made to remove an immediate hazard to the subject. 
I will provide copies of the protocol and all pertinent information to all individuals responsible to 
me who assist in the conduct of this study. I will discuss this material with them to ensure that they 
are fully informed regarding the study treatment, the conduct of the study, and the obligations of 
confidentiality. 
This document is signed electronically through submission and approval by the Principal 
Investigator at Huntsman Cancer Institute in the University of Utah IRB Electronic Research 
Integrity and Compliance Administration (ERICA) system. For this reason, the Principal 
Investigator at Huntsman Cancer Institute will not have a hand-written signature on this signature 
page.  
Instructions to multi-site Principal Investigators at locations other than Huntsman Cancer Institute: 
SIGN and DATE this signature page and PRINT your name. Return the original, completed and 
signed, to the HCI Research Compliance Office. Retain a copy in the regulatory binder.  
 
 
 
____________________________________ 
_______________ 
Signature of Principal Investigator  
 
Date 
 
 
 
____________________________________ 
Principal Investigator Name (Print) 
 
 
 
____________________________________ 
Name of Institution 
 
 
 


Short Title: ACADEMIC: ADT + Docetaxel vs ADT + Abiraterone  
Version Date: 13MAR2019 
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STUDY SUMMARY 
Title 
A Randomized Phase II Clinical Trial of ADT 
Combined with Abiraterone or Docetaxel in 
Metastatic Hormone Sensitive Prostate Cancer.  
Short Title 
ACADEMIC 
Protocol Identifiers (IRB – internal) 
IRB 115099 - HCI-18-GU-11 
IND number 
Exempt 
Phase 
Phase II 
Design 
This is an open label, randomized prospective 
study of ADT + Abiraterone vs. ADT + 
Docetaxel in men with metastatic hormone 
sensitive prostate cancer. 
Study Duration 
This study is expected to enroll for 24 months. 
Patients will be followed for 18 months or until 
disease progression, whichever occurs first. It 
will take approximately 3.5 years to complete 
the study. 
Study Center(s) 
This will be a multi-institution trial conducted at 
the Huntsman Cancer Institute, at the University 
of Utah. Up to 7 additional centers may be 
opened. 
Objectives 
The primary objective of this study is to assess 
the difference in QOL from baseline to month 
12 between ADT + Docetaxel vs ADT + 
Abiraterone. 
Number of Subjects 
89 patients will be enrolled. Patients will be 
randomized 1:1 to each treatment arm. 
Diagnosis and Main Eligibility Criteria 
- Male subject aged ≥ 18 years. 
- Histologically diagnosed adenocarcinoma of 
the prostate by WHO. 
- Radiographically confirmed metastatic disease 
prior to patient enrollment. Metastatic disease 
can be confirmed based on conventional 
imaging (CT, MRI, nuclear medicine bone scan) 
or molecular imaging (fluciclovine-PET/CT, 
PSMA-PET/CT, Choline-PET/CT etc). 
- ECOG ≤ 2. 
- Prior therapy with ADT or first generation 
anti-androgen receptor therapy (example: 
bicalutamide) is allowed. 
- Prior abiraterone or docetaxel use for 
metastatic hormone sensitive prostate cancer is 
not allowed. 


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- Completed any hormone therapy for localized 
prostate cancer and testosterone has recovered.  
- Patients must not have a histologic diagnosis of 
small cell prostate cancer or pure squamous cell 
prostate cancer.  
 
Study Product, Dose, Route, Regimen,  
Duration of administration 
All patients will be treated with ongoing 
standard of care ADT (surgical or medical 
castration, documented testosterone should be < 
50 ng/dL while on study.)  
 
Arm A: ADT + 75mg/m2 Docetaxel IV 
Q3weeks x 6 cycles.  
 
Arm B: ADT + Abiraterone PO continuous until 
disease progression. 
 
Statistical Methodology 
Statistical analysis will be performed in 
collaboration with HCI biostatistical support and 
use descriptive statistics as well as the Kaplan-
Meier estimates and the log-rank test. 
 
 


Short Title: ACADEMIC: ADT + Docetaxel vs ADT + Abiraterone 
Version Date:  13MAR2019 
Principal Investigator: Benjamin Maughan, MD, PharmD 
 
 
SCHEMA 
 
 
 
 


Short Title: ACADEMIC: ADT + Docetaxel vs ADT + Abiraterone 
Version Date:  13MAR2019 
Principal Investigator: Benjamin Maughan, MD, PharmD 
 
 
1 
OBJECTIVES 
1.1 
Primary Objective 
To assess the impact of abiraterone and docetaxel on total quality of life between screening 
and month 12 of the study.  
Primary Endpoint: The FACT-P questionnaire will be administered at baseline and month 12. 
Total Scores will be quantified and compared between treatment arms.  
1.2 
Secondary Objectives 
1. To assess PSA response rates across the entire population and compared between groups.  
Secondary Endpoint: PSA evaluations will occur every 3 months while on study. The 
Prostate Cancer Working Group 3 criteria (PCWG3) will be used to define PSA response 
rates of 50% and 90% reductions.  
2. To assess impact of abiraterone and docetaxel on additional quality of life measurements 
and quality of life trends throughout the duration of the study. 
Secondary Endpoint: Patient reported questionnaires—including FACT-P, FACT/GOG-
NTX, and PROMIS Fatigue—will be administered at baseline and months 3, 6, 9, 12, and 
18. Total scores, subscale scores, and trends will be analyzed. 
3. To assess the potential clinical efficacy between treatment groups.  
Secondary Endpoint: To assess the PSA progression free survival (PSA-PFS) between 
treatment arms. PSA-PFS is defined based on PCWG3 criteria.  
1.3 
Exploratory Objectives 
1. To assess biomarkers that may predict treatment response to hormonal therapy versus 
chemotherapy. Changes to tumor suppressors and the androgen receptor as well as other 
mechanisms will be analyzed from urine, blood and tumor tissue molecular analysis.  
Exploratory Endpoint: Patients will have tissue collected during this study for correlative 
analysis. Blood will be collected at baseline, and months 3, 6, and 18. Also, archival tissue 
will be collected (if available) as well as an optional soft-tissue biopsy at the time of disease 
progression.  
2. To assess additional measures of overall quality of life between groups.  
Exploratory Endpoint: The Overall Treatment Utility (OTU) form, Was It Worth It (WIWI) 
questionnaire, and End of Study Evaluation Form will be administered to patients for 
exploratory purposes. The OTU form should be completed by the treating physician at the 
patient’s 3 month visit and the WIWI questionnaire and End of Study Evaluation Form 
administered to the patient at the end of treatment (month 18 or progression visit, 
whichever comes first).   
 


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2 
BACKGROUND 
2.1 
Hypothesis 
Currently there are two competing standards of care for first-line treatment of patients with 
metastatic hormone sensitive prostate cancer (mHSPC), with docetaxel plus ADT and 
abiraterone plus ADT both demonstrating improved disease control over ADT alone. No direct 
comparisons have been done between these therapies, so the optimal treatment for these 
patients is currently not clear.  
The first studies published to demonstrate improved overall survival over monotherapy of 
androgen deprivation therapy (ADT) alone were the CHAARTED1 and STAMPEDE2 (arms 
A, B, C and E) prospective clinical trials. In the CHAARTED study, 790 patients were 
randomized to ADT alone versus ADT plus 6 cycles of docetaxel. The median overall survival 
(OS) with the addition of docetaxel was significantly longer 57.6 months vs. 44.0 months 
(hazard ratio {HR} 0.61; 95% confidence interval {CI}, 0.47—0.80; P<0.001). These finding 
were verified in the STAMPEDE trial where six cycles of docetaxel plus ADT also improved 
clinical outcomes over ADT alone. The two docetaxel arms resulted in significant 
improvement to OS compared to the two ADT alone arms with hazard ratios of 0.78 (95% CI, 
0.66—093; p=0.006) and 0.82 (95% CI, 0.69—0.97; p=0.022) respectively.  
Two studies have shown superior outcomes with the addition of abiraterone to ADT in 
mHSPC, the LATITUDE3 and STAMPEDE4 (arms A and G) clinical trials. The LATITUDE 
trial randomized 1199 patients and the STAMPEDE randomized 1917 patients to ADT versus 
ADT plus abiraterone. The combination improved the median OS in the LATITUDE trial (not 
reached vs. 34.7 months; HR 0.62; 95% CI, 0.51—0.76; P<0.001) and improved 3 year 
survival in the STAMPEDE trial at 83% vs 76% (HR 0.63; 95% CI 0.52—0.76; P<0.001).  
These two approaches of combination therapy have not been directly compared so no high-
level evidence is available to make optimal treatment choices based on clinical outcomes. 
Treatment decision is instead based on other clinical factors such as drug availability, fitness 
for chemotherapy, toxicity or cost.5  
There is likely a difference in these treatments regarding toxicities and cost. For instance, 
docetaxel is known to cause alopecia, febrile neutropenia fatigue and neuropathy. Abiraterone 
is known to cause fatigue, drug induced hepatitis and hypertension. There are differences in 
the treatment duration as well with docetaxel given for 6 cycles (approximately 4 months) 
whereas abiraterone is given until disease progression which may result in differences in 
quality of life and does result in difference in financial expense.6 The patient reported outcomes 
in the LATITUDE study favored the combination group7. The reported quality of life was 
initially worse with docetaxel than ADT alone at three months, but better than ADT alone at 
12 months in the CHAARTED study.8   
Finally, there might be molecularly identified subgroups that will preferentially respond to a 
hormonal based treatment (i.e. ADT + abiraterone) or a chemotherapy based treatment (i.e. 
ADT + docetaxel). For instance, previous studies have demonstrated some subgroups of 
patients in the castration-resistant setting that are more sensitive to docetaxel over 
abiraterone.9-11 
We hypothesize that treatment efficacy will be similar across the entire population studied in 
this clinical trial between ADT + docetaxel versus ADT + abiraterone. However, we 


