Clinical trial NCT02711956
Conditions: Metastatic Castration-Resistant Prostate Cancer
Keywords: Metastatic Castration-Resistant Prostate Cancer (mCRPC) Phase 1b/2a Prostate Cancer Pharmacokinetics (PK) ZEN003694 ZEN-3694 Metastatic Castrate-Resistant Prostate Cancer BET inhibitor (BETi) Bromodomain Pharmacodynamics (PD) Enzalutamide XTANDI MDV3100 Epigenetics
Sponsor: Zenith Epigenetics
Start date: 2016-12-01; Completion date: 2019-11-01
Enrollment: 75 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label, non-randomized, Phase 1b/2a, dose escalation and dose confirmation study of ZEN003694 in combination with enzalutamide in patients with mCRPC.

Detailed description:

Arms: arm 1: Dose Escalation (DE) and Dose Confirmation (DC): ZEN003694 will be administered orally once daily with enzalutamide in 28-day cycles, enrolling mCRPC patients.

Two patient populations will be enrolled in DE and DC. Cohort A: Patients with prior progression on enzalutamide or apalutamide by PCWG2 criteria who were receiving a stable dose of enzalutamide at the time of study entry. Cohort B: Patients who were enzalutamide-naïve with prior progression on abiraterone by Prostate Cancer Working Group 2 (PCWG2) criteria.
Interventions: intervention 1: ZEN003694 intervention 2: Enzalutamide
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
Document Type 
Clinical Study Protocol 
Official Protocol Title 
A Phase 1b/2a Safety and Tolerability Study of ZEN003694 in 
Combination With Enzalutamide in Patients With Metastatic 
Castration-Resistant Prostate Cancer 
NCT Number 
NCT02711956 
Document Date 
05 Nov 2018 
 


 
ZEN003694-002 Clinical Study Protocol 
 
Version:  Final 
Amendment 10 
 
05 November 2018 
Zenith Epigenetics Ltd. 
Confidential 
Page 1 of 170 
 CLINICAL STUDY PROTOCOL 
TITLE 
A Phase 1b Safety and Tolerability Study of ZEN003694 in 
Combination with Enzalutamide or Abiraterone in Patients with 
Metastatic Castration-Resistant Prostate Cancer 
INVESTIGATIONAL 
NEW DRUG NUMBER 
127235 
STUDY DRUG 
ZEN003694 
PROTOCOL NUMBER ZEN003694-002 
SPONSOR 
Zenith Epigenetics Ltd. 
SPONSOR’S HEAD 
OFFICE 
Suite 300, 4820 Richard Road SW 
Calgary, Alberta 
Canada 
T3E 6L1 
SPONSOR’S 
REPRESENTATIVE  
US OFFICE 
 
  
 
 
 
 
 
SPONSOR’S  
MEDICAL MONITOR  
US OFFICE 
 
  
 
 
 
 
 
PROTOCOL  
AMENDMENT DATE 
Amendment 10 
05 November 2018 
 
Confidentiality Statement 
This document contains proprietary and confidential information of Zenith Epigenetics Ltd. 
Acceptance of this document constitutes agreement by the recipient that no previously 
unpublished information contained herein will be published or disclosed without the prior written 
approval of Zenith Epigenetics Ltd. with the exception that this document may be disclosed to 
study personnel under your supervision who need to know the contents for conducting the study 
and appropriate Ethics Committees/Institutional Review Boards under the condition that the 
personnel have agreed to keep this information confidential.  The foregoing shall not apply to 
disclosure required by governmental regulations or laws; however, Zenith Epigenetics Ltd. shall 
be promptly notified of any such disclosure. 


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LIST OF ABBREVIATIONS AND ACRONYMS 
5-HT3 
5-hydroxytryptamine type 3 
ADL 
Activities of daily living 
ADT 
Androgen deprivation therapy 
AE 
Adverse event 
AML 
Acute myeloid leukemia 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AR 
Androgen receptor 
ARSI 
Androgen receptor signaling inhibitor 
AR-V7 
Androgen receptor splice variant 7 
ASCO 
American Society of Oncology 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
AUC0-∞ 
Area under the curve, from time zero to infinity 
AUC0-24 
Area under the curve, from time zero to 24 hours 
AUC0-last 
Area under the curve, from time zero to last time point with a 
quantifiable level of drug 
BCL-2 
B-cell lymphoma 2 
BCL2L1 
B-cell lymphoma 2-like 1 
BET 
Bromodomain and extra-terminal motif 
BETi 
BET bromodomain inhibitor 
BID 
Twice Daily 
BRD2 
Bromodomain-containing protein 2 
BRD3 
Bromodomain-containing protein 3 
BRD4 
Bromodomain-containing protein 4 
BRDT 
Bromodomain-testis-specific containing protein T 
BUN 
Blood urea nitrogen 
Cmax 
Maximum or peak concentration 
Cmin 
Minimum or trough concentration 
Css 
Concentration steady-state 
CBC 
Complete blood count 
CCR1 
Chemokine (C-C motif) receptor 1 
CDMS 
Clinical data management system 
cfDNA 
Cell-free deoxyribonucleic acid (DNA) 
 
 
CNS 
Central nervous system 
CR 
Complete response 
CRC 
Cohort Review Committee 
CRF 
Case report form 
CRPC 
Castration-resistant prostate cancer 
CT 
Computed tomography 
CTC(s) 
Circulating tumor cell(s) 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor deoxyribonucleic acid (DNA) 


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CYP 
Cytochrome  P450 
CYP1A2 
Cytochrome P450, family 1, subfamily A, polypeptide 2 
CYP2C8 
Cytochrome P450, family 2, subfamily C, polypeptide 8 
CYP2C9 
Cytochrome P450, family 2, subfamily C, polypeptide 9 
CYP2C19 
Cytochrome P450, family 2, subfamily C polypeptide 19 
CYP3A4 
Cytochrome P450, family 3, subfamily A, polypeptide 4 
CYP17A1 
Cytochrome P450, family 17, subfamily A, polypeptide 1, or 
steroid 17-alpha-hydroxylase/17,20 lyase 
DC 
Dose confirmation 
DE 
Dose escalation 
dL 
Decilitre 
DLT 
Dose-limiting toxicity 
DMP 
Data management plan 
 
 
 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ERG 
V-Ets avian erythroblastosis virus E26 oncogene 
ETS 
E26 transformation-specific 
ETV1 
ETS translocation variant 1 
FDA 
Food and Drug Administration 
FIH 
First-in-human 
 
 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GPR183 
G Protein-Coupled Receptor 183 
GR 
Glucocorticoid receptor 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HED 
Human equivalent dose 
hERG 
Human ether-à-go-go related gene (an ion channel found in 
cardiac cell membranes ) 
HIST2H2BE 
Histone gene cluster 1, H2BE histone family member E 
HIV 
Human immunodeficiency virus 
HNSTD 
Highest non-severely toxic dose 
HRR 
Hardy Rand and Rittler (plates for testing color vision) 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IL1RN 
Interleukin 1 receptor antagonist 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous  
kg 
Kilogram(s) 


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L 
Litre 
LC-MS/MS 
Liquid chromatography-tandem mass spectrometry  
LD 
Longest diameter 
LDH 
Lactate dehydrogenase 
mCRPC 
Metastatic castration-resistant prostate cancer 
mg 
Milligram(s) 
min 
Minute(s) 
mm3 
Cubic milimeter 
MRI 
Magnetic resonance imaging 
mRNA 
Messenger ribonucleic acid 
msec 
Millisecond(s) 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition (scan) 
MYC 
V-Myc avian myelocytomatosis viral oncogene homolog 
NCI 
National Cancer Institute 
NF-kB 
Nuclear factor kappa-light-chain-enhancer of activated B cells  
ng 
Nanogram(s) 
OCT 
Optical Coherence tomography 
PCWG2 
Prostate Cancer Working Group 2 
PD 
Pharmacodynamics 
PD 
Progressive disease 
PK 
Pharmacokinetics 
PR 
Partial response 
PRES 
Posterior reversible encephalopathy syndrome 
PSA 
Prostate-specific antigen 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QD 
Once daily 
qPCR 
Quantitative polymerase chain reaction  
QTcF 
QT interval corrected by the Fridericia correction formula 
RP2D 
Recommended Phase 2 dose 
RECIST 1.1 
Response Evaluation Criteria in Solid Tumors 1.1 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Stable disease 
STD10 
Severely toxic dose in approximately 10% of animals  
SUSAR 
Suspected unexpected serious adverse event 
t1/2 
Half-life 
Tech-99 
Technetium-99 
Tmax 
Time to maximum concentration 
TGI 
Tumor growth inhibition 
ULN 
Upper limit of normal 
 


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Table of Contents 
1. 
SYNOPSIS ................................................................................................................. 11 
2. 
BACKGROUND ....................................................................................................... 39 
2.1 
BET Inhibitors in Cancer ............................................................................................ 39 
2.2 
Rationale and Mechanism for BET Inhibitors in Metastatic Castration-resistant 
Prostate Cancer ........................................................................................................... 39 
2.3 
ZEN003694 ................................................................................................................. 41 
2.4 
Nonclinical Data ......................................................................................................... 41 
2.5 
Clinical Data ............................................................................................................... 43 
2.6 
Study Rationale ........................................................................................................... 44 
2.7 
Dosing Rationale ......................................................................................................... 45 
3. 
OBJECTIVES ........................................................................................................... 48 
3.1 
PART 1 OBJECTIVES: ZEN003694 in combination with enzalutamide ................. 48 
3.1.1 
Part 1: Primary ............................................................................................................ 48 
3.1.2 
Part 1: Secondary ........................................................................................................ 48 
3.1.3 
Part 1: Exploratory ...................................................................................................... 48 
3.2 
PART 2 OBJECTIVES: ZEN003694 in combination with abiraterone ..................... 49 
3.2.1 
Part 2: Primary ............................................................................................................ 49 
3.2.2 
Part 2: Secondary ........................................................................................................ 49 
3.2.3 
Part 2: Exploratory ...................................................................................................... 49 
4. 
PATIENT SELECTION .......................................................................................... 50 
4.1 
Part 1: ZEN003694 in combination with enzalutamide .............................................. 50 
4.1.1 
Part 1: Inclusion Criteria ............................................................................................. 50 
4.1.2 
Part 1: Exclusion Criteria ............................................................................................ 51 
4.2 
Part 2: ZEN003694 in combination with abiraterone ................................................. 53 
4.2.1 
Part 2: Inclusion Criteria ............................................................................................. 53 
4.2.2 
Part 2: Exclusion Criteria ............................................................................................ 54 
5. 
STUDY PLAN ........................................................................................................... 56 
5.1 
Study Design ............................................................................................................... 56 
5.1.1 
Dose Escalation ........................................................................................................... 56 
5.1.2 
Definition of Dose-limiting Toxicity .......................................................................... 59 
5.1.3 
Definition of the Maximum Tolerated Dose ............................................................... 61 
5.1.4 
Definition of the Recommended Phase 2 Dose .......................................................... 61 
5.1.5 
Dose Confirmation ...................................................................................................... 61 
5.2 
Safety Review ............................................................................................................. 62 
5.3 
Number of Sites and Patients ...................................................................................... 63 
5.4 
Study Duration ............................................................................................................ 63 
5.5 
Premature Study Termination or Suspension of Enrollment ...................................... 63 
6. 
STUDY DRUG AND CONCOMITANT TREATMENT ..................................... 64 
6.1 
ZEN003694 ................................................................................................................. 64 
6.2 
Enzalutamide............................................................................................................... 64 
6.3 
Abiraterone ................................................................................................................. 64 
6.4 
Guidelines for Dose Escalation, Dose Modification and Management of ZEN003694-
related Toxicity ........................................................................................................... 65 
6.4.1 
Dose Escalation in the Dose Escalation Phase of the Study ....................................... 65 


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6.4.2 
Management of ZEN003694-related Toxicity in the Dose Escalation and Dose 
Confirmation Phases ................................................................................................... 65 
6.5 
Part 1: Management of Enzalutamide-related Toxicity in the Dose Escalation and 
Dose Confirmation Phases .......................................................................................... 67 
6.6 
Part 2: Management of Abiraterone-related Toxicity in the Dose Escalation and Dose 
Confirmation Phases ................................................................................................... 68 
6.7 
Treatment Compliance ................................................................................................ 69 
6.8 
Concomitant Medications and Therapies.................................................................... 69 
6.8.1 
Part 1 and Part 2: Prohibited Concomitant Medications and Therapies with 
ZEN003694 ................................................................................................................. 69 
6.8.2 
Part 1: Prohibited Concomitant Medications and Therapies with  Enzalutamide ...... 69 
6.8.3 
Part 2: Prohibited Concomitant Medications and Therapies with Abiraterone .......... 71 
6.8.4 
Permitted Concomitant Medications and Therapies ................................................... 72 
7. 
STUDY DRUG AND MATERIALS ....................................................................... 74 
7.1 
Study Drug Description .............................................................................................. 74 
7.1.1 
Formulation ................................................................................................................. 74 
7.1.2 
Storage Conditions ...................................................................................................... 74 
7.2 
Enzalutamide............................................................................................................... 74 
7.3 
Abiraterone ................................................................................................................. 75 
7.4 
Study Drug Accountability ......................................................................................... 75 
8. 
STUDY PROCEDURES AND ASSESSMENTS ................................................... 76 
8.1 
Study Procedures by Visit ........................................................................................... 76 
8.1.1 
Screening Visit ............................................................................................................ 76 
8.1.2 
Cycle 1 Lead-in for Dose Escalation & Dose Confirmation (required for Cohorts DE-
B, DC-B, DE-D, DC-D; also required for patients requiring enzalutamide Lead-in 
(Part 1: Sub-arm A2) or abiraterone Lead-in (Part 2: Sub-arm C2) ........................... 77 
8.1.3 
Cycle 1 Dose Escalation and Dose Confirmation ....................................................... 78 
8.1.4 
Cycle 2 ........................................................................................................................ 82 
8.1.5 
Cycles 3, 4 and onward ............................................................................................... 84 
8.1.6 
Cycle 3 and every other cycle onward (Cycles 5, 7, etc.) ........................................... 85 
8.1.7 
Cycle 3 and every 3 cycles onward (Cycles 6, 9, etc.) ............................................... 85 
8.1.8 
Unscheduled Visits and Assessments ......................................................................... 86 
8.1.9 
End of Treatment Visit................................................................................................ 86 
8.1.10 
Safety Follow-up Visit ................................................................................................ 87 
8.2 
Study Assessments ...................................................................................................... 88 
8.2.1 
Informed Consent........................................................................................................ 88 
8.2.2 
Inclusion/Exclusion Criteria ....................................................................................... 88 
8.2.3 
Medical History and Demographics ........................................................................... 88 
8.2.4 
Physical Examination/Symptom-directed Physical Examination ............................... 89 
8.2.5 
Height and Weight ...................................................................................................... 89 
8.2.6 
ECOG Performance Status ......................................................................................... 89 
8.2.7 
Vital Signs ................................................................................................................... 89 
8.2.8 
Laboratory Parameters ................................................................................................ 89 
8.2.9 
Echocardiogram or MUGA ......................................................................................... 90 
8.2.10 
12-lead ECG................................................................................................................ 90 
8.2.11 
Pharmacokinetic Sampling ......................................................................................... 90 


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8.2.12 
Pharmacodynamic Sampling ...................................................................................... 91 
8.2.13 
Adverse Events ........................................................................................................... 93 
8.2.14 
Concomitant Medications ........................................................................................... 94 
8.2.15 
Tumor Assessment – Imaging/Radiologic Evaluation ............................................... 94 
8.2.16 
Ophthalmology Assessments ...................................................................................... 94 
9. 
WITHDRAWAL OR EARLY TERMINATION OF PATIENTS ....................... 94 
10. 
SAFETY ASSESSMENTS ....................................................................................... 96 
10.1 
Adverse Event and Suspected Unexpected Serious Adverse Reaction Definitions ... 96 
10.1.1 
Adverse Event ............................................................................................................. 96 
10.1.2 
Serious Adverse Event ................................................................................................ 96 
10.1.3 
Suspected Unexpected Serious Adverse Reaction ...................................................... 97 
10.2 
Reporting Serious Adverse Events and Suspected Unexpected Serious Adverse 
Reactions ..................................................................................................................... 97 
10.2.1 
Disease-related Events That Are Endpoints ............................................................... 98 
10.3 
Adverse Events ........................................................................................................... 98 
10.3.1 
Classification of Adverse Events by Severity ............................................................. 99 
10.3.2 
Classification of Adverse Events by Relationship to Study Drug .............................. 99 
10.4 
Abnormal Laboratory Results ................................................................................... 100 
10.5 
Overdose ................................................................................................................... 100 
10.6 
Study Safety Monitoring and Dose Escalation or Modification ............................... 100 
10.7 
Reporting Safety Information to the Institutional Review Board ............................. 101 
11. 
STUDY ENDPOINTS ............................................................................................. 102 
11.1 
Primary Endpoints .................................................................................................... 102 
11.2 
Secondary Endpoints ................................................................................................ 102 
11.3 
Exploratory Endpoints .............................................................................................. 102 
12. 
STATISTICS ........................................................................................................... 104 
12.1 
General Considerations ............................................................................................. 104 
12.2 
Sample Size Determination....................................................................................... 104 
12.3 
Analysis Populations ................................................................................................. 104 
12.4 
Data Handling ........................................................................................................... 105 
12.5 
Statistical Analyses ................................................................................................... 105 
13. 
QUALITY CONTROL AND QUALITY ASSURANCE .................................... 106 
13.1 
Study Monitoring ...................................................................................................... 106 
13.2 
Audit and Inspection ................................................................................................. 107 
13.3 
Regulatory Authority Correspondence ..................................................................... 107 
14. 
ETHICAL AND LEGAL ISSUES ......................................................................... 108 
14.1 
Statement of Compliance .......................................................................................... 108 
14.2 
Ethics Committee or Institutional Review Board Approval ..................................... 108 
14.3 
Patient Informed Consent/Assent ............................................................................. 109 
14.4 
Patient Compensation for Adverse Effects on Health .............................................. 109 
14.5 
Changes to the Conduct of the Study, Protocol and Study Termination .................. 109 
14.5.1 
Protocol Amendments ............................................................................................... 109 
14.5.2 
Study Termination .................................................................................................... 109 
15. 
INVESTIGATOR RESPONSIBILITIES ............................................................. 110 
15.1 
Staff Training ............................................................................................................ 110 
15.2 
Study Conduct ........................................................................................................... 110 


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15.3 
Recordkeeping .......................................................................................................... 111 
16. 
PUBLICATIONS .................................................................................................... 113 
17. 
CONFIDENTIALITY ............................................................................................ 114 
18. 
REFERENCES ........................................................................................................ 115 
 
 
 


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LIST OF TABLES 
Table 1:  PART 1 ONLY:  ZEN003694 + Enzalutamide ..............................................................28 
Table 2:  PART 2 ONLY:  ZEN003694 + Abiraterone .................................................................34 
Table 3:  Dose-limiting Toxicity and Cohort Management ...........................................................57 
Table 4:  Part 1 Dose Escalation Scheme ......................................................................................58 
Table 5:  Part 2 Dose Escalation Scheme ......................................................................................59 
Table 6:  ZEN003694-Related Dose Adjustment and Toxicity Management Guidelines .............66 
Table 7:  Part 1 Inhibitors and Inducers of Relevant Drug-metabolizing Enzymes ......................70 
Table 8:  Part 2 Inhibitors and Inducers of Relevant Drug-metabolizing Enzymes ......................72 
 
 
 


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LIST OF APPENDICES 
Appendix 1:  ECOG Performance Status.....................................................................................120 
Appendix 2:  NCI CTCAE Version 4.03 Adverse Event Severity Grading ................................121 
Appendix 3:  Prostate Cancer Clinical Trials Working Group 2 Criteria ....................................122 
Appendix 4:  XTANDI Package Insert .....................................................................................126 
Appendix 5:  ZYTIGA® Package Insert .....................................................................................147 
Appendix 6:  Investigator Agreement Page .................................................................................170 
 
 
 
 
 
 


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1. 
SYNOPSIS 
TITLE:  A Phase 1b Safety and Tolerability Study of ZEN003694 in Combination with 
Enzalutamide or Abiraterone in Patients with Metastatic Castration-Resistant Prostate Cancer 
PROTOCOL NUMBER:  ZEN003694-002 
STUDY PHASE:  Phase 1 
 
INVESTIGATIONAL DRUG:  ZEN003694 
OBJECTIVES: 
Part 1: ZEN003694 in combination with enzalutamide 
Primary 
 
To determine the safety, tolerability and maximum tolerated dose (MTD) of ZEN003694 in 
combination with enzalutamide or apalutamide in patients with metastatic castration-resistant 
prostate cancer (mCRPC) who have progressed during prior treatment with enzalutamide or 
apalutamide (Cohort DE-A) or  abiraterone (Cohort DE-B) by Prostate Cancer Working Group 
2 (PCWG2) criteria 2007 (dose escalation) 
 To confirm the safety and tolerability of the MTD and recommended Phase 2 dose (RP2D) of 
ZEN003694 in combination with enzalutamide in the following two cohorts of patients with 
mCRPC (dose confirmation): 
o Cohort DC-A:  Patients with prior progression on enzalutamide or apalutamide 
by PCWG2 criteria who are currently or will be receiving a stable dose of 
enzalutamide 
o Cohort DC-B:  Patients who are enzalutamide-naïve and apalutamide-naive with 
prior progression on abiraterone by PCWG2 criteria 
Secondary 
 To determine the pharmacokinetics (PK) of ZEN003694 and the PK of enzalutamide along 
with their primary active metabolites when administered in combination  
 To evaluate the preliminary clinical activity of ZEN003694 in combination with enzalutamide 
as applicable:  
o PSA response rate by PCWG2 criteria 
o Radiographic response rate by PCWG2 criteria 
o Median progression-free survival by PCWG2 criteria 
o Circulating tumor cell (CTC) response rate (dose confirmation only) 
Exploratory 
 
To explore pharmacodynamics (PD), prognostic and/or predictive biomarkers of ZEN003694 
in combination with enzalutamide in whole blood, plasma and tumor samples in the dose 
escalation phase and/or dose confirmation phase as follows:  
o Possible relationship of baseline tumor abnormalities (such as mutations, 


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translocations, messenger ribonucleic acid [mRNA], protein expression and 
localization), in circulating tumor DNA (ctDNA), circulating tumor cells 
(CTC) and tumor biopsies and/or on-treatment changes with any observed 
antitumor activity 
 
To explore the effects of ZEN003694 on immuno-oncology markers in tumor tissue and 
peripheral blood mononuclear cells  
Part 2: ZEN003694 in combination with abiraterone 
Primary 
 To determine the safety, tolerability and recommended Phase 2 dose (RP2D) of ZEN003694 in 
combination with abiraterone in patients with metastatic castration-resistant prostate cancer 
(mCRPC) who have progressed during prior treatment with abiraterone (Cohort DE-C) or  
enzalutamide or apalutamide (Cohort DE-D) by Prostate Cancer Working Group 2 (PCWG2) 
criteria 2007 (Dose Escalation) 
 To confirm the safety and tolerability of the recommended Phase 2 dose (RP2D) of 
ZEN003694 in combination with abiraterone in the following two cohorts of patients with 
mCRPC (dose confirmation): 
o Cohort DC-C:  Patients currently receiving abiraterone who have experienced 
progression by PCWG2 criteria  
o Cohort DC-D:  Patients who are abiraterone-naïve with prior progression on 
enzalutamide or apalutamide by PCWG2 criteria 
Secondary 
 To determine the pharmacokinetics (PK) of ZEN003694 and the PK of abiraterone along with 
their primary active metabolites when administered in combination  
 To evaluate the preliminary clinical activity of ZEN003694 in combination with abiraterone as 
applicable:  
o PSA response rate by PCWG2 criteria 
o Radiographic response rate by PCWG2 criteria 
o Median progression-free survival by PCWG2 criteria 
o Circulating tumor cell (CTC) response rate (dose confirmation only) 
Exploratory 
 
To explore pharmacodynamics (PD), prognostic and/or predictive biomarkers of ZEN003694 
in combination with abiraterone in whole blood, plasma and tumor samples in the dose 
escalation phase and/or dose confirmation phase as follows:  
o Possible relationship of baseline tumor abnormalities (such as mutations, 
translocations, messenger ribonucleic acid [mRNA], protein expression and 
localization), in circulating tumor DNA (ctDNA), circulating tumor cells 
(CTC) and tumor biopsies and/or on-treatment changes with any observed 
antitumor activity 
 


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STUDY DESIGN: 
This is an open label, non-randomized, Phase 1 dose escalation/dose confirmation study of 
ZEN003694 in combination with enzalutamide (Part 1) and abiraterone (Part 2) in patients with 
mCRPC.  
Dose Escalation 
A standard 3+3 cohort design will be utilized for each study Part.  Cohorts of up to 6 patients will 
be enrolled at each dose level, and each patient will participate in only one cohort.  Each cycle will 
be 28 days in duration.    
 
Part 1, ZEN003694 in combination with enzalutamide:  
For patients who have progressed on abiraterone (Cohort DE-B), enzalutamide will be administered 
orally as a single agent daily for 14 days prior to the initiation of the combination therapy (Lead-in) 
to reach enzalutamide steady-state concentration (Css) during Cycle 1. After the Lead-in, if 
applicable, ZEN003694 will be administered orally in combination with daily enzalutamide for 28-
day cycles. Patients who are progressing on enzalutamide or apalutamide (Cohort DE-A, Sub-Arm 
A1) and currently receiving a stable dose of enzalutamide will continue to receive enzalutamide in 
combination with ZEN003694, if eligibility criteria are met.  For patients who have progressed on 
enzalutamide or apalutamide (Cohort DE-A, Sub-Arm A2) but are not currently taking 
enzalutamide or apalutamide or are currently taking apalutamide, enzalutamide will be administered 
orally as a single agent daily for 14 days prior to the initiation of the combination therapy (Lead-in) 
to reach enzalutamide steady-state concentration (Css) during Cycle 1.  
 
Part 2, ZEN003694 in combination with abiraterone: 
For patients who have progressed on enzalutamide or apalutamide (Cohort DE-D), abiraterone will 
be administered orally as a single agent daily for 14 days prior to the initiation of the combination 
therapy (Lead-in) to reach abiraterone steady-state concentration (Css) during Cycle 1. After the 
Lead-in, if applicable, ZEN003694 will be administered orally in combination with daily 
abiraterone for 28-day cycles. Patients who are progressing on abiraterone (Cohort DE-C, Sub-Arm 
C1) and currently receiving a stable dose of abiraterone will continue to receive abiraterone in 
combination with ZEN003694, if eligibility criteria are met.  For patients who have progressed on 
abiraterone (Cohort DE-C, Sub-Arm C2) but are not currently taking abiraterone, abiraterone will 
be administered orally as a single agent daily for 14 days prior to the initiation of the combination 
therapy (Lead-in) to reach abiraterone steady-state concentration (Css) during Cycle 1.  
 
Part 1 and Part 2: 
After the Lead-in, if applicable, ZEN003694 will be administered orally in combination with daily 
enzalutamide (Part 1) or abiraterone (Part 2) for 28-day cycles. The first patient at each dose level 
will be treated with ZEN003694 for one week before the second patient at the same dose level is 
allowed to  receive their first dose of ZEN003694.  Patients at each dose level will be treated (for 28 
days on ZEN003694) and observed through the end of the first cycle before treatment of patients at 
the next higher dose level can begin.  If alternative dosing regimens are explored, the one week 
delay of enrollment between the first and subsequent patients may be waived by the Cohort Review 
Committee (CRC) as long as the daily exposure is known to be tolerated. 
 
ZEN003694-related adverse events (AEs) for determination of DLTs will be assessed for each 
patient during the 28 days of Cycle 1.  The most common AEs for enzalutamide and abiraterone are 
well-known.  As such, the Investigator should to the best of his/her ability assess the relatedness of 
an AE observed as attributable to either enzalutamide (Part 1) or abiraterone (Part 2) or ZEN003694 


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alone, or if unable to do so, as attributable to the combination of enzalutamide (Part 1) or 
abiraterone (Part 2) and ZEN003694.   
Dose escalation will continue after all patients enrolled within a cohort have completed the 28-day 
Cycle 1 DLT observation period with either 0 of 3 patients, or no more than 1 out of 6 patients in a 
cohort experiencing a DLT, with the proviso that dose escalation to MTD may be waived in Part 2.  
Dose escalation decisions will be made based on clinical safety and (when available) PK data 
(maximum or peak concentration [Cmax] and area under the curve [AUC]) after review by the CRC, 
consisting of all Investigators and the Zenith Medical Monitor.  If a DLT is observed in 1 of 
3 patients in a cohort and confirmed by the CRC, 3 additional patients will be enrolled into that 
cohort.  If 1 of 6 patients in a cohort experiences a DLT, then dose escalation may continue in the 
next cohort or the MTD of the combination can be declared.  If ≥ 2 of 3 – 6 patients experience 
DLTs within a cohort, then the MTD will be considered to have been exceeded and further dose 
escalation will cease.  In this case, if fewer than 6 patients have been enrolled at the previous dose 
level, that cohort will be expanded to 6 patients to confirm the MTD.  Should the MTD of the 
combination be exceeded at Dose Level 1, a cohort may be explored with a reduced dose of 
ZEN003694 or enzalutamide at the discretion of the CRC. Cohort management is summarized 
below. 
Number of Patients with 
Dose-limiting Toxicity 
Action 
1 of 1 
Add 5 more patients 
0 of 3 
Proceed to next dose level 
1 of 3 
Add 3 more patients 
1 of 6 
Proceed to next dose level 
≥ 2 of 3 or ≥ 2 of 6 
Add 3 more patients in the next lower dose level if only 
3 patients were treated in the next lower dose.  If 6 patients 
were treated at the next lower dose level and no more than 
one patient had DLT, then the next lower dose is the 
MTD. 
 
Part 1: Enrollment in Part 1 of the study with ZEN003694 in combination with enzalutamide 
will commence with 36 mg as the starting dose for ZEN003694 and 160 mg dose of enzalutamide 
(or at a lower stable dose for patients in DE-A or DC-A).   The dose of enzalutamide will be held 
constant throughout Cycle 1 of Dose Escalation. After Cycle 1, enzalutamide toxicity may be 
managed per the XTANDI® Package Insert. Dose escalation will proceed per the schema below 
unless intervening toxicity is observed.  
 
Dose Level 
ZEN003694 (mg) 
Fold Increase from 
Prior Dose Level 
1 
36 
-- 
2 
48 
1.33 
3 
60 
1.25 
4 
72 
1.20 
5 
96 
1.33 
Additional levels may be explored at the discretion of the CRC 


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Part 2: Enrollment in Part 2 of the study with ZEN003694 in combination with abiraterone 
will commence with 72 mg as the starting dose for ZEN003694 and 1000 mg dose of abiraterone 
once daily.   The dose of abiraterone 1000 mg will be held constant throughout Cycle 1 of Dose 
Escalation. After Cycle 1, abiraterone toxicity may be managed per the ZYTIGA® Package Insert. 
Dose escalation/de-escalation will proceed per the schema below unless intervening toxicity is 
observed.  
 
Dose Level 
ZEN003694 (mg) * 
Fold Increase from 
Prior Dose Level 
-1 
48 
0.67 
1 
72 
-- 
2 
96 
1.33 
* Dose de-escalation from 72 mg is allowed by cohort.  Additional dose levels may 
be explored based on safety and at the discretion of the CRC, with the proviso that 
dose escalation to MTD may be waived in Part 2. 
Part 1 and Part 2: Dose escalation increments between cohorts will be determined by the CRC based 
on safety and available PK data (e.g., Cmax and AUC) based on the following schema:  
 
Dose escalation up to 2-fold is allowed in Dose Level 2 and 3 unless one drug-related 
Grade 2 event is observed in Dose Level 1 and 2, respectively 
 
Subsequent dose escalation up to 1.5-fold is allowed until a DLT is observed 
 
Subsequent dose escalation up to 1.33-fold is allowed until MTD is established, or, in 
Part 2, if MTD is waived and RP2D is declared 
All dose escalations will be guided by the available PK data (e.g., Cmax and AUC) from both 
ZEN003694-001 and this study, ZEN003694-002, with respect to the combined AUC0-24 of 
ZEN003694 and its active metabolite ZEN003791.  
 
 
 
 
 
Intermediate doses and/or alternative dosing schedules may be evaluated to best determine the 
MTD and/or RP2D of ZEN003694 in combination with enzalutamide (Part 1) and abiraterone (Part 
2) based on evaluation of clinical safety and available PK data (e.g., Cmax and AUC) and upon 
agreement of the CRC members.  No intra-patient dose escalation is allowed during the first three 
cycles of therapy.  If a patient has not experienced any Grade 2 or higher drug-related AEs after 
three cycles, dose escalation up to the highest dose currently declared tolerable by the CRC will be 
allowed and further intra-patient dose escalation(s) will be determined on a cycle-by-cycle basis at 
the discretion of the Investigator and with approval from the CRC.   
Teleconferences with members of the CRC will be held during the dose escalation phase to discuss 
any suspected DLTs that have occurred in patients within each cohort.  The frequency of the 
teleconference calls will be determined by the rate of enrollment, data review, frequency of DLT 
notifications, discussions with investigational sites and other factors.  Approximately one week after 
the last patient in a dose cohort completes Cycle 1 and prior to escalating to the next dose level (or 
de-escalating), the CRC will review toxicities and available PK (e.g., Cmax and AUC) from the 
current cohort of the study during a teleconference.  


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Definition of Dose-limiting Toxicity 
Determination of DLT will be made during the first 28 days of treatment (i.e., Cycle 1) in the dose 
escalation phase.  Toxicity will be graded and recorded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03.  A DLT is defined 
as a clinically significant AE or laboratory abnormality that is considered possibly, probably or 
definitely related to ZEN003694 and which meets any of the following criteria: 
 
Grade 3 or greater non-hematologic clinical toxicity with the exception of Grade 3 nausea 
or Grade 3/4 vomiting and diarrhea persisting less than 72 hours in the absence of maximal 
medical therapy  
 
Grade 4 neutropenia lasting more than 5 days 
 
Grade 3 or greater febrile neutropenia (temperature ≥ 38.5ºC) 
 
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with clinically significant 
bleeding, or any requirement for platelet transfusion 
 
Any other Grade 3 or 4 laboratory abnormality that requires hospitalization 
 
An ALT > 3x ULN with concomitant total bilirubin > 2x ULN 
 
Any ZEN003694-related toxicity that results in more than 25% of missed doses during 
Cycle 1 of treatment 
 
In the situation where toxicity requires withholding ZEN003694 following the receipt of at 
least 75% of scheduled dosing during Cycle 1: Failure to begin Cycle 2 within 1 week of 
the scheduled start date due to ongoing toxicity. 
All patients experiencing a DLT must discontinue dosing with ZEN003694; patients must complete 
the Safety Follow-up visit prior to discontinuation from the study.   
Determination of evaluability will be made during the first 28 days of ZEN003694 treatment (i.e., 
Cycle 1) in the dose escalation phase.  Patients meeting one or more of the following will be 
considered unevaluable and will be replaced: 
 
Patients who miss more than 25% of ZEN003694 and/or enzalutamide or abiraterone doses 
or fail to begin Cycle 2 within 1 week of the scheduled start date for reasons other than 
ZEN003694-related toxicity 
 
Patients who require enzalutamide or abiraterone dose hold or modification in Cycle 1, 
including during the 14-day Lead-in period for reasons other than ZEN003694-related 
toxicity.     
 
Part 1 only: If a patient is unable to tolerate enzalutamide for any reason at dose of 160 mg 
during the 14 day Lead-in prior to first dose of ZEN003694, then the patient should not 
receive ZEN003694, and be withdrawn from the study and replaced. 
 
Part 2 only: If a patient is unable to tolerate for any reason abiraterone at dose of 1000 mg 
once daily during the 14 day Lead-in prior to first dose of ZEN003694, then the patient 
should not receive ZEN003694, and be withdrawn from the study and replaced 
Definition of the Maximum Tolerated Dose 
 
 


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The MTD is defined as the highest dose level of ZEN003694 in combination with enzalutamide 
(Part 1) or abiraterone (Part 2; if MTD is determined) at which no more than 1 of 6 patients 
experiences a DLT during the first cycle of therapy. MTD may be declared independently for any 
given dosing regimen, i.e., the respective MTDs for once daily dosing, twice daily dosing, and any 
alternative dosing regimen(s) need not be at the same dose. 
Definition of the Recommended Phase 2 Dose 
The RP2D is defined as the dose level of ZEN003694 in combination with enzalutamide (Part 1) or 
abiraterone (Part 2) recommended for further clinical study.  In Part 1 of this study, the RP2D may 
be the same as the MTD or modified from the MTD based on assessment of overall exposure, safety 
experience in Cycle 2 and beyond, PD and clinical benefit data.  In Part 2 of this study, the MTD 
establishment may be waived and the RP2D will then be based on assessment of overall exposure, 
safety experience in Cycle 2 and beyond, PD and clinical benefit data; alternatively, it may be based 
on the MTD established. The RP2D of ZEN003694 in combination with enzalutamide (Part 1) or 
abiraterone (Part 2) will be determined in the dose confirmation phase of the study. RP2D may be 
declared independently for any given Part of the study  or dosing regimen, i.e., the respective 
RP2Ds for once daily dosing, twice daily dosing, and any alternative dosing regimen(s) need not be 
at the same dose. 
Dose Confirmation  
Part 1 only: Once the MTD of ZEN003694 in combination with enzalutamide has been determined 
in the dose escalation portion of Part 1 of the study, up to 20 patients who meet the 
inclusion/exclusion criteria for Cohort DC-A and up to 20 patients who meet the 
inclusion/exclusion criteria for Cohort DC-B of the dose confirmation phase will be enrolled for 
further evaluation of safety, PK, PD and preliminary clinical activity.   
Enzalutamide-naive and apalutamide-naïve patients in Cohort DC-B will be administered 
enzalutamide (160 mg) orally once daily for 14 days prior to the initiation of the combination 
therapy (Lead-in) to reach enzalutamide Css during Cycle 1.  After the Lead-in, ZEN003694 will be 
administered orally in combination with daily enzalutamide for 28-day cycles.  Patients in Cohort 
DC-A who are currently receiving a stable dose of enzalutamide (Sub-arm A1) will continue to 
receive enzalutamide and will not participate in the Lead-in. Patients in Cohort DC-A who are not 
currently receiving enzalutamide or apalutamide or are currently taking apalutamide (Sub-arm A2) 
will be administered enzalutamide orally once daily for 14 days prior to the initiation of the 
combination therapy (Lead-in) to reach enzalutamide Css.  After the Lead-in, ZEN003694 will be 
administered orally in combination with daily enzalutamide for 28-day cycles.   
Part 2 only: Once the CRC has determined a recommended phase 2 dose of ZEN003694 in 
combination with abiraterone in the dose escalation portion of Part 2 of the study, up to 20 patients 
who meet the inclusion/exclusion criteria for Cohort DC-C and up to 20 patients who meet the 
inclusion/exclusion criteria for Cohort DC-D of the dose confirmation phase will be enrolled for 
further evaluation of safety, PK, PD and preliminary clinical activity.  
Abiraterone-naïve patients in Cohort DC-D will be administered abiraterone (1000 mg once daily) 
orally for 14 days prior to the initiation of the combination therapy (Lead-in) to reach abiraterone 
Css during Cycle 1.  After the Lead-in, ZEN003694 will be administered orally in combination with 
daily abiraterone for 28-day cycles.  Patients in Cohort DC-C who are currently receiving a stable 
dose of abiraterone (Sub-arm C1) will continue to receive abiraterone when enrolled in the dose 
confirmation phase of the study and will not participate in the Lead-in.  Patients in Cohort DC-C 
who are not currently receiving abiratertone (Sub-Arm C2) will be administered abiraterone orally 


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once daily for 14 days prior to the initiation of the combination therapy (Lead-in) to reach 
abiraterone Css.  After the Lead-in, ZEN003694 will be administered orally in combination with 
daily abiraterone for 28-day cycles.   
Part 1 and Part 2: When the 6th patient in each cohort in the dose confirmation phase has 
completed one cycle of therapy, or earlier if clinically indicated, the CRC will review the safety 
data.  If  ≥ 2 patients have experienced drug-related SAEs or DLT-equivalent events, the CRC may 
recommend a modification in the dose or regimen of ZEN003694 in combination with enzalutamide 
for the dose confirmation phase. 
NUMBER OF SITES:  
Up to 10 sites in the United States may participate in this study.  
NUMBER OF PATIENTS: 
Part 1: Up to 80 evaluable patients will be enrolled in the study; approximately 40 patients will be 
enrolled in the dose escalation phase and up to 40 patients will be enrolled in the dose confirmation 
phase. 
Part 2: Up to 55 evaluable patients will be enrolled in the study; approximately 15 patients will be 
enrolled in the dose escalation phase and up to 40 patients will be enrolled in the dose confirmation 
phase. 
ESTIMATED STUDY DURATION: 
The study duration including the enrollment period and follow-up for both the dose escalation and 
dose confirmation phases is approximately 36 months for Part 1 and 24 months for Part 2, 
depending upon total enrollment.   
ELIGIBILITY CRITERIA: 
Part 1:, ZEN003694 in combination with enzalutamide 
Part 1 Inclusion Criteria 
Patients must meet the following inclusion criteria to be eligible for the study. 
Part 1 All Patients 
1. Males age ≥ 18 years 
2. Metastatic, castrate resistant, histologically confirmed prostate cancer; surgically castrated 
or continuous medical castration for ≥ 8 weeks prior to screening 
3. Serum testosterone < 50 ng/dL determined within 4 weeks of first administration of study 
drug 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
5. Adequate laboratory parameters at Screening including: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
b. Platelet count ≥ 100,000/mm3 


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c. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.0 x 
ULN (≤ 5 x ULN if liver metastases are present) 
d. Total bilirubin ≤ 1.25 x ULN  
e. Serum creatinine ≤ 1.5 x ULN or calculated (Cockcroft-Gault formula) or 
measured creatinine clearance ≥ 60 mL/min 
f. Prothrombin time (PT), international normalized ratio (INR) and partial 
thromboplastin time (PTT) < 1.5 x ULN 
6. Use of corticosteroids is allowed up to a daily dose of 10 mg prednisone or equivalent 
provided that the dose has been stable for at least 2 weeks prior to first administration of 
study drug and will remain stable during study drug and enzalutamide dosing  
7. Patients must be surgically sterile or must agree to use physician-approved contraception 
during the study and for 30 days following the last study drug administration 
8. Ability to swallow capsules and comply with study procedures  
9. Ability to understand and willingness to sign informed consent form prior to initiation of 
any study procedures 
Part 1 Dose Escalation only  
10. Cohort DE-A: Prior progression on enzalutamide or apalutamide at any time by PCWG2 
criteria and is or will be receiving a stable dose of enzalutamide (defined as a dose that has 
not changed for at least 2 weeks prior to Cycle 1 Day 1 and is not expected to change on 
study).  Patients may or may not have experienced prior progression on abiraterone. 
11. Cohort DE-B: Enzalutamide-naïve and apalutamide-naïve patients following prior 
progression on abiraterone by PCWG2 criteria.   
Part 1 Dose Confirmation only 
12. Cohort DC-A:  Prior progression on enzalutamide or apalutamide at any time by PCWG2 
criteria and is or will be receiving a stable dose of enzalutamide (defined as a dose that has 
not changed for at least 2 weeks prior to Cycle 1 Day 1 and is not expected to change on 
study).  Patients may or may not have experienced prior progression on abiraterone.  
13. Cohort DC-B:  Enzalutamide-naïve and apalutamide-naïve patients following prior 
progression on abiraterone by PCWG2 criteria. 
Part 1 Exclusion Criteria 
Patients who meet any of the following exclusion criteria will not be eligible to participate in the 
study. 
1. Any history of brain metastases or prior seizure or conditions predisposing to seizure 
activity 
2. Have previously received an investigational BET inhibitor (including previous participation 
in this study or Study ZEN003694-001)  


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3. Have received prior systemic anti-cancer therapy (including abiraterone) or investigational 
therapy within 2 weeks or five half-lives, whichever is shorter, prior to the first 
administration of study drug  
4. Failure to recover to Grade 1 or lower toxicity related to prior systemic therapy (excluding 
alopecia and neuropathy) prior to study entry  
5. Radiation therapy within 2 weeks of the first administration of study drug 
6. Treatment with a bone-targeted radionuclide within 6 weeks of first administration of study 
drug (enzalutamide in DE-B and DC-B or ZEN003694 in DE-A and DC-A) 
7. Have received prior chemotherapy in the metastatic castration-resistant setting (prior 
chemotherapy in the hormone-sensitive setting is allowed provided last dose was at least 
6 months prior to study entry) 
8. Have received prior investigational anti-androgen therapy 
9. Currently receiving medications known to be strong inhibitors of cytochrome (CYP)2C8, 
strong inducers (except enzalutamide or apalutamide) or inhibitors of CYP3A4 and 
substrates of CYP1A2, CYP3A4, CYP2C9 and CYP2C19 with a narrow therapeutic 
window.  Strong inducers, inhibitors and substrates must be discontinued at least 7 days 
prior to the first administration of study drug.  
10. Not a candidate for enzalutamide treatment, in the opinion of the Investigator 
11. Left ventricular ejection fraction less than the lower of 50% or the lower limit of 
institution’s normal range 
12. QTcF interval > 450 msec 
13. Known impaired cardiac function or clinically significant cardiac disease such as 
uncontrolled supraventricular arrhythmia, ventricular arrhythmia requiring therapy, or 
congestive heart failure (New York Heart Association functional class III or IV)  
14. Myocardial infarction or unstable angina within 6 months prior to the first administration of 
study drug 
15. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active 
central nervous system disease, active, uncontrolled bacterial, viral, or fungal infection(s) 
requiring systemic therapy, or any other condition that could compromise safety or the 
patient’s participation in the study 
16. Other known active cancer requiring therapy at time of study entry 
17. Historically positive (screening tests not required) for human immunodeficiency virus 
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) or with active infections.  HBV 
positivity defined by positive hepatitis B surface antigen (HBsAg).  HCV positivity defined 
as positive HCV viral load 
18. Major surgery other than diagnostic surgery, dental surgery or stenting within 4 weeks prior 
to the first administration of study drug 
19. History of congenital or other deficiency in platelet function, any known inherent or 


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acquired coagulopathy, or therapeutic anticoagulation with warfarin or apixaban (low-dose 
warfarin for port patency or prophylactic anti-platelet agents are allowed) 
20. Concurrent participation in another clinical investigational treatment trial 
21. Any other reason that in the opinion of the Investigator would prevent the patient from 
completing participation or following the study schedule 
Part 2 Only, ZEN003694 in combination with abiraterone: 
Part 2 Inclusion Criteria 
Patients must meet the following inclusion criteria to be eligible for the study. 
Part 2 All Patients 
1. Males age ≥ 18 years 
2. Metastatic, castrate resistant, histologically confirmed prostate cancer; surgically castrated 
or continuous medical castration for ≥ 8 weeks prior to screening 
3. Serum testosterone < 50 ng/dL determined within 4 weeks of first administration of study 
drug 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
5. Adequate laboratory parameters at Screening including: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
b. Platelet count ≥ 100,000/mm3 
c. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.0 x 
ULN (≤ 5 x ULN if liver metastases are present) 
d. Total bilirubin ≤ 1.25 x ULN  
e. Serum creatinine ≤ 1.5 x ULN or calculated (Cockcroft-Gault formula) or 
measured creatinine clearance ≥ 60 mL/min 
f. Prothrombin time (PT), international normalized ratio (INR) and partial 
thromboplastin time (PTT) < 1.5 x ULN 
6. Use of corticosteroids is allowed up to a daily dose of 10 mg prednisone or equivalent 
provided that the dose has been stable for at least 2 weeks prior to first administration of 
study drug and will remain stable during study drug and abiraterone dosing  
7. Patients must be surgically sterile or must agree to use physician-approved contraception 
during the study and for 30 days following the last study drug administration 
8. Ability to swallow capsules and comply with study procedures  
9. Ability to understand and willingness to sign informed consent form prior to initiation of 
any study procedures 


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Part 2 Dose Escalation only  
10. Cohort DE-C: Prior progression on abiraterone at any time by PCWG2 criteria and is or 
will be receiving a stable dose of abiraterone (defined as a dose that has not changed for at 
least 2 weeks prior to Cycle 1 Day 1 and is not expected to change on study).  Patients may 
or may not have experienced prior progression on enzalutamide or apalutamide.  
11. Cohort DE-D: Abiraterone-naïve patients following prior progression on enzalutamide or 
apalutamide by PCWG2 criteria.   
Part 2 Dose Confirmation only 
12. Cohort DC-C:  Prior progression on abiraterone at any time by PCWG2 criteria and is or 
will be receiving a stable dose of abiraterone (defined as a dose that has not changed for at 
least 2 weeks prior to Cycle 1 Day 1 and is not expected to change on study).  Patients may 
or may not have experienced prior progression on enzalutamide or apalutamide. 
13. Cohort DC-D:  Abiraterone-naïve patients following prior progression on enzalutamide or 
apalutamide by PCWG2 criteria.   
Part 2 Exclusion Criteria 
Patients who meet any of the following exclusion criteria will not be eligible to participate in the 
study. 
1. Have previously received an investigational BET inhibitor (including previous participation 
in this study or Study ZEN003694-001)  
2. Have received prior systemic anti-cancer therapy or investigational therapy within 2 weeks 
or five half-lives, whichever is shorter, prior to the first administration of study drug. 
(Patients progressing on enzalutamide or apalutamide require a 2 week wash-out prior to 
start of abiraterone Cycle 1 Lead-in where applicable)  
3. Failure to recover to Grade 1 or lower toxicity related to prior systemic therapy (excluding 
alopecia and neuropathy) prior to study entry  
4. Radiation therapy within 2 weeks of the first administration of study drug 
5. Treatment with a bone-targeted radionuclide within 6 weeks of first administration of study 
drug (abiraterone in DE-D and DC-D or ZEN003694 in DE-C and DC-C) 
6. Have received prior chemotherapy in the metastatic castration-resistant setting (prior 
chemotherapy in the hormone-sensitive setting is allowed provided last dose was at least 
6 months prior to study entry) 
7. Have received prior investigational anti-androgen therapy 
8. Currently receiving medications known to be substrates of CYP1A2 or CYP2D6 with a 
narrow therapeutic window.  Major substrates must be discontinued at least 7 days prior to 
the first administration of study drug.  
9. Not a candidate for abiraterone treatment, in the opinion of the Investigator 
10. Left ventricular ejection fraction less than the lower of 50% or the lower limit of 


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institution’s normal range 
11. QTcF interval > 450 msec 
12. Known impaired cardiac function or clinically significant cardiac disease such as 
uncontrolled supraventricular arrhythmia, ventricular arrhythmia requiring therapy, or 
congestive heart failure (New York Heart Association functional class III or IV)  
13. Myocardial infarction or unstable angina within 6 months prior to the first administration of 
study drug 
14. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active 
central nervous system disease, active, uncontrolled bacterial, viral, or fungal infection(s) 
requiring systemic therapy, or any other condition that could compromise safety or the 
patient’s participation in the study 
15. Other known active cancer requiring therapy at time of study entry 
16. Historically positive (screening tests not required) for human immunodeficiency virus 
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) or with active infections.  HBV 
positivity defined by positive hepatitis B surface antigen (HBsAg).  HCV positivity defined 
as positive HCV viral load 
17. Major surgery other than diagnostic surgery, dental surgery or stenting within 4 weeks prior 
to the first administration of study drug 
18. History of congenital or other deficiency in platelet function, any known inherent or 
acquired coagulopathy, or therapeutic anticoagulation with warfarin or apixaban (low-dose 
warfarin for port patency or prophylactic anti-platelet agents are allowed) 
19. Concurrent participation in another clinical investigational treatment trial 
20. Any other reason that in the opinion of the Investigator would prevent the patient from 
completing participation or following the study schedule 


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DOSE, REGIMEN AND ROUTE OF ADMINISTRATION: 
ZEN003694 
ZEN003694 is a novel, potent BET bromodomain inhibitor currently under clinical investigation.  
ZEN003694 will be supplied in capsules of two different dosage strengths:  12 mg and 48 mg.   
Part 1: The starting dose for this study is 36 mg daily.  Dosing in initial cohorts will commence with 
ZEN003694 administered once daily ZEN003694 in combination with enzalutamide (160 mg or at 
a lower stable dose for patients in DE-A or DC-A).  Alternative dosing regimens (i.e., twice daily 
dosing, on/off schedules) may be explored in separate dose cohorts based on CRC safety review 
and approval. 
Part 2: The starting dose for this study is 72 mg daily.  Dosing in initial cohorts will commence with 
ZEN003694 administered once daily ZEN003694 in combination with abiraterone (1000 mg once 
daily) orally.  Alternative dosing regimens (i.e., twice daily dosing, on/off schedules) may be 
explored in separate dose cohorts based on CRC safety review and approval. 
Both Part 1 and Part 2: ZEN003694 will be administered orally in 28-day cycles and should be 
ingested with a full (8-ounce) glass of water at least 1 hour before eating or 2 hours after eating 
(fasting). 
Part 1: Enzalutamide 
Enzalutamide is an androgen receptor inhibitor indicated for the treatment of patients with mCRPC.  
Enzalutamide 160 mg (four 40 mg capsules) will be administered orally once daily according to the 
XTANDI® Package Insert without food in 28-day cycles for all enzalutamide-naïve patients (DE-B 
and DC-B cohorts).  For patients in DE-A and DC-A cohorts, enzalutamide will be administered at 
the dose level previously determined to be stable and that has not changed for at least two weeks 
prior to starting Cycle 1 Day 1 combination study treatment or restarting enzalutamide treatment in 
the Lead-in phase.  In Dose Escalation, the dose of enzalutamide will be held constant throughout 
Cycle 1 of the study. After Cycle 1, the dose of enzalutamide may be modified for toxicity per the 
XTANDI® Package Insert. 
Patients may continue receiving ZEN003694 in combination with enzalutamide until disease 
progression by PCWG2 criteria, unacceptable toxicity, requirement for non-protocol therapy or 
patient withdrawal from study.  Patients with PSA-only progression may remain on study until 
clinical and/or radiographic evidence of progression by PCWG2 criteria. 
Part 2: Abiraterone 
Abiraterone is an androgen synthesis inhibitor indicated for the treatment of patients with mCRPC.  
Abiraterone 1000 mg (four 250 mg capsules) will be administered orally once daily according to the 
ZYTIGA® Package Insert without food in 28-day cycles.  In Dose Escalation, the dose of 
abiraterone will be held constant at 1000 mg throughout Cycle 1 of the study. After Cycle 1, the 
dose of abiraterone may be modified for toxicity per the ZYTIGA® Package Insert. 
Patients may continue receiving ZEN003694 in combination with abiraterone until disease 
progression by PCWG2 criteria, unacceptable toxicity, requirement for non-protocol therapy or 
patient withdrawal from study.  Patients with PSA-only progression may remain on study until 
clinical and/or radiographic evidence of progression by PCWG2 criteria. 
 


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STUDY ASSESSMENTS: 
Safety 
Safety will be assessed by periodic physical examinations, weight, ECOG performance status, vital 
signs, clinical laboratory assessments (hematology, serum chemistries, serum troponin, coagulation 
tests and urinalysis), 12-lead electrocardiogram (ECG) and monitoring of AEs (see Schedule of 
Events).  
Pharmacokinetics 
Part 1: Plasma samples will be collected to assess the PK properties of ZEN003694 and the 
metabolite ZEN003791, and enzalutamide and the metabolite des-methyl enzalutamide. Urine 
samples may also be collected at the direction of Zenith in the Dose Confirmation phase to assess 
ZEN003694 and its metabolites, including ZEN003791.   Plasma and urine concentrations of 
ZEN003694, the metabolite ZEN003791, enzalutamide and des-methyl enzalutamide will be 
determined by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) 
bioanalytical method.  Samples will be collected as indicated in the Schedule of Events. 
Part 2: Plasma samples will be collected to assess the PK properties of ZEN003694 and the 
metabolite ZEN003791, and abiraterone.  Plasma concentrations of ZEN003694, the metabolite 
ZEN003791, and abiraterone will be determined by a validated liquid chromatography-tandem mass 
spectrometry (LC-MS/MS) bioanalytical method.  Samples will be collected as indicated in the 
Schedule of Events. 
Pharmacodynamics 
Blood samples will be drawn for analyses of BET inhibitor gene expression profile, cell-free DNA 
and circulating tumor DNA, CTCs and exploratory biomarkers (dose confirmation only) as 
indicated in the Schedule of Events.  Blood samples for analyses of immuno-oncology biomarkers 
will also be drawn at selected clinical sites.  Tumor tissue will be obtained for histological and 
immunohistochemical analyses, expression of V-Myc avian myelocytomatosis viral oncogene 
homolog (MYC), glucocorticoid receptor (GR) and androgen receptor (AR), and RNA sequencing 
(and DNA sequencing if adequate tumor tissue is available) analysis to identify somatic mutations, 
alternative splicing, fusions and alterations in gene expression.  Tumor tissue will be obtained as 
indicated in the Schedule of Events. 
Response 
Whole 
body 
radionuclide 
imaging 
(Tech-99) 
and 
cross-sectional 
imaging 
of 
the 
chest/abdomen/pelvis should be performed in accordance with institutional standards.  Use of 
intravenous contrast is required unless contraindicated.  Magnetic resonance imaging (MRI) may be 
substituted for computed tomography (CT) per the Investigator’s discretion.  Disease status should 
be assessed using the PCWG2 criteria as indicated in the Schedule of Events. 
Blood samples will be drawn to measure PSA levels as indicated in the Schedule of Events. 
Whole blood samples will be drawn for enumeration of CTCs as indicated in the Schedule of 
Events. 
 
 


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STATISTICAL METHODS:  
The primary statistical analysis of the data will be descriptive in nature.  For continuous variables 
this means calculation of the number of observations, mean, standard deviation, median, minimum, 
and maximum.  Categorical variables will be summarized by patient counts and related percentages.  
For ordinal-scaled variables, a combination of the above may be employed as appropriate:  
frequency and percentage of observations within a category and means and standard deviations of 
the scores of the categories.  For categorical and ordinal variables, percentages will be calculated 
based on non-missing data. 
Based on the characteristics of the study design and lack of a concurrent control arm, formal testing 
of treatment effects (i.e., inferential statistics) will not be performed.  However, some measures will 
be summarized by both point estimates and the associated 95% confidence intervals. 
Sample Size Determination 
A conventional algorithm (3+3 patients per dose level) will be used to identify the MTD, escalating 
on 0 of 3 or 1 of 6 DLTs, and de-escalating if 2 DLTs are encountered.  The MTD will be the 
highest dose level at which 0 of 3 or 1 of 6 patients experience a DLT, with the next higher dose 
having at least 2 of 3 or 2 of 6 patients experiencing a DLT.  With this design, there is a 71% 
chance of escalation if the true but unknown rate of DLT is 20%, and less than 50% chance of 
escalation if the true but unknown rate of DLT is higher than 30%. 
Part 1: Approximately 40 patients may be enrolled in the dose escalation phase of the study.  Up to 
40 patients in the dose confirmation phase  may be enrolled at the MTD or RP2D.  The sample size 
is sufficient to support preliminary safety and pharmacologic assessments. 
Part 2: Approximately 15 patients may be enrolled in the dose escalation phase of the study.  Up to 
40 patients in the dose confirmation phase  may be enrolled at the MTD or RP2D.  The sample size 
is sufficient to support preliminary safety and pharmacologic assessments. 
Analysis Populations  
The following populations will be analyzed by Part: 
Safety population:  Patients who receive at least one dose of ZEN003694. 
DLT population:  Patients who experience a DLT as defined by this protocol.  Patients who 
experience a DLT within the first cycle of treatment and drop out of the study will be considered 
evaluable for DLT and will not be replaced.  
 
Part 1 only: No dose modification of enzalutamide (160 mg) is permitted during Cycle 1, 
including the 14-day Lead-in period; patients requiring dose modification during Cycle 1 
must discontinue the study and will be replaced.  Patients, who for reasons other than a 
DLT, discontinue the study prior to completion of the first cycle will be considered 
unevaluable and will be replaced.  
 
Part 2 only: No dose modification of abiraterone (1000 mg) is permitted during Cycle 1, 
including the 14-day Lead-in period; patients requiring dose modification during Cycle 1 
must discontinue the study and will be replaced.  Patients, who for reasons other than a 
DLT, discontinue the study prior to completion of the first cycle will be considered 
unevaluable and will be replaced.  


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Statistical Analyses 
Prior to the analysis of the final study data, a detailed statistical analysis plan (SAP) will be written.  
Detailed information regarding analysis datasets, summarization of the data and analyses will be 
provided in the SAP.   