Short Title: ACADEMIC: ADT + Docetaxel vs ADT + Abiraterone  
Version Date: 13MAR2019 
Page 13 of 52 
hypothesize that quality of life will be superior throughout the study for the abiraterone treated 
patients. Doing this clinical trial directly comparing these two treatment options will also allow 
for exploratory analysis of biomarkers of treatment response between hormonal versus 
chemotherapy treatment in this population of patients which may identify additional factors 
that may be important in the treatment selection between docetaxel and abiraterone for this 
patient population.  
3 
DRUG INFORMATION 
3.1 
Androgen Deprivation Therapy 
All subjects must receive ADT of Investigator’s choice (LHRH agonist or antagonist, or 
orchiectomy) per FDA approved dosing regulations as standard therapy for the duration of the 
clinical trial. Patients should maintain a castrate level testosterone concentration (i.e. total 
testosterone ≤ 50 ng/dL) as validation of therapeutic efficacy for the chosen ADT therapy.  
3.2 
Docetaxel (Taxotere) 
Docetaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells 
that is essential for mitotic and interphase cellular functions.  
Refer to Sanofi Package Insert for detail regarding clinical administration of TAXOTERE. The 
following information is taken from the Package Insert 
3.2.1 
Pharmacology 
Docetaxel binds to free tubulin and promotes the assembly of tubulin into stable microtubules 
while simultaneously inhibiting their disassembly. This leads to the production of microtubule 
bundles without normal function and to the stabilization of microtubules, which results in the 
inhibition of mitosis in cells. 
The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration 
of 20 mg/m2 to 115 mg/m2 in phase 1 studies. The area under the curve (AUC) was dose 
proportional following doses of 70 mg/m2 to 115 mg/m2 with infusion times of 1 to 2 hours. 
Docetaxel’s pharmacokinetic profile is consistent with a three-compartment pharmacokinetic 
model, with half-lives for the α, β, and γ phases of 4 min, 36 min, and 11.1 hr, respectively. 
Mean total body clearance was 21 L/h/m2.  
Distribution: The initial rapid decline represents distribution to the peripheral compartments 
and the late (terminal) phase is due, in part, to a relatively slow efflux of docetaxel from the 
peripheral compartment. Mean steady state volume of distribution was 113 L. In vitro studies 
showed that docetaxel is about 94% protein bound, mainly to α1-acid glycoprotein, albumin, 
and lipoproteins. In three cancer patients, the in vitro binding to plasma proteins was found to 
be approximately 97%. Dexamethasone does not affect the protein binding of docetaxel.  
Metabolism: In vitro drug interaction studies revealed that docetaxel is metabolized by the 
CYP3A4 isoenzyme, and its metabolism may be modified by the concomitant administration 
of compounds that induce, inhibit, or are metabolized by cytochrome P450 3A4.  
Elimination: A study of 14C-docetaxel was conducted in three cancer patients. Docetaxel was 
eliminated in both the urine and feces following oxidative metabolism of the tert-butyl ester 


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group, but fecal excretion was the main elimination route. Within 7 days, urinary and fecal 
excretion accounted for approximately 6% and 75% of the administered radioactivity, 
respectively. About 80% of the radioactivity recovered in feces is excreted during the first 48 
hours as 1 major and 3 minor metabolites with very small amounts (less than 8%) of unchanged 
drug 
3.2.2 
Pharmaceutical Properties and Formulation  
Docetaxel is an antineoplastic agent belonging to the taxoid family. It is prepared by 
semisynthesis beginning with a precursor extracted from the renewable needle biomass of yew 
plants. The chemical name for docetaxel is (2R,3S)-N-carboxy-3-phenylisoserine,N-tert-butyl 
ester, 13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one 4-acetate 2-
benzoate, trihydrate. Docetaxel is a white to almost-white powder with an empirical formula 
of C43H53NO14• 3H2O, and a molecular weight of 861.9. It is highly lipophilic and 
practically insoluble in water 
3.2.3 
Clinical Safety 
The following data are based on the experience of 332 prostate cancer patients, who were 
treated with TAXOTERE 75 mg/m² every 3 weeks in combination with prednisone 5 mg orally 
twice daily: 
 


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3.3 
Abiraterone Acetate (Abiraterone) 
Abiraterone is an inhibitor of CYP17 (17α-hydroxylase/C17,20-lyase). 
Abiraterone for this trial will be dispensed as part of the patient’s standard of care therapy. 
Depending on insurance and/or physician preference, Zytiga, Yonsa, or a generic abiraterone 
acetate will be allowed. Dosing for each regimen should be consistent with FDA prescribing 
information. 
Refer to Package Insert for detail regarding clinical administration of Zytiga, Yonsa, or generic 
abiraterone acetate. The following information is taken from these documents: 
3.3.1 
Pharmacology 
Abiraterone acetate (abiraterone) is converted in vivo to abiraterone, an androgen biosynthesis 
inhibitor, that inhibits 17 α-hydroxylase/C17,20-lyase (CYP17). This enzyme is expressed in 
testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis. 
CYP17 catalyzes two sequential reactions: 1) the conversion of pregnenolone and progesterone 
to their 17α-hydroxy derivatives by 17α-hydroxylase activity and 2) the subsequent formation 
of dehydroepiandrosterone (DHEA) and androstenedione, respectively, by C17, 20 lyase 
activity. DHEA and androstenedione are androgens and are precursors of testosterone. 


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Inhibition of CYP17 by abiraterone can also result in increased mineralocorticoid production 
by the adrenals. Androgen sensitive prostatic carcinoma responds to treatment that decreases 
androgen levels. Androgen deprivation therapies, such as treatment with GnRH agonists or 
orchiectomy, decrease androgen production in the testes but do not affect androgen production 
by the adrenals or in the tumor. Abiraterone decreased serum testosterone and other androgens 
in patients in the placebo-controlled clinical trial. It is not necessary to monitor the effect of 
Abiraterone on serum testosterone levels. Changes in serum prostate specific antigen (PSA) 
levels may be observed but have not been shown to correlate with clinical benefit in individual 
patients.  
3.3.2 
Physical and Chemical Properties 
Abiraterone acetate is a white to off-white, non-hygroscopic, crystalline powder. Its molecular 
formula is C26H33NO2 and it has a molecular weight of 391.55. Abiraterone acetate is a 
lipophilic compound with an octanol-water partition coefficient of 5.12 (Log P) and is 
practically insoluble in water. The pKa of the aromatic nitrogen is 5.19. 
3.3.3 
Pharmaceutical Properties and Formulation  
Zytiga 
Each Zytiga tablet contains either 250 mg or 500 mg of abiraterone acetate. Abiraterone acetate 
is designated chemically as (3β)-17-(3-pyridinyl) androsta5,16-dien-3-yl acetate.  
Zytiga tablets are available in 500  mg film-coated tablets, 250 mg film-coated tablets and 
250 mg uncoated tablets with the following inactive ingredients:  
 • 500 mg film-coated tablets: colloidal silicon dioxide, croscarmellose sodium, hypromellose, 
lactose monohydrate, magnesium stearate, silicified microcrystalline cellulose, and sodium 
lauryl sulfate. The coating, Opadry® II Purple, contains iron oxide black, iron oxide red, 
polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. 
• 250 mg film-coated tablets: colloidal silicon dioxide, croscarmellose sodium, lactose 
monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl 
sulfate. The coating, Opadry® II Beige, contains iron oxide red, iron oxide yellow, 
polyethylene glycol, polyvinyl alcohol, talc, and titanium dioxide. 
• 250 mg uncoated tablets: colloidal silicon dioxide, croscarmellose sodium, lactose 
monohydrate, magnesium stearate, microcrystalline cellulose, povidone, and sodium lauryl 
sulfate 
Yonsa 
Yonsa (abiraterone acetate) tablets, 125 mg, are white to off-white, oval-shaped tablets 
debossed with “125 FP” on one side. 
3.3.4 
Clinical Safety 
Zytiga 
In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-
resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist 
or were previously treated with orchiectomy, abiraterone was administered at a dose of 1,000 
mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 


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791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The 
median duration of treatment with Abiraterone was 8 months. The most common adverse drug 
reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, 
edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, 
arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection. The 
most common adverse drug reactions that resulted in drug discontinuation were aspartate 
aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure 
(each in <1% of patients taking abiraterone). 
Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were 
reported more commonly in patients treated with abiraterone than in patients treated with 
placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention 
(edema) 27% versus 18%, respectively. In patients treated with abiraterone, grades 3 to 4 
hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of 
patients. 
Cardiovascular Adverse Reactions: 
The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates 
in the two arms. There was one death associated with arrhythmia and one patient with sudden 
death in the abiraterone arm. No patients had sudden death or arrhythmia associated with death 
in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the 
placebo arm and 1 death in the abiraterone arm. Cardiac failure resulting in death occurred in 
1 patient on both arms. 
Hepatotoxicity: 
Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported 
in patients treated with abiraterone. Across all clinical trials, liver function test elevations (ALT 
or AST increases of > 5X ULN) were reported in 2.3% of patients who received abiraterone, 
typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose 
baseline ALT or AST were elevated were more likely to experience liver function test 
elevations than those beginning with normal values. When elevations of either ALT or AST > 
5X ULN, or elevations in bilirubin > 3X ULN were observed, abiraterone was withheld or 
discontinued. In two instances marked increases in liver function tests occurred. These two 
patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X 
ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of abiraterone, both patients 
had normalization of their liver function tests and one patient was re-treated with 
ABIRATERONE without recurrence of the elevations. In clinical trials, the following patients 
were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X 
ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the 
presence of liver metastases. Abnormal liver function tests developing in patients participating 
in clinical trials were managed by treatment interruption, dose modification and/or 
discontinuation [see Dosage and Administration (2.2) and Warnings and Precautions (5.3)]. 
Patients with elevations of ALT or AST > 20X ULN were not re-treated.  


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Yonsa 
Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: 
Yonsa may cause hypertension, hypokalemia, and fluid retention as a consequence of increased 
mineralocorticoid levels resulting from CYP17 inhibition. Monitor patients for hypertension, 
hypokalemia, and fluid retention at least once a month. Control hypertension and correct 
hypokalemia before and during treatment with Yonsa.  
In the two randomized clinical trials, grade 3 to 4 hypertension occurred in 2% of patients, 
grade 3 to 4 hypokalemia in 4% of patients, and grade 3 to 4 edema in 1% of patients treated 
with abiraterone acetate.  
Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, 
resulting in a reduction in the incidence and severity of these adverse reactions. Closely 
monitor patients whose underlying medical conditions might be compromised by increases in 
blood pressure, hypokalemia or fluid retention, such as those with heart failure, recent 
myocardial infarction, cardiovascular disease, or ventricular arrhythmia. The safety of Yonsa 
in patients with left ventricular ejection fraction < 50% or New York Heart Association 
(NYHA) Class III or IV heart failure (in Study 1) or NYHA Class II to IV heart failure (in 
Study 2) was not established because these patients were excluded from these randomized 
clinical trials. 
Adrenocortical Insufficiency:  
Adrenal insufficiency occurred in the two randomized clinical studies in 0.5% of patients 
taking abiraterone acetate and in 0.2% of patients taking placebo. Adrenocortical insufficiency 
was reported in patients receiving abiraterone acetate in combination with corticosteroid, 
following interruption of daily steroids and/or with concurrent infection or stress.  
Monitor patients for symptoms and signs of adrenocortical insufficiency, particularly if 
patients are withdrawn from corticosteroids, have corticosteroid dose reductions, or experience 
unusual stress. Symptoms and signs of adrenocortical insufficiency may be masked by adverse 
reactions associated with mineralocorticoid excess seen in patients treated with Yonsa. If 
clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical 
insufficiency. Increased dosage of corticosteroids may be indicated before, during and after 
stressful situations. 
Hepatotoxicity:  
In postmarketing experience, there have been abiraterone acetate-associated severe hepatic 
toxicity, including fulminant hepatitis, acute liver failure and deaths.  
In the two randomized clinical trials, grade 3 or 4 ALT or AST increases (at least 5X ULN) 
were reported in 4% of patients who received abiraterone acetate, typically during the first 3 
months after starting treatment. Patients whose baseline ALT or AST were elevated were more 
likely to experience liver test elevation than those beginning with normal values. Treatment 
discontinuation due to liver enzyme increases occurred in 1% of patients taking abiraterone 
acetate. No deaths clearly related to abiraterone acetate were reported due to hepatotoxicity 
events.  
Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment 
with Yonsa, every two weeks for the first three months of treatment and monthly thereafter. In 


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patients with baseline moderate hepatic impairment receiving a reduced Yonsa dose of 125 
mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first 
month, every two weeks for the following two months of treatment and monthly thereafter. 
Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs 
suggestive of hepatotoxicity develop. Elevations of AST, ALT, or bilirubin from the patient's 
baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five 
times the ULN, or the bilirubin rises above three times the ULN, interrupt Yonsa treatment and 
closely monitor liver function.  
Re-treatment with Yonsa at a reduced dose level may take place only after return of liver 
function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and 
total bilirubin less than or equal to 1.5X ULN. Permanently discontinue treatment with 
abiraterone acetate for patients who develop a concurrent elevation of ALT greater than 3 x 
ULN and total bilirubin greater than 2 x ULN in the absence of biliary obstruction or other 
causes responsible for the concurrent elevation. The safety of YONSA re-treatment of patients 
who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or 
equal to 10X ULN is unknown. 
4 
STUDY DESIGN 
4.1 
Description 
This is an open label, randomized prospective clinical trial. All patients will be treated with 
ongoing standard of care ADT (surgical or medical castration, documented testosterone < 50 
ng/dL while on study) plus either docetaxel intravenously (75mg/m2) once every 3 weeks for 
6 cycles or abiraterone orally until disease progression. Treatment will occur per standard of 
care at the discretion of the treating physician. Radiographic disease assessment will be 
performed per clinical indication. Study visits time points will be based on day 1 of treatment 
and follow a consistent schedule, regardless of treatment delays. Patients will be followed until 
disease progression or for 18 months, whichever occurs first. 
4.2 
Number of Patients 
A total of 89 subjects will be enrolled. 
4.3 
Number of Study Centers 
This will be a multi-institution trial conducted at the Huntsman Cancer Institute, at the 
University of Utah. Up to an additional 7 other centers may be opened. 
4.4 
Study Duration  
This trial is expected complete enrollment within 24 months. Treatment is expected to continue 
for an additional 18 months. The study will be completed after approximately 42 months. 
 