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Table 1:  PART 1 ONLY:  ZEN003694 + Enzalutamide  
Schedule of Events – Dose Escalation (DE) and Dose Confirmation (DC) 
 
Screening 
(Within 28 
Days of C1D-14 
for DE-B and 
DC-B or C1D1 
for DE-A and 
DC-A) 
Cycle 1 
(Days -14 through -1) 
Cycle 1 
(Days 1 – 28) 
Cycle 2 
(Days 1 – 28) 
Cycle 3 
Onward 
(Days 1 – 28) 
Unscheduled 
Visit 
v 
End of 
Treatment 
w 
Safety 
Follow-up 
(30 Days 
after 
End of 
Treatment)x 
Medical, Surgical, Malignancy 
History, Prior Cancer 
Treatments, Demographics 
X 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Physical Examination, Weight, 
Height, ECOG Performance 
Status, Vital Signs a 
X 
 
Days 1, 8, 15, 22 
Days 1, 15 
Days 1 
X 
X 
X 
Hematology b 
X 
DE-B and DC-B: 
*Day -14 
DE-A and DC-A 
Sub-arm A2^ 
Days 1*, 8, 15, 
22 
Days 1, 8, 15, 22 
Days 1, 15 
X 
X 
X 
Coagulation Tests c 
X 
DE-B and DC-B: 
*Day -14 
DE-A and DC-A 
Sub-arm A2^ 
Days 1*, 15 
Day 1 
Day 1 
X 
 
 
Serum Chemistries d 
X 
DE-B and DC-B: 
*Day -14 
DE-A and DC-A 
Sub-arm A2^ 
Days 1*, 8, 15, 
22 
Days 1, 8, 15, 22 
Days 1, 15 
X 
X 
X 
Troponin e 
 
 
Days 1, 15 
Day 1 
Day 1 
 
X 
 
Serum Prostate-specific Antigen  
X 
DE-B and DC-B: 
*Day -14 
DE-A and DC-A 
Sub-arm A2^ 
 
Day 1* 
Day 1 
Day 1 
 
X 
X 
Urinalysis f 
X 
DE-B and DC-B: 
*Day -14 
DE-A and DC-A  
Sub-arm A2^ 
Day 1* 
Day 1 
Day 1 
X 
X 
X 
Serum Testosterone 
X 
 
Day 1 
Day 1 
Day 1 
 
X 
X 


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Screening 
(Within 28 
Days of C1D-14 
for DE-B and 
DC-B or C1D1 
for DE-A and 
DC-A) 
Cycle 1 
(Days -14 through -1) 
Cycle 1 
(Days 1 – 28) 
Cycle 2 
(Days 1 – 28) 
Cycle 3 
Onward 
(Days 1 – 28) 
Unscheduled 
Visit 
v 
End of 
Treatment 
w 
Safety 
Follow-up 
(30 Days 
after 
End of 
Treatment)x 
Echocardiogram or Multigated 
Acquisition Scan g 
X 
 
 
 
 
 
 
 
Triplicate 12-Lead 
Electrocardiogram h 
X 
 
Days 1, 15 
Day 1 
Day 1 h 
X 
 
 
Ophthalmology Assessmentsi 
X i 
 
 
Day 1 
Cycle 6 Day 1 
onward i 
X i 
X 
X i 
Qualitative Exploration of Visual 
Symptoms i 
X 
X 
Days 1, 8, 15, 22 
Days 1, 15 
Days 1 
 
X 
X 
Fresh Tumor and Archival 
Tumor Tissue Collection 
(Optional for DE, Mandatory for 
DC for Patients with Accessible 
Tumors) 
X j 
 
 
 
X k 
 
X l 
 
Pharmacokinetics m 
 
 
Days 1, 2, 15 
Day 1 
 
 
 
 
BET Inhibitor Gene Expression 
Profile n 
 
 
Days 1, 2 
 
 
 
 
 
Circulating Tumor Cells (CTCs) 
for 
Pharmacodynamic/Correlative 
Evaluation o 
 
DE-B and DC-B: 
Day -14 
DE-A and DC-A 
Sub-arm A2^ 
Day 1 
 
Day 1 
o 
 
 
 
X 
 
CTCs for Enumeration/Response 
Analysis p 
 
DE-B and DC-B: 
Day -14 
DE-A and DC-A 
Sub-arm A2^ 
Day 1 
 
Day 1 
p 
 
X 
 
Exploratory PD Biomarkers (DC 
Only) q 
 
DC-B: 
Day -14 
DC-A 
Sub-arm A2^ 
Day 1 
Day 1 
 
 
X 
 
Exploratory Immuno-Oncology 
Biomarkers r (DE Only, select 
sites only) 
Xr 
 
Days 1 r, 8, 22 
 
 
 
 
 
ZEN003694 Administration s 
 
 
Days 1 through 28 of each cycle 
 
 
 
Enzalutamide Administration t 
 
DE-B and DC-B:  
Days -14 through -1 
Days 1 through 28 of each cycle 
 
 
 


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Screening 
(Within 28 
Days of C1D-14 
for DE-B and 
DC-B or C1D1 
for DE-A and 
DC-A) 
Cycle 1 
(Days -14 through -1) 
Cycle 1 
(Days 1 – 28) 
Cycle 2 
(Days 1 – 28) 
Cycle 3 
Onward 
(Days 1 – 28) 
Unscheduled 
Visit 
v 
End of 
Treatment 
w 
Safety 
Follow-up 
(30 Days 
after 
End of 
Treatment)x 
DE-A and DC-A 
Sub-arm A2^ 
Adverse Events 
 
DE-B and DC-B: 
Day -14 
DE-A and DC-A 
Sub-arm A2^ 
Days 1, 8, 15, 22 
Days 1, 15 
Day 1 
X 
X 
X 
Prior/Concomitant Medications 
X 
DE-B and DC-B: 
Day -14 
DE-A and DC-A  
Sub-arm A2^ 
Days 1, 8, 15, 22 
Days 1, 15 
Day 1 
X 
X 
X 
Tumor Assessment u 
X 
 
 
 
X u 
X 
X 
 
Exploratory BET Inhibitor Blood 
Signature (DC only) y 
 
 
Day 1 
Day 1 
X y 
 
X 
 
Urinalysis for Renal Clearance 
(DC Only) z 
 
 
Day 15 
 
 
 
 
 
Exploratory cfDNA and ctDNAaa 
 
DE-B and DC-B 
Day -14 
DE-A and DC-A  
Sub-arm A2^ 
Day 1 
 
Day 1 
 
X 
 
Cycle 1 Day -14 Enzalutamide Lead-in should begin -14 days ± 1 day from Cycle 1 Day 1. All other scheduled clinic attendance should occur within ± 3 days of the specified 
dates at all visits unless otherwise specified.  Imaging for tumor assessments may be scheduled up to 7 days prior to the scheduled clinic visit day. 
* For patients requiring enzalutamide Lead-in, perform laboratory tests at Cycle 1 Day -14 only if Screening visit tests were performed more than 7 days prior to the Cycle 1 Day -
14 visit. For patients that do not require enzalutamide Lead-in, perform laboratory tests at Cycle 1 Day 1 only if Screening visit tests were performed more than 7 days prior to the 
Cycle 1 Day 1 visit. 
^ Only for patients in DE-A or DC-A who are not currently taking enzalutamide or are currently taking apalutamide, enzalutamide is to be (re)started with a 14 day Lead-in and 
Visit C1D-14 shall be conducted for applicable patients (DE-A and DC-A Sub-arm A2)  
All assessments and tests/samples should be obtained pre-dose unless specified otherwise, and are to be performed even if dosing is not required (i.e., due to an on/off 
schedule) on the specified study visit day.  Note:  The visits in Cycle 2, on Days 8 and 22 and in Cycle 3 onward, on Day 15, will only include blood draws for safety 
laboratory testing and may be drawn after the patient has taken his dose (if dosing is required on that day). 
Footnotes:  
a Complete physical examination to be performed at the Screening visit and a symptom-directed physical examination thereafter.  Height to be measured at the Screening Visit 
only. Vital signs: body temperature, blood pressure and heart rate.  
b Hematology: complete blood count (CBC) with differential and absolute neutrophil count (ANC). Day 15 hematology can be waived at Investigator discretion starting in Cycle 6 
onward as long as platelets are stable and there are no other laboratory concerns in the opinion of the Investigator.   
c Coagulation tests:  prothrombin time (PT) or international normalized ratio (INR) and partial thromboplastin time (PTT)  


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d Serum chemistry:  albumin, alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase, amylase, bicarbonate, total bilirubin, blood urea nitrogen 
(BUN), total calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), lipase, sodium, potassium, phosphorus and magnesium.  Note:  Serum testosterone will be 
collected at screening , Day 1 of each cycle, and at EOT and Safety Follow-up. Day 15 serum chemistries can be waived at Investigator discretion starting in Cycle 6 onward as 
long as platelets are stable and there are no other laboratory concerns in the opinion of the Investigator.  
e  Troponin: serum samples will be drawn for analyses of troponin T and/or I proteins, based on local laboratory procedure. For any individual patient, the same method will be 
used at each timepoint. 
f Urinalysis: dipstick with micro-analysis if clinically indicated.  
g  Cardiac echocardiogram or multigated acquisition (MUGA) scan for left ventricular ejection fraction   
h Triplicate 12-lead electrocardiogram (ECG) to be performed as follows for each Part.  For DE, DC-A and DC-B: Cycle 1 Day 1: pre-dose and 1 hour (±15 min) post-ZEN003694 
and enzalutamide doses; Cycle 1 Day 15: pre-dose and 1 hour (±15 min) post-ZEN003694 and enzalutamide doses; Cycle 2 Day 1: pre-ZEN003694 and enzalutamide doses; Cycle 
3 Day 1 and every other cycle onward (C5D1, C7D1, etc.):  pre-ZEN003694 and enzalutamide doses. 
i Ophthalmology assessments will be performed at Screening, C2D1, C6D1 (and every sixth cycle onward) and at the End of Treatment (±7 days at each visit).  Screening 
ophthalmology assessments are to be performed prior to C1D1 and after all entry criteria have been assessed and the subject is approved for enrollment in the study.  If 
abnormalities are detected or there are visual disturbances noted at the End of Treatment, ophthalmology assessments are to be performed at the Safety Follow-Up visit.  At any 
time during the study should a clinically meaningful change in visual symptoms occur, unscheduled assessments are to be performed.  Ophthalmology assessments will include:  
Ophthalmic history, Snellen best corrected visual acuity (including refraction, if needed), color vision testing (using standard HRR pseudoisochromatic plates), pupillometry, 
confrontational visual field testing, intraocular pressure (using Goldmann tonometry or TonoPen tonometry), external eye and ocular motility exam and slit lamp biomicroscopy, 
indirect ophthalmoscopy, OCT optic nerve and macula tests, fundus photography, and other exams as clinically indicated. Completion of the Qualitative Exploration of Visual 
Symptoms form (provided by the Sponsor) is required at every clinic visit.      
j Fresh tumor sample collections are optional and encouraged at Screening during the DE phase.  Fresh tumor samples are mandatory at Screening during the DC phase for patients 
with accessible lesions.  During each biopsy procedure, 2-4 tumor tissue cores (optimally 4 cores) should be obtained.  For those patients in DE-A or DC-A who are not currently 
taking enzalutamide and require 14 day Lead-in, the screening fresh tumor biopsy can be collected from time of consent through Cycle 1 Day -1, preferably during the 14 day 
enzalutamide Lead-in. Archival tumor samples (initial diagnostic tissue or from prostatectomy or other resected tissue), if available and with the patient’s consent, will be collected 
during the Screening period through the end of Cycle 2 or the End of Treatment, whichever occurs first. 
k Fresh tumor sample collections at Cycle 3 Day 1 (± 15 days) during the DE phase are encouraged yet optional. Fresh tumor sample collections at Cycle 3 Day 1 (± 15 days) 
during the DC phase are mandatory if the tumor is accessible.  During each biopsy procedure, 2-4 tumor tissue cores (optimally 4 cores) should be obtained. 
l An optional biopsy will be taken at the time of disease progression by Prostate Cancer Working Group 2 (PCWG2) criteria for patients in DE or DC phases of the study. 
Whenever possible, this biopsy should be performed while the patient is still receiving ZEN003694 and enzalutamide, and 2 to 4 hours following administration of ZEN003694 
and enzalutamide on the day of biopsy.  
m Blood (plasma) for pharmacokinetic (PK) profile of ZEN003694 and enzalutamide and their active metabolites will be collected in DE, DC-A and DC-B as specified below: 
 
C1D1:  pre-ZEN003964 and enzalutamide doses 
 
C1D1:  15 min (±5 min), 30 min (±5 min), 1 hour (±5 min), 2 hours (±10 min), 4 hours (±15 min), 6 hours (±15 min) and 8 hours (±30 min) post-ZEN003694 and 
enzalutamide doses 
 
C1D2:  pre-ZEN003694 and enzalutamide doses  
 
C1D15:  pre-ZEN003964 and enzalutamide doses 
 
C1D15:  15 min (±5 min), 30 min (±5 min), 1 hour (±5 min), 2 hours (±10 min), 4 hours (±15 min), 6 hours (±15 min) and 8 hours (±30 min) post-ZEN003694 and 
enzalutamide doses 
 
C2D1:  pre-ZEN003964 and enzalutamide doses 
 
If enzalutamide dose is reduced in DE any time after Cycle 1 or in DC at any time, PK samples are to be collected 28 days ±7 days following dose modification: pre-
ZEN003964 and enzalutamide doses, and 15 min (±5 min), 30 min (±5 min), 1 hour (±5 min), 2 hours (±10 min), 4 hours (±15 min), 6 hours (±15 min) and 8 hours 
(±30 min) post-ZEN003694 and enzalutamide doses 
n Blood samples (whole blood) for BET inhibitor gene expression profile: 
 
C1D1:  pre-ZEN003694 and enzalutamide doses 
 
C1D1:  2 hours (±15 min), 4 hours (±15 min), and 6 hour (±15 min) post-ZEN003694 and enzalutamide doses 


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 
C1D2:  pre-ZEN003694 and enzalutamide doses 
 
Unscheduled blood samples (whole blood) for BET inhibitor gene expression profile at pre-dose, 2 hours (±15 min), 4 hours (±15 min), and/or 6 hour (±15 min) post-
ZEN003694 and enzalutamide doses may also be drawn at later time-points, upon direction by Zenith 
o Blood samples (whole blood) for CTCs for PD/correlative evaluation: 
 
C1D-14:  pre-enzalutamide dose (for all patients requiring enzalutamide Lead-in) 
 
C1D1:  pre-ZEN003694 and enzalutamide doses 
 
C3D1:  pre-ZEN003694 and enzalutamide doses 
 
Every third cycle D1 (C6D1, C9D1, etc.):  pre-ZEN003694 and enzalutamide doses 
 
At disease progression and at the time of PSA or radiographic response 
p Blood samples (whole blood) for CTCs for enumeration/response analysis: 
 
C1D-14:  pre-enzalutamide dose (for all patients requiring enzalutamide Lead-in) 
 
C1D1:  pre-ZEN003694 and enzalutamide doses 
 
C3D1:  pre-ZEN003694 and enzalutamide doses 
 
Every third cycle D1 (C6D1, C9D1, etc.):  pre-ZEN003694 and enzalutamide doses 
 
At disease progression and at the time of PSA or radiographic response 
q Blood samples (plasma) for exploratory PD assessments (DC-A and DC-B): 
 
C1D-14:  pre-enzalutamide dose (for all patients requiring enzalutamide Lead-in)  
 
C1D1:  pre-ZEN003694 and enzalutamide doses  
 
C2D1:  pre-ZEN003694 and enzalutamide doses  
 
At study treatment discontinuation 
r Blood samples (whole blood) for immuno-oncology biomarker assessments (DE Only, at selected clinical sites only)   
 
Screening (Prior to the first dose of enzalutamide for the Day -14 Lead-in for all patients requiring enzalutamide Lead-in.  Prior to ZEN003694 dosing on C1D1 of DE-A 
or DC-A for patients who do not require enzalutamide Lead-in.)   
 
C1D1:  For all patients requiring enzalutamide Lead-in, pre-ZEN003694 and pre-enzalutamide dosing 
 
C1D8:  pre-ZEN003694 and pre-enzalutamide dosing 
 
C1D22:  pre-ZEN003694 and pre-enzalutamide dosing 
s ZEN003694 should be taken at the same time as enzalutamide starting on C1D1. 
t Enzalutamide  will be given as a single agent for 14 days (C1D -14 through -1) prior to the initiation of the combination therapy on C1D1 (Lead-in).  The Lead-in period occurs 
only for Cycle 1 in DE-B and DC-B phases, and for those patients in DE-A or DC-A who are not currently taking enzalutamide and require the 14 day Lead-in.  Enzalutamide 
should be taken once daily starting on C1D-14. 
u Tumor assessment to include whole body radionuclide imaging (Tech-99) + cross-sectional imaging of the chest/abdomen/pelvis.  Use of IV contrast is required unless contra-
indicated.  Magnetic resonance imaging (MRI) may be substituted for computed tomography (CT) per Investigator’s discretion.  Tumor assessment are to be performed during the 
Screening period, Cycle 3 Day 1 and every 3 cycles onward (C6D1, C9D1, etc.).  Imaging may be scheduled up to 7 days prior to the scheduled clinic visit day. 
v Physical examination, vital signs, hematology, coagulation tests, serum chemistry, urinalysis, ECG, tumor assessments, and/or other assessments may be performed as clinically 
indicated during any unscheduled visit 
w At the End of Treatment if a subject’s dose was held and treatment was not resumed after a two week period, the scheduling of the EOT visit from the date of last study drug is 
extended from 7 days to 14 days (±3 days). 
x The Safety Follow-Up Visit should be completed 30 days (±3 days) after the End of Treatment visit or prior to the subject beginning a new anti-cancer treatment, whichever 
occurs first.  If the subject begins a new anti-cancer treatment within 7 days following the End of Treatment visit, the Safety Follow-Up visit is not required. 
y Blood samples (whole blood) for Exploratory BET inhibitor blood signature (DC-A and DC-B): 
 
C1D1: pre-ZEN003694 and enzalutamide doses 
 
C1D1: 4 hours (±15 min) post-ZEN003694 and enzalutamide doses 
 
C2D1: pre-ZEN003694 and enzalutamide doses 


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 
C3D1: pre-ZEN003694 and enzalutamide doses  
 
Every 3 cycles onward (C6D1, C9D1, etc.): pre-ZEN003694 and enzalutamide doses 
 
End of Treatment Visit 
z Urine samples for renal clearance of ZEN003694 and its metabolites for up to 8 hours may be collected at C1D15 upon direction from Zenith (DC Only) 
aa Blood samples (whole blood) for exploratory cfDNA and ctDNA assessments 
 
C1D-14 pre- enzalutamide dose (DE-B and DC-B and DE-A or DC-A Sub-Arm A2: all patients requiring the enzalutamide Lead-in) 
 
C1D1 pre-ZEN003694 and enzalutamide doses 
 
C3D1 pre-ZEN003694 and enzalutamide doses 
 
End of Treatment Visit 
 
In selected patients who have shown evidence of response or progression, an unscheduled pre-dose sample may be collected during the course of the response based 
upon agreement between the Sponsor and Investigator 
 
 


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Table 2:  PART 2 ONLY:  ZEN003694 + Abiraterone  
Schedule of Events – Dose Escalation (DE) and Dose Confirmation (DC) 
 
Screening 
(Within 28 
Days of C1D-14 
for DE-B and 
DC-B or C1D1 
for DE-A and 
DC-A) 
Cycle 1 
(Days -14 through -1) 
Cycle 1 
(Days 1 – 28) 
Cycle 2 
(Days 1 – 28) 
Cycle 3 
Onward 
(Days 1 – 28) 
Unscheduled 
Visit 
v 
End of 
Treatment 
w 
Safety 
Follow-up 
(30 Days 
after 
End of 
Treatment)x 
Medical, Surgical, Malignancy 
History, Prior Cancer 
Treatments, Demographics 
X 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Physical Examination, Weight, 
Height, ECOG Performance 
Status, Vital Signs a 
X 
 
Days 1, 8, 15, 22 
Days 1, 15 
Days 1 
X 
X 
X 
Hematology b 
X 
DE-D and DC-D: 
*Day -14 
DE-C and DC-C 
Sub-arm C2^ 
Days 1*, 8, 15, 
22 
Days 1, 8, 15, 22 
Days 1, 15 
X 
X 
X 
Coagulation Tests c 
X 
DE-D and DC-D: 
*Day -14 
DE-C and DC-C 
Sub-arm C2^ 
Days 1*, 15 
Day 1 
Day 1 
X 
 
 
Serum Chemistries d 
X 
DE-D and DC-D: 
*Day -14 
DE-C and DC-C 
Sub-arm C2^ 
Days 1*, 8, 15, 
22 
Days 1, 8, 15, 22 
Days 1, 15 
X 
X 
X 
Troponin e 
 
 
Days 1, 15 
Day 1 
Day 1 
 
X 
 
Serum Prostate-specific Antigen  
X 
DE-D and DC-D: 
*Day -14 
DE-C and DC-C 
Sub-arm C2^ 
 
Day 1* 
Day 1 
Day 1 
 
X 
X 
Urinalysis f 
X 
DE-D and DC-D: 
*Day -14 
DE-C and DC-C 
Sub-arm C2^ 
Day 1* 
Day 1 
Day 1 
X 
X 
X 
Serum Testosterone 
X 
 
Day 1 
Day 1 
Day 1 
 
X 
X 


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Screening 
(Within 28 
Days of C1D-14 
for DE-B and 
DC-B or C1D1 
for DE-A and 
DC-A) 
Cycle 1 
(Days -14 through -1) 
Cycle 1 
(Days 1 – 28) 
Cycle 2 
(Days 1 – 28) 
Cycle 3 
Onward 
(Days 1 – 28) 
Unscheduled 
Visit 
v 
End of 
Treatment 
w 
Safety 
Follow-up 
(30 Days 
after 
End of 
Treatment)x 
Echocardiogram or Multigated 
Acquisition Scan g 
X 
 
 
 
 
 
 
 
Triplicate 12-Lead 
Electrocardiogram h 
X 
 
Days 1, 15 
Day 1 
Day 1 h 
X 
 
 
Ophthalmology Assessmentsi 
X i 
 
 
 
 
X i 
 
 
Qualitative Exploration of Visual 
Symptoms i 
 
X 
Day 1 
Day 1 
 
 
X 
 
Fresh Tumor and Archival 
Tumor Tissue Collection 
(Optional for DE, Mandatory for 
DC for Patients with Accessible 
Tumors) 
X j 
 
 
 
X k 
 
X l 
 
Pharmacokinetics m 
 
 
Days 1, 2, 15 
Day 1 
 
 
 
 
BET Inhibitor Gene Expression 
Profile n 
 
 
Days 1, 2 
 
 
 
 
 
Circulating Tumor Cells (CTCs) 
for 
Pharmacodynamic/Correlative 
Evaluation o 
 
DE-D and DC-D: 
Day -14 
DE-C and DC-C 
Sub-arm C2^ 
Day 1 
 
Day 1 
o 
 
 
 
X 
 
CTCs for Enumeration/Response 
Analysis p 
 
DE-D and DC-D: 
Day -14 
DE-C and DC-C 
Sub-arm C2^ 
Day 1 
 
Day 1 
p 
 
X 
 
Exploratory PD Biomarkers (DC 
Only) q 
 
DC-D: 
Day -14 
DC-C 
Sub-arm C2^ 
Day 1 
Day 1 
 
 
X 
 
ZEN003694 Administration s 
 
 
Days 1 through 28 of each cycle 
 
 
 
Abiraterone Administration t 
 
DE-D and DC-D:  
Days -14 through -1 
DE-C and DC-C 
Sub-arm C2^ 
Days 1 through 28 of each cycle 
 
 
 
Adverse Events 
 
DE-D and DC-D: 
Day -14 
Days 1, 8, 15, 22 
Days 1, 15 
Day 1 
X 
X 
X 


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Screening 
(Within 28 
Days of C1D-14 
for DE-B and 
DC-B or C1D1 
for DE-A and 
DC-A) 
Cycle 1 
(Days -14 through -1) 
Cycle 1 
(Days 1 – 28) 
Cycle 2 
(Days 1 – 28) 
Cycle 3 
Onward 
(Days 1 – 28) 
Unscheduled 
Visit 
v 
End of 
Treatment 
w 
Safety 
Follow-up 
(30 Days 
after 
End of 
Treatment)x 
DE-C and DC-C 
Sub-arm C2^ 
Prior/Concomitant Medications 
X 
DE-D and DC-D: 
Day -14 
DE-C and DC-C 
Sub-arm C2^ 
Days 1, 8, 15, 22 
Days 1, 15 
Day 1 
X 
X 
X 
Tumor Assessment u 
X 
 
 
 
X u 
X 
X 
 
Exploratory BET Inhibitor Blood 
Signature (DC only) y 
 
 
Day 1 
Day 1 
X y 
 
X 
 
Exploratory cfDNA and ctDNAaa 
 
DE-D and DC-D 
Day -14 
DE-C and DC-C 
Sub-arm C2^ 
Day 1 
 
Day 1 
 
X 
 
 
Cycle 1 Day -14 Abiraterone Lead-in should begin -14 days ± 1 day from Cycle 1 Day 1. All other scheduled clinic attendance should occur within ± 3 days of the specified dates 
at all visits unless otherwise specified.  Imaging for tumor assessments may be scheduled up to 7 days prior to the scheduled clinic visit day. 
* For patients requiring abiraterone Lead-in, perform laboratory tests at Cycle 1 Day -14 only if Screening visit tests were performed more than 7 days prior to the Cycle 1 Day -14 
visit. For patients that do not require abiraterone Lead-in, perform laboratory tests at Cycle 1 Day 1 only if Screening visit tests were performed more than 7 days prior to the Cycle 
1 Day 1 visit. 
^ Only for patients in DE-C or DC-C who are not currently taking abiraterone, abiraterone is to be re-started with a 14 day Lead-in and Visit C1D-14 shall be conducted for 
applicable patients (DE-C or DC-C Sub-arm C2) 
All assessments and tests/samples should be obtained pre-dose unless specified otherwise, and are to be performed even if dosing is not required (i.e., due to an on/off 
schedule) on the specified study visit day.  Note:  The visits in Cycle 2, on Days 8 and 22 and in Cycle 3 onward, on Day 15, will only include blood draws for safety 
laboratory testing and may be drawn after the patient has taken his dose (if dosing is required on that day). 
Footnotes:  
a Complete physical examination to be performed at the Screening visit and a symptom-directed physical examination thereafter.  Height to be measured at the Screening Visit 
only. Vital signs: body temperature, blood pressure and heart rate.  
b Hematology: complete blood count (CBC) with differential and absolute neutrophil count (ANC). Day 15 hematology can be waived at Investigator discretion starting in Cycle 6 
onward as long as platelets are stable and there are no other laboratory concerns in the opinion of the Investigator.  
c Coagulation tests:  prothrombin time (PT) or international normalized ratio (INR) and partial thromboplastin time (PTT)  
d Serum chemistry:  albumin, alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase, amylase, bicarbonate, total bilirubin, blood urea nitrogen 
(BUN), total calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), lipase, sodium, potassium, phosphorus and magnesium.  Note:  Serum testosterone will be 
collected at screening, Day 1 of each cycle, and at EOT and Safety Follow-up. Day 15 serum chemistries can be waived at Investigator discretion starting in Cycle 6 onward as 
long as platelets are stable and there are no other laboratory concerns in the opinion of the Investigator.  


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e  Troponin: serum samples will be drawn for analyses of troponin T and/or I proteins, based on local laboratory procedure. For any individual patient, the same method will be 
used at each timepoint. 
f Urinalysis: dipstick with micro-analysis if clinically indicated.  
g  Cardiac echocardiogram or multigated acquisition (MUGA) scan for left ventricular ejection fraction   
h Triplicate 12-lead electrocardiogram (ECG) to be performed as follows for each Part.  For DE, DC-C and DC-D: Cycle 1 Day 1: pre-dose and 1 hour (±15 min) post-ZEN003694 
and abiraterone doses; Cycle 1 Day 15: pre-dose and 1 hour (±15 min) post-ZEN003694 and abiraterone doses; Cycle 2 Day 1: pre-ZEN003694 and abiraterone doses; Cycle 3 
Day 1 and every other cycle onward (C5D1, C7D1, etc.):  pre-ZEN003694 and abiraterone doses. 
i Ophthalmology assessments will be performed at Screening prior to C1D1 and after all entry criteria have been assessed and the subject is approved for enrollment in the study. 
At any time during the study should a clinically meaningful change in visual symptoms occur, repeat assessments are to be performed and may be recorded as an Unscheduled 
Visit. Ophthalmology assessments will include: Ophthalmic history, Snellen best corrected visual acuity (including refraction, if needed), color vision testing (using standard HRR 
pseudoisochromatic plates), pupillometry, OCT optic nerve and macula tests, fundus photography, and other exams as clinically indicated. The Visual Symptoms form (provided 
by the Sponsor) is to be administered by study personnel and completed at pre-dose on Cycle 1 Day-14, Cycle 1 Day 1, Cycle 2 Day 1 and at the EOT visit.       
j Fresh tumor sample collections are optional and encouraged at Screening during the DE phase.  Fresh tumor samples are mandatory at Screening during the DC phase for patients 
with accessible lesions.  During each biopsy procedure, 2-4 tumor tissue cores (optimally 4 cores) should be obtained.  For those patients in DE-C or DC-C who are not currently 
taking abiraterone and require 14 day Lead-in, the screening fresh tumor biopsy can be collected from time of consent through Cycle 1 Day -1, preferably during the 14 day 
abiraterone Lead-in. Archival tumor samples (initial diagnostic tissue or from prostatectomy or other resected tissue), if available and with the patient’s consent, will be collected 
during the Screening period through the end of Cycle 2 or the End of Treatment, whichever occurs first. 
k Fresh tumor sample collections at Cycle 3 Day 1 (± 15 days) during the DE phase are encouraged yet optional. Fresh tumor sample collections at Cycle 3 Day 1 (± 15 days) 
during the DC phase are mandatory if the tumor is accessible.  During each biopsy procedure, 2-4 tumor tissue cores (optimally 4 cores) should be obtained. 
l An optional biopsy will be taken at the time of disease progression by Prostate Cancer Working Group 2 (PCWG2) criteria for patients in the DE phase or DC phase of the study. 
Whenever possible, this biopsy should be performed while the patient is still receiving ZEN003694 and abiraterone, and 2 to 4 hours following administration of ZEN003694 and 
abiraterone on the day of biopsy.  
m Blood (plasma) for pharmacokinetic (PK) profile of ZEN003694 and abiraterone and their active metabolites will be collected in DE, DC-C and DC-D as specified below: 
 
C1D1:  pre-ZEN003964 and abiraterone doses 
 
C1D1:  15 min (±5 min), 30 min (±5 min), 1 hour (±5 min), 2 hours (±10 min), 4 hours (±15 min), 6 hours (±15 min) and 8 hours (±30 min) post-ZEN003694 and 
abiraterone doses 
 
C1D2:  pre-ZEN003694 and abiraterone doses  
 
C1D15:  pre-ZEN003964 and abiraterone doses 
 
C1D15:  15 min (±5 min), 30 min (±5 min), 1 hour (±5 min), 2 hours (±10 min), 4 hours (±15 min), 6 hours (±15 min) and 8 hours (±30 min) post-ZEN003694 and 
abiraterone doses 
 
C2D1:  pre-ZEN003964 and abiraterone doses 
 
If abiraterone dose is reduced in DE any time after Cycle 1 or in DC at any time, optional PK samples are to be collected at the discretion of the sponsor following dose 
modification: pre-ZEN003964 and abiraterone doses, and 15 min (±5 min), 30 min (±5 min), 1 hour (±5 min), 2 hours (±10 min), 4 hours (±15 min), 6 hours (±15 min) 
and 8 hours (±30 min) post-ZEN003694 and abiraterone doses 
n Blood samples (whole blood) for BET inhibitor gene expression profile: 
 
C1D1:  pre-ZEN003694 and abiraterone doses 
 
C1D1:  2 hours (±15 min), 4 hours (±15 min), and 6 hour (±15 min) post-ZEN003694 and abiraterone doses 
 
C1D2:  pre-ZEN003694 and abiraterone doses 
 
Unscheduled blood samples (whole blood) for BET inhibitor gene expression profile at pre-dose, 2 hours (±15 min), 4 hours (±15 min), and/or 6 hour (±15 min) post-
ZEN003694 and abiraterone doses may also be drawn at later time-points, upon direction by Zenith 
o Blood samples (whole blood) for CTCs for PD/correlative evaluation: 
 
C1D-14:  pre-abiraterone dose (for all patients requiring abiraterone Lead-in) 
 
C1D1:  pre-ZEN003694 and abiraterone doses 


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 
C3D1:  pre-ZEN003694 and abiraterone doses 
 
Every third cycle D1 (C6D1, C9D1, etc.):  pre-ZEN003694 and abiraterone doses 
 
At disease progression and at the time of PSA or radiographic response 
p Blood samples (whole blood) for CTCs for enumeration/response analysis: 
 
C1D-14:  pre-abiraterone dose (for all patients requiring abiraterone Lead-in) 
 
C1D1:  pre-ZEN003694 and abiraterone doses 
 
C3D1:  pre-ZEN003694 and abiraterone doses 
 
Every third cycle D1 (C6D1, C9D1, etc.):  pre-ZEN003694 and abiraterone doses 
 
At disease progression and at the time of PSA or radiographic response 
q Blood samples (plasma) for exploratory PD assessments (DC only): 
 