 


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5 
ELIGIBILITY CRITERIA 
This eligibility checklist is used to determine patient eligibility and filed with the enrolling 
investigator’s signature in the patient research chart.  
Patient No. ______________________ 
Patient’s Initials: (L,F,M) _________________ 
5.1 
Inclusion Criteria 
Yes/No (Response of “no” = patient ineligible) 
5.1.1 
_____ Male subject aged ≥ 18 years. 
5.1.2 
_____ Histologically diagnosed adenocarcinoma of the prostate. 
5.1.3 
_____ Radiographically confirmed metastatic disease prior to patient enrollment. 
Metastatic disease can be confirmed based on conventional imaging (CT, MRI, 
nuclear medicine bone scan) or molecular imaging (fluciclovine-PET/CT, PSMA-
PET/CT, Choline-PET/CT etc).  
5.1.4 
_____ ECOG Performance Status ≤ 2. 
5.1.5 
_____ Adequate organ function as defined as:  
• Hematologic:  
o Absolute neutrophil count (ANC) ≥ 1.5 k/µL. 
o Platelets ≥ 100 k/µL. 
o Hemoglobin ≥ 9 g/dL. 
• Hepatic:  
o Serum total bilirubin ≤ 1.5 times upper limit of normal (ULN) OR direct 
bilirubin ≤ ULN for subjects with total bilirubin ≥ 1.5 × ULN.  
o AST or ALT ≤ 2.5 × ULN OR ≤ 4 × ULN for subjects with liver 
metastases. 
• Renal:  
o Creatinine < 1.5 × ULN OR 
o Creatinine clearance > 50 mL/min for subject with creatinine levels > 1.5 
× ULN by Cockcroft-Gault fomula or standard institutional practice:  
 Males: 
(140−𝑎𝑎𝑎𝑎𝑎𝑎)×𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡[𝑘𝑘𝑘𝑘]
𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 ቂ𝑚𝑚𝑚𝑚
𝑑𝑑𝑑𝑑ቃ×72 
 Females: ቆ
(140−𝑎𝑎𝑎𝑎𝑎𝑎)×𝑤𝑤𝑤𝑤𝑤𝑤𝑤𝑤ℎ𝑡𝑡[𝑘𝑘𝑘𝑘]
𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 ቂ𝑚𝑚𝑚𝑚
𝑑𝑑𝑑𝑑ቃ×72ቇ× 0.85  
 


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5.1.6 
____ Highly effective method of contraception for both male and female partners of 
subjects throughout the study and for at least 3 months after last study treatment 
administration if the risk of conception exists. 
5.1.7 
_____ Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any 
prior treatments, unless AE(s) are clinically nonsignificant and/or stable on 
supportive therapy as defined by the treating physician. 
5.1.8 
_____ Able to provide informed consent and willing to sign an approved consent 
form that conforms to federal and institutional guidelines. 
5.2 
Exclusion Criteria 
Yes/No (Response of “yes” = patient ineligible) 
5.2.1 
_____ No prior abiraterone or docetaxel therapy for metastatic hormone sensitive 
prostate cancer. Prior therapy with ADT or first generation anti-androgen receptor 
therapy (example: bicalutamide) is allowed. 
5.2.2 
_____ Completed any hormone therapy for localized prostate cancer and have 
recovery of testosterone (i.e. testosterone level is >50ng/dL).  
5.2.3 
_____ Patients have a histologic diagnosis of small cell prostate cancer or pure 
squamous cell prostate cancer.  
5.2.4 
_____ Known brain metastases or cranial epidural disease unless adequately treated 
with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 
weeks before first dose of study treatment. Eligible subjects must be neurologically 
asymptomatic and without corticosteroid treatment at the time of first dose of study 
treatment.  
5.2.5 
_____ The subject has uncontrolled, significant intercurrent or recent illness 
including, but not limited to, the following conditions: 
• Cardiovascular disorders: 
o Congestive heart failure New York Heart Association Class 3 or 4, unstable 
angina pectoris, serious cardiac arrhythmias within 3 months of study 
enrollment.  
o Uncontrolled hypertension defined as sustained blood pressure (BP) > 170 
mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive 
treatment. 
o Stroke (including transient ischemic attack [TIA]), myocardial infarction 
(MI), or other ischemic event, or arterial thromboembolic event within 3 
months before first dose.  
• Other clinically significant disorders that would preclude safe study participation. 
As defined by the treating physician  


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5.2.6 
_____ Known history of testing positive for HIV and CD4 count is below 200 or 
known acquired immunodeficiency syndrome diagnosis. 
5.2.7 
_____ Known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection 
at screening (positive HBV surface antigen or detectable HCV RNA if anti-HCV 
antibody screening test positive) and a detectable viral count at screening.  
5.2.8 
_____ Use of live virus vaccine within 4 weeks of the first dose of treatment or 
planned use while on trial for the duration of potential docetaxel treatment. Live 
vaccine use is acceptable after chemotherapy or for patients randomized to the 
abiraterone arm. There are no restrictions on inactive viruses. 
5.2.9 
_____ Known prior severe hypersensitivity to investigational product or any 
component in its formulations (NCI CTCAE v5.0 Grade ≥ 3). 
I certify that this patient meets all inclusion and exclusion criteria for enrollment onto this 
study.  
__________________________________  
 
 
_________ 
_______ 
Investigator Signature  
 
 
 
 
 
Date  
Time 
 
 
 
 


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5.3 
Recruitment Strategies 
Potential patients will be identified by Investigators in the setting of their outpatient clinics. 
6 
RANDOMIZATION 
Patients will be randomized in a 1:1 manner. Patients will be stratified based on Gleason score 
(< 8 versus ≥ 8) and the presence of visceral metastasis (yes versus no). Visceral metastasis is 
defined as liver, lung, or central nervous system (CNS) involvement.  
7 
TREATMENT PLAN 
7.1 
Administration Schedule 
Treatment will occur per standard of care at the discretion of the treating physician. All study 
drugs will be provided by commercial supply. Study visits will be anchored to day 1 of 
treatment, without regard for changes to treatment schedule. 
Patients who are unable to initiate docetaxel or abiraterone therapy within 42 days of 
randomization will be replaced. 
7.2 
Docetaxel 
7.2.1 
How Supplied, Stored, Packaged and Labeled 
Docetaxel Injection Concentrate is a clear yellow to brownish-yellow viscous solution. 
Docetaxel is sterile, non-pyrogenic, and is available in single-dose vials containing 20 mg (0.5 
mL) or 80 mg (2 mL) docetaxel (anhydrous). Each mL contains 40 mg docetaxel (anhydrous) 
and 1040 mg polysorbate 80.  
TAXOTERE Injection Concentrate requires dilution with Diluent prior to addition to the 
infusion bag. A sterile, non-pyrogenic, single-dose diluent is supplied for that purpose. The 
diluent for TAXOTERE contains 13% ethanol in water for injection, and is supplied in vials. 
7.2.2 
Preparation and Administration 
The docetaxel should be dosed and administered per institutional standards in accordance with 
FDA approved usage. Cycles should be repeated approximately every 3 weeks for 6 cycles. 
Treatment delays and potential dose modifications will occur per standard of care at the 
discretion of the treating physician, to reflect the clinical setting as much as possible. 
The recommended pre–medication regimen is oral dexamethasone 8 mg, 12 hours, 3 hours and 
1 hour before the docetaxel infusion. However, other schedules or use of a different 
corticosteroid is also acceptable consistent with local practice. Anti-emetic regimens are 
recommended as per local clinical practice. 
Preparation procedures are detailed in the package insert.  