C1D-14:  pre-abiraterone dose (for all patients requiring abiraterone Lead-in)  
 
C1D1:  pre-ZEN003694 and abiraterone doses  
 
C2D1:  pre-ZEN003694 and abiraterone doses  
 
At study treatment discontinuation 
s ZEN003694 should be taken at the same time as abiraterone starting on C1D1. 
t Abiraterone  will be given as a single agent for 14 days (C1D -14 through -1) prior to the initiation of the combination therapy on C1D1 (Lead-in).  The Lead-in period occurs 
only for Cycle 1 in DE-D and DC-D phases, and for those patients in DE-C or DC-C who are not currently taking abiraterone and require the 14 day Lead-in.  Abiraterone should 
be taken once daily starting on C1D-14. 
u Tumor assessment to include whole body radionuclide imaging (Tech-99) + cross-sectional imaging of the chest/abdomen/pelvis.  Use of IV contrast is required unless contra-
indicated.  Magnetic resonance imaging (MRI) may be substituted for computed tomography (CT) per Investigator’s discretion.  Tumor assessment are to be performed during the 
Screening period, Cycle 3 Day 1 and every 3 cycles onward (C6D1, C9D1, etc.).  Imaging may be scheduled up to 7 days prior to the scheduled clinic visit day. 
v Physical examination, vital signs, hematology, coagulation tests, serum chemistry, urinalysis, ECG, tumor assessments, and/or other assessments may be performed as clinically 
indicated during any unscheduled visit 
w At the End of Treatment if a subject’s dose was held and treatment was not resumed after a two week period, the scheduling of the EOT visit from the date of last study drug is 
extended from 7 days to 14 days (±3 days). 
x The Safety Follow-Up Visit should be completed 30 days (±3 days) after the End of Treatment visit or prior to the subject beginning a new anti-cancer treatment, whichever 
occurs first.  If the subject begins a new anti-cancer treatment within 7 days following the End of Treatment visit, the Safety Follow-Up visit is not required. 
y Blood samples (whole blood) for Exploratory BET inhibitor blood signature (DC-C and DC-D): 
 
C1D1: pre-ZEN003694 and abiraterone doses 
 
C1D1: 4 hours (±15 min) post-ZEN003694 and abiraterone doses 
 
C2D1: pre-ZEN003694 and abiraterone doses 
 
C3D1: pre-ZEN003694 and abiraterone doses  
 
Every 3 cycles onward (C6D1, C9D1, etc.): pre-ZEN003694 and abiraterone doses 
 
End of Treatment Visit 
aa Blood samples (whole blood) for exploratory cfDNA and ctDNA assessments 
 
C1D-14 pre- abiraterone dose (DE-D and DC-D and DE-C or DC-C Sub-arm C2:  all patients requiring abiraterone Lead-in) 
 
C1D1 pre-ZEN003694 and abiraterone doses 
 
C3D1 pre-ZEN003694 and abiraterone doses 
 
End of Treatment Visit 
 
In selected patients who have shown evidence of response or progression, an unscheduled pre-dose sample may be collected during the course of the response based 
upon agreement between the Sponsor and Investigator 


 
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2. 
BACKGROUND 
2.1 
BET Inhibitors in Cancer 
The bromodomain and extra terminal domain (BET) proteins comprise four closely related 
bromodomain-containing proteins (BRD2, BRD3, BRD4, and BRDT) that are a subset of the 
larger family of 46 bromodomain-containing proteins.  The BET proteins are epigenetic readers 
that regulate transcription in part by binding acetylated lysines on histones and transcription 
factors.  BET proteins have generated a lot of interest due to their potential to target the 
expression of oncogenes including V-Myc avian myelocytomatosis viral oncogene homolog 
(MYC), B-cell lymphoma 2 (BCL-2) and B-cell lymphoma 2-like 1 (BCL2L1) as well as for 
their involvement in mediating drug resistance (Dawson, Kouzarides, & Huntly, 2012; 
Dawson et al., 2011; Goodell & Godley, 2013; Neff & Armstrong, 2013; Shi & Vakoc, 2014; 
Zuber et al., 2011).  Expression of multiple oncogenes is also driven by BRD4 recruitment at 
super-enhancers, providing a rationale for the activity of BET inhibitors (BETi) beyond the 
MYC family (Hnisz et al., 2013; Loven et al., 2013).  All of the BETi currently in clinical trials 
target all members of the BET family, although the anti-proliferative activity of BETi in cancer 
cells may be mediated, in large part, through inhibition of BRD4 (Filippakopoulos & Knapp, 
2014). 
In vitro cell line analyses have shown that targeting BET proteins leads to inhibition of tumor 
growth in multiple cancer types, including both solid tumors and hematological malignancies 
through cell cycle arrest, and induction of senescence and apoptosis. 
2.2 
Rationale and Mechanism for BET Inhibitors in Metastatic Castration-
resistant Prostate Cancer  
Metastatic castration-resistant prostate cancer (mCRPC) is characterized by the persistence of 
signaling of the androgen receptor (AR) to drive cancer proliferation, tumor invasion, and 
metastasis (Wyatt & Gleave, 2015).  Initial therapies of prostate cancer include either surgical 
or chemical castration, followed by androgen-deprivation therapy (ADT).  In many instances, 
further progression and metastases of the cancer is observed, hence the term metastatic castration 
resistant prostate cancer.  First line standard of care therapies for mCRPC include the AR 
antagonist enzalutamide, androgen synthesis inhibitors such as the cytochrome steroid 17-alpha-
hydroxylase/17,20 lyase (CYP17A1) inhibitor abiraterone and in some cases chemotherapy.  
However, recent studies have shown that patients become resistant to these first line treatments 
over time and require additional drug therapy (Wyatt & Gleave, 2015).  Currently, there is no 
standard of care for second line mCRPC as the efficacy of AR modulators or chemotherapy in 
the second line setting is moderate.  Furthermore, it has been suggested that the resistance 
mechanisms of abiraterone and enzalutamide overlap  (Azad, Volik, et al., 2015; Bianchini et 
al., 2014; Loriot et al., 2013; Noonan et al., 2013; Schrader et al., 2014). 


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Mechanisms of resistance to enzalutamide and abiraterone include alternative splicing of the AR 
resulting in the loss of the ligand binding domain and constitutively active androgen signaling 
(Nakazawa, Antonarakis, & Luo, 2014), up-regulation of alternate pathways such as 
glucocorticoid receptor (GR) (Arora et al., 2013; Isikbay et al., 2014), nuclear factor kappa-
light-chain-enhancer of activated B cells (NF-κB) (Jin et al., 2013; Nadiminty et al., 2013), or 
MYC signaling pathways (Lamb, Massie, & Neal, 2014; Nadiminty et al., 2013; Zeng et al., 
2015), as well as neuroendocrine differentiation (Aggarwal, Zhang, Small, & Armstrong, 
2014; Beltran et al., 2014; Dang et al., 2015).  Several of these resistance mechanisms, have 
either been shown to be regulated by the BET proteins in prostate cancer (MYC expression: 
(Gao et al., 2013) AR splice variants: (S. C. Chan et al., 2015); GR: (Shah et al., 2015) or in 
other cancers, NF-κB: (Ceribelli et al., 2014; Gallagher et al., 2014; Zou et al., 2014)), 
suggesting that BETi could be beneficial for patients with mCRPC that are resistant to 
enzalutamide and abiraterone.  In particular, the androgen receptor splice variant 7 (AR-V7)  was 
recently suggested to be involved in the resistance to enzalutamide and abiraterone 
(Antonarakis et al., 2014), and cell lines expressing these variants are sensitive to ZEN003694 
and other BETi in culture and in xenografts (Asangani et al., 2014; S. C. Chan et al., 2015; 
Gao et al., 2013; Wyce et al., 2013).  One of the proposed mechanisms of action of the BETi is 
to prevent the BET proteins from interacting with the N-terminus of the AR and activating 
downstream androgen signaling pathways (Asangani et al., 2014).  This mechanism would also 
explain how the activity of ZEN003694 would not be abrogated by the AR splice variants, as the 
N-terminus is still intact.  Also, BETi prevent binding of the AR to their downstream effectors, 
including the E26 transformation-specific (ETS) family of proteins (e.g., ETV1 and ERG), well 
known oncogenic drivers in prostate adenocarcinoma and neuroendocrine prostate cancer (Gasi 
Tandefelt, Boormans, Hermans, & Trapman, 2014; Lotan et al., 2011; Williamson et al., 
2011), thus providing several possible mechanisms whereby BETi could act in patients with 
prostate cancers of different etiologies. 
BETi are also postulated to be good combination agents due to their novel involvement in the 
transcriptional up-regulation of several key oncogenic pathways (Hnisz et al., 2013).  In 
mCRPC, the combination of BETi with enzalutamide could further abrogate AR signaling and 
inhibit tumor progression.  Several clinical studies have reported that enzalutamide treatment of 
post-abiraterone patients elicits a poor to moderate response rate (Azad, Eigl, Murray, 
Kollmannsberger, & Chi, 2015; Bianchini et al., 2014; Loriot et al., 2013; Noonan et al., 
2013; Schrader et al., 2014), supporting the evaluation of BETi such as ZEN003694 in post-
abiraterone patients, either as a single agent, or in combination with enzalutamide.  
Recent preclinical studies have suggested that SPOP mutant CRPC might be less sensitive to 
BETi, mainly due to the upregulation of the BET proteins, which are natural substrates of the 
SPOP ubiquitin ligase (Dai et al., 2017; Janouskova et al., 2017; P. Zhang et al., 2017).  
However, SPOP is also involved in DNA damage repair (D. Zhang et al., 2014), and SPOP 
mutations were found to activate AR and PI3K/mTOR signaling (Blattner et al., 2017) and lead 
to genomic instability (Boysen et al., 2015).  Therefore, it remains to be determined if this 


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altered sensitivity is also found in the clinic, and more importantly, if combination with either 
enzalutamide or abiraterone could be beneficial in that patient population. 
2.3 
ZEN003694 
ZEN003694 is a structurally novel, orally bioavailable small molecule that epigenetically 
regulates gene expression through bromodomain and extra-terminal domain (BET) inhibition.  
 
 
 
  ZEN003694 was discovered and developed by Zenith Epigenetics Ltd. and has 
broad potential as an anti-proliferative agent in solid tumors and hematologic malignancies.  
2.4 
Nonclinical Data  
For full information regarding ZEN003694, refer to the Investigator’s Brochure. 
ZEN003694 and its major active metabolite, ZEN003791, bind BET bromodomains and 
selectively inhibit the BET family member BRD4 binding to  super-enhancers in chromatin, in 
turn inhibiting expression of BRD4-dependent genes MYC and BCL-2 family members that 
drive proliferation and inhibit apoptosis of cancer cells.  ZEN003694 and ZEN003791 were 
equipotent biochemically and in cell assays.  
 
  
 
 
 
 
 
 
 
 
  Based on extensive 
in vitro binding studies, ZEN003694 and ZEN003791 are considered to have low potential for 
off-target pharmacologic effects.  
ZEN003694 showed potent cell growth inhibition in multiple solid tumor and hematological 
cancer cell lines as a single agent, and displayed synergy or additivity when combined with 
different anti-cancer agents.  In castration-resistant prostate cancer (CRPC) cell lines that were 
insensitive to enzalutamide, ZEN003694 showed potent activity as a single agent and synergy in 
combination with enzalutamide in a cell line with mild sensitivity to enzalutamide.   
In vivo preclinical data demonstrated that ZEN003694 dose-dependently inhibited tumor growth 
and MYC gene expression in CRPC (VCaP and 22Rv1) cell line-derived subcutaneous mouse 
xenografts. ZEN003694 was well tolerated at the dose range tested (up to 100 mg/kg 
 
[QD]) and robustly inhibited the expression of MYC in xenograft tumors. ZEN003694 was also 
evaluated in combination with enzalutamide in these xenograft mouse models.  VCaP cells are 
sensitive while 22Rv1 are resistant to enzalutamide treatment.  
In the 22Rv1 xenograft model, ZEN003694 exhibited robust tumor growth inhibition (TGI), 
which was significantly more efficacious than that of enzalutamide.  The combination was well 
tolerated and based on the administered doses (mg/kg), there was no improvement in efficacy 




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Most adverse effects observed in the toxicology studies were considered likely to be mechanism-
based or sequelae; all significant adverse effects were considered to be discernable by clinical 
evaluation, physical examination, and/or standard laboratory analyses and medically 
manageable.  ZEN003694 did not inhibit hERG in patch-clamp assays and did not have an effect 
on the standard 10-lead electrocardiographic evaluations in the GLP compliant toxicology study 
in monkey.  ZEN003694 did not have any functional effect in respiratory and central nervous 
system (CNS) assessments at any dose level in the GLP-complaint toxicology studies.  
Furthermore, ZEN003694 was negative in the Ames mutagenicity study.  
Based on the nonclinical profile, results from animal toxicology studies and the structural 
compound, theoretical risks of human exposure to ZEN003694 include the following: 
 Anorexia and weight loss 
 Nausea and other gastrointestinal symptoms 
 Myelosuppression (with consequences of anemia, neutropenia and/or thrombocytopenia) 
 Susceptibility to infection 
 Bleeding 
 Aberrations in clinical chemistry parameters 
Other drugs with similar mechanism of action, to the extent they have been studied in the clinic, 
have been associated with adverse events of diarrhea, nausea, vomiting, anorexia, rash, asthenia, 
thrombocytopenia, 
neutropenia, 
anemia, 
dysgeusia, 
fever, 
hyperglycemia, 
mucositis, 
coagulopathy, hemorrhage and aberrations of clinical chemistry parameters (Thieblemont et al., 
2014). 
2.5 
Clinical Data 
Based on data collected through the end of December 2017, the combined Phase 1 clinical data 
(44 patients) reported to date across both studies (this study and the ZEN003694-001 Single 
Agent Study) have identified the following adverse drug reactions (drug related and occurring in 
> 2 patients): visual impairment (typically a transitory perception of brighter lights and/or light 
flashes, with or without visual color tinges, and with no functional consequences), nausea, 
fatigue, decreased appetite, vomiting, creatinine increase, platelet decrease, diarrhea, 
dehydration, decreased weight, dizziness, dysgeusia, and thrombocytopenia. These ZEN003694-
related adverse events (AEs) were generally Grade 1 or 2 in severity, were managed clinically, 
did not result in long-term sequelae, and resolved in the absence of drug exposure. 
 
 
 
 
  
 


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2.6 
Study Rationale  
Several studies using cell lines and xenografts in prostate cancer have shown that BET proteins 
interact with the AR to modulate AR signaling.  BETi were shown to induce apoptotic activity, 
and inhibit cell proliferation and tumor growth of different CRPC models (Asangani et al., 
2014; C. H. Chan et al., 2015; Cho et al., 2014; Gao et al., 2013; Wyce et al., 2013).  
Furthermore, recent studies have shown that the BET proteins are directly involved in resistance 
mechanisms to ARSI (Shah et al., 2017) 
ZEN003694 inhibits proliferation in several prostate cancer cell lines as well as in cell lines 
resistant to the ARSIs enzalutamide and abiraterone.  ZEN003694 also inhibits AR signaling in 
cells expressing high ratios of the AR-V7 (22Rv1) splice variant compared to the full-length AR, 
which lack the androgen binding domain and results in constitutive activation of AR signaling. 
Pre-clinical in vitro data also show that ZEN003694 synergizes with enzalutamide in inhibiting 
cell growth of a CRPC cell line and synergizes with abiraterone to inhibit the proliferation of a 
different CRPC cell line. 
In vivo preclinical data demonstrate that ZEN003694 dose-dependently inhibited tumor growth 
in CRPC (VCaP and 22Rv1) cell line-derived subcutaneous mouse xenografts.  ZEN003694 was 
well tolerated at the dose range tested (up to 100 mg/kg q.d.) and robustly inhibited the 
expression of MYC in xenograft tumors.  ZEN003694 was also evaluated as a single agent and 
in combination with enzalutamide in the CRPC (VCaP and 22Rv1) xenograft mouse models.  
VCaP cells are sensitive while 22Rv1 are resistant to enzalutamide treatment.  In the VCaP 
xenograft model, ZEN003694 showed robust dose-dependent efficacy and was equivalent to the 
efficacy of enzalutamide.  In the 22Rv1 xenograft model, ZEN003694 had robust efficacy and 
was more efficacious than enzalutamide.  
In the 22Rv1 model, the combination treatment of ZEN003694 and enzalutamide was evaluated 
at limited dose range combinations.  The combination was well tolerated and based on TGI 
normalized to the combination exposures of ZEN003694 and the active metabolite ZEN003791 
showed an additive effect at the evaluated concentrations. 
The in vivo models evaluated are limited in their capabilities to assess the combined effect of 
ARSIs and ZEN003694 as they do not necessarily represent the study populations:  
(1) enzalutamide-naïve patients that have progressed on abiraterone (or vice-versa) and (2) 
patients taking an ARSI and progressing by PCWG2 criteria.  Despite the limitations of these 
models, the data show that ZEN003694 is active in a model that is resistant to enzalutamide and 


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has equivalent activity to enzalutamide in an enzalutamide-sensitive model.  The data also show 
that the effect of enzalutamide and ZEN003694 is additive in an enzalutamide resistant model. 
In summary, these results suggest that ZEN003694 inhibits persistant AR signaling even in cases 
associated with resistance to ARSI therapies, and inhibits tumor growth in prostate cancer in 
vivo models that are either resistant or sensitive to enzalutamide.  These data provide a rationale 
for studying ZEN003694 in combination with either enzalutamide or abiraterone in mCRPC 
patients who are likely to benefit from treatment.   
2.7 
Dosing Rationale  
The safe starting dose of ZEN003694 was determined in concordance with the International 
Conference on Harmonization (ICH) S9 Guidance.  Zenith has calculated the starting dose for 
ZEN003694 in the Phase 1 single agent study, ZEN003694-001, from the toxicology studies, that 
were dosed on a mg/kg basis, to derive a flat dose (48 mg) for the initial starting dose of 
ZEN003694 in this first-in-human (FIH) Phase 1 study.   
 
 
 
 
 
 
 
 
 
 
 
 
 
Part 1: The starting dose of ZEN003694 in this combination treatment study, ZEN003694-002, 
is therefore being selected as 36mg/day 
 
 The dose of enzalutamide will be held constant at 160 mg/day 
through Cycle 1 of  the study in Dose Escalation. Furthermore, since enzalutamide is a CYP3A4 
inducer and ZEN003694 is a substrate of CYP3A4, the plasma concentration of ZEN003694 
dosed in combination with enzalutamide is expected to be lower than single agent administration 
at equivalent doses of ZEN003694. The dose of 36 mg/day is expected to produce tolerable 
exposure while being close to the therapeutic range. Finally no overlapping toxicities are 
expected with ZEN003694 in combination with enzalutamide further justifying the starting dose. 
Part 2:  
Based on the safety and PK/PD data from the ongoing investigation of Part 1 of the current 


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The data show that DLT events occurred in patients with exposures (ZEN003694 + ZEN003791) 
greater than approximately 7500 ng*h/ml. The data also show that the PK  interaction with 
enzalutamide  has been minimal and the exposures of ZEN003694 + ZEN003791 were not 
significantly impacted by enzalutamide. The average exposure at the 72 mg dose in the single 
agent and the combination with enzalutamide study is 5250 ng*h/ml and less than 7500 ng*h/ml, 
and also less than the Day 1 average AUC0-24 of 7048 ng*h/ml reported at the 96mg dose. 
Therefore, starting at a dose of 72 mg QD is reasonable for ZEN003694 in combination with 
abiraterone. Abiraterone is not expected to affect the exposure of ZEN003694 based on its CYP 
profile.  
Integrated data on PK and safety to date supports the use of 72 mg as the starting dose for the 
ZEN003694 + abiraterone combination study.  Given that the maximum tolerated human dose of 
ZEN003694 as monotherapy and in combination with enzalutamide will both be determined 
before dose-escalation starts in Part 2 of this trial, dose-escalation of ZEN003694 in combination 
with abiraterone may not be sought in Part 2. 
 
 


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3. OBJECTIVES 
3.1 
PART 1 OBJECTIVES: ZEN003694 in combination with enzalutamide 
3.1.1 
Part 1: Primary 
 To determine the safety, tolerability and maximum tolerated dose (MTD) of 
ZEN003694 in combination with enzalutamide in patients with mCRPC who have 
progressed during prior treatment with enzalutamide or apalutamide (Cohort DE-A) 
or with abiraterone (Cohort DE-B) by Prostate Cancer Working Group 2 (PCWG2) 
criteria 2007 (Scher et al., 2008) (dose escalation) 
 To confirm the safety and tolerability of the MTD and recommended Phase 2 dose 
(RP2D) of ZEN003694 in combination with enzalutamide in the following two 
cohorts of patients with mCRPC (dose confirmation): 
o Cohort DC-A:  Patients with prior progression on enzalutamide or apalutamide 
by PCWG2 criteria who are currently or will be receiving a stable dose of 
enzalutamide  
o Cohort DC-B:  Patients who are enzalutamide-naïve with prior progression on 
abiraterone by PCWG2 criteria 
3.1.2 
Part 1: Secondary 
 To determine the PK of ZEN003694 and the PK of enzalutamide along with their 
primary active metabolites when administered in combination  
 To evaluate the preliminary clinical activity of ZEN003694 in combination with 
enzalutamide as applicable:  
o PSA response rate by PCWG2 criteria 
o Radiographic response rate by PCWG2 criteria 
o Median progression-free survival by PCWG2 criteria 
o Circulating tumor cell (CTC) response rate  
3.1.3 
Part 1: Exploratory 
 To explore pharmacodynamics (PD), prognostic and/or predictive biomarkers of 
ZEN003694 in combination with enzalutamide in whole blood, plasma and tumor 
samples in the dose escalation phase and/or dose confirmation phase as follows:  
o  Possible relationship of baseline tumor abnormalities (such as mutations, 
translocations, mRNA, protein expression and localization), in circulating tumor 
DNA (ctDNA), circulating tumor cells (CTC) and tumor biopsies and/or on-
treatment changes with any observed antitumor activity 


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 To explore the effects of ZEN003694 on immuno-oncology markers in tumor tissue 
and peripheral blood mononuclear cells 
3.2 
PART 2 OBJECTIVES: ZEN003694 in combination with abiraterone  
3.2.1 
Part 2: Primary 
 To determine the safety, tolerability and recommended Phase 2 dose (RP2D) of 
ZEN003694 in combination with abiraterone in patients with metastatic castration-
resistant prostate cancer (mCRPC) who have progressed during prior treatment with 
abiraterone (Cohort DE-C) or  enzalutamide or apalutamide (Cohort DE-D) by 
Prostate Cancer Working Group 2  criteria 2007 (Scher et al., 2008) (dose 
escalation) 
 To confirm the safety and tolerability of the recommended Phase 2 dose (RP2D) of 
ZEN003694 in combination with abiraterone in the following two cohorts of 
patients with mCRPC (dose confirmation): 
o Cohort DC-C:  Patients currently receiving abiraterone who have experienced 
progression by PCWG2 criteria  
o Cohort DC-D:  Patients who are abiraterone-naïve with prior progression on 
enzalutamide or apalutamide by PCWG2 criteria 
3.2.2 
Part 2: Secondary 
 To determine the PK of ZEN003694 and the PK of abiraterone along with their 
primary active metabolites when administered in combination  
 To evaluate the preliminary clinical activity of ZEN003694 in combination with 
abiraterone as applicable:  
o PSA response rate by PCWG2 criteria 
o Radiographic response rate by PCWG2 criteria 
o Median progression-free survival by PCWG2 criteria 
o Circulating tumor cell (CTC) response rate  
3.2.3 
Part 2: Exploratory 
 To explore pharmacodynamics (PD), prognostic and/or predictive biomarkers of 
ZEN003694 in combination with abiraterone in whole blood, plasma and tumor 
samples in the dose escalation phase and/or dose confirmation phase as follows:  
o Possible relationship of baseline tumor abnormalities (such as mutations, 
translocations, mRNA, protein expression and localization), in circulating tumor 
DNA (ctDNA), circulating tumor cells (CTC) and tumor biopsies and/or on-
treatment changes with any observed antitumor activity 


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4. 
PATIENT SELECTION 
4.1 
Part 1: ZEN003694 in combination with enzalutamide 
4.1.1 
Part 1: Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for the study. 
Part 1 All Patients 
1. Males age ≥ 18 years 
2. Metastatic, castrate resistant histologically confirmed prostate cancer; surgically 
castrated or continuous medical castration for ≥ 8 weeks prior to screening 
3. Serum testosterone < 50 ng/dL determined within 4 weeks of first administration of 
study drug 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
5. Adequate laboratory parameters at Screening including: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
b. Platelet count ≥ 100,000/mm3 
c. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.0 x ULN 
(≤ 5 x ULN if liver metastases are present) 
d. Total bilirubin ≤ 1.25 x ULN  
e. Serum creatinine ≤ 1.5 x ULN or calculated (Cockcroft-Gault formula) or measured 
creatinine clearance ≥ 60 mL/min 
f. Prothrombin time (PT), international normalized ratio (INR) and partial 
thromboplastin time (PTT) < 1.5 x ULN 
6. Use of corticosteroids is allowed up to a daily dose of 10 mg prednisone or equivalent 
provided that the dose has been stable for at least 2 weeks prior to first administration of 
study drug and will remain stable during study drug and enzalutamide dosing  
7. Patients must be surgically sterile or must agree to use physician-approved contraception 
during the study and for 30 days following the last study drug administration 
8. Ability to swallow capsules and comply with study procedures  
9. Ability to understand and willingness to sign informed consent form prior to initiation of 
any study procedures 


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Part 1 Dose Escalation  
10. Cohort DE-A: Prior progression on enzalutamide or apalutamide at any time by PCWG2 
criteria and is or will be receiving a stable dose of enzalutamide (defined as a dose that 
has not changed for at least 2 weeks prior to Cycle 1 Day 1 and is not expected to 
change on study).  Patients may or may not have experienced prior progression on 
abiraterone. 
11. Cohort DE-B: Enzalutamide-naïve and apalutamide-naïve patients following prior 
progression on abiraterone by PCWG2 criteria  
Part 1 Dose Confirmation 
12. Cohort DC-A:  Prior progression on enzalutamide or apalutamide at any time by PCWG2 
criteria and is or will be receiving a stable dose of enzalutamide (defined as a dose that 
has not changed for at least 2 weeks prior to Cycle 1 Day 1 and is not expected to change 
on study).  Patients may or may not have experienced prior progression on abiraterone.  
13. Cohort DC-B:  Enzalutamide-naïve patients and apalutamide-naïve following prior 
progression on abiraterone by PCWG2 criteria. 
4.1.2 
Part 1: Exclusion Criteria 
Patients who meet any of the following exclusion criteria will not be eligible to participate in the 
study. 
Part 1 All Patients 
1. Any history of brain metastases or prior seizure or conditions predisposing to seizure 
activity 
2. Have previously received an investigational BET inhibitor (including previous 
participation in this study or Study ZEN003694-001)  
3. Have received prior systemic anti-cancer therapy (including abiraterone) or 
investigational therapy within 2 weeks or five half-lives, whichever is shorter, prior to the 
first administration of study drug  
4. Failure to recover to Grade 1 or lower toxicity related to prior systemic therapy 
(excluding alopecia and neuropathy) prior to study entry  
5. Radiation therapy within 2 weeks of the first administration of study drug  
6. Treatment with a bone-targeted radionuclide within 6 weeks of first administration of 
study drug (enzalutamide in DE-B and DC-B or ZEN003694 in DE-A and DC-A)  


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7. Have received prior chemotherapy in the metastatic castration-resistant setting (prior 
chemotherapy in the hormone-sensitive setting is allowed provided last dose was at least 
6 months prior to study entry) 
8. Have received prior investigational anti-androgen therapy 
9. Currently receiving medications known to be strong inhibitors of CYP2C8, strong 
inducers (except enzalutamide or apalutamide) or inhibitors of CYP3A4 and substrates of 
CYP1A2, CYP3A4, CYP2C9 and CYP2C19 with a narrow therapeutic window. See 
Section 6.8.1.  Strong inducers, inhibitors and substrates must be discontinued at least 7 
days prior to the first administration of study drug.  
10. Not a candidate for enzalutamide treatment, in the opinion of the Investigator 
11. Left ventricular ejection fraction less than the lower of 50% or the lower limit of 
institution’s normal range 
12. QTcF interval > 450 msec 
13. Known impaired cardiac function or clinically significant cardiac disease such as 
uncontrolled supraventricular arrhythmia, ventricular arrhythmia requiring therapy, or 
congestive heart failure (New York Heart Association functional class III or IV)  
14. Myocardial infarction or unstable angina within 6 months prior to the first administration 
of study drug 
15. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, 
active CNS disease, active, uncontrolled bacterial, viral, or fungal infection(s) requiring 
systemic therapy, or any other condition that could compromise safety or the patient’s 
participation in the study 
16. Other known active cancer requiring therapy at time of study entry 
17. Historically positive (screening tests not required) for human immunodeficiency virus 
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) or with active infections.  
HBV positivity defined by positive hepatitis B surface antigen (HBsAg).  HCV positivity 
defined as positive HCV viral load.   
18. Major surgery other than diagnostic surgery, dental surgery or stenting within 4 weeks 
prior to the first administration of study drug 
19. History of congenital or other deficiency in platelet function, any known inherent or 
acquired coagulopathy, or therapeutic anticoagulation with warfarin or apixaban (low-
dose warfarin for port patency or prophylactic anti-platelet agents are allowed) 
20. Concurrent participation in another clinical investigational treatment trial 


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21. Any other reason that in the opinion of the Investigator would prevent the patient from 
completing participation or following the study schedule 
4.2 
Part 2: ZEN003694 in combination with abiraterone 
4.2.1 
Part 2: Inclusion Criteria 
Patients must meet all of the following inclusion criteria to be eligible for the study. 
Part 2 All Patients 
1. Males age ≥ 18 years 
2. Metastatic, castrate resistant, histologically confirmed prostate cancer; surgically 
castrated or continuous medical castration for ≥ 8 weeks prior to screening 
3. Serum testosterone < 50 ng/dL determined within 4 weeks of first administration of 
study drug 
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
5. Adequate laboratory parameters at Screening including: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L 
b. Platelet count ≥ 100,000/mm3 
c. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.0 x 
ULN (≤ 5 x ULN if liver metastases are present) 
d. Total bilirubin ≤ 1.25 x ULN  
e. Serum creatinine ≤ 1.5 x ULN or calculated (Cockcroft-Gault formula) or 
measured creatinine clearance ≥ 60 mL/min 
f. Prothrombin time (PT), international normalized ratio (INR) and partial 
thromboplastin time (PTT) < 1.5 x ULN 
6. Use of corticosteroids is allowed up to a daily dose of 10 mg prednisone or equivalent 
provided that the dose has been stable for at least 2 weeks prior to first administration of 
study drug and will remain stable during study drug and abiraterone dosing  
7. Patients must be surgically sterile or must agree to use physician-approved contraception 
during the study and for 30 days following the last study drug administration 
8. Ability to swallow capsules and comply with study procedures  
9. Ability to understand and willingness to sign informed consent form prior to initiation of 


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any study procedures 
Part 2 Dose Escalation  
10. Cohort DE-C: Prior progression on abiraterone at any time by PCWG2 criteria and is or 
will be receiving a stable dose of abiraterone (defined as a dose that has not changed for 
at least 2 weeks prior to Cycle 1 Day 1 and is not expected to change on study).  Patients 
may or may not have experienced prior progression on enzalutamide or apalutamide.  
11. Cohort DE-D: Abiraterone-naïve patients following prior progression on enzalutamide 
or apalutamide by PCWG2 criteria.   
Part 2 Dose Confirmation 
12. Cohort DC-C:  Prior progression on abiraterone at any time by PCWG2 criteria and is or 
will be receiving a stable dose of abiraterone (defined as a dose that has not changed for 
at least 2 weeks prior to Cycle 1 Day 1 and is not expected to change on study).  Patients 
may or may not have experienced prior progression on enzalutamide or apalutamide. 
13. Cohort DC-D:  Abiraterone-naïve patients following prior progression on enzalutamideor 
apalutamide by PCWG2 criteria.   
4.2.2 
Part 2: Exclusion Criteria 
Patients who meet any of the following exclusion criteria will not be eligible to participate in the 
study. 
Part 2 All Patients 
1. Have previously received an investigational BET inhibitor (including previous 
participation in this study or Study ZEN003694-001)  
2. Have received prior systemic anti-cancer therapy or investigational therapy within 
2 weeks or five half-lives, whichever is shorter, prior to the first administration of study 
drug. (Patients progressing on enzalutamide or apalutamide require a 2 week wash-out 
prior to start of abiraterone Cycle 1 Lead-in where applicable)  
3. Failure to recover to Grade 1 or lower toxicity related to prior systemic therapy 
(excluding alopecia and neuropathy) prior to study entry  
4. Radiation therapy within 2 weeks of the first administration of study drug 
5. Treatment with a bone-targeted radionuclide within 6 weeks of first administration of 
study drug (abiraterone in DE-D and DC-D or ZEN003694 in DE-C and DC-C) 
6. Have received prior chemotherapy in the metastatic castration-resistant setting (prior 
chemotherapy in the hormone-sensitive setting is allowed provided last dose was at least 


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6 months prior to study entry) 
7. Have received prior investigational anti-androgen therapy 
8. Currently receiving medications known to be substrates of CYP1A2 or CYP2D6 with a 
narrow therapeutic window.  Major substrates must be discontinued at least 7 days prior 
to the first administration of study drug.  
9. Not a candidate for abiraterone treatment, in the opinion of the Investigator 
10. Left ventricular ejection fraction less than the lower of 50% or the lower limit of 
institution’s normal range 
11. QTcF interval > 450 msec 
12. Known impaired cardiac function or clinically significant cardiac disease such as 
uncontrolled supraventricular arrhythmia, ventricular arrhythmia requiring therapy, or 
congestive heart failure (New York Heart Association functional class III or IV)  
13. Myocardial infarction or unstable angina within 6 months prior to the first administration 
of study drug 
14. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, 
active central nervous system disease, active, uncontrolled bacterial, viral, or fungal 
infection(s) requiring systemic therapy, or any other condition that could compromise 
safety or the patient’s participation in the study 
15. Other known active cancer requiring therapy at time of study entry 
16. Historically positive (screening tests not required) for human immunodeficiency virus 
(HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) or with active infections.  
HBV positivity defined by positive hepatitis B surface antigen (HBsAg).  HCV positivity 
defined as positive HCV viral load 
17. Major surgery other than diagnostic surgery, dental surgery or stenting within 4 weeks 
prior to the first administration of study drug 
18. History of congenital or other deficiency in platelet function, any known inherent or 
acquired coagulopathy, or therapeutic anticoagulation with warfarin or apixaban (low-
dose warfarin for port patency or prophylactic anti-platelet agents are allowed) 
19. Concurrent participation in another clinical investigational treatment trial 
20. Any other reason that in the opinion of the Investigator would prevent the patient from 
completing participation or following the study schedule 
 


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5. 
STUDY PLAN  
5.1 
Study Design 
This is an open label, non-randomized, Phase 1 dose escalation/dose confirmation study of 
ZEN003694 in combination with enzalutamide (Part 1) or abiraterone (Part 2) in patients with 
mCRPC.  
5.1.1 
Dose Escalation 
A standard 3+3 cohort design will be utilized for each study Part.  Cohorts of up to 6 patients 
will be enrolled at each dose level, and each patient will participate in only one cohort.  Each 
cycle will be 28 days in duration.   
 
Part 1, ZEN003694 in combination with enzalutamide: 
For patients who have progressed on abiraterone, (Cohort DE-B) enzalutamide will be 
administered orally as a single agent daily for 14 days prior to the initiation of the combination 
therapy (Lead-in) to reach enzalutamide steady-state concentration (Css) during Cycle 1.  After 
the Lead-in, if applicable, ZEN003694 will be administered orally in combination with daily 
enzalutamide for 28-day cycles. Patients who are progressing on enzalutamide or apalutamide 
(Cohort DE-A, Sub-arm A1) and who are currently receiving a stable dose of enzalutamide will 
continue to receive enzalutamide in combination with ZEN003694, if eligibility criteria are met. 
Patients in Cohort DE-A who are not currently receiving enzalutamide or apalutamide or are 
currently taking apalutamide (Sub-arm A2) will be administered enzalutamide orally once daily 
for 14 days prior to the initiation of the combination therapy (Lead-in) to reach enzalutamide Css 
during Cycle 1.   
 
Part 2, ZEN003694 in combination with abiraterone: 
For patients who have progressed on enzalutamide or apalutamide (Cohort DE-D), abiraterone 
will be administered orally as a single agent daily for 14 days prior to the initiation of the 
combination therapy (Lead-in) to reach abiraterone steady-state concentration (Css) during Cycle 
1. After the Lead-in, if applicable, ZEN003694 will be administered orally in combination with 
daily abiraterone for 28-day cycles. Patients who are progressing on abiraterone (Cohort DE-C, 
Sub-arm C1) and currently receiving a stable dose of abiraterone will continue to receive 
abiraterone in combination with ZEN003694, if eligibility criteria are met.  For patients who 
have progressed on abiraterone (Cohort DE-C, Sub-Arm C2) but are not currently taking 
abiraterone, abiraterone will be administered orally as a single agent daily for 14 days prior to 
the initiation of the combination therapy (Lead-in) to reach abiraterone steady-state 
concentration (Css) during Cycle 1.  
 
Part 1 and Part 2: 
After the Lead-in, ZEN003694 will be administered orally in combination with daily 
enzalutamide (Part 1) or abiraterone (Part 2) for 28-day cycles.  The first patient at each dose 
level will be treated with ZEN003694 for one week before the second patient at the same dose 


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level is allowed to receive their first dose of ZEN003694.  Patients at each dose level will be 
treated (for 28 days) and observed through the end of the first cycle before treatment of patients 
at the next higher dose level can begin.  In unusual circumstances, (e.g., if there is 1 slot 
remaining to fill a cohort and 2 prospective enrollees are being screened and qualify 
simultaneously) the sponsor may allow an extra subject to enter a cohort, although the same rules 
for determining MTD will apply. 
 
ZEN003694-related adverse events (AEs) for determination of DLTs will be assessed for each 
patient during the 28 days of Cycle 1.  The most common AEs for enzalutamide and abiraterone 
are well-known (see Appendix 4 for XTANDI Package Insert and Appendix 5 for ZYTIGA® 
Package Insert).  As such, the Investigator should to the best of his/her ability assess the 
relatedness of an AE observed as attributable to either enzalutamide (Part 1) or abiraterone (Part 
2) or ZEN003694 alone, or if unable to do so, as attributable to the combination of enzalutamide 
(Part 1) or abiraterone (Part 2) and ZEN003694.   
Dose escalation will continue after all patients enrolled within a cohort have completed the 
28-day Cycle 1 DLT observation period with either 0 of 3 patients, or no more than 1 out of 
6 patients in a cohort experiencing a DLT, with the proviso that dose escalation to MTD may be 
waived in Part 2.  Dose escalation decisions will be made based on clinical safety and (when 
available) PK data (maximum or peak concentration [Cmax] and AUC) after review by the Cohort 
Review Committee (CRC), consisting of all Investigators and the Zenith Medical Monitor.  If a 
DLT is observed in 1 of 3 patients in a cohort and confirmed by the CRC, 3 additional patients 
will be enrolled into that cohort.  If 1 of 6 patients in a cohort experiences a DLT, then dose 
escalation may continue in the next cohort or the MTD of the combination can be declared.  If 
≥ 2 of 3 – 6 patients experience DLTs within a cohort, then the MTD will be considered to have 
been exceeded and further dose escalation will cease.  In this case, if fewer than 6 patients have 
been enrolled at the previous dose level, that cohort will be expanded to 6 patients to confirm the 
MTD.  Should the MTD of the combination be exceeded at Dose Level 1, a cohort may be 
explored with a reduced dose of ZEN003694 or enzalutamide (Part 1) or abiraterone (Part 2) at 
the discretion of the CRC.  Cohort management is summarized in Table 3. 
Table 3:  Dose-limiting Toxicity and Cohort Management  
Number of Patients with 
Dose-limiting Toxicity 
Action 
1 of 1 
Add 5 more patients 
0 of 3 
Proceed to next dose level 
1 of 3 
Add 3 more patients 
1 of 6 
Proceed to next dose level 
≥ 2 of 3 or ≥ 2 of 6 
Add 3 more patients in the next lower dose level if 
only 3 patients were treated in the next lower dose.  If 
6 patients were treated at the next lower dose level and 
no more than one patient had DLT, then the next lower 


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dose is the MTD. 
Part 1: Enzalutamide is a strong inducer of CYP3A4.  Treatment with enzalutamide reduces the 
Cmax and AUC of the sensitive CYP3A4 substrate midazolam approximately 7- and 4-fold, 
respectively.  ZEN003694 is also a CYP3A4 substrate and therefore the levels of ZEN003694 
may be substantially lower when administrated to patients treated with enzalutamide due to 
increased clearance of ZEN003694 compared to ZEN003694 treatment alone.  Enrollment in this 
study with ZEN003694 in combination with enzalutamide will  commence with 36 mg as the 
starting dose for ZEN003694 and 160 mg dose of enzalutamide (or at a lower stable dose for 
patients in DE-A or DC-A).   The dose of enzalutamide will be held constant through Cycle 1 of 
the Dose Escalation. After Cycle 1, the dose of enzalutamide may be modified for toxicity per 
the XTANDI® Package Insert. Due to the possible higher clearance of ZEN003694 during co-
administration with enzalutamide, higher doses of ZEN003694 may be needed to achieve 
sufficient ZEN003694 exposure with the combination treatment than with ZEN003694 alone.  If 
enzalutamide dose is reduced at any time after Cycle 1, PK samples are to be obtained 28 Days 
(±7 Days) following dose modification. Dose escalation of ZEN003694 in this study will 
proceed as follows in Table 4 unless intervening toxicity is observed. 
Table 4:  Part 1 Dose Escalation Scheme 
Dose Level 
ZEN003694 (mg) 
Fold Increase from 
Prior Dose Level 
1 
36 
-- 
2 
48 
1.33 
3 
60 
1.25 
4 
72 
1.20 
5 
96 
1.33* 
Additional levels may be explored at the discretion of the CRC 
Part 2: 
 
 
 
 
 
Enrollment in this study with ZEN003694 in combination with 
abiraterone will therefore commence with 72 mg QD as the starting dose for ZEN003694 and 
1000 mg dose of abiraterone once.   The dose of abiraterone will be held constant at 1000 mg 
through Cycle 1 of the Dose Escalation. After Cycle 1, the dose of abiraterone may be modified 
for toxicity per the ZYTIGA® Package Insert. Dose escalation/de-escalation of ZEN003694 in
this study will proceed as follows in Table 5 unless intervening toxicity is observed. 


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Table 5:  Part 2 Dose Escalation Scheme 
Dose Level 
ZEN003694 (mg) * 
Fold Increase from 
Prior Dose Level 
-1
48 
0.67 
1 
72 
-- 
2 
96 
1.33 
* Dose de-escalation from 72 mg is allowed by cohort.  Additional dose levels may be
explored based on safety and at the discretion of the CRC, with the proviso that dose
escalation to MTD may be waived in Part 2.
Part 1 and Part 2: 
Dose escalation increments between cohorts will be determined by the CRC based on safety and 
available PK data (e.g., Cmax and AUC) based on the following schema: 

Dose escalation up to 2-fold is allowed in Dose Level 2 and 3 unless one drug-related
Grade 2 event is observed in Dose Level 1 and 2, respectively

Subsequent dose escalation up to 1.5-fold is allowed until a DLT is observed

Subsequent dose escalation up to 1.33-fold is allowed until MTD is established, or, in
Part 2, if MTD is waived and RP2D is declared
All dose escalations will be guided by the available PK data (e.g., Cmax and AUC) from both 
ZEN003694-001 and this study, ZEN003694-002, with respect to the combined AUC0-24 of 
ZEN003694 and its active metabolite ZEN003791.  
 
 
 
 
 
Intermediate doses and/or alternative dosing schedules may be evaluated to best determine the 
MTD and/or RP2D of ZEN003694 in combination with enzalutamide (Part 1) or abiraterone 
(Part 2) based on evaluation of clinical safety and available PK data (e.g., Cmax and AUC) and 
upon agreement of the CRC members.  No intra-patient dose escalation is allowed during the 
first three cycles of therapy.  If a patient has not experienced any Grade 2 or higher drug-related 
AEs after three cycles, dose escalation up to the highest dose currently declared tolerable by the 
CRC will be allowed and further intra-patient dose escalation(s) will be determined on a cycle-
by-cycle basis at the discretion of the Investigator and with approval from the CRC.   
5.1.2 
Definition of Dose-limiting Toxicity 
Determination of DLT will be made during the first 28 days of treatment (i.e., Cycle 1) in the 
dose escalation phase.  Toxicity will be graded and recorded according to National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03 (see 
Appendix 2).  A DLT is defined as a clinically significant AE or laboratory abnormality that is 


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considered possibly, probably or definitely related to ZEN003694 and which meets any of the 
following criteria: 
 Grade 3 or greater non-hematologic clinical toxicity with the exception of Grade 3 
nausea or Grade 3/4 vomiting and diarrhea persisting less than 72 hours in the absence 
of maximal medical therapy  
 Grade 4 neutropenia lasting more than 5 days 
 Grade 3 or greater febrile neutropenia (temperature ≥ 38.5ºC) 
 Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with clinically significant 
bleeding, or any requirement for platelet transfusion 
 Any other Grade 3 or 4 laboratory abnormality that requires hospitalization 
 An ALT > 3x ULN with concomitant total bilirubin > 2x ULN 
 
Any ZEN003694-related toxicity that results in more than 25% of missed doses during 
Cycle 1 of treatment  
 In the situation where toxicity requires withholding ZEN003694 following the receipt 
of at least 75% of scheduled dosing during Cycle 1: Failure to begin Cycle 2 within 1 
week of the scheduled start date due to ongoing toxicity 
All patients experiencing a DLT must discontinue dosing with ZEN003694; patients must 
complete the Safety Follow-up visit prior to discontinuation from the study.   
Determination of evaluability will be made during the first 28 days of ZEN003694 treatment 
(i.e., Cycle 1) in the dose escalation phase. Patients meeting one or more of the following will be 
considered unevaluable and will be replaced: 
 Patients who miss more than 25% of ZEN003694 and/or enzalutamide or abiraterone 
doses or fail to begin Cycle 2 within 1 week of the scheduled start date for reasons other 
than ZEN003694-related toxicity 
 Patients who require enzalutamide or abiraterone dose hold or modification in Cycle 1, 
including during the 14-day Lead-in period for reasons other than ZEN003694-related 
toxicity 
 
Part 1 only: If a patient is unable to tolerate enzalutamide for any reason at dose of 160 
mg during the 14 day Lead-in prior to first dose of ZEN003694, then the patient should 
not receive ZEN003694, and be withdrawn from the study and replaced 
 Part 2 only: If a patient is unable to tolerate for any reason abiraterone at dose of 1000 
mg once daily during the 14 day Lead-in prior to first dose of ZEN003694, then the 
patient should not receive ZEN003694, and be withdrawn from the study and replaced 
 


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5.1.3 
Definition of the Maximum Tolerated Dose 
The MTD is defined as the highest dose level of ZEN003694 in combination with enzalutamide 
(Part 1) and abiraterone (Part 2; if MTD is determined) at which no more than 1 of 6 patients 
experiences a DLT during the first cycle of therapy. MTD may be declared independently for 
any given dosing regimen, i.e., the respective MTDs for once daily dosing, twice daily dosing, 
and any alternative dosing regimen(s) need not be at the same dose. 
5.1.4 
Definition of the Recommended Phase 2 Dose 
The RP2D is defined as the dose level of ZEN003694 in combination with enzalutamide (Part 1) 
and abiraterone (Part 2) recommended for further clinical study.  In Part of this study the RP2D 
may be the same as the MTD or modified from the MTD based on assessments of overall 
exposure, safety experience in Cycle 2 and beyond, PD and clinical benefit data.  In Part 2 of this 
study the determination of an MTD may be waived and the RP2D may be declared based on 
assessment of overall exposure, safety experience , PD and clinical benefit data.  The RP2D of 
ZEN003694 in combination with enzalutamide (Part 1) or abiraterone (Part 2) will be determined 
in the dose confirmation phase of the study. RP2D may be declared independently for any given 
Part or dosing regimen, i.e., the respective RP2Ds for once daily dosing, twice daily dosing, and 
any alternative dosing regimen(s) need not be at the same dose. 
5.1.5 
Dose Confirmation  
Part 1, ZEN003694 in combination with enzalutamide: Once the MTD of ZEN003694 in 
combination with enzalutamide has been determined in the dose escalation portion of Part 1 of 
the study, up to 20 patients who meet the inclusion/exclusion criteria for Cohort A and up to 20 
patients who meet the inclusion/exclusion criteria for Cohort B of the dose confirmation phase 
will be enrolled for further evaluation of safety, PK, PD and preliminary clinical activity.   
Enzalutamide-naïve and apalutamide-naïve patients in Cohort DC-B will be administered 
enzalutamide (160 mg) orally once daily for 14 days prior to the initiation of the combination 
therapy (Lead-in) to reach enzalutamide Css during Cycle 1.  After the Lead-in, ZEN003694 will 
be administered orally in combination with daily enzalutamide for 28-day cycles.  Patients in 
Cohort DC-A who are currently receiving a stable dose of enzalutamide  will continue to receive 
enzalutamide and will not participate in the Lead-in. Patients in Cohort DC-A who are not 
currently receiving enzalutamide or apalutamide or are currently taking apalutamide will be 
administered enzalutamide orally once daily for 14 days prior to the initiation of the combination 
therapy (Lead-in) to reach enzalutamide Css during Cycle 1.  After the Lead-in, ZEN003694 will 
be administered orally in combination with daily enzalutamide for 28-day cycles.   
Part 2, ZEN003694 in combination with abiraterone: Once the CRC has determined a 
recommended phase 2 dose (RP2D) of ZEN003694 in combination with abiraterone in the dose 
escalation portion of Part 2 of the study, up to 20 patients who meet the inclusion/exclusion 
criteria for Cohort DC-C and up to 20 patients who meet the inclusion/exclusion criteria for 


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Cohort DC-D of the dose confirmation phase will be enrolled for further evaluation of safety, 
PK, PD and preliminary clinical activity.  
 Cohort DC-D: Abiraterone-naïve patients in Cohort DC-D will be administered 
abiraterone (1000 mg once daily) orally for 14 days prior to the initiation of the 
combination therapy (Lead-in) to reach abiraterone Css during Cycle 1.  After the Lead-
in, ZEN003694 will be administered orally in combination with daily for 28-day cycles.   
 Cohort DC-C: Patients in Cohort DC-C are currently receiving a stable dose of 
abiraterone (as part of the study entry criteria for this cohort) and will continue to receive 
abiraterone when enrolled in the dose confirmation phase of the study and will not 
participate in the Lead-in. 
Part 1 and Part 2: When the 6th patient in each cohort in the dose confirmation phase has 
completed one cycle of therapy, or earlier if clinically indicated, the CRC will review the safety 
data.  If  ≥ 2 patients have experienced drug-related SAEs or DLT-equivalent events, the CRC 
may recommend a modification in the dose or regimen of ZEN003694 in combination with 
enzalutamide (Part 1) or abiraterone (Part 2) for the dose confirmation phase. 
5.2 
Safety Review 
Safety will be assessed by periodic physical examinations, weight, ECOG performance status, 
vital signs, clinical laboratory assessments including serum troponin, 12-lead electrocardiogram 
(ECG) and monitoring of AEs (see Schedule of Events Table 1 & Table 2).  AEs will be graded 
using NCI CTCAE Version 4.03 (see Appendix 2).  Teleconferences with members of the CRC 
will be held during the dose escalation phase to discuss any suspected DLTs that have occurred 
in patients within each cohort.  The frequency of the teleconference calls will be determined by 
the rate of enrollment, data review, frequency of DLT notifications, discussions with 
investigational sites and other factors.  Approximately one week after the last patient in a dose 
cohort completes Cycle 1 and prior to escalating to the next dose level (or de-escalating), the 
CRC will review toxicities and available PK (e.g., Cmax and AUC) from the current cohort of the 
study during a teleconference.   
The CRC‘s responsibilities during the course of the study include: 
 Review all relevant safety findings and confirm all DLTs  
 Review and approve all intra-patient dose escalation(s)  
 Determine all cohort dose escalation and de-escalation decisions during the dose 
escalation phase 
 Recommend alternative dose and regimen as appropriate  


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 Determine the MTD and RP2D; and, in Part 2, determine whether MTD should be 
determined or, alternatively, that the RP2D may be declared without establishing MTD 
per the protocol definition (Section 5.1.3) 
 Recommend the dose(s) and regimen(s) to extend into the dose confirmation phase 
 Consider any relevant safety data from Study ZEN003694-001 
 Further monitor safety during the dose confirmation phase, including review of the safety 
data after the sixth patient completes Cycle 1  
5.3 
Number of Sites and Patients 
Part 1: Up to 80 evaluable patients will be enrolled in the study at up to 10 sites in the United 
States.  Approximately 40 patients will be enrolled in the dose escalation phase and up to 40 
patients will be enrolled in the dose confirmation phase. 
Part 2: Up to 55 evaluable patients will be enrolled in the study at up to 10 sites in the United 
States.  Approximately 15 patients will be enrolled in the dose escalation phase and up to 40 
patients will be enrolled in the dose confirmation phase. 
5.4 
Study Duration 
The study duration by Part including the enrollment period and follow-up for both the dose 
escalation and dose confirmation phases is approximately 36 months, depending upon total 
enrollment.  Patients may continue receiving ZEN003694 in combination with enzalutamide 
(Part 1) or abiraterone (Part 2) until disease progression by PCWG2 criteria, unacceptable 
toxicity, requirement for non-protocol therapy or patient withdrawal from study.  Patients with 
PSA-only progression may remain on study until clinical and/or radiographic evidence of 
progression by PCWG2 criteria. 
5.5 
Premature Study Termination or Suspension of Enrollment 
Zenith has the right to terminate the participation of an individual study site, study Part, or the 
entire study, at any time, for any reason.  Reasons for terminating the study include, but are not 
limited to, the following: 
 The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients 
 Patient enrollment is unsatisfactory 
 Data records are inaccurate or incomplete 
 The Investigator does not adhere to the protocol or applicable regulatory guidelines in 
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 A decision on the part of Zenith to suspend or discontinue testing, evaluation or 
development of ZEN003694 
In addition, Zenith may suspend enrollment in the study at any time for any reason. 
All Investigators and appropriate Regulatory Authorities will be promptly notified upon early 
termination of the study.  In addition, Investigators and Regulatory Authorities will be promptly 
notified if enrollment is terminated or suspended for any reason. 
6. 
STUDY DRUG AND CONCOMITANT TREATMENT 
6.1 
ZEN003694 
ZEN003694 is a novel, potent BET inhibitor currently under clinical investigation.  It is provided 
in two dosage strengths:  12 mg and 48 mg.  ZEN003694 will be administered orally in 28-day 
cycles and should be ingested with a full (8-ounce) glass of water at least 1 hour before eating or 
2 hours after eating (fasting).  Each capsule should be swallowed whole.  Patients should be 
advised not to chew, dissolve, or open the capsules. Patients should also be advised to minimize 
their exposure to sunlight. 
6.2 
Enzalutamide 
Enzalutamide is an androgen receptor inhibitor indicated for the treatment of patients with 
mCRPC.  Enzalutamide 160 mg (four 40 mg capsules) will be administered orally once daily 
according to the XTANDI® Package Insert without food in 28-day cycles through Cycle 1 in 
Dose Escalation for all enzalutamide-naïve patients (DE-B and DC-B cohorts).  For patients in 
DE-A and DC-A cohorts, enzalutamide will be administered at the dose level previously 
determined to be stable and that has not changed for at least two weeks prior to starting Cycle 1 
Day 1 combination study treatment or restarting enzalutamide treatment in the Lead-in phase.  
After Cycle 1 of Dose Escalation or any time in Dose Confirmation, the dose of enzalutamide 
may be modified for toxicity per the XTANDI® Package Insert.  Each capsule should be 
swallowed whole.  Patients should be advised not to chew, dissolve, or open the capsules. 
6.3 Abiraterone 
Abiraterone is an androgen synthesis inhibitor indicated for the treatment of patients with 
mCRPC.  Abiraterone 1000 mg (four 250 mg capsules) will be administered orally once daily 
according to the ZYTIGA® Package Insert without food in 28-day cycles. Prednisone 5 mg (one 
5 mg capsule) will be administered orally twice daily in 28-day cycles. In Dose Escalation, the 
dose of abiraterone will be held constant at 1000 mg throughout Cycle 1 of the study. After 
Cycle 1, the dose of abiraterone may be modified for toxicity per the ZYTIGA® Package Insert. 


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6.4 
Guidelines for Dose Escalation, Dose Modification and Management of 
ZEN003694-related Toxicity 
6.4.1 
Dose Escalation in the Dose Escalation Phase of the Study 
No intra-patient dose escalation is allowed during the first three cycles of treatment.  If a patient 
has not experienced any Grade 2 or higher drug-related AEs after three cycles, dose escalation up 
to the highest dose currently declared tolerable by the CRC will be allowed and further intra-
patient dose escalation(s) will be determined on a cycle-by-cycle basis at the discretion of the 
Investigator and with approval from the CRC.  Patients who required a dose reduction due to 
toxicity at any time will not be allowed to re-escalate to a higher dose level.  
6.4.2 
Management of ZEN003694-related Toxicity in the Dose Escalation and Dose 
Confirmation Phases  
Dose adjustment (hold or reduction) of ZEN003694 is allowed in the dose escalation phase of 
the study beyond Cycle 1 and will be based on the toxicities that are deemed possibly, probably 
or definitely related to ZEN003694.  Dose reductions of ZEN003694 during Cycle 1 will not be 
allowed however ZEN003694 doses may be held due to treatment-related toxicity.  If 
ZEN003694 treatment is withheld for toxicity attributed by the Investigator to ZEN003694 
alone, then enzalutamide dosing may continue unmodified.  For guidance regarding what 
ZEN003694-related toxicities qualify as a DLT in Cycle 1 of the dose escalation phase of the 
study, refer to Section 5.1.2 Definition of Dose Limiting Toxicity.   
Dose adjustment (hold or reduction) of ZEN003694 is allowed in the dose confirmation phase of 
the study at any time and will be based on the toxicities that are deemed possibly, probably or 
definitely related to ZEN003694.  If ZEN003694 treatment is withheld for toxicity attributed by 
the Investigator to ZEN003694 alone, then enzalutamide dosing may continue unmodified. 
Dose adjustment and toxicity management guidelines are summarized in Table 6. 


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Table 6:  ZEN003694-Related Dose Adjustment and Toxicity Management Guidelines 
Event 
Hematologic & Non-hematologic Toxicity 
(Excluding Anemia) 
Grade 1  
No change 
Grade 2 
No change required; but a dose hold for Grade 2 laboratory toxicity or 
a laboratory trend of concern is allowed based on Investigator 
discretion. 
 
In cases where the dose is held, if toxicity or trend is reduced to a 
Grade 1 within 14 days, treatment may resume at a dose level and 
regimen determined by mutual agreement between the Investigator 
and Zenith. 
Grade 3 
Hold treatment.   
 
If toxicity resolves to baseline or Grade 1 within 14 days, treatment 
may resume at the same dose level.  
 
If toxicity is reduced to Grade 2 within 14 days, treatment may 
resume at one dose level below or at a reduced frequency (except in 
Cycle 1 of dose escalation) with mutual agreement between the 
Investigator and Zenith.  
Grade 4 
Hold treatment.   
 
If toxicity is resolved to Grade ≤ 2 within 14 days, treatment may 
resume at one dose level below or at a reduced frequency (except in 
Cycle 1 of dose escalation) with mutual agreement between the 
Investigator and Zenith. 
Dose interruption caused by any ZEN003694-related toxicities lasting longer than 14 days 
(hematologic or non-hematologic toxicity) will result in study drug discontinuation unless there 
is objective evidence of benefit.  Any subject experiencing concomitant ALT elevation to > 3x 
ULN and bilirubin elevation to > 2x ULN will be permanently discontinued from dosing with 
ZEN003694.   
Only one re-challenge at the same dose level is allowed and two dose reductions and/or decrease 
in dosing frequency is allowed. 