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7.3 
Zytiga (Abiraterone) 
7.3.1 
How Supplied, Stored, Packaged and Labeled 
Zytiga 
250 mg tablets are white to off-white, oval tablets debossed with AA250 on one side. Zytiga 
250 mg tablets are available in high-density polyethylene bottles of 120 tablets.  
Store at 20o C to 25o C (68o F to 77o F); excursions permitted to 15o C to 30o C (59o F to 86°F). 
Based on its mechanism of action, Zytiga may harm a developing fetus. Therefore, women 
who are pregnant or women who may be pregnant should not handle Zytiga without protection 
(e.g., gloves). 
Yonsa 
Tablets, 125 mg, are white to off-white, oval-shaped tablets debossed with “125 FP” on one 
side. 
Store at 20o C to 25o C (68o F to 77o F); excursions permitted to 15o C to 30o C (59o F to 86°F). 
Women who are pregnant or women who may be pregnant should not handle Yonsa without 
protection, e.g., gloves. 
7.3.2 
Preparation and Administration 
Zytiga  
The Zytiga should be dosed and administered per institutional standards and in accordance 
with FDA approved use. The package insert recommends 1,000 mg administered orally once 
daily in combination with prednisone 5 mg administered orally twice daily. No food should be 
consumed for at least two hours before the dose of Zytiga is taken and for at least one hour 
after the dose of Zytiga is taken. 
Yonsa 
The Yonsa should be dosed and administered per institutional standards and in accordance 
with FDA approved use. The recommended dose of YONSA is 500 mg (four 125 mg tablets) 
administered orally once daily in combination with methylprednisolone 4 mg administered 
orally twice daily with or without food. 
7.3.3 
Accountability and Compliance 
Abiraterone tablets will be supplied per standard practice of the treating physician and 
pharmacy. 
7.4 
Concomitant Medications and Therapies 
7.4.1 
Prohibited Therapy 
7.4.1.1 Docetaxel 
Docetaxel is a CYP3A4 substrate. In vitro studies have shown that the metabolism of 
docetaxel may be modified by the concomitant administration of compounds that 
induce, inhibit, or are metabolized by cytochrome P450 3A4. In vivo studies showed 


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that the exposure of docetaxel increased 2.2-fold when it was coadministered with 
ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, 
may increase the exposure of docetaxel. Concomitant use of docetaxel and drugs that 
inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. In patients 
receiving treatment with docetaxel, close monitoring for toxicity and a docetaxel dose 
reduction could be considered if systemic administration of a potent CYP3A4 inhibitor 
cannot be avoided 
7.4.1.2 
Abiraterone 
Abiraterone is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a 
CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan 
(CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when 
dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 
mg twice daily. Avoid coadministration of abiraterone acetate with substrates of 
CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments 
cannot be used, exercise caution and consider a dose reduction of the concomitant 
CYP2D6 substrate drug. 
Abiraterone is also a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors 
(e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, 
telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, 
carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics 
of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong 
inhibitors and inducers of CYP3A4 during abiraterone treatment. 
7.5 
Duration of Therapy 
Arm A: Patients will receive 6 cycles of docetaxel, given approximately every 3 weeks, in 
addition to physician’s choice ADT. 
Arm B: Patients will receive abiraterone continuously, in addition to physician’s choice ADT, 
until disease progression. 
7.5.1 
Criteria for discontinuation of treatment (“off treatment”) 
The following will result in treatment discontinuation: 
• Subject withdraws consent from the study treatment and/or study procedures.  
• Diagnosis of progression, per the discretion of the treating physician. The protocol 
suggests defining progression based on radiographic or clinical progression and not 
PSA only progression.  
• AEs or intercurrent illness that in the opinion of the investigator warrants the subject’s 
withdrawal from study treatment. 
• Significant noncompliance with the protocol schedule or treatment administration in 
the opinion of the investigator.  
7.5.2 
Criteria for discontinuation of study (“off study”) 
Subjects will be taken off study for the following: 


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• Completed study follow-up period 
• Participant requests to be withdrawn from study 
• Death 
• Subject is lost to follow-up 
8 
TOXICITIES AND DOSEAGE MODIFICATION 
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for adverse event and serious adverse event reporting. 
8.1 
Dose Modifications and Guidelines for Adverse Event Management  
8.1.1 
Dose Modifications 
Dose adjustments for ADT, docetaxel, and abiraterone will be left to the discretion of treating 
investigator. Toxicities should be monitored and managed per institutional practice. 
8.2 
Supportive Care 
All supportive measures consistent with optimal patient care may be given throughout the 
study. 
8.3 
Contraception 
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Male subjects of reproductive potential must agree to avoid impregnating a partner while 
receiving study drug and for 3 months after the last dose of study drug by complying with one 
of the following:  
(1) practice abstinence from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡: 
• Single method (one of the following is acceptable): 
o intrauterine device (IUD) 
o contraceptive rod implanted into the skin 
• Combination method (requires use of two of the following): 
o diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
o cervical cap with spermicide (nulliparous women only)   
o contraceptive sponge (nulliparous women only)  
o male condom or female condom (cannot be used together) 


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o hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
Subjects should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to 
participate in the study subjects of childbearing potential must adhere to the contraception 
requirement (described above) from the day of study medication initiation (or 14 days prior 
to the initiation of study medication for oral contraception) throughout the study period up 
to 3 months for males after the last dose of trial therapy. If there is any question that a 
subject of childbearing potential will not reliably comply with the requirements for 
contraception, that subject should not be entered into the study. 
 


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9 
STUDY CALENDAR 
Note: All visits will be based on treatment start date and will be performed independent of treatment cycles and/or delays. 1 
month will be defined as 28 days. 
 
 
Protocol Procedures 
Screening1 
Months (+/- 4 days) 
Progression11 
M0 
(Day 1) 
M3 
M6 
M9 
M12 
M18 
Informed Consent 
X 
 
  
  
  
  
  
 
Inclusion/Exclusion Criteria 
X 
 
  
  
  
  
  
 
Vital Signs 
X2 
 
 
 
 
 
 
 
Physical Exam with ECOG 
X 
 
 
 
 
 
 
 
Complete Blood Count (CBC) with Platelet Count, Differential 
X 
 
 
 
 
 
 
 
Comprehensive Metabolic Panel (CMP) 
X 
 
 
 
 
 
 
 
Urinalysis 
X 
 
  
  
  
  
  
 
Testosterone 
X 
X9 
 
PSA 
 
X8 
X 
X 
 X 
X 
X 
X 
CT – Chest/Abdomen/Pelvis10 
X 
X3 
X 
Whole Body Bone Scan 
X 
X3 
X 
Archival Tissue Submission (if available) 
 
X4 
  
  
  
  
 
 
Fresh Tissue Collection 
X5 
Correlative Blood Collection6  
 
X8 
X 
X 
 
 
X 
X 
ADT + Docetaxel or ADT + Abiraterone 
  
X7 
 
Questionnaires – FACT P, FACT/GOG-NTX, PROMIS Fatigue 
  
X8 
X 
X 
X  
X 
X 
 
Adverse Event Collection13 
 
X 
X 
X 
X 
X 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
Exploratory Questionnaires12  
 
 
X 
 
 
 
X 
X 
Extent of Metastases Form (Appendix I) 
X 
 
 
 
 
 
 
 


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1) Screening procedures should be performed within 28 days of Day 1 (Treatment initiation). There is no window designated for the screening diagnostic 
CT and/or bone scan prior to study enrollment. 
2) Vitals include height, weight, blood pressure, pulse, and temperature. 
3) To be repeated per clinical indication. 
4) To be performed prior M3 visit. 
5) If the patient has consented to optional tissue collection, tissue may be collected from any SOC biopsy performed while on trial or at the end of treatment 
(month 18 or progression visit, whichever comes first).  
6) If the patient consents to optional blood collection, blood will be collected at month 0 (prior to treatment), month 3, month 6 and the end of treatment 
(month 18 or progression visit, whichever comes first). 
7) Treatment length will depend on randomization assignment. Arm A will receive ADT + Docetaxel IV approximately Q3weeks x 6 cycles. Arm B will 
receive ADT + Abiraterone PO (per drug-specific dosing guidelines), unless there is disease progression. 
8) To be performed prior to treatment initiation on Day 1. If treatment initiation is delayed by >4 days after completion of baseline questionnaires, these 
should be repeated. 
9) Testosterone should be monitored monthly, or per institutional standard of care, to confirm castrate level testosterone concentration (i.e. total 
testosterone ≤ 50 ng/dL). 
10) Imaging techniques and sequences should be performed per institutional standard of care. Axumin PET CT Skull Base to Mid-Thigh will be allowed 
at screening. 
11) Procedures required at the time of progression will be performed within +/- 30 days of diagnosis of progression. Diagnosis of progression is per the 
discretion of the treating physician. The protocol suggests defining progression based on radiographic or clinical progression and not PSA only 
progression.  
12) The Overall Treatment Utility (OTU) form, Was It Worth It (WIWI) questionnaire, and End of Study Evaluation Form will be administered to patients 
for exploratory purposes. The OTU for should be completed by the treating physician at the patient’s 3 month visit and the WIWI questionnaire and 
End of Study Evaluation Form administered to the patient at the end of treatment (month 18 or progression visit, whichever comes first). 
13) Due to extensive characterization of study treatment regimens through previous clinical trials and in the standard clinical context, adverse event 
collection will be limited in scope and occur in accordance with recording and reporting guidelines set forth in Section 16.2.  
 