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6.5 
Part 1: Management of Enzalutamide-related Toxicity in the Dose 
Escalation and Dose Confirmation Phases 
No dose adjustment (hold or reduction) of enzalutamide is allowed during Cycle 1 in the dose 
escalation phase of the study. For toxicities in dose escalation Cycle 1 that, in the opinion of the 
investigator, could reasonably be attributed to either study drug (eg, fatigue, nausea), the 
investigator should hold ZEN003694 first as a “therapeutic trial”, and only hold enzalutamide in 
addition if the trial hold of ZEN003694 is unsuccessful in managing toxicity. Holding 
enzalutamide in dose escalation Cycle 1 will render the subject unevaluable for DLT 
determination (5.1.2 Definition of Dose Limiting Toxicity), although the subject may continue in 
the trial if recommended by the investigator and approved by Zenith.  
If a patient in Dose Escalation or Dose Confirmation Cohort B is unable to tolerate enzalutamide 
for any reason at dose of 160 mg during the 14 day Lead-in prior to first dose of ZEN003694, 
then the patient should not receive ZEN003694, and be withdrawn from the study and replaced. 
Beyond Cycle 1 in the dose escalation phase and any time during the dose confirmation phase, 
enzalutamide toxicity may be managed per the XTANDI Package Insert.  In the case that 
enzalutamide is held to manage enzalutamide-related toxicity, the Investigator should contact 
Zenith to discuss possible dose adjustment or hold of ZEN003694. If enzalutamide is held 
greater than 14 days the subject must withdraw from the study unless he is, in the Investigator's 
judgment, clearly benefitting from ZEN003694 treatment alone, in which case the Investigator 
must consult with Zenith regarding continuing ZEN003694 monotherapy with possible 
modification of the dose. If enzalutamide dose is reduced at any time after Cycle 1 in Dose 
Escalation or any time in Dose Confirmation, PK samples are to be obtained 28 Days (±7 Days) 
following dose modification at the following time-points: pre-ZEN003964 and enzalutamide 
doses, and 15 minutes (±5 min), 30 min (±5 min), 1 hour (±5 min), 2 hours (±10 min), 4 hours 
(±15 min), 6 hours (±15 min) and 8 hours (±30 min) post-ZEN003694 and enzalutamide doses. 
Commonly reported adverse reactions with enzalutamide include asthenia/fatigue, back pain, 
decrease appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, 
peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension and 
dizziness/vertigo.  In patients who have previously received docetaxel treatment, neutropenia and 
infections have been reported.  Falls and hypertension have also been reported.  Management of 
enzalutamide side effects are at the discretion of the Investigator.  Refer to XTANDI Package 
Insert in Appendix 4 for further information. 
Warning and precautions with enzalutamide include:  
 Seizures in patients with mCRPC who previously received docetaxel.  
 Posterior reversible encephalopathy syndrome (PRES) in post approval reports.  PRES 
diagnosis should be confirmed by brain imaging and enzalutamide should be 


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discontinued.  Symptoms present as seizures, headache, lethargy, confusion, blindness 
and other visual and neurological disturbances, with or without associated hypertension. 
Patients who experience seizures or PRES must discontinue the study. 
6.6   Part 2: Management of Abiraterone-related Toxicity in the Dose Escalation 
and Dose Confirmation Phases 
No dose adjustment (hold or reduction) of abiraterone is allowed during Cycle 1 in the dose 
escalation phase of the study. For toxicities in dose escalation Cycle 1 where, in the opinion of 
the investigator, the attribuation to one drug or the other is unclear, the investigator should hold 
ZEN003694 first as a “therapeutic trial”, and only hold abiraterone in addition if the trial hold of 
ZEN003694 is unsuccessful in managing toxicity. Holding abiraterone in dose escalation Cycle 1 
will render the subject unevaluable for DLT determination (5.1.2 Definition of Dose Limiting 
Toxicity), although the subject may continue in the trial if recommended by the investigator and 
approved by Zenith.  
If a patient in Dose Escalation or Dose Confirmation Cohort D is unable to tolerate abiraterone 
for any reason at dose of 1000 mg during the 14 day Lead-in prior to first dose of ZEN003694, 
then the patient should not receive ZEN003694, and be withdrawn from the study and replaced. 
Beyond Cycle 1 in the dose escalation phase and any time during the dose confirmation phase, 
enzalutamide toxicity may be managed per the ZYTIGA Package Insert.   
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 ZYTIGA).  Management of 
abiraterone side effects are at the discretion of the Investigator.  Refer to ZYTIGA Package 
Insert in Appendix 5 for further information. 
 
Warning and precautions with abiraterone include:  
• 
Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess  
• 
Adrenocortical insufficiency  
• 
Hepatotoxicity  
 


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6.7 
Treatment Compliance 
Trained study personnel will dispense ZEN003694 and will instruct the patients on drug 
administration at least 1 hour before eating or 2 hours after eating (fasting).  Treatment 
compliance will be monitored by the review of the patient’s dosing diary and drug accountability 
records.  Study treatment administration data will be recorded in the patient’s medical record and 
on the Drug Administration electronic case report forms (eCRFs).   
6.8 
Concomitant Medications and Therapies 
6.8.1 
Part 1 and Part 2: Prohibited Concomitant Medications and Therapies with 
ZEN003694  
ZEN003694 is primarily metabolized by CYP3A4.  Therefore, strong inhibitors and inducers of 
CYP3A4 (except enzalutamide) must be excluded during ZEN003694 administration.  
 
 
 
 
 
Because of the known risk of QT/QTc prolongation from 5-hydroxytryptamine type 3 (5-HT3) 
receptor anti-emetics, 5-HT3 receptor antagonist antiemetic drugs should be used with 
Investigator discretion, if alternative drugs are not available.  Dolasetron should be avoided, as 
the prolongation of QTc may be greater with this drug based upon American Society of Clinical 
Oncology (ASCO) guidelines (Basch et al., 2011). To date, ZEN003694 has shown no evidence 
of QT prolongation, suggesting that drugs such as 5-HT3 antagonists may be safely used 
concomitantly where indicated by the Investigator's clinical judgment. 
During the study, other chemotherapy, immunotherapy, radiation (except, if ≤ 5 fractions for 
palliative care of solitary bone lesions), bone-targeting radionuclides, or surgery is also 
prohibited. Therapeutic anticoagulation with warfarin, apixaban, or other anti-factor agents is not 
permitted, but low-dose warfarin for maintenance of port patency or prophylactic anti-platelet 
agents are allowed. 
6.8.2 
Part 
1: 
Prohibited 
Concomitant 
Medications 
and 
Therapies 
with  
Enzalutamide 
Enzalutamide is a substrate of CYP2C8 and therefore use of strong CYP2C8 inhibitors should be 
avoided because CYP2C8 inhibitors increase the plasma exposure of enzalutamide. 
Enzalutamide is also a moderate inducer of CYP2C9 and CYP2C19; thus enzalutamide may 
decrease plasma exposures of these drugs that are significant substrates of these enzymes. 
Refer to XTANDI (enzalutamide) Package Insert in Appendix 4 for further information 
regarding potential drug-drug interactions. 


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Enzalutamide is a strong inducer of CYP3A4, and thus may alter the kinetics of ZEN003694. 
Use of moderate CYP3A4 inhibitors and inducers, significant CYP1A2 substrates, CYP2C8 
inhibitors, or significant CYP3A4, CYP2C9 and CYP2C19 substrates will be determined on a 
case-by-case basis at the discretion of the Investigator and with approval from Zenith.  
A list of inhibitors, inducers and substrates are listed in Table 7.  This list is not comprehensive; 
when considering use of a medication that could be a potential CYP3A4 inhibitor or inducer, 
CYP1A2 substrate, CYP2C8 inhibitor or significant CYP3A4, CYP2C9 or CYP2C19 substrate, 
the Investigator should consult with Zenith. 
 
Table 7:  Part 1 Inhibitors and Inducers of Relevant Drug-metabolizing Enzymes 
Category 
Inhibitors 
of CYP3A4 
(May increase 
ZEN003694 
exposure) 
Inducers 
of CYP3A4 
(May decrease 
ZEN003694 
exposure) 
Substrates 
of CYP1A2 
 
 
 
 
AVOID 
boceprevir 
clarithromycin 
conivaptan 
grapefruit juice 
indinavir 
itraconazole 
ketoconazole  
lopinavir/ritonavir 
mibefradil 
nefazodone 
nelfinavir 
posaconazole 
ritonavir  
saquinavir 
telaprevir 
telithromycin 
voriconazole 
avasimibe 
rifampin 
St. John’s wort 
 
ramelteon 
tizanidine 
theophylline 
Source:  http://www fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/  
ucm093664 htm 
Sites are to consider the following potential drug interactions when enrolling patients: 
 
 
  
 
  
 Gemfibrozil inhibits CYP2C8 and may increase exposure to enzalutamide 


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 The following are substrates of CYP3A4/CYP2C9/CYP2C19 and exposure to these drugs 
may be decreased by enzalutamide:  
o CYP3A4: alfentanil, astemizole, cyclosporine, dihydroergotamine, ergotamine, 
fentanyl, pimozide, quinidine, sirolimus, tacrolimus, Cannabidiol (CBD) enriched 
products, midazolam, triazolam, lovastatin, simvastatin 
o CYP2C9: warfarin, phenytoin, celecoxib 
o CYP2C19: S-mephenytoin 
 
Any CYP3A4 inhibitors, inducers and substrates, CYP2C8 inhibitors, and CYP3A4, CYP1A2, 
CYP2C9 and CYP2C19 substrates taken by the patient during the study period must be 
documented in the patient’s chart and on the Concomitant Medications eCRF.  If Zenith’s 
approval is not obtained prior to administration of these medications, the patient may be 
withdrawn from the study by Zenith. 
6.8.3 
Part 2: Prohibited Concomitant Medications and Therapies with 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. Avoid coadministration of abiraterone acetate with substrates of 
CYP2D6 with a narrow therapeutic index (e.g., thioridazine). 
Abiraterone is a substrate of CYP3A4, but in vivo the strong CYP3A4 inhibitor ketoconazole 
had no clinically meaningful impact on abiraterone exposure. The strong CYP3A4 inducer 
rifampicin decreased abiraterone exposure by half. Hence, strong CYP3A4 inducers should be 
avoided or used with caution as they may diminish the effectiveness of abiraterone. 
A list of inhibitors, inducers and substrates are listed in Table 8.  This list is not comprehensive; 
when considering use of a medication the Investigator should consult with Zenith. 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 8:  Part 2 Inhibitors and Inducers of Relevant Drug-metabolizing Enzymes 
Category 
Inhibitors 
of CYP3A4 
(May increase 
ZEN003694 
exposure) 
Inducers 
of CYP3A4 
(May decrease 
abiraterone 
and/or 
ZEN003694 
exposure) 
Substrates 
of CYP2D6 
(exposure 
may be 
increased by 
abiraterone) 
Substrates 
of CYP1A2 
 
 
 
 
AVOID 
boceprevir 
clarithromycin 
conivaptan 
grapefruit juice 
indinavir 
itraconazole 
ketoconazole  
lopinavir/ritonavir 
mibefradil 
nefazodone 
nelfinavir 
posaconazole 
ritonavir  
saquinavir 
telaprevir 
telithromycin 
voriconazole 
avasimibe 
rifampin 
St. John’s wort 
 
thioridazine 
ramelteon 
tizanidine 
theophylline 
Source:  http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/  
ucm093664 htm 
Any CYP3A4 inhibitors, inducers and substrates, CYP1A2 and CYP2D6 substrates taken by the 
patient during the study period must be documented in the patient’s chart and on the 
Concomitant Medications eCRF.  If Zenith’s approval is not obtained prior to administration of 
these medications, the patient may be withdrawn from the study by Zenith. 
6.8.4 
Permitted Concomitant Medications and Therapies 
Use of corticosteroids is allowed up to a daily dose of 10 mg prednisone or equivalent provided 
that the dose has been stable for at least 2 weeks prior to the start of ZEN003694 dosing and will 
remain stable during ZEN003694 treatment.  
Unlike the reported experience with other BET Inhibitors, ZEN003694 treatment has not been 
associated with clinically important thrombocytopenia in the 75 patients treated with 
ZEN003694 to date. Therefore, the prophylactic use of anti-platelet agents (eg, low-dose aspirin, 
clodiprogel) is permitted but should be carefully reassessed in any patient in whom 
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Treatment with antiemetic therapy will be permitted, if clinically indicated. Based on experience, 
Investigators are encouraged to instruct their patients to take anti-emetics and maintain adequate 
hydration at first signs of GI intolerance. Patients should be provided ‘filled’ prescriptions for an 
anti-emetic, if possible, or ensure patients fill their prescriptions of an anti-emetic on the first day 
of dosing (C1D1). Patients are to be instructed to take the anti-emetic at first signs of nausea. 
Treatment with filgrastim or other colony stimulating factors will be permitted for Grade 3 or 
higher hematologic toxicity as per Package Insert, but may not be used prophylactically.  Patients 
should receive full supportive care, including hematopoietic growth factors based upon ASCO 
guidelines (Smith et al., 2015), if clinically indicated.  
Treatment required for care of complications/adverse events arising from the cancer and/or 
treatment will be permitted.  
All concomitant medications must be recorded on the Concomitant Medications eCRF. 




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7.3 
Abiraterone 
See ZYTIGA Package Insert (Appendix 5) for detailed information on abiraterone description, 
formulation, and storage conditions. 
7.4 
Study Drug Accountability 
The Investigator, pharmacist or qualified designee is responsible for making an inventory of 
study drug upon receipt.  All used and unused study drug must be retained until final 
reconciliation or as indicated by Zenith.  The study drug is to be administered/dispensed by the 
Investigator or appropriately qualified site personnel named on the delegation of authority log.  
Under no circumstances will the Investigator allow the study drug to be used other than as 
directed by this protocol.  Although appropriate personnel may be designated to 
administer/dispense drug and maintain drug accountability records, the Investigator is ultimately 
responsible for all drug accountability. 
The Investigator or designee must maintain accurate records of the receipt, disposition and return 
of study drug.  Documentation of drug disposition/return should identify the patient receiving the 
study drug, the quantities (by dosage strength) of study drug dispensed/returned and dates study 
drug were dispensed/returned/destroyed.    This documentation is required in addition to drug 
accountability information recorded on eCRFs.  A copy of the reconciled drug inventory record 
will be provided to Zenith or its designee, and the study site will retain the original record.  A 
written explanation must be provided for any discrepancies. 
Zenith representatives will authorize the return or destruction of all used, partially used, and 
unused bottles of study drug.  If the study site is capable of destroying study drug it may do so 
upon authorization by Zenith.  Records will include date of destruction or return, and quantities 
destroyed or returned to Zenith or its designee.  Detailed instructions on study drug 
accountability will be provided in a study reference manual. 
Part 1 only: Enzalutamide will be used by patients as Standard of Care.  Patients will record 
their daily administration of enzalutamide in an Enzalutamide Dosing Diary. Enzalutamide 
Dosing Diaries will be reviewed for subject compliance by appropriate site staff. Detailed 
instructions regarding enzalutamide compliance will be provided in a study reference manual. 
Part 2 Only: Abiraterone will be used by patients as Standard of Care.  Patients will record their 
daily administration of abiraterone in an Abiraterone Dosing Diary. Abiraterone Dosing Diaries 
will be reviewed for subject compliance by appropriate site staff. Detailed instructions regarding 
abiraterone compliance will be provided in a study reference manual. Prednisone will be 
documented as a concomitant medication on the applicable log in patient source documentation. 
 


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8. 
STUDY PROCEDURES AND ASSESSMENTS 
The Schedule of Events (Table 1 & Table 2) is given as an aid to patient management.  This 
section describes evaluations to be performed before, during and after treatment.  Scheduled 
clinic attendance should occur within ± 3 days of the specified dates at all visits.  Where this is 
not possible because of extenuating circumstances (e.g., holidays, vacations), the reason should 
be noted in the patient’s chart.  
All AEs that occur anytime during the study and any concomitant medication use should be 
recorded on the CRFs.  Patients with Grade 2, 3 or 4 study drug-related toxicity should be 
followed as the Investigator deems clinically appropriate.  The duration and time to resolution of 
AEs should be evaluated and recorded in the patient’s chart and on the AE eCRF.  Additional 
evaluations may be performed as necessary.   
8.1 
Study Procedures by Visit 
8.1.1 
Screening Visit  
All screening tests must be performed within 28 days before the first day of treatment (Cycle 1, 
Day -14 if enzalutamide or abiraterone Lead-in is required).  The informed consent form (ICF) 
must be signed before screening procedures are performed (see Section 8.2.1).  
Screening will include: 
 Collection of information on status of inclusion and exclusion criteria (see Section 8.2.2) 
 Complete medical history, including cancer history, prior PSA data, prior cancer-related 
surgery and treatments, and demographic history (see Section 8.2.3) 
 Listing of all medications taken within 21 days of enrollment and any ongoing 
medications 
 Physical examination including height (cm) and weight (kg) (see Sections 8.2.4 and 
8.2.5) 
 ECOG performance status (see Section 8.2.6 and Appendix 1) 
 Vital signs (temperature [Fº], blood pressure and heart rate) (see Section 8.2.7) 
 Hematology (see Section 8.2.8)  
 Coagulation tests (see Section 8.2.8)   
 Serum chemistries (see Section 8.2.8): including serum testosterone 
 PSA  


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 Urinalysis (see Section 8.2.8) 
 Echocardiogram or multigated acquisition (MUGA) scan (see Section 8.2.9) 
 Triplicate 12-lead ECG (see Section 8.2.10) 
 Ophthalmology assessments (see Section 8.2.16)  To be performed prior to first dose of 
ZEN003694 and after all entry criteria have been satisfied and enrollment is approved 
 Part 1 Only: Qualitative Exploration of Visual Symptoms (see Section 8.2.16) 
 PD samples:  whole blood for exploratory immuno-oncology biomarkers (Only in Part 1, 
DE Only) (at selected clinical sites only; see Section 8.2.12): (Prior to the Day -14 Lead-
in for patients requiring enzalutamide Lead-in (Part 1))   
 Fresh tumor biopsy samples (optional during dose escalation phase, mandatory during 
dose confirmation phase). For those patients in DE-A or DC-A (Part 1) or DE-C or DC-C 
(Part 2) who are not currently taking enzalutamide (Part 1) or abiraterone (Part 2) and 
require the 14 day Lead-in, the screening fresh tumor biopsy samples can be collected 
from time of consent through Cycle 1 Day -1, preferably during the 14 day enzalutamide 
(Part 1) or abiraterone (Part 2) Lead-in. (see Section 8.2.12) 
 Tumor assessment (see Section 8.2.15)  Imaging for tumor assessments may be scheduled 
up to 7 days prior to the scheduled clinic visit day. 
8.1.2 
Cycle 1 Lead-in for Dose Escalation & Dose Confirmation (required for 
Cohorts DE-B, DC-B, DE-D, DC-D; also required for patients requiring enzalutamide 
Lead-in (Part 1: Sub-arm A2) or abiraterone Lead-in (Part 2: Sub-arm C2) 
Day -14 (-14 days ± 1 day from Cycle 1 Day 1) (Pre-enzalutamide Dose (Part 1) / Pre-
abiraterone dose (Part 2)) 
 Hematology (if Screening visit tests were performed more than 7 days prior to this visit) 
 Coagulation tests (if Screening visit tests were performed more than 7 days prior to this 
visit) 
 Serum chemistries tests (if Screening visit tests were performed more than 7 days prior to 
this visit) 
 Urinalysis (if Screening visit tests were performed more than 7 days prior to this visit) 
 PSA tests (if Screening visit tests were performed more than 7 days prior to this visit) 
 Qualitative Exploration of Visual Symptoms (see Section 8.2.16) 


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 PD samples:  whole blood for CTCs for enumeration and PD (DE and DC), and plasma 
for exploratory PD (DC only) (see Section 8.2.12)   
 PD samples: whole blood for exploratory cfDNA and ctDNA (For all patients requiring 
enzalutamide Lead-in (Part 1: DE-B and DC-B and DE-A and DC-A Sub-arm A2) & 
for all patients requiring abiraterone Lead-in (Part 2: DE-D and DC-D and DE-C and 
DC-C Sub-arm C2) 
Day -14 (Enzalutamide (Part 1) or Abiraterone (Part 2) Dosing) 
 Part 1: Enzalutamide daily at least 1 hour before eating or 2 hours after eating 
 Part 2: Abiraterone once daily at least 1 hour before eating or 2 hours after eating  
Day -14 (Post-enzalutamide Dose (Part 1) or Post-abiraterone Dose (Part 2)) 
 AEs (see Section 8.2.13) 
 Concomitant medications (see Section 8.2.14) 
8.1.3 
Cycle 1 Dose Escalation and Dose Confirmation  
Day 1 (Pre-dose) 
 Symptom-directed physical examination and weight 
 ECOG performance status 
 Vital signs (temperature [Fº], blood pressure and heart rate)  
 Hematology (Collect for all patients requiring Cycle 1 Lead-in. For patients who do not  
require Cycle 1 Lead-in, collect if Screening visit tests were performed more than 7 days 
prior to this visit) 
 Coagulation tests (Collect for all patients requiring Cycle 1 Lead-in. For patients who do 
not  require Cycle 1 Lead-in, collect if Screening visit tests were performed more than 7 
days prior to this visit) 
 Serum chemistries including serum testosterone (Collect for all patients requiring Cycle 1 
Lead-in. For patients who do not  require Cycle 1 Lead-in, collect if Screening visit tests 
were performed more than 7 days prior to this visit) 
 Serum troponin level 
 PSA (Collect for all patients requiring Cycle 1 Lead-in. For patients who do not  require 
Cycle 1 Lead-in, collect if Screening visit tests were performed more than 7 days prior to 
this visit) 


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 Urinalysis (Collect for all patients requiring Cycle 1 Lead-in. For patients who do not  
require Cycle 1 Lead-in, collect if Screening visit tests were performed more than 7 days 
prior to this visit) 
 Triplicate 12-lead ECG 
 PK sample for ZEN003694 and enzalutamide (Part 1) or abiraterone (Part 2) (see Section 
8.2.11) 
 PD samples:  whole blood for BET inhibitor gene expression profile (DE and DC), 
exploratory BET inhibitor blood signature (DC only), and for CTCs for enumeration and 
PD (DE and DC); plasma for exploratory PD (DC only) 
 PD samples:  whole blood for exploratory immuno-oncology biomarkers (at selected 
clinical sites only; see Section 8.2.12).  (Only in Part 1, DE only:  for all patients 
requiring enzalutamide Lead-in) 
 PD samples: whole blood for exploratory cfDNA and ctDNA 
 AEs (for all patients requiring Lead-in) 
 Qualitative Exploration of Visual Symptoms (see Section 8.2.16) 
 Concomitant medications  
Day 1 (Dosing) 
 Part 1: ZEN003694 and enzalutamide at least 1 hour before eating or 2 hours after eating 
 Part 2: Abiraterone once daily at least 1 hour before eating or 2 hours after eating 
Day 1 (Post-dose) 
 PK samples for ZEN003694 and enzalutamide (Part 1) or abiraterone (Part 2) 
o 15 minutes (±5 min), 30 minutes (±5 min), 1 hour (±5 min), 2 hours (±10 min), 
4 hours (±15 min), 6 hours (±15 min) and 8 hours (±30 min) post-ZEN003694 and 
enzalutamide (Part 1) or abiraterone (Part 2) doses  
 PD samples:  whole blood for BET inhibitor gene expression (all patients) at 2 hours 
(±15 min), 4 hours (±15 min), and 6 hours (±15 min)  and Exploratory BET inhibitor 
blood signature (DC only) 4 hours (±15 min) post- ZEN003694 and enzalutamide (Part 
1) or abiraterone (Part 2) doses  
 
 Triplicate 12-lead ECG:  1 hour (± 15 min) post-ZEN003694 and enzalutamide (Part 1) 
or abiraterone (Part 2) doses  


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 AEs 
 Concomitant medications 
Day 2 (Pre-dose) 
 PK sample for ZEN003694 and enzalutamide (Part 1) or abiraterone (Part 2):  24 hours 
(±1 hour) after Cycle 1 Day 1 ZEN003694 and enzalutamide (Part 1) or abiraterone (Part 
2) doses 
 PD sample:  whole blood for BET inhibitor gene expression 24 hours (±1 hour) after 
Day 1 ZEN003694 and enzalutamide (Part 1) or abiraterone (Part 2) doses 
Days 2 – 28 (Dosing as per dosing regimen – QD, BID, on/off schedule) 
 Part 1: ZEN003694 and enzalutamide daily at least 1 hour before eating or 2 hours after 
eating 
 Part 2: Abiraterone once daily at least 1 hour before eating or 2 hours after eating 
Note:  Instruct patients not to take study drug and enzalutamide (Part 1) or abiraterone 
(Part 2) before their clinic visits on Days 8, 15 and 22. 
Note: All assessments and tests/samples described below are to be performed PRE-DOSE, 
unless specified otherwise, and are to be performed even if dosing is not required (ie., due 
to an on/off schedule) on the specified study visit day. 
Day 8 (Pre-dose) 
 Symptom-directed physical examination and weight 
 ECOG performance status 
 Vital signs (temperature [Fº], blood pressure and heart rate)  
 Hematology 
 Serum chemistries 
 PD sample:  whole blood for exploratory immuno-oncology biomarkers (at selected 
clinical sites only) (Part 1 DE Only) 
 AEs 
 Concomitant medications  
 Qualitative Exploration of Visual Symptoms (see Section 8.2.16)   


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Day 15 (Pre-dose) 
 Symptom-directed physical examination and weight 
 ECOG performance status 
 Vital signs (temperature [Fº], blood pressure and heart rate)  
 Hematology  
 Coagulation tests 
 Serum chemistries 
 Serum troponin level  
 Triplicate 12-lead ECG 
 PK sample for ZEN003694 and enzalutamide (Part 1) or abiraterone (Part 2) 
 AEs 
 Qualitative Exploration of Visual Symptoms (see Section 8.2.16) 
 Concomitant medications  
Day 15 (Dosing) 
 Part 1: ZEN003694 and enzalutamide at least 1 hour before eating or 2 hours after eating 
 Part 2: Abiraterone once daily at least 1 hour before eating or 2 hours after eating  
Day 15 (Post-dose) 
 PK samples for ZEN003694 and enzalutamide (Part 1) or abiraterone (Part 2) 
o 15 minutes (±5 min), 30 min (±5 min), 1 hour (±5 min), 2 hours (±10 min), 4 hours 
(±15 min), 6 hours (±15 min) and 8 hours (±30 min) post-ZEN003694 and 
enzalutamide (Part 1) or abiraterone (Part 2) doses 
 Triplicate 12-lead ECG:  1 hour (± 15 min) post-ZEN003694 and enzalutamide (Part 1) 
or abiraterone (Part 2) doses  
 Part 1 only: Urine collection for renal clearance may be requested by Zenith for up to 8 
hours post-ZEN003694 and enzalutamide doses 
Day 22 (Pre-dose or in the morning if dosing is not required on this day due to an alternate 
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 Symptom-directed physical examination and weight 
 ECOG performance status 
 Vital signs (temperature [Fº], blood pressure and heart rate)  
 Hematology 
 Serum chemistries 
 PD sample:  whole blood for exploratory immuno-oncology biomarkers (at selected 
clinical sites only) (Part 1 DE Only) 
 AEs 
 Concomitant medications  
 Qualitative Exploration of Visual Symptoms (see Section 8.2.16)   
8.1.4 
Cycle 2  
Part 1: From Cycle 2, Day 1 onward, if the enzalutamide dose is reduced, PK samples are to be 
obtained 28 Days (±7 Days) following modification at the following time-points: pre-
ZEN003964 and enzalutamide doses, and 15 minutes (±5 min), 30 min (±5 min), 1 hour (±5 
min), 2 hours (±10 min), 4 hours (±15 min), 6 hours (±15 min) and 8 hours (±30 min) post-
ZEN003694 and enzalutamide doses.    
Part 2: From Cycle 2, Day 1 onward, if the ZEN003694 or abiraterone doses are modified, 
optional PK samples are to be obtained at the discretion of the sponsor following modification at 
the following time-points: pre-ZEN003964 and abiraterone doses, and 15 minutes (±5 min), 30 
min (±5 min), 1 hour (±5 min), 2 hours (±10 min), 4 hours (±15 min), 6 hours (±15 min) and 8 
hours (±30 min) post-ZEN003694 and abiraterone doses.    
Part 1 and Part 2: 
Day 1 (Pre-dose) 
 Symptom-directed physical examination and weight 
 ECOG performance status 
 Vital signs (temperature [Fº], blood pressure and heart rate)  
 Hematology 
 Coagulation tests 


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 Serum chemistries: including serum testosterone 
 Serum troponin level 
 PSA 
 Urinalysis 
 Triplicate 12-lead ECG 
 Part 1 only: Ophthalmology assessments (±7 days) (see Section 8.2.16)  
 PK sample for ZEN003694 and enzalutamide (Part 1) or abiraterone (Part 2) 
 PD samples:  plasma for exploratory PD (DC only) 
 PD sample:  whole blood for Exploratory BET inhibitor blood signature (DC only) 
 AEs 
 Qualitative Exploration of Visual Symptoms (see Section 8.2.16) 
 Concomitant medications 
Days 1 – 28 (Dosing as per dosing regimen – QD, BID, on/off schedule, etc.) 
 Part 1: ZEN003694 dosing and enzalutamide daily at least 1 hour before eating or 2 hours 
after eating 
 Part 2: Abiraterone once daily at least 1 hour before eating or 2 hours after eating  
Note:  Instruct patients not to take study drug and enzalutamide (Part 1) or abiraterone 
(Part 2) before their clinic visit on Day 15. 
Note: All assessments and tests/samples described below are to be performed PRE-DOSE, 
unless specified otherwise, and are to be performed even if dosing is not required (i.e., due 
to an on/off schedule) on the specified study visit day. 
Day 8 (The Cycle 2, Day 8 visit will only include blood draws for safety laboratory testing 
and may be drawn after the patient has taken his dose) 
 Hematology 
 Serum chemistries 
Day 15 (Pre-dose) 
 Symptom-directed physical examination and weight 


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 ECOG performance status 
 Vital signs (temperature [Fº], blood pressure and heart rate)  
 Hematology 
 Serum chemistries 
 AEs 
 Part 1 Only: Qualitative Exploration of Visual Symptoms (see Section 8.2.16) 
 Concomitant medications  
Day 22 (The Cycle 2, Day 22 visit will only include blood draws for safety laboratory 
testing and may be drawn after the patient has taken his dose) 
 Hematology 
 Serum chemistries 
8.1.5 
Cycles 3, 4 and onward  
Day 1 (Pre-dose) 
 Symptom-directed physical examination and weight 
 ECOG performance status 
 Vital signs (temperature [Fº], blood pressure and heart rate) Hematology (may be drawn 
after the patient has taken his dose) 
 Coagulation tests (may be drawn after the patient has taken his dose) 
 Serum chemistries: including serum testosterone (may be drawn after the patient has 
taken his dose) 
 Serum troponin level (may be drawn after the patient has taken his dose) 
 PSA (may be drawn after the patient has taken his dose) 
 Urinalysis (may be drawn after the patient has taken his dose) 
 AEs 
 Part 1 Only: Qualitative Exploration of Visual Symptoms (see Section 8.2.16) 
 Concomitant medications  


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 Cycle 3 Only: Fresh tumor biopsy samples (optional in DE, mandatory in DC) ± 15 days 
are to be performed on a ZEN003694 dosing day (see Section 8.2.12). The on-treatment 
biopsy should be collected 2-4 hours after ZEN003694 administration, if possible. 
 Cycle 3 Only: PD samples: whole blood for exploratory cfDNA and ctDNA 
Days 1 – 28 (Dosing as per dosing regimen – QD, BID, on/off schedule) 
 Part 1: ZEN003694 and enzalutamide at least 1 hour before eating or 2 hours after eating 
 Part 2: Abiraterone once daily at least 1 hour before eating or 2 hours after eating  
Note:  Instruct patients not to take study drug and enzalutamide (Part 1) or abiraterone 
(Part 2) before their clinic visit on Day 1 of each cycle. 
Day 15 (For Cycles 3 and onwards, the Day 15 visit will only include blood draws for safety 
laboratory testing and may be drawn after the patient has taken his dose. Day 15 
hematology and/or serum chemistries can be waived at Investigator discretion starting in 
Cycle 6 onward as long as platelets are stable and there are no other laboratory concerns in 
the opinion of the Investigator.) 
 Hematology 
 Serum chemistries 
8.1.6 
Cycle 3 and every other cycle onward (Cycles 5, 7, etc.) 
Day 1 (Pre-dose) 
 Triplicate 12-lead ECG 
8.1.7 
Cycle 3 and every 3 cycles onward (Cycles 6, 9, etc.) 
Day 1 (Pre-dose) 
 PD samples:  whole blood for CTCs for enumeration and PD.  Note:  Additional whole 
blood for CTCs for enumeration and PD to be obtained at the time of disease progression 
as well at the time of PSA or radiographic response. 
 PD sample:  whole blood for Exploratory BET inhibitor blood signature (DC only) 
 Tumor assessment (see Section 8.2.15)  Imaging for tumor assessments may be scheduled 
up to 7 days prior to the scheduled clinic visit day. 
 Part 1 Only: Ophthalmology assessments:  At Cycle 6 and every 6 cycles onward (±7 
days) (see Section 8.2.16) 


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8.1.8 
Unscheduled Visits and Assessments 
Any of the following assessments and tests (as well as others) may be performed as clinically 
indicated or to assess PD/biomarker responses as agreed upon by the investigator. Additionally, 
unscheduled assessments or sample collections may occur during a scheduled visit as required. 
 Symptom-directed physical examination and weight 
 ECOG performance status 
 Vital signs (temperature [Fº], blood pressure and heart rate)  
 Hematology 
 Coagulation tests 
 Serum chemistries 
 Urinalysis 
 Triplicate 12-lead ECGAEs 
 Concomitant medications  
 Tumor assessment 
 Ophthalmology assessments 
8.1.9 
End of Treatment Visit  
The following assessments should be performed within one week (± 3 days) of discontinuation 
of ZEN003694 treatment:  If a subject’s dose was held and treatment was not resumed after a 
two week period, the scheduling of the EOT visit from the date of last study drug is extended to 
14 days ±3 days. 
 Symptom-directed physical examination and weight 
 ECOG performance status 
 Vital signs (temperature [Fº], blood pressure and heart rate)  
 Hematology 
 Serum chemistries: including serum testosterone 
 Serum troponin level 


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 PSA 
 Urinalysis 
 PD sample:  plasma for exploratory PD (DC only) 
 PD sample:  whole blood for Exploratory BET inhibitor blood signature (DC only) 
 PD samples:  whole blood for CTCs for enumeration and PD at time of disease 
progression and time of PSA or radiographic response 
 PD samples: whole blood for exploratory cfDNA and ctDNA 
 Part 1 Only: Ophthalmology assessments (±7 days) (see Section 8.2.16) 
 Qualitative Exploration of Visual Symptoms (see Section 8.2.16)   
 AEs 
 Concomitant medications  
 Fresh tumor biopsy sample (optional during dose escalation and dose confirmation). The 
biopsies are to be collected at the time of disease progression, if possible.    The biopsy 
collected at the time of progression should be collected 2-4 hours after ZEN003694 
administration, if possible. 
 Tumor assessment (if not performed within the last 3 months) 
8.1.10 
Safety Follow-up Visit 
Thirty days after the End of Treatment visit or prior to beginning a new anti-cancer treatment, 
whichever occurs first.  If a new cancer therapy is started within 7 days following the End of 
Treatment visit, the Safety Follow-up visit is not required.  The patient should return to the clinic 
for a final safety evaluation, including the following assessments:  
 Symptom-directed physical examination and weight 
 ECOG performance status 
 Vital signs (temperature [Fº], blood pressure and heart rate)  
 Hematology 
 Serum chemistries: including serum testosterone 
 Urinalysis 


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 PSA 
 Part 1 Only: Ophthalmology assessments (see Section 8.2.16) (±7 days Collected at 
Safety Follow-up  only if EOT assessments were abnormal or if there were visual 
disturbances) 
 Part 1 Only: Qualitative Exploration of Visual Symptoms (see Section 8.2.16)    
 AEs 
 Concomitant medications  
8.2 
Study Assessments 
8.2.1 
Informed Consent 
The Investigator or designee must present and explain the study protocol to prospective study 
patients before the screening procedures are performed.  The ICF presented to the patient must 
be in a language that the patient can read and understand.  Once the patient has had an 
opportunity to read the ICF, the Investigator or designee must be available to answer any 
questions the patient may have regarding the study protocol and procedures.  The Investigator or 
designee must explain that the patient is not obliged to enter the study, and is free to withdraw 
from it at any time for any reason.  If new safety information becomes available and results in 
significant changes in risk/benefit assessment, the ICF should be reviewed and updated if 
necessary.  Under this circumstance, all patients, including those already being treated, should be 
given the new information, given a copy of the revised ICF, and allowed to re-evaluate their 
consent to continue in the study. 
A copy of the signed and dated ICF will be provided to the patient.  The Investigator will retain 
the original signed ICF. 
8.2.2 
Inclusion/Exclusion Criteria 
Review the inclusion/exclusion criteria (see Section 4) at the Screening visit to ensure that the 
patient qualifies for the study.  The patient may be enrolled into the study if inclusion criteria are 
met and none of the exclusion criteria are met. 
8.2.3 
Medical History and Demographics 
Obtain a complete medical history (significant past and ongoing conditions) including cancer 
history, prior PSA data, prior cancer treatments and surgeries, and demographic information at 
the Screening visit.  Previous history of allergies/ allergic reactions should also be captured on 
the Medical History eCRF. 


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8.2.4 
Physical Examination/Symptom-directed Physical Examination 
Physical 
examination 
including 
ears/eyes/nose/throat/neck, 
respiratory, 
cardiovascular, 
gastrointestinal, musculoskeletal, central and peripheral nervous system, and dermatologic 
assessments will be performed at the Screening visit.  A symptom-directed physical examination, 
including evaluation of new symptoms and follow-up findings from previous physical 
examinations, should be performed at each study visit pre-ZEN003694 and enzalutamide (Part 1) 
or abiraterone (Part 2) dosing per the Schedule of Events.  
8.2.5 
Height and Weight 
Height (cm) should be recorded only at the Screening visit and weight (kg) measurements should 
be measured per the Schedule of Events.  
8.2.6 
ECOG Performance Status 
ECOG performance status will be assessed using the criteria described in Appendix 1.  
8.2.7 
Vital Signs 
Vital signs include temperature (Fº), blood pressure and heart rate. 
8.2.8 
Laboratory Parameters 
The following laboratory parameters will be performed at the indicated time points in the 
Schedule of Events (Table 1 & Table 2).  The Investigator must evaluate all results outside the 
reference range and determine the clinical significance (clinically significant or not clinically 
significant) of each result.   
 Hematology:  hemoglobin, hematocrit, red blood cell count, while blood cell count, 
neutrophils (absolute), lymphocytes (absolute), monocytes (absolute), eosinophils 
(absolute), basophil (absolute), mean corpuscular volume and platelet count  
 Coagulation tests: INR or PT and PTT 
 Serum chemistries:  albumin, ALT, AST, alkaline phosphatase, amylase, bicarbonate, 
total bilirubin, blood urea nitrogen, calcium, chloride, creatinine, glucose, lactate 
dehydrogenase (LDH), lipase, sodium, potassium, phosphorus and magnesium.  Serum 
testosterone at Screening visit, Day 1 of each Cycle, EOT, and Safety Follow-up. 
 Serum troponin:  serum samples will be drawn for analyses of troponin T and/or I 
proteins, based on local laboratory procedure. For any individual patient, the same 
method will be used at each timepoint.  
 PSA 


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 Urinalysis:  dipstick with micro-analysis if clinically indicated 
Note: Day 15 safety labs (hematology and/or serum chemistries) can be waived at Investigator 
discretion starting in Cycle 6 onward as long as platelets are stable and there are no other 
laboratory concerns in the opinion of the Investigator. 
8.2.9 
Echocardiogram or MUGA 
Echocardiogram or MUGA scan with left ventricular ejection fraction will be obtained during 
the Screening period. 
8.2.10 
12-lead ECG 
Triplicate 12-lead ECGs will be obtained at the indicated time points in the protocol and 
Schedule of Events.  Note: The timing of post-dose ECG assessments in Cycle 1 on Days 1 and 
15 may be adjusted so that they are performed around the Cmax and Css of ZEN003694 and the 
active metabolite, ZEN003791.  This adjustment to the timing of the ECG assessments will occur 
no later than the start of the third dose level.  This will enable a more accurate estimation of the 
time to maximum concentration (Tmax) of ZEN003694 from the PK data obtained from the 
patients in Dose Levels 1 and 2. 
8.2.11 
Pharmacokinetic Sampling 
Plasma samples will be collected to assess the PK properties of ZEN003694 and  the metabolite 
ZEN003791,  
PK analyses of plasma ZEN003694 and ZEN003791 will be performed at the following 
timepoints: 
 Pre-ZEN003694 and enzalutamide (Part 1) or abiraterone (Part 2) dose, 15 minutes (±5 
min), 30 minutes (±5 min), 1 hour (±5 min), 2 hours (±10 min), 4 hours (±15 min), 6 
hours (±15 min) and 8 hours (±30 min) post-ZEN003694 and enzalutamide (Part 1) or 
abiraterone (Part 2 doses  
PK analyses of urine ZEN003694 and its metabolites, including ZEN003791 will be performed 
on C1D15 for up to 8 hours post-dose in the Dose Confirmation phase at the direction of Zenith. 
Plasma and urine concentrations will be determined by a validated liquid chromatography-
tandem mass spectrometry (LC-MS/MS) bioanalytical method.  Samples will be collected as 
indicated in the Schedule of Events and the laboratory manual.  Exploratory analyses for other 
metabolites may be conducted by Zenith and reported separately. 
Part 1: PK properties of enzalutamide and the metabolite des-methyl enzalutamide will be 
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PK analyses of plasma enzalutamide and des-methyl enzalutamide will be performed at the 
following timepoints: 
 Pre-enzalutamide and ZEN003694 dose, 1 hour (±5 min), 2 hours (±10 min), 4 hours 
(±15 min) and 8 hours (±30 min) post- ZEN003694 and enzalutamide doses  
If enzalutamide dose is reduced at any time after Cycle 1, PK samples are to be obtained 28 Days 
(±7 Days) following modification: pre-ZEN003964 and enzalutamide doses, and 15 minutes (±5 
min), 30 min (±5 min), 1 hour (±5 min), 2 hours (±10 min), 4 hours (±15 min), 6 hours (±15 
min) and 8 hours (±30 min) post-ZEN003694 and enzalutamide doses. 
 
Part 2: PK analyses of abiraterone will be performed at the following timepoints: 
 Pre-abiraterone and ZEN003694 dose, 15 minutes (±5 min), 30 minutes (±5 min), 1 hour 
(±5 min), 2 hours (±10 min), 4 hours (±15 min), 6 hours (±15 min) and 8 hours (±30 min) 
post-ZEN003694 and abiraterone doses  
Unscheduled plasma samples for PK analysis may be requested by Zenith following ZEN003694 
or abiraterone dose changes. 
8.2.12 
Pharmacodynamic Sampling 
Blood samples will be drawn for analyses of CTCs (enumeration and PD), cell-free DNA and 
circulating tumor DNA, exploratory biomarkers and BET inhibitor gene expression profile as 
indicated in the Schedule of Events.  Tumor tissue will be obtained for histological and 
immunohistochemical analyses, expression of MYC, GR and AR, and RNA sequencing analysis 
to identify somatic mutations, alternative splicing, fusions and alterations in gene expression.  
Tumor tissue will be obtained as indicated in the Schedule of Events.  Protocols for blood 
collection and processing whole blood, plasma and CTCs; tumor biopsy; tissue collection; and 
all sample storage and transportation will be provided in the study reference manual. 
 Whole Blood CTC:  Whole blood will be collected for the following analyses:  
CTC enumeration, AR-N/AR-C expression to assess AR splice variants.  
CTCs will be identified and quantified (“enumerated”) on the basis of nuclear staining 
with 4,6-diamidino-2-phenylindole, anti-cytokeratin and anti-CD45 antibodies (which 
distinguishes CD45- epithelial cells from CD45 leukocytes).  Slides will be prepared and 
analyzed for CTC enumeration and 5-plex AR-N/AR-C expression (dose confirmation 
phase only).  
One of the resistance mechanisms of ADT is the synthesis of constitutively active AR 
splice variants lacking the canonical ligand binding domain.  Since BETi are predicted to 
exert anti-tumor activity on both AR (native form) and ligand-independent AR splice 
variants, it is predicted that ZEN003694 would have anti-tumor activity in patients 
independent of AR splice isoforms.  Monitoring the AR variants will provide important 


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clinical data regarding the activity of BETi on mCRPC patients with AR variants (Ware, 
Garcia-Blanco, Armstrong, & Dehm, 2014).  Furthermore, an increase in the AR splice 
variants has been associated with resistance to enzalutamide and abiraterone 
(Antonarakis et al., 2014), which is the patient population selected for treatment with 
ZEN003694. 
 Plasma:  Plasma samples will be collected and banked for biomarker analysis.  Plasma 
samples will be analyzed for protein-based biomarkers using either the Myriad RBM 
OncoMAP (124 analytes) or the Somalogic Somascan (~1000 analytes).  The objective 
will be to find plasma-based biomarkers with potential correlation to tumor response, 
which will be further evaluated in Phase 2.  In addition, patients that show response 
(i.e., decrease tumor mass or CTCs) will be analyzed for metabolites and exosomes.  
Samples will be analyzed in batch upon completion of the dose confirmation phase.  
Plasma biomarkers correlating with AR versus AR splice variants may also be identified 
with this analysis. 
 Whole blood BETi gene expression analysis:  Whole blood will be collected.  In 
Cycle 1, RNA will be extracted from these tubes and expression of 6 BETi responsive 
genes, along with a housekeeping control gene (cyclophilin), will be measured using 
quantitative polymerase chain reaction (qPCR).  Preclinical studies with normal and 
patient whole blood have shown that the expression of 5 of these genes (MYC, BCL2, 
chemokine (C-C motif) receptor 1[CCR1], interleukin 1 receptor antagonist [IL1RN], 
G protein-coupled receptor 183 [GPR183]) is inhibited in a BETi (ZEN003694) dose-
dependent manner, while a sixth gene, histone gene cluster 1, H2BE histone family 
member E (HIST2H2BE), increases in a ZEN003694 dose-dependent manner.  
Monitoring the expression of these genes at baseline, 2, 4, 6 and 24 hours after 
ZEN003694 and enzalutamide administration will provide important PD data to help 
determine when active drug concentrations have been attained. 
 
 Exploratory whole blood cfDNA and ctDNA: Whole blood will be collected from 
patients to isolate plasma and the buffy coat.  The plasma will be used to purify cfDNA 
and compare to DNA extracted from the buffy coat in order to identify circulating DNA 
that is derived from the tumors (ctDNA).  It will possibly allow a survey of the different 
mutations present in tumors across the body, monitor changes in the tumor cell 
population over the course of the trial, and possibly identify mechanisms of resistance to 
ZEN003694.  Changes in the percentage of ctDNA fraction and mutational spectrum of 
ctDNA over the course of the treatment will be monitored and compared to the biopsies 
obtained from the same patient to potentially establish correlations with the patient’s 
response, similarly to what has been recently published for ARSIs  (Annala et al., 2018; 
Wyatt et al., 2017; Wyatt et al., 2016) and PARP inhibitors (Goodall et al., 2017; 
Quigley et al., 2017)). 


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 Exploratory BETi blood signature:  Whole blood will be collected at different time-
points during the trial per the Table 1 & Table 2: Schedule of Events to measure changes 
in gene expression during the course of the study.  To measure gene expression, RNA 
will be extracted from the blood, and all the RNA molecules will be sequenced by RNA-
Seq to allow quantification of all the genes expressed in the sample.  By comparing the 
changes in RNA expression through the study, potential genes associated with response 
and/or resistance to ZEN003694 might be identified, and they are sometimes referred to 
as biomarkers.  These biomarkers could be further evaluated in future studies and used to 
predict responses to ZEN003694, and/or select a treatment regimen using whole blood. 
 
 
Tumor Biopsy:  Metastatic tumor biopsies will be taken with core needle or excisional 
biopsy.  Fine needle aspiration is not allowed.  It is encouraged that 4 core samples be 
collected from a single site with a minimum of 2 core samples collected.  The biopsy 
sample will be split into two components, one formalin fixed for histological and 
immunohistochemical analyses, as well as possible DNA mutation analysis. The other 
component will be flash frozen for RNA isolation and sequencing.  In addition to the 
typical hematoxylin and eosin staining for tumor morphology and histologic 
classification, the expression and nuclear localization of AR, GR and MYC will be 
assessed by immunohistochemistry.  For RNA sequencing analysis, paired end 
sequencing (100 bp, 45-50x106 reads) will be used to identify somatic mutations, 
alternative splicing, fusions and alterations in gene expression.  An RNA aliquot will be 
taken from the frozen samples to detect the presence of the AR-V7 splice variant as well.   
In the dose confirmation phase, sampling accessible tumors is mandatory at baseline and 
during the course of treatment and optional at disease progression to help identify 
potential biomarkers for tumor response as well as tumor resistance. Archival tumor 
samples (initial diagnostic biopsy or biopsy at time of prostatectomy or other resected 
tissue), if available, will be collected during the Screening period through the end of 
Cycle 2 or the End of Treatment, whichever occurs first. 
 
 Immuno-Oncology samples:  At selected sites only in dose escalation of Part 1, whole 
blood will be collected for the following analyses:  T-cell receptor (TCR) sequencing in 
PBMCs and flow cytometry in PBMCs.   TCR sequencing will analyze both clonotype 
frequency and diversity of tumor-specific T-cell responses in the entire TCR repertoire.  
Flow cytometry will measure populations of T-helper subsets, cytotoxic and memory T-
cells, T-regs, B-cells, myeloid cell populations as well as LAG3, CTLA4 and PD-1 cell 
populations. In addition, PD-L1 and CD8 cells will be possibly evaluated by 
immunohistochemistry in tumor samples.   
 
8.2.13 
Adverse Events 
Adverse events will be collected as defined in Sections 10.1, 10.2 and 10.3. 


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8.2.14 
Concomitant Medications 
All prior cancer-related treatment and procedures will be captured on the eCRFs.  All 
concomitant medications (dose and regimen) taken during the course of the study must be 
recorded on the Concomitant Medications eCRF.  In addition, any medications taken 21 days 
prior to enrollment in the study should be recorded on the Concomitant Medications eCRF. 
8.2.15 
Tumor Assessment – Imaging/Radiologic Evaluation 
Whole body 
radionuclide imaging (Tech-99) and cross-sectional imaging of the 
chest/abdomen/pelvis should be performed in accordance with institutional standards.  Use of 
intravenous contrast is required unless contraindicated.  Magnetic resonance imaging (MRI) may 
be substituted for computed tomography (CT) per the Investigator’s discretion.  Disease status 
should be assessed using the PCWG2 criteria (see Appendix 3).   
Note:  To be assigned a status of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments no less than 4 weeks after the criteria for response are 
first met. 
 
8.2.16 
Ophthalmology Assessments 
Ophthalmology assessments are to be performed by an ophthalmologist and will include:   
 Part 1: Ophthalmic history, Snellen best corrected visual acuity (including refraction, if 
needed), color vision testing (using standard HRR pseudoisochromatic plates), 
pupillometry, confrontational visual field testing, intraocular pressure (using Goldmann 
tonometry or TonoPen tonometry), external eye and ocular motility exam and slit lamp 
biomicroscopy, indirect ophthalmoscopy, OCT optic nerve and macula tests, fundus 
photography, and other exams as clinically indicated. 
 Part 2: Ophthalmic history, Snellen best corrected visual acuity (including refraction, if 
needed), color vision testing (using standard HRR pseudoisochromatic plates), 
pupillometry, OCT optic nerve and macula tests, fundus photography, and other exams as 
clinically indicated. 
 
In both parts of the study, completion of the Qualitative Exploration of Visual Symptoms form 
(provided by the Sponsor) is required at time-points detailed in the Schedule of Assessments. 
 
At any time during the study should a clinically meaningful change in visual symptoms occur, 
unscheduled ophthalmology assessments are to be performed. 
9. 
WITHDRAWAL OR EARLY TERMINATION OF PATIENTS 
Patients are free to withdraw from study participation at any time for any reason.  Patients may 
discontinue treatment with ZEN003694 either at their request, at the discretion of the 
Investigator for medically indicated reasons or for protocol noncompliance.   


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In the event of early termination, the patient should be instructed to report to the clinic as early as 
possible but within 1 week after the decision to terminate from the study has been made or for 
the next scheduled clinic visit.  All End of Treatment visit procedures (see Section 8.1.9) and all 
Safety Follow-up visit procedures (see Section 8.1.10) are to be conducted.  The Investigator 
shall make his or her best efforts to perform these procedures.  The Investigator should make all 
attempts to accurately identify the reason a patient withdrew from the study, while respecting the 
patient’s privacy.  The primary reason for the patient discontinuation should be documented as 
one of the following: 
 Clinical progression by PCWG2 criteria 
 Clinical progression by PCWG2 criteria with PSA progression 
 Radiographic progression by PCWG2 criteria 
 Radiographic progression by PCWG2 criteria with PSA progression 
 DLT 
 Adverse event  
 Treatment with or need for prohibited concomitant medication 
 Withdrawal by patient 
 Withdrawal by physician 
 Non-compliance 
 Lost to follow-up 
 Death 
 


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10. 
SAFETY ASSESSMENTS 
Safety parameters monitored and recorded during this study include, physical examination 
findings, weight, vital signs, ECOG performance status, ECGs, AEs, laboratory variables 
(hematology, serum chemistries, serum troponin, coagulation tests and urinalysis).    
10.1 
Adverse Event and Suspected Unexpected Serious Adverse Reaction 
Definitions 
10.1.1 
Adverse Event 
An AE is any unfavorable or unintended sign, symptom, or disease temporally associated with 
the use of a pharmaceutical product (i.e., study drug), whether or not considered related to the 
pharmaceutical product.   
The recording of AEs will begin at the start of the administration of the first dose of 
enzalutamide in the Lead-in phase of the study.  AEs should record the development of an 
undesirable medical condition, worsening of a pre-existing medical condition and any change in 
severity (increase or decrease) of a previously recorded AE, during or following exposure to 
study drug, regardless of relationship to study drug.  See Section 10.3 for additional information. 
10.1.2 
Serious Adverse Event 
A serious adverse event (SAE) is any AE that: 
 Results in death 
 Is life-threatening 
o A life-threatening SAE is any AE that places the patient at immediate risk of death 
from the reaction as it occurred, as assessed by the Investigator.  This definition does 
not include a reaction that might have caused death if it occurred in a more severe 
form. 
 Requires in-patient hospitalization or prolongs existing hospitalization 
o For the purposes of this protocol, any hospital admission will be considered an in-
patient hospitalization, regardless of duration.  An emergency room visit without 
hospital admission will not be recorded as a SAE under this criterion, nor will 
hospitalizations for a procedure scheduled before study enrollment (first dose of study 
drug) or elective procedures scheduled during the study.  However, unexpected 
complications that occur during elective surgery should be recorded as AEs and 
assessed for seriousness. 
 Results in persistent or significant incapacity or substantial disruption of the ability to 
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 Results in a congenital anomaly or birth defect 
 Is any other important medical event 
 Other medical events may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the other outcomes in the SAE definition.  Examples 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in hospitalization of the patient, 
or the development of drug dependency or drug abuse.   
10.1.3 
Suspected Unexpected Serious Adverse Reaction   
A suspected unexpected serious adverse reaction (SUSAR) is any AE for which there is evidence 
to suggest a causal relationship between the study drug and the AE (e.g., assessed as possibly or 
probably related), and which is both unexpected and serious.  An unexpected adverse reaction 
(i.e., any untoward and unintended response to the study drug) is one for which the nature and 
severity is inconsistent with the applicable reference safety information (e.g., Investigator’s 
Brochure). 
10.2 
Reporting Serious Adverse Events and Suspected Unexpected Serious 
Adverse Reactions 
Report all SAEs and SUSARs to Drug Safety WITHIN ONE BUSINESS DAY of discovery or 
notification.  Record event information on the SAE Report Form, and submit the completed form 
with any other available pertinent information (e.g., hospital records, laboratory results, etc.) to 
Drug Safety (contact information are provided in the study reference manual).  The minimum 
required information for an initial report is:  
 Reporter’s name and contact information 
 Protocol number 
 Site and patient identification information 
 Event term(s) (with a brief summary of the event[s] and causality assessment) 
If additional follow-up information is required or becomes available for a previously reported 
SAE or SUSAR, a follow-up SAE Report Form with the new information should be prepared 
and submitted WITHIN ONE BUSINESS DAY.  
For hospitalizations, all attempts to obtain the hospital record should be documented in the study 
file.  Complete an SAE Report Form with any known information on the hospitalization, 
however minimal, and submit it to Drug Safety (detailed contact information is provided in the 
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10.2.1 
Disease-related Events That Are Endpoints 
For the purposes of this study, progression of the patient’s underlying disease (“disease 
progression”) should generally not be reported as an AE or SAE.  However, if the Investigator 
determines that there is evidence suggesting a causal relationship between the event and the 
study medication, immediately report the event to Drug Safety and record as an AE or SAE. 
Any event that results in death is to be reported as an SAE. Death is an outcome of an adverse 
event and not an adverse event in itself.  The underlying event leading to death is reported as the 
SAE. 
10.3 
Adverse Events 
Events that occur before the first administration of study drug are not considered AEs, by 
definition (Section 10.1.1); record these events on the Medical History CRF.   
The Investigator or a qualified designee will question and examine patients for evidence of AEs.  
Patients should not be asked about specific AEs.  Instead, they should be asked general questions 
(e.g. “How have you been feeling since your last visit?”).  Record all AEs on the AE CRF.  If a 
previously reported AE changes in severity, record the change in the AE severity on the AE 
CRF. 
For an event to be recorded as an AE, the onset must occur during or after the patient’s first 
exposure to study drug and no later than 30 days after the last study drug dose.  However, there 
is no limit on reporting SAEs considered reasonably related to ZEN003694.  Immediately report 
all SAEs and deaths to Drug Safety (Section 10.2).  This requirement includes deaths within 
30 days of the last dose of study drug, or before the last formal follow-up contact, whichever 
occurs later.  The Investigator should follow all AEs that are considered reasonably related to 
study drug until resolution or stabilization.  All other AEs should be followed until resolution or 
stabilization or until the final visit, whichever occurs first. 
Record syndromes rather than individual signs or symptoms in order to avoid double reporting of 
events and facilitate meaningful interpretation of data.  For example, a patient presenting with 
rhinitis, fever, and headache should be reported as having “flu-like symptoms,” without 
independently recording each accompanying sign.  When no clearly recognizable clinical 
syndrome can be described, record individual clinical signs and symptoms. 
All AEs that occur during the study should be treated appropriately to protect and ensure the 
patient’s well-being.  If such treatment constitutes a deviation from this protocol, Drug Safety 
must be notified and the Investigator should comply with applicable Ethics Committee (EC) or 
Institutional Review Board (IRB) reporting requirements. 
The Investigator is responsible for determining whether or not an AE is severe enough to require 
the patient’s removal from treatment.  A patient may also voluntarily withdraw from treatment 
because of an AE.  If either occurs, the patient must receive appropriate medical care, and the 


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Investigator must strongly encourage the patient to return to the study site for the final protocol-
specified visits and assessments, and to continue returning to the study site for follow-up 
evaluations until the AE resolves or stabilizes.  All AEs, serious or not, that result in permanent 
withdrawal from the study treatment should be immediately reported to Drug Safety. 
Zenith will conduct reviews of all available AEs approximately once every 3 months.  During 
dose escalation, these review timelines may be modified to coincide with enrollment and dose-
escalation safety data.  The study sites are to ensure timely entry of AEs on the CRFs to facilitate 
these reviews. 
10.3.1 
Classification of Adverse Events by Severity 
The Investigator must categorize the severity of each AE using the NCI CTCAE Version 4.03 
(see Appendix 2).   
It is important to distinguish between AE seriousness and severity; these terms are not 
interchangeable.  Severity is a measure of intensity whereas seriousness is defined by the criteria 
in Section 10.1.2. 
10.3.2 
Classification of Adverse Events by Relationship to Study Drug 
For each AE, the Investigator must decide whether there is a reasonable possibility that the event 
was caused by administration of ZEN003694 (i.e., that the event was a suspected adverse 
reaction).  The Investigator should make this decision after careful consideration of the following 
questions: 
 Does the AE follow a reasonable temporal sequence from administration of study drug? 
 Can the AE be reasonably explained by the known characteristics of the patient’s clinical 
state, environmental or toxic factors, or other therapy? 
 Do the AE symptoms disappear or decrease on cessation of study drug or reduction in 
study drug dose?  (There are exceptions when an AE does not disappear on 
discontinuation of the drug, yet drug relatedness clearly exists [e.g., bone marrow 
depression, fixed drug eruptions, tardive dyskinesia, etc.]). 
 Does the AE reappear or worsen when the study drug is re-administered? 
 Does the AE follow an expected response pattern based on the established pharmacologic 
and toxicologic effects of the study drug? 
 Does the AE follow an expected response pattern based on the known effects of other 
products in the same class? 
For this assessment, the Investigator will classify each AE as one of the following: 


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 Yes, Related: The AE is definitely related or even considered possibly or probably 
related to study drug administration.  
 Not Related: The AE is clearly due to other causes (e.g. concurrent medication, 
underlying disease, etc.). 
10.4 
Abnormal Laboratory Results 
Abnormal laboratory results may occur in the context of an AE that is a clinical syndrome 
(e.g., elevated BUN and creatinine in the setting of an AE of renal failure, or elevated AST/ALT 
in the setting of an AE of hepatitis).  In these cases, do not record the abnormality itself as an 
AE. 
However, in the absence of an AE that encompasses an observed abnormal laboratory result, 
report the abnormality as an AE if the Investigator judges it to be clinically significant for the 
patient.  
For the purposes of this study, the criteria for a "clinically significant" abnormal laboratory result 
are any of the following: 
 It leads to DLT 
 It results in any therapeutic intervention 
 It is judged by the Investigator to be of other particular clinical relevance 
10.5 
Overdose 
All study drug will be administered orally.   
There is no data regarding ZEN003694 overdose in humans.  An overdose and AEs should be 
treated as per standard medical practice. 
Dosing details should be captured on the Study Drug CRF.  If the patient receives a dose of a 
study drug that exceeds protocol specifications and the patient is symptomatic, then the 
symptom(s) should be documented on the AE CRF and on a SAE form as appropriate.  Do not 
capture the event on the AE CRF or SAE form if the patient is not symptomatic. 
Should an overdose occur, the Investigator should also monitor the patient with appropriate 
blood counts and serum chemistry tests and should also provide supportive therapies as 
necessary.   
10.6 
Study Safety Monitoring and Dose Escalation or Modification 
The CRC will review safety and available PK data (e.g., Cmax and AUC) for each cohort in the 
dose escalation phase to decide when it is permissible to open a new cohort per the study design 


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described in the protocol.  Safety data will include but are not limited to SAEs, AEs and 
laboratory (protocol specified or ad hoc) data, as well as additional information provided by the 
treating Investigators.  Additionally, the accruing safety data for all patients to date will be 
included in the decision making process for dose escalation or modification.  Dose escalation or 
modifications will be allowed in the absence of an unreasonable and significant risk of illness or 
injury to patients.  In addition, Zenith will review the study safety data on an ongoing basis.  An 
independent specialist may participate in the safety review, if appropriate. 
10.7 
Reporting Safety Information to the Institutional Review Board 
Zenith or its designee will provide written safety reports or other safety-related communications 
to the Investigator.  The Investigator will ensure that these reports are reviewed and processed in 
accordance with regulatory and EC/IRB requirements and archived in the site’s study file.   
At the completion or early termination of the study, the Investigator will submit a final report to 
the EC/IRB in accordance with local requirements. 
 