 


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10 
STUDY PROCEDURES 
10.1 
Screening Evaluations 
• Informed Consent 
• Review of Inclusion/Exclusion Criteria 
• Review of Medical History 
• Vital Signs, including height, weight, blood pressure, pulse, and temperature 
• Physical Exam 
• ECOG Performance Status 
• Laboratory assessments: 
o CBC with differential 
o CMP, including Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Alanine 
Aminotransferase, Total Bilirubin, Calcium, Carbon Dioxide, Creatinine, Chloride, 
Glucose, Potassium, Protein, Sodium, and Urea Nitrogen 
o Urinalysis 
o Prostate-specific antigen (PSA) 
o Testosterone 
• CT scans of chest/abdomen/pelvis 
• Whole body bone scan 
10.2 
On Treatment Evaluations 
After the patient is determined to be eligible and is registered on the trial he will be randomized 
1:1 using block randomization to ADT + abiraterone or ADT + docetaxel. Treatment will occur 
per standard of care at the discretion of the treating physician. Radiographic disease assessment 
will be performed per clinical indication and at the time of progression. Study visits time points 
will be based on day 1 of treatment and follow a consistent schedule, regardless of treatment 
delays. Patients will be followed until disease progression or for 18 months, whichever occurs 
first. 
10.2.1 
Day 1 (Month 0) and at Months 3, 6, 9, 12, 18 
• Archival Tissue Submission. This should be performed anytime between registration and 
prior M3 visit. 
• Laboratory assessments: 
o Prostate-specific antigen (PSA) 
• Correlative Blood Collection – Only months 0 (prior to treatment), 3, 6, and 18 or at 
progression, if prior. (optional) 
• Questionnaires: 
o FACT-P-TOI 
o FACT/GOG-NTX 


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 To avoid duplicate FACT answers, subjects only need to complete the 
11 additional questions that specifically address sensory and motor 
neuropathy symptoms within the FACT/GOG-NTX. [Appendix C] 
o PROMIS Fatigue 
• Tissue may be procured from a standard of care biopsy at any point while on study. 
• Month 3 Only – Overall Treatment Utility (OTU) form to be completed by treating 
physician 
• Month 18 Only, if patient has not progressed prior - Was It Worth It (WIWI) questionnaire 
and End of Study Evaluation Form to be completed by patient 
10.2.2 
At the time of Progression, if prior to M18 visit 
• Correlative Blood Collection  
• Tissue may be procured from a standard of care biopsy at the time of progression. 
• CT scans of chest/abdomen/pelvis  
• Whole body bone scan 
• Was It Worth It (WIWI) questionnaire and End of Study Evaluation Form to be completed 
by patient 
11 
CRITERIA FOR EVALUATION AND ENDPOINT 
11.1 
Safety 
Routine safety and tolerability may be evaluated from the results of reported signs and 
symptoms, scheduled physical examinations, vital sign measurements, and clinical laboratory 
test results. More frequent safety evaluations may be performed if clinically indicated or at the 
discretion of the investigator.  
Physical Examination 
Complete and symptom-directed physical examinations will be performed by a licensed 
physician (or physician’s assistant or nurse practitioner). 
Vital Signs 
Vital signs (blood pressure, respiratory rate, pulse rate and temperature) will be obtained per 
institutional practice. Height and weight will be taken at screening. 
Safety Laboratory Determinations 
Laboratory evaluations will be performed as noted in the flow chart. 
11.2 
Efficacy 
Prostate-specific antigen will be evaluated throughout treatment to determine optimal PSA 
response in both arms as well as PSA-PFS time points between treatment arms. This study will 
use the PCGW3 criteria to define PSA-PFS18. PCWG3 defines PSA progression as the date 
that an increase of 25% or more and absolute increase of 2 ng/mL or more from the nadir are 
documented. For patients who had an initial PSA decline during treatment, this must be 
confirmed by a second value 3 or more weeks later. 


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12 
STATISTICAL CONSIDERATIONS 
12.1 
Primary Objective and Endpoint 
To assess the impact of abiraterone and docetaxel on total quality of life between screening 
and month 12 of the study.  The Functional Assessment of Cancer Therapy -Prostate (FACT-
P) questionnaire will be administered at baseline and month 12. The FACT-P is a 39 item 
questionnaire that measures health-related quality of life in men with prostate cancer.14 The 
FACT-P Trial Outcome Index (TOI) is the sum of the Physical Well-Being (PWB), Functional 
Well-Being (FWB), and Prostate Cancer Subscales (PCS). TOI Scores will be quantified and 
compared between treatment arms. 
12.2 
Statistical Hypothesis 
We hypothesize that abiraterone will have improved quality of life measurements at month 12 
compared to docetaxel based on comparison of data from CHAARTED8 and LATITUDE.7  
12.3 
Secondary Objective and Endpoint 
- 
FACT/GOG-NTX: The FACT/GOG-NTX is a 38 item questionnaire that assesses patient 
self-report of neuropathy.15 It is a combination of the 27-item FACT-G (which is also part 
of the FACT-P) plus 11 additional questions that specifically address sensory and motor 
neuropathy symptoms. 
- 
PROMIS Fatigue: The PROMIS Fatigue scale is a 7-item self-report measure designed to 
assess severity, frequency, and daily pattern of fatigue (www.nihpromis.com). It has been 
validated in cancer populations.16 
12.4 
Sample Size Determination 
We hypothesize that patients on the ADT + Abiraterone arm will experience a superior overall 
QOL at month 12 after enrollment in the study. Cella (2008) reports that a minimally important 
difference in FACT-P TOI is a (standardized) effect size of 0.42 – 0.57.  Power was calculated 
via simulations in R using a Gaussian approximation for FACT-TOI analyzed using a mixed 
effects model with fixed effects for treatment arm and categorical assessment time and a 
random intercept for each subject. We assumed correlation = 0.5 between baseline and follow 
up FACT-P TOI. We computed power for a comparison of the standardized change in FACT-
P TOI from baseline to 12 months. With the above assumption 40 subjects with complete data 
per group will provide 80% power to detect a standardized effect size difference of 0.56 
between the randomized groups at two sided alpha = 0.05.  
The sample size of 80 patients is calculated based on the number of patients with complete 
data.  If there are patients with incomplete follow up data, they will contribute to the intent to 
treat population. We assume 10% of patients will have incomplete data. To account for this 
increased uncertainty the sample size will be increased to 89. 
12.5 
Statistical Methods 
Quality Of Life Endpoints 
The primary and secondary outcome variables are patient reported quality of life, including the 
FACT-P TOI (the primary outcome variable), and FACT/GOG NTX and PROMIS Fatigue 


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(secondary outcome variables) assessed at baseline, 3, 6, 9, 12, and 18 months. Each of these 
outcomes will be analyzed using Gaussian repeated measures mixed-effects models. The 
models will contain random intercepts, fixed effects for each follow up assessment time and 
interaction terms for treatment arm and follow up assessment time. The primary analysis will 
be use a modified intent-to-treat strategy. Multiple imputation methods will be used to impute 
missing questionnaire data for each subject who completes a baseline questionnaire. The mixed 
effects models will also be used to report the mean and standard error of the change from 
baseline at each of the follow up time points at which the questionnaires are administered (3, 
6, 9, 12, 18 months).  The area under the curve from 0 to 12 months will also be reported. Joint 
modeling of longitudinal FACT-P TOI and survival may be used as an additional sensitivity 
analysis to explore changes in QOL over time. 
The primary hypothesis is that patients on the ADT + Abiraterone arm will experience a 
superior overall QOL at month 12 after enrollment in the study. This single primary hypothesis 
will be tested at the two sided 0.05 significance level (unadjusted) using the interaction term 
between treatment arm and the 12 month follow up time from the mixed effects model for 
FACT-P TOI described above. Tests of interaction between treatment arm and the 12 month 
follow up time will also be performed for the models for FACT/GOG NTX and PROMIS 
Fatigue at the two sided 0.05 significance level (unadjusted). 
PSA Response and PSA Progression Free Survival 
PSA will be measured every three months while on study. The proportion of subjects 
experiencing a 50% and 90% reduction in PSA as defined by the Prostate Cancer Working 
Group 3 will be reported for each study arm, along with exact 95% confidence intervals 
(Clopper-Pearson). The proportion of PSA responders as defined by each of the above criteria 
will be compared between treatment arms using Fisher’s Exact test at the two sided 0.05 
significance level (unadjusted).  
PSA Progression free survival (PSA-PSF) will be plotted using Kaplan-Meier methods. PSA-
PFS will be compared between the treatment arms using a log-rank test at the two sided 0.05 
significance level (unadjusted). Subjects that have not experience PSA progression at the end 
of study will be censored for PSA progression at the time of last on-study PSA evaluation.   
13 
REGISTRATION GUIDELINES 
Study related screening procedures can only begin once the patient has signed a consent 
form.  
Patients must meet all of the eligibility requirements listed above prior to registration.  
Patients must be registered before receiving any study treatment and must begin treatment 
within 42  days after randomization.  
To register eligible patients on study, complete a Clinical Trials Office Patient Registration Form 
and submit to CTORegistrations@hci.utah.edu. 
14 
DATA SUBMISSION SCHEDULE 
The Case Report Forms (CRFs) are a set of (electronic or paper) forms for each patient that 
provides a record of the data generated according to the protocol. CRF’s should be created prior 


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to the study being initiated and updated (if applicable) when amendments to the protocol are IRB 
approved. These forms will be completed on an on-going basis during the study. The medical 
records will be source of verification of the data. During the study, the CRFs will be monitored for 
completeness, accuracy, legibility and attention to detail by a member of the Research Compliance 
Office. The CRFs will be completed by the Investigator or a member of the study team as listed 
on the Delegation of Duties Log. The data will be reviewed no less than annually by the Data and 
Safety Monitoring Committee. The Investigator will allow the Data and Safety Monitoring 
Committee or Research Compliance Office personnel access to the patient source documents, 
clinical supplies dispensing and storage area, and study documentation for the above-mentioned 
purpose. The Investigator further agrees to assist the site visitors in their activities. 
Data capture should be restricted to endpoints and relevant patient information required for 
planned manuscripts. 
15 
SPECIAL INSTRUCTIONS  
15.1 
Correlative Studies 
15.1.1 
Correlative Tissue Samples  
Available archival tissue will be sent to Foundation Medicine to test for biomarkers of disease 
response and prediction of treatment effect, such as, but not limited to: next generation 
sequencing of tumor DNA and whole transcriptome analysis. NGS may be performed to assess 
for changes to tumor suppressors and the androgen receptor, as these have been demonstrated 
to be mechanisms of resistance to therapy.  
If the patient consents to the optional tissue, up to 4 research cores will be collected any time 
the patient has a standard of care biopsy while on study.  Testing may include, but is not limited 
to: 
• 
Multiomics platforms 
• 
Immunohistochemistry 
• 
Flow cytometry 
Specimen collection and processing instructions can be found in the lab manual. 
15.1.2 
Correlative Blood Samples  
If the patient consents to provide optional blood samples, up to 54mL of peripheral blood will 
be collected at the timepoints listed in the study calendar. Testing may include, but is not 
limited to: 
• 
Circulating tumor cells (CTC) detection, enumeration, and characterization 
• 
Cytokine/chemokine/interferon assays 
• 
Genomic analysis 
• 
Proteomic analyses 
• 
Flow Cytometry 
• 
Detection of somatic and germline DNA alterations by targeted sequencing of cell-
free DNA. 


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• 
Detection of androgen receptor splice variant 7 (ARV7) by droplet digital PCR 
(ddPCR). 
 
Specimen collection and processing instructions can be found in the lab manual. 
16 
ETHICAL AND REGULATORY CONSIDERATIONS 
16.1 
Informed consent  
Informed consent will be obtained from all research participants prior to performing any study 
procedures using the most recent IRB-approved version.  
16.1.1 
Participation of Children 
Patients must be at least 18 years of age to participate. 
16.2 
Institutional Review 
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment materials (eg, 
advertisements) and any other applicable patient-facing documents. The investigator should 
also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling 
information. 
The investigator or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according 
to regulatory requirements or institution procedures. Data and Safety Monitoring Plan 
A Data and Safety Monitoring Committee (DSMC) is established at Huntsman Cancer Institute 
(HCI) to ensure the well-being of patients enrolled on Investigator Initiated Trials that do not 
have an outside monitoring review. The roles and responsibilities of the DSMC are set forth in 
the NCI-approved Data and Safety Monitoring (DSM) plan. The activities of the committee 
include reviewing adverse events (including SAEs), deviations, important medical events, 
significant revisions or amendments to the protocol, and approving cohort/dose escalations. If 
the DSMC and/or the PI have concerns about unexpected safety issues, the study will be 
stopped and will not be resumed until the issues are resolved. The DSMC also reviews and 
approves audit reports generated by the Research Compliance Office. 
This is a multicenter treatment study classified as high risk per the NCI-approved DSM plan.  
Each high-risk study will be assigned a physician member of the DSMC as medical monitor, 
or in rare cases, an external medical monitor. The medical monitor will be notified of all serious 
adverse events (SAEs). Specific notifications will also be issued when a dose-limiting toxicity 
is encountered and when the MTD dose is defined. Approval of the medical monitor is required 
for all dose escalations. All serious adverse events (SAEs) occurring in patients treated at HCI 
or its affiliates will also be reviewed by the full DSMC monthly. The full committee will also 
review all toxicities for patients on treatment and within 30 days of their last treatment on a 
quarterly basis.  


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Each high-risk study will also be assigned a dedicated research compliance officer who will 
monitor the trial. High-risk studies will be monitored by RCO personnel after the first patient 
is enrolled and every three months thereafter during active enrollment. The RCO monitor will 
review the study status and summarize enrollment, toxicities, SAEs, dose escalation, statistical 
endpoints (e.g., stopping rules), deviations, etc. for the full DSMC membership at the regularly 
scheduled meetings. Amendments which increase risk, change dosing, or impact study 
objectives will be reviewed by the DSMC and approved by the PRMC and IRB. High-risk 
trials will be formally reviewed by the DSMC after the first patient is enrolled and then 
quarterly thereafter. 
An initial audit of high-risk studies will be conducted by the RCO approximately one year 
after enrollment begins and annually thereafter. Audits of high-risk studies may be conducted 
more frequently as requested by the DSMC, IRB, PRMC, RCO management, or the PI. 
Adverse Events and Serious Adverse Events  
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for AE and SAE reporting.  
16.2.1 
Adverse Events (AEs) 
An adverse event is the appearance or worsening of any undesirable sign, symptom, or medical 
condition occurring after starting the study drug even if the event is not considered to be related 
to study drug. For the purposes of this study, the terms toxicity and adverse event are used 
interchangeably. Medical conditions/diseases present before starting study drug are only 
considered adverse events if they worsen after starting study drug. Abnormal laboratory values 
or test results constitute adverse events only if they are considered clinically significant by the 
treating investigator, or require therapy to treat. 
Collection of adverse events will begin after the first dose of study drug and end at the Month 
18 visit or 30 days after the last dose of study drug if the patient is removed for progression 
prior to this time point.  
The safety profile for the drugs involved in this study have been characterized extensively in 
previous clinical trials and standard clinical contexts. As such, safety data collection for this 
study will be limited to ≥ Grade 3 adverse events as defined by CTCAE v5.0.  
Information about adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be abstracted from standard investigator clinic notes and recorded in the patient’s 
study chart, at the interval noted in the study calendar. 
Adverse events meeting the aforementioned recording criteria should be further evaluated, 
either through abstraction of standard investigator clinic notes or through direct 
correspondence with the treating investigator to determine: 
1. The severity grade based on CTCAE v5.0 (grade 1-5) 
2. Its relationship to the study drugs (definite, probable, possible, unlikely, not related) 
3. Its duration (start and end dates or if continuing at final exam) 


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4. Action taken (no action taken; study drug dosage adjusted/temporarily interrupted; 
study drug permanently discontinued due to this adverse event; concomitant 
medication taken; non-drug therapy given; hospitalization/prolonged hospitalization) 
5. Whether it constitutes an SAE 
All adverse events will be treated as medically appropriate.  
All CTCAE v5.0 Grade 3 and above adverse events should be followed until its resolution or 
the patient discontinues study, and assessment should be made at the interval noted in the study 
calendar (or more frequently, if necessary) of any changes in severity, suspected relationship 
to the study intervention, interventions employed to treat it, and outcome. 
16.2.2 Serious Adverse Event (SAE) 
Information about all serious adverse events, as defined below, will be collected and recorded. 
A serious adverse event is an undesirable sign, symptom or medical condition which: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Causes congenital anomaly or birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
o Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (procedures such as central line placements, paracentesis, 
pain control) 
o Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since the start of study drug 
o Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
o Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
Collection of serious adverse events will begin at enrollment and end 30 after the last dose of 
study treatment or until a new cancer treatment is initiated, whichever happens the soonest. 
Any death from any cause while a patient is receiving treatment on this protocol or up to 30 
days after the last dose of protocol treatment, or any death which occurs more than 30 days 
after protocol treatment has ended but which is felt to be treatment related, must be reported. 
Toxicities which fall within the definitions listed above must be reported as an SAE regardless 
if they are felt to be treatment related or not.  


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16.3 
SAE Reporting Requirements 
A MedWatch 3500A form must be completed to document each observed SAE and submitted 
to compliance@hci.utah.edu as soon as possible, but no later than 1 working day of first 
knowledge or notification of event. 
The Research Compliance Office will appropriately report these SAEs to the DSMC and/or 
the IRB of record according to the requirements described below: 
DSMC Notifications: 
• Fatal or life-threatening events meeting the definition of an SAE will be reported within 7 
calendar days after first knowledge of the event by the investigator. 
• All other events meeting the SAE criteria above will be reported within 15 calendar days 
after first knowledge of the event by the investigator.  
• Events that meet expedited reporting (serious, unexpected suspected adverse reactions) 
will be reported to the FDA and IRB, as applicable. 
IRB Notification: 
1. Events will be submitted to the IRB of record per local guidelines. 
16.4 
Reporting of Pregnancy  
Although pregnancy is not considered an adverse event, it is the responsibility of investigators 
or their designees to report the pregnancy of a male subjects’ female partner as an unanticipated 
problem involving risk as noted above. Pregnancies or lactation that occurs during the course 
of the trial or within 30 days of completing the trial must be reported to the DSMC, IRB, and 
FDA as applicable. All female partners of subjects who become pregnant must be followed to 
the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events.  
16.5 
Protocol Amendments 
Any amendments or administrative changes to an IRB approved protocol will not be initiated 
without submission of an amendment for IRB review and approval.   
These requirements for approval will in no way prevent any immediate action from being taken 
by the investigator in the interests of preserving the safety of all subjects included in the trial.  
Any amendments to the protocol that significantly affect the safety of subjects, scope of the 
investigation, or the scientific quality of the study are required to submit the amendment for 
FDA review. 
16.6 
Protocol Deviations 
A protocol deviation (or violation) is any departure from the defined procedures and treatment 
plans as outlined in the protocol version submitted and previously approved by the IRB. 
Protocol deviations have the potential to place participants at risk and can also undermine the 
scientific integrity of the study thus jeopardizing the justification for the research. Protocol 
deviations are unplanned and unintentional events.  


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Because some protocol deviations pose no conceivable threat to participant safety or scientific 
integrity, reporting is left to the discretion of the PI within the context of the guidelines below. 
The sponsor requires the prompt reporting to HCI RCO of protocol deviations which are: 
• 
Exceptions to eligibility criteria. 
• 
Intended to eliminate apparent immediate hazard to a research participant or  
• 
Harmful (caused harm to participants or others, or place them at increased risk of 
harm - including physical, psychological, economic, or social harm), or  
• 
Possible serious or continued noncompliance  
16.7 
FDA Annual Reporting  
This study is IND exempt therefore there are no annual reporting requirements to the FDA.   
16.8 
Clinical Trials Data Bank  
The study will be registered on http://clinicaltrials.gov and the NCI CTRP (Clinical Trials 
Reporting Program) by the Clinical Trials Office. 
16.9 
Record Keeping 
Per 21 CFR 312.57, the Investigator records shall be maintained for a period of 2 years 
following the date a marketing application is approved; or, if no application is filed or the 
application is not approved, until 2 years after the investigation is discontinued and the FDA 
is notified. 
 
 


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17 
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17. Tunes da Silva G, Logan BR, Klein JP: Methods for equivalence and noninferiority testing. 
Biol Blood Marrow Transplant 15:120-7, 2009 
18. Scher HI, Morris MJ, Stadler WM, et al: DOI: 10.1200/JCO.2015.64.2702 Journal of Clinical 
Oncology 34, no. 12 (April 20 2016) 1402-1418. 
 
 
 


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Appendix A: FACIT Administration Guidelines 
The FACIT scales are designed for patient self-administration, but can also be administered by 
interview format.  For self-administration, patients should be instructed to read the brief directions 
at the top of the page. After the patient's correct understanding has been confirmed, he/she should 
be encouraged to complete every item in order without skipping any.  Some patients may feel that 
a given question is not applicable to them and will therefore skip the item altogether.  Patients 
should be encouraged to circle the response that is most applicable. If, for example, a patient 
is not currently receiving any treatment, the patient should circle “not at all” to the question “I am 
bothered by side effects of treatment.”  
 
 


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Appendix B: FACT-P 
 
Patient Name: _______________________  
 
          Patient ID: _______________ 
 
Date: _______________ 
 


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Appendix C: FACT/GOG – NTX 
 
Patient Name: _______________________  
 
        Patient ID: _______________ 
 
Date: _______________ 
 


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Appendix D: PROMIS Fatigue 
 
Patient Name: _______________________  
 
        Patient ID: _______________ 
 
Date: _______________ 
 
 


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Appendix E: ECOG/KPS Conversion Table 
 
ECOG PERFORMANCE STATUS 
KARNOFSKY PERFORMANCE STATUS 
0—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—Restricted in physically strenuous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
80—Normal activity with effort, some signs or 
symptoms of disease  
 
70—Cares for self but unable to carry on normal 
activity or to do active work 
2—Ambulatory and capable of all selfcare 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 personal needs  
 
50—Requires considerable assistance and 
frequent medical care 
3—Capable of only limited selfcare; confined to bed or 
chair more than 50% of waking hours 
40—Disabled; requires special care and 
assistance  
 
30—Severely disabled; hospitalization is 
indicated although death not imminent 
4—Completely disabled; cannot carry on any selfcare; 
totally confined to bed or chair 
20—Very ill; hospitalization and active 
supportive care necessary  
 
10—Moribund 
5—Dead 
0—Dead 
*Karnofsky D, Burchenal J, The clinical evaluation of chemotherapeutic agents in cancer. In: MacLeod C, ed. 
Evaluation of Chemotherapeutic Agents. New York, NY: Columbia University Press; 1949:191–205. 
**Zubrod C, et al. Appraisal of methods for the study of chemotherapy in man: Comparative therapeutic trial of 
nitrogen mustard and thiophosphoramide. Journal of Chronic Diseases; 1960:11:7-33. 
 
 


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Appendix F: Overall Treatment Utility Form 
 
 Patient Name: _______________________  
 
        Patient ID: _______________ 
 
Date: _______________ 
 
 
___________________________________________________________________________ 
Investigator Signature 
Date 


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Appendix G: Was It Worth It Questionnaire 
 
 
 


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Appendix H: End of Study Evaluation Form 
 
 
Patient Name: _______________________  
 
         Patient ID: _______________ 
 
Date: _______________ 
 
 
 
 


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Appendix I: Extent of Metastases Form 
 
 
Patient Name: _______________________  
 
        Patient ID: _______________ 
 
Date: _______________ 
 
For purposes of this study, extent of metastases will be defined in accordance with the 
CHAARTED trial. ‘High Volume’ disease is defined as ‘Yes’ to question 1. Also patient may 
qualify as ‘High Volume’ by answering ‘Yes’ to question 2 and 3. Otherwise, patients are 
defined as ‘Low Volume’. 
 
1. Presence of visceral metastases (Y/N): ______________ 
2. ≥ 4 Bone lesions (Y/N):___________ 
3. ≥1 bone lesion outside of the vertebral column and pelvis (Y/N): ____________  
Extent of disease determination (High/Low Volume):_______________________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
___________________________________________________________________________ 
Investigator Signature 
Date