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11. 
STUDY ENDPOINTS  
11.1 
Primary Endpoints 
 Safety profile of ZEN003694 in combination with enzalutamide (Part 1) and 
abiraterone (Part 2) 
 DLT characteristics and MTD determination for ZEN003694 in combination with 
enzalutamide (Part 1) and abiraterone (Part 2, if MTD is determined) 
 RP2D of ZEN003694 in combination with enzalutamide (Part 1) and abiraterone 
(Part 2) for further clinical investigation 
11.2 
Secondary Endpoints 
 Part 1: Plasma concentrations of ZEN003694, the active metabolite ZEN003791 
and enzalutamide and the active metabolite des-methyl enzalutamide.  The 
following PK parameters, at a minimum, will be calculated as appropriate: AUC0-last 
and AUC0-inf, Cmax and minimum or trough concentration (Cmin), dosing interval, 
and Tmax and half-life (t1/2) 
 Part 2: Plasma concentrations of ZEN003694, the active metabolite ZEN003791 
and abiraterone.  The following PK parameters, at a minimum, will be calculated as 
appropriate: AUC0-last and AUC0-inf, Cmax and minimum or trough concentration 
(Cmin), dosing interval, and Tmax and half-life (t1/2) 
 Overall response rate, complete response (CR) and partial response (PR) by 
PCWG2 criteria 
 PSA response by PCWG2 criteria 
 Median progression-free survival by PCWG2 criteria 
 CTC response (dose confirmation) 
11.3 
Exploratory Endpoints 
 Baseline and change from baseline post-treatment in BET gene expression in whole 
blood  
 Baseline and change from baseline post-treatment in quantification of AR splice 
variants in blood (dose confirmation) and post-treatment in tumor tissue* and 
response (CR, PR, PD) 
 Baseline and change from baseline post-treatment in MYC expression in tumor 
tissue* and response (CR, PR, PD) 


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 Baseline and change from baseline post-treatment in GR expression in tumor 
tissue* and response (CR, PR, PD) 
 Possible relationship of baseline tumor abnormalities (such as mutations, 
translocations, mRNA, protein expression and localization), in circulating tumor 
DNA (ctDNA), circulating tumor cells (CTC) and tumor biopsies and/or on-
treatment changes with any observed antitumor activity 
 Baseline and change from baseline post-treatment in immuno-oncology biomarkers, 
if observed. 
 Part 1: Correlation between ZEN003694, ZEN003791, enzalutamide and des-
methyl enzalutamide plasma exposure levels and PD responses 
 Part 2: Correlation between ZEN003694, ZEN003791, abiraterone plasma exposure 
levels and PD responses 
 Correlation between PSA and radiographic response (CR, PR, PD) 
* Tumor biopsies are optional at baseline, on-study treatment, and at the time of 
progression in dose escalation; mandatory at baseline, on-study treatment, and 
optional at the time of progression in dose confirmation 
 


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12. 
STATISTICS 
12.1 
General Considerations  
The primary statistical analysis of the data will be descriptive in nature.  For continuous variables 
this means calculation of the number of observations, mean, standard deviation, median, 
minimum, and maximum.  Categorical variables will be summarized by patient counts and 
related percentages.  For ordinal-scaled variables, a combination of the above may be employed 
as appropriate:  frequency and percentage of observations within a category and means and 
standard deviations of the scores of the categories.  For categorical and ordinal variables, 
percentages will be calculated based on non-missing data. 
Based on the characteristics of the study design and lack of a concurrent control arm, formal 
testing of treatment effects (i.e., inferential statistics) will not be performed.  However, some 
measures will be summarized by both point estimates and the associated 95% confidence 
intervals. 
12.2 
Sample Size Determination 
A conventional algorithm (3+3 patients per dose level) will be used to identify the MTD, 
escalating on 0 of 3 or 1 of 6 DLTs, and de-escalating if 2 DLTs are encountered.  The MTD will 
be the highest dose level at which 0 of 3 or 1 of 6 patients experience a DLT, with the next 
higher dose having at least 2 of 3 or 2 of 6 patients experiencing a DLT.  With this design, there 
is a 71% chance of escalation if the true but unknown rate of DLT is 20%, and less than 50% 
chance of escalation if the true but unknown rate of DLT is higher than 30%. 
Part 1: Approximately 40 patients may be enrolled in the dose escalation phase of the study.  Up 
to 40 patients in the dose confirmation phase may be enrolled at the MTD or RP2D.  The sample 
size is sufficient to support preliminary safety and pharmacologic assessments. 
Part 2: Approximately 15 patients may be enrolled in the dose escalation phase of the study.  Up 
to 40 patients in the dose confirmation phase may be enrolled at the MTD or RP2D.  The sample 
size is sufficient to support preliminary safety and pharmacologic assessments. 
12.3 
Analysis Populations  
Safety population:  Patients who receive at least one dose of ZEN003694. 
DLT population:  Patients who experience a DLT as defined in Section 5.1.2.  Patients who 
experience a DLT within the first cycle of treatment and drop out of the study will be considered 
evaluable for DLT and will not be replaced.  
Part 1: No dose modification of enzalutamide (160 mg) is permitted during Cycle 1, including 
the 14-day Lead-in period; patients requiring dose modification during Cycle 1 must discontinue 
the study and will be replaced.  Patients, who for reasons other than a DLT, discontinue the study 
prior to completion of the first cycle will be considered unevaluable and will be replaced.  


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Part 2: No dose modification of abiraterone (1000 mg) is permitted during Cycle 1, including the 
14-day Lead-in period; patients requiring dose modification during Cycle 1 must discontinue the 
study and will be replaced.  Patients, who for reasons other than a DLT, discontinue the study 
prior to completion of the first cycle will be considered unevaluable and will be replaced. 
12.4 
Data Handling 
Clinical data will be entered into a clinical data management system (CDMS), involving 
electronic data capture.  Criteria for such a CDMS are that it is Part 11 compliant, web-based and 
supports remote monitoring.  The handling of data, including data quality assurance, will comply 
with regulatory guidelines, and will be defined in the study-specific data management plan 
(DMP).  The DMP will define roles and responsibilities in regard to data quality processes and 
expectations, from study start-up to final database lock.    
12.5 
Statistical Analyses 
Prior to the analysis of the final study data, a detailed statistical analysis plan (SAP) will be 
written.  Detailed information regarding analysis datasets, summarization of the data and 
analyses will be provided in the SAP.  The SAP will contain any modifications to the analyses 
described in this section. 
 


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13. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Prior to participation in this study, investigational sites and Investigators will be evaluated for 
appropriate qualifications and ability to properly execute the study.  Each investigational site 
must undergo proper training on the study protocol and ancillary study procedures/documents 
through participation in an initiation visit or Investigator meeting.  Such training must take place 
before any patients are enrolled at that site.  Initiation visits and Investigator meetings will 
include but may not be limited to review of Good Clinical Practice (GCP) guidelines, study drug 
procedures, data collection requirements and patient eligibility requirements. 
Zenith or designee will make periodic visits to the investigational site to assess compliance with 
study procedures and regulatory requirements; to ensure that the safety, welfare and privacy of 
patients are being protected; and to verify the accuracy and integrity of the study data.   
In addition, Zenith will periodically review the study data to ensure that data are being 
appropriately collected and reported.  Logic checks will be also programmed and run to identify 
errors and data discrepancies.  Discrepancies will be reviewed with investigational site 
personnel, corrections will be made to the database, and a validated audit trail will be 
maintained.  The database will be locked and audited before it is released for analysis. 
13.1 
Study Monitoring 
Before the initiation of the study, a representative from Zenith will visit the investigational site 
to: 
 Determine the adequacy of the facilities 
 Discuss the responsibilities of the Investigator(s) and other personnel involved with the 
study with regard to protocol adherence and the responsibilities of Zenith and their 
representatives 
During the study, the Study Monitor will have regular contact with the investigational site, 
including visits to: 
 Provide information and support to the Investigator(s) 
 Confirm that facilities remain acceptable 
 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded on the CRFs, and that the investigational product accountability is 
being performed. 
 Perform source data verification (a comparison of the data on the CRFs with the patient’s 
records at the hospital or practice, and other records relevant to the study). This will 
require direct access to all original records for each patient e.g., clinic charts.  Incorrect or 
missing entries on to the CRFs will be queried and must be corrected immediately. 


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13.2 
Audit and Inspection 
During or after the study is completed, Zenith, its representatives or a Regulatory Authority may 
wish to carry out an audit or inspection.  These representatives must have the same access to 
study data and patient source data as the Study Monitor. 
13.3 
Regulatory Authority Correspondence 
The Investigator will notify Zenith or designee immediately following any regulatory contact 
with the investigational site.  The Investigator will provide requested copies of all 
correspondence with the Regulatory Authority that may affect the review of the current study 
(e.g., Form 483, Inspectional Observations).  Zenith or their designee reserves the right to be at 
the investigational site during any regulatory inspection that involves this protocol. 


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14. 
ETHICAL AND LEGAL ISSUES 
14.1 
Statement of Compliance 
This study will be conducted in accordance with the following: 
 Protocol-related and study-related documents 
 GCP as outlined in the International Conference on Harmonization (ICH) E6 guideline 
and regional regulations 
 Regional required patient data protection laws and regulations 
 Applicable regional regulations 
14.2 
Ethics Committee or Institutional Review Board Approval 
The Principal Investigator at each site is responsible for obtaining regional EC or IRB approval 
for the final protocol, Zenith-approved ICF/assent, patient information sheet, if applicable, and 
any advertisements to recruit patients.  Written approval of these documents must be obtained 
from the EC/IRB and a copy submitted to Zenith before any patient is enrolled at an 
investigational site. 
The Principal Investigator is also responsible for the following interactions with the regional 
EC/IRB. 
 Obtaining EC/IRB approval for any protocol amendments and ICF/assent revisions 
before implementing the changes 
 Providing the EC/IRB with any required information before or during the study 
 Submitting progress reports to the EC/IRB as required during the conduct of the study, 
requesting re-review and approval of the study as needed, and providing copies of all 
EC/IRB renewal of approvals and relevant communication to Zenith and/or its 
representative 
 Notifying the EC/IRB of all serious and unexpected AEs related to the study medication 
reported by Zenith and/or its representative, as required 
 Notifying the EC/IRB at the end of the study, in accordance with regional guidelines and 
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14.3 
Patient Informed Consent/Assent 
The Investigator’s draft ICF/assent must be reviewed by Zenith and/or its representative prior to 
submission to a regional EC/IRB for approval.  A copy of the ICF/assent approved by the 
EC/IRB must be forwarded to Zenith and/or its representative. 
The consent of the patient to participate in the study has to be given in writing prior to 
enrollment.  It must be signed and personally dated by the patient, parent, legal guardian or 
caretaker and by the Investigator, Sub-investigator or study coordinator designated by the 
Investigator to conduct the informed consent discussion.  The signed and dated declaration of 
informed consent will remain at the Investigators’ site and must be safely archived by the 
Investigator so that the forms can be retrieved at any time for monitoring, auditing and inspection 
purposes.  A copy of the signed and dated ICF should be provided to the patient prior to 
participation and the original maintained in the patient’s source documents or in a separate 
archive file for the informed consent documents for the study. 
14.4 
Patient Compensation for Adverse Effects on Health 
Zenith and/or its representative will adhere to regional regulations regarding clinical trial 
compensation to patients whose health is adversely affected by participation in the study. 
14.5 
Changes to the Conduct of the Study, Protocol and Study Termination 
14.5.1 
Protocol Amendments 
Changes in the study protocol shall be in the form of written study protocol amendments.  These 
will require the approval of all signatories of the final protocol.  Any substantial amendments to 
the protocol that affect the patient, e.g., changes in procedures/assessments or matters relating to 
patient safety, require a favorable opinion from the EC/IRB for the study sites prior to 
implementation.  Changes of a purely administrative nature should be notified to the 
committee(s) as applicable, but do not require formal approval.  However, a change to the 
protocol to eliminate an apparent immediate hazard to the patient may be implemented 
immediately provided the EC/IRB and applicable Regulatory Authorities are subsequently 
notified by protocol amendment.  Any amendment affecting the patient requires further informed 
consent from each patient before implementation.  
14.5.2 
Study Termination 
Zenith reserves the right to terminate the study at any time for any reason.  The Investigator 
should notify the EC/IRB in writing of the completion or early termination of the study.  Zenith 
will promptly notify US FDA and other Regulatory Authorities if enrollment is terminated or 
suspended for any reason.  Upon study completion or termination, applicable regulatory 
reporting requirements will be followed. 
 
 


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15. 
INVESTIGATOR RESPONSIBILITIES 
The Investigators shall be responsible for ensuring that the study is performed in accordance with 
the protocol, Food and Drug Administration (FDA)/ICH GCP regulations and applicable 
regional regulatory requirements.  
15.1 
Staff Training  
The Investigator will maintain a record of all individuals involved in the study.  He or she will 
ensure that appropriate training relevant to the study is given to all staff members involved in this 
study, and that they will receive any new information of relevance to the performance of this 
study.  The Investigator should maintain a list of appropriately trained persons to whom the 
Investigator has delegated trial-related duties. 
15.2 
Study Conduct 
In signing this protocol, the Investigator agrees to: 
 Conduct the study in accordance with the relevant, current protocol and make changes 
only after notifying Zenith or its representative, except where necessary to eliminate 
apparent immediate hazards to human patients 
 Comply with the ICH guidelines on GCPs plus appropriate regional regulatory laws and 
requirements 
 Personally conduct or supervise the described investigation 
 Inform any patients or persons used as controls that the study drugs are being used for 
investigational purposes 
 Ensure requirements relating to obtaining informed consent and EC or IRB approval have 
been met 
 Report to Zenith or its representative any AEs that occur in the course of the 
investigations, as specified in Section 10  
 Read and understand the Investigator’s Brochure, including potential risks and side 
effects of the drug 
 Ensure all associates, colleagues, and employees assisting in the conduct of the study are 
informed of their obligations in meeting their commitments 
 Maintain adequate and accurate records and make these available for inspection by 
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 Promptly report to the EC or IRB all changes in research activity and all unanticipated 
problems involving risks to human patients or others 
 Comply with all other requirements regarding the obligations of clinical Investigators and 
all other pertinent requirements 
 Administer study drug only to patients who meet study entry criteria and are enrolled in 
the study, and only according to the guidelines set forth in this protocol 
15.3 
Recordkeeping 
The Investigator is responsible for maintaining adequate records to fully document the conduct 
of the study, including but not limited to the following: 
 All versions of the Investigator’s Brochure and the signed protocol and amendments in 
effect during the conduct of the study 
 Signed ICFs/assents 
 Source documents including adequate case histories 
 Signed, dated and completed CRFs or data collection forms and documentation of data 
corrections 
 Notification of SAEs and related reports 
 Investigational product accountability logs and documentation of return of unused and 
used investigational product, if applicable 
 Dated and documented EC/IRB approvals 
 Normal laboratory test values and laboratory certifications, if applicable 
 Curricula vitae of all clinical Investigators 
 Completed Forms US FDA 1572 
 Trial initiation documentation 
 Delegation of Authority Log 
 Signed Signature of Agreement for Protocol and Amendment and agreements between 
involved parties 
 Relevant communication, including that related to the Study Monitor’s site visits 
(e.g., letters, meeting notes, notes from telephone calls) 


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 Interim, annual or final reports to ECs/IRBs 
 Patient screening log, patient identification code list and patient enrollment log 
 Audit certificate if applicable 
 


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16. 
PUBLICATIONS 
The data and information generated in this study are the exclusive property of Zenith and are 
confidential.   
To avoid disclosures that could jeopardize proprietary rights, the investigator agrees to give 
Zenith the right to review all manuscripts, abstracts, and presentations related to this study at 
least 30 days prior to their submission for publication or presentation.  Authorship among 
Investigators generally will be based on the extent of significant contribution, including scientific 
and clinical, to the publication.  
 
 
 


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17. 
CONFIDENTIALITY 
The Investigators as well as their staff, and all its representatives must agree to maintain the 
confidentiality of the study at all times and must not reveal information relating to the 
Investigator’s Brochure, protocol, CRFs or associated documents to unauthorized third parties. 
 
 


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Nature, 478(7370), 524-528. doi:10.1038/nature10334 
 
 


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Appendix 1:  ECOG Performance Status  
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities.  
Up and about more than 50% of waking hours. 
3 
Capable of only limited self care, confined to bed or chair more than 50% of waking 
hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair. 
5 
Dead. 
Source: (Oken et al., 1982) 
 
 
 


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Appendix 2:  NCI CTCAE Version 4.03 Adverse Event Severity Grading 
Grade refers to the severity of the AE.  The NCI CTCAE displays Grades 1 through 5 with 
unique clinical descriptions of severity for each AE based on this general guideline as shown in 
the table below. 
Adverse Event Severity Grading — NCI CTCAE 
  
Description 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated 
2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADLa 
3 
Severe or medically significant but not immediately life threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care AD.b 
4 
Life-threatening consequences; urgent intervention indicated 
5 
Death related to AE 
A semicolon (;) indicates “or” within the description of the grade.  A single dash (–) indicates a grade is not available.  Not all 
grades are appropriate for all AEs; therefore, some AEs are listed with fewer than 5 options for grade selection. 
Grade 5 (Death) is not appropriate for some AEs and therefore is not an option. 
Activities of Daily Living (ADL) 
a  Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc. 
b Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden 
 
 
 
 


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Appendix 3:  Prostate Cancer Clinical Trials Working Group 2 Criteria  
MEASUREMENT OF RESPONSE 
Measurement of response in patients with measurable disease 
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) criteria (Eisenhauer et 
al., 2009).  Changes in the sum of the diameters of target lesions of the tumor lesions are used in 
the RECIST criteria. 
Note: lesions are either measurable or non-measurable using the criteria provided 
below. The term “evaluable” in reference to measurability will not be used 
because it does not provide additional meaning or accuracy.  All measurements 
should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning 
of treatment and never more than 30 days before the beginning of the treatment.  
The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.  
Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
Clinical lesions.  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable. 
Conventional CT and MRI.  These techniques should be performed with cuts of 10 mm or less 
in slice thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Head and 
neck tumors and those of extremities usually require specific protocols. 
Measurable disease/ Target lesions 
All measurable lesions (lesions that can be accurately measured in at least one dimension 
[longest diameter to be recorded except for target lymph nodes with are measured on the 
short axis] as ≥ 10mm with spiral CT) up to a maximum of 2 lesions per organ and 
5 lesions total, representative of all involved organs, should be identified as target lesions 
and recorded and measured at baseline.  Target lesions should be selected on the basis of 
their size (lesions with the longest diameter) and the suitability for accurate repeated 
measurements (either by imaging techniques or clinically).  A sum of the LD for all target 
lesions will be calculated and reported as the baseline sum LD.  The baseline sum LD 
will be used as a reference by which to characterize the objective tumor response. 


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Lymph node metastases must measure 1.5 cm or greater in short axis diameter to be 
considered target lesions, while other target lesions must measure 1 cm or greater (with 
spiral CT scans).  
Complete Response (CR): 
Disappearance of all target lesions 
Partial Response (PR): 
At least a 30% decrease in the sum of the 
longest diameter (LD) of target lesions, taking as 
reference the baseline sum LD 
Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of 
target lesions, taking as reference the smallest 
sum LD recorded since the treatment started 
(including baseline LD), or the appearance of 
one or more new lesions 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and 
normalization of tumor marker level 
Incomplete Response/ 
Stable Disease (SD): 
Persistence of one or more non-target lesion(s), 
and/or maintenance of tumor marker level above 
the normal limits 
Progressive Disease (PD): 
Appearance of one or more new lesions, and/or 
unequivocal progression of existing non-target 
lesions 
Although a clear progression of non-target lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression 
status should be confirmed later on by the study chair. 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started, including baseline; see table 
below).  The patient's best response assignment will depend on the achievement of both 
measurement and confirmation criteria. 
Confirmation 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat studies no less than 4 weeks after the criteria for response are first met.  In the 


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case of SD, follow-up measurements must have met the SD criteria at least once after 
study entry at a minimum of 12 weeks after study entry. 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are met 
for CR/PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The duration of overall 
complete response is measured from the time measurement criteria are first met for CR 
until the first date that recurrent disease is objectively documented. 
Target Lesions 
Non-Target Lesions 
New Lesions 
Response 
CR 
CR 
No 
CR 
CR 
Incomplete 
response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Evaluation of non-measurable bone disease  
Bone scans obtained after the baseline evaluation will be used to evaluate post-treatment 
changes.  Bone scans obtained will be evaluated as either “no new lesions” or “new lesions” on 
the tumor measurement forms. 
a. For the first scheduled reassessment:  New lesions at the first scheduled evaluation will 
require a confirmatory bone scan 6 or more weeks later.  If no new lesions are observed 
on the confirmatory bone scan, study therapy is continued.  If additional new lesions are 
observed, then the patient has experienced progression.  Progression in this situation is 
dated as the time of the first reassessment scan. 
b. For subsequent scheduled reassessments:  If no new lesions are observed, study therapy 
will continue. If new lesions are observed, this is evidence of disease progression.  Date 
of progression is the date at which the scan was obtained. 
Post-treatment PSA Changes 
All patients, with or without measurable or non-measurable disease, will be evaluated for PSA 
decline.  Patients with disease that is not measurable will be eligible for this study and will be 
assessed for response based on changes in PSA and serial bone scans (if appropriate).  The 


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baseline serum PSA must be at least 2 ng/mL.  Patients who show PSA increases will not be 
evaluated for PSA progression prior to 12 weeks of study therapy. 
a. 30% and 50% PSA Decline:  PSA decline of at least 30% and 50%, respectively, from 
baseline confirmed by a second measurement at least 3 weeks later.  The reference for 
these declines should be a PSA measured within 2 weeks prior to starting therapy.  
b. PSA Progression:  PCWG2 Criteria will be reported.  PSA progression occurs when the 
PSA has increased 25% or greater above nadir and an absolute increase of 2 ng/mL or 
more from the nadir is documented.  Where no decline is observed, PSA progression 
similarly occurs when a 25% increase from baseline value along with an increase in 
absolute value of 2 ng/mL or more.  Patients will receive a minimum of 12 weeks of 
therapy prior to being evaluable for this endpoint.  PSA progression (without evidence of 
progression on scans) will not be criteria for discontinuation of study therapy. 
c. PSA Response Duration:  The PSA response duration commences on the date of the first 
50% decline in PSA.  The response duration ends when the PSA value increases by 25% 
above the nadir, provided that the increase in the absolute-value PSA level is at least 
5 ng/mL or back to baseline, whichever is lower. 
d. Progressive Disease by PSA (as defined by PSA Progression above) 
e. Time to PSA Progression:  The start of the time to PSA progression is the day treatment 
is initiated.  The end date is the date of the first PSA rise over the determined PSA PD 
value. 
Progressive disease (PD) 
Progressive disease will be defined by any one of the following: 
a. Appearance of new metastatic lesions outside the bone 
b. New metastatic lesions on bone scan confirmed as described above 
c. Development of an indication for radiotherapy while on treatment 
d. Unequivocal progression of non-target lesions 
e. Global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression 
Note that PSA progression (as defined above) alone does not meet the criteria for 
progressive disease. 
Source: (Scher et al., 2008) 
 
 
 


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Appendix 5:  ZYTIGA® Package Insert 
 
 
 


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Appendix 6:  Investigator Agreement Page 
 
Phase 1b Safety and Tolerability Study of ZEN003694 in Combination with Enzalutamide 
or Abiraterone in Patients with Metastatic Castration-resistant  
Prostate Cancer 
 
Protocol ZEN003694-002 
Amendment 10:  05 November 2018 
 
I have read the protocol, including all appendices, and I agree that it contains all necessary 
details for me and my staff to conduct this study as described.  I will conduct this study as 
outlined herein and will make a reasonable effort to complete the study within the time 
designated.  Further, I agree to conduct this study in accordance with ICH Guidelines, all 
applicable United States (US) Regulations (21 CFR parts 50, 54, 56 and 312) and Good Clinical 
Practice and applicable regulatory requirements. 
The information contained in this protocol is proprietary and provided to me in confidence, and 
may not be disclosed to any other party, in any form, without prior authorization from Zenith 
Epigenetics Ltd., except to the extent necessary for the conduct of the study at this study site. 
I will provide all study personnel under my supervision copies of the protocol and access to all 
information provided by Zenith Epigenetics Ltd.  I will discuss this material with them to ensure 
that they are fully informed about the drugs and the study. 
 
Principal Investigator’s Signature 
 
Date 
Principal Investigator’s Name: 
(Print) 
 
Institution’s Name, City, State: 
 
 
 
 
 
 

SAP_001.pdf: 
Document Type 
SAP 
Official Protocol Title 
A Phase 1b/2a Safety and Tolerability Study of ZEN003694 in 
Combination With Enzalutamide in Patients With Metastatic 
Castration-Resistant Prostate Cancer 
NCT Number 
NCT02711956 
Document Date 
27 Jan 2020 
 






 
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TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ....................................................................................................... 5 
DEFINITIONS ............................................................................................................................... 7 
1. 
INTRODUCTION .................................................................................................................. 9 
2. 
STUDY DOCUMENTS ......................................................................................................... 9 
3. 
STUDY OBJECTIVES .......................................................................................................... 9 
3.1 
PRIMARY OBJECTIVE ..................................................................................................... 9 
3.2 
SECONDARY OBJECTIVE .............................................................................................. 10 
3.3 
EXPLORATORY OBJECTIVES ........................................................................................ 10 
4. 
STUDY DESIGN AND PLAN ............................................................................................ 10 
5. 
DETERMINATION OF SAMPLE SIZE .......................................................................... 14 
6. 
GENERAL ANALYSIS CONSIDERATIONS ................................................................. 14 
7. 
NOTATION OF TREATMENT GROUPS AND VISITS ............................................... 15 
8. 
ANALYSIS POPULATIONS .............................................................................................. 16 
9. 
STUDY POPULATION....................................................................................................... 17 
9.1 
PATIENT DISPOSITION .................................................................................................. 17 
9.2 
PROTOCOL DEVIATIONS .............................................................................................. 17 
9.3 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ..................................................... 17 
9.4 
PRIOR CANCER THERAPY, CHEMOTHERAPY TREATMENT, SURGICAL TREATMENT, AND 
RADIOTHERAPY TREATMENT ................................................................................................. 18 
9.5 
PRIOR AND CONCOMITANT MEDICATIONS .................................................................. 18 
10. CLINICAL ACTIVITY ANALYSES ................................................................................ 18 
10.1 CLINICAL ACTIVITY VARIABLES ................................................................................. 18 
10.2 BASELINE VALUES ....................................................................................................... 20 
10.3 ADJUSTMENTS FOR COVARIATES ................................................................................ 20 
10.4 HANDLING OF DROPOUTS OR MISSING DATA ............................................................. 20 
10.5 INTERIM ANALYSIS AND DATA MONITORING ............................................................. 20 
10.6 EXAMINATION OF SUBGROUPS .................................................................................... 20 
10.7 MULTIPLE COMPARISON/MULTIPLICITY ..................................................................... 20 
10.8 MULTICENTER STUDIES ............................................................................................... 20 
11. DEFINITIONS OF CLINICAL ACTIVITY ENDPOINTS ............................................. 20 
11.1 RADIOGRAPHIC TUMOR RESPONSE (OVERALL RESPONSE RATE) BY PCWG2 CRITERIA
 
20 
11.2 PSA RESPONSE RATE BY PCWG2 CRITERIA .............................................................. 23 
11.3 PROGRESSION-FREE SURVIVAL BY PCWG2 CRITERIA ............................................... 24 
11.3.1 OVERALL PROGRESSION-FREE SURVIVAL BY PCWG2 CRITERIA............................... 24 
11.3.2 RADIOGRAPHIC PROGRESSION-FREE SURVIVAL BY PCWG2 CRITERIA ..................... 25 
11.3.3 TIME TO PSA PROGRESSION BY PCWG2 CRITERIA .................................................... 25 
11.4 CTC RESPONSE ............................................................................................................ 26 
11.5 EXPLORATORY ANALYSIS ........................................................................................... 26 


 
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12. METHODS OF CLINICAL ACTIVITY ANALYSES ..................................................... 26 
12.1 RESPONSE RATE ENDPOINTS ....................................................................................... 26 
12.2 TIME TO EVENT ENDPOINTS ........................................................................................ 26 
13. PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES .......................... 27 
14. SAFETY ANALYSES .......................................................................................................... 27 
14.1 EXTENT OF EXPOSURE ................................................................................................. 27 
14.2 ADVERSE EVENTS ........................................................................................................ 27 
14.3 CLINICAL LABORATORY EVALUATION ....................................................................... 28 
14.4 VITAL SIGNS ................................................................................................................ 29 
14.5 PHYSICAL EXAMINATION ............................................................................................ 29 
14.6 ECHOCARDIOGRAM OR MULTIGATED ACQUISITION (MUGA) SCAN ......................... 29 
14.7 ELECTROCARDIOGRAM ................................................................................................ 29 
14.8 EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS ......... 30 
14.9 OPHTHALMOLOGY ASSESSMENTS ............................................................................... 30 
15. CHANGES TO PROTOCOL-SPECIFIED ANALYSES ................................................ 31 
17. REFERENCES ..................................................................................................................... 32 
18. APPENDICES ...................................................................................................................... 33 
APPENDIX A:  PRESENTATION OF DATA AND PROGRAMMING SPECIFICATIONS ................... 33 
APPENDIX B: SAS PROGRAMMING QC REQUIREMENTS ........................................................ 37 
APPENDIX C:  PROSTATE CANCER WORKING GROUP 2 (PCWG2) CRITERIA ........................ 48 
APPENDIX D: NCI CTCAE V4.03 TOXICITY GRADES FOR CLINICAL LABORATORY ABNORMALITIES
 
50 
APPENDIX E:  LIST OF TABLES, FIGURES, AND LISTINGS ....................................................... 52 
APPENDIX F:  TABLE LAYOUTS .............................................................................................. 59 
APPENDIX G:  FIGURE LAYOUTS .......................................................................................... 145 
APPENDIX H:  LISTING LAYOUTS ......................................................................................... 156 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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LIST OF ABBREVIATIONS 
ADaM 
Analysis data model 
AE 
Adverse event 
ARSI 
Androgen receptor signaling inhibitor 
ATC 
Anatomical Therapeutic Chemical 
AUC0-inf 
Area under the curve, from time zero to infinity with a quantifiable level 
of drug  
AUC0-last 
Area under the curve, from time zero to last time point with a quantifiable 
level of drug  
BET 
Bromodomain and extra-terminal domain 
BMI 
Body mass index  
Cmax 
Maximum plasma concentration 
Cmin 
Minimum or trough concentration 
CR 
Complete response 
CRF 
Case report form 
CSR 
Clinical study report 
Css 
Concentration steady-state  
CTC 
Circulating tumor cell(s) 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
DC cohort 
Dose confirmation group 
DE cohort 
Dose escalation group 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic case report form 
ICH 
International Council for Harmonisation 
INR 
International normalized ratio  
mCRPC 
Metastatic castration-resistant prostate cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRNA 
Messenger ribonucleic acid 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition (scan) 
MYC 
V-Myc avian myelocytomatosis viral oncogene homolog 
NE 
Not evaluable  


 
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OCT 
Optical coherence tomography 
PCWG2 
Prostate Cancer Working Group 2 
PD 
Progressive disease 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PSA 
Prostate-specific antigen 
QTc 
Corrected QT interval 
QTcF 
Corrected QT interval according to Fridericia formula 
RECIST 
Response Evaluation Criteria in Solid tumors 
rPFS 
Radiographic progression-free survival 
RTF 
Rich text format 
SAP 
Statistical analysis plan 
SD 
Stable disease 
t1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
TLFs 
Tables, listings, and figures 
Tmax 
Time to reach maximum plasma concentration 
WHO 
World Health Organization 
 
 
 


 
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DEFINITIONS 
Adverse Event  
An adverse event (AE) is any reaction, side effect, or 
other untoward event, regardless of relationship to study 
drug, which occurs anytime during or after the patient’s 
first exposure to study drug. For an event to be recorded 
as an AE, the onset must occur during or after the 
patient’s first exposure to study drug and no later than 
30 days after the last study drug dose. 
 
PSA Evaluable Population Patients who receive at least 1 dose of ZEN003694, have 
a non-missing baseline prostate-specific antigen (PSA), 
and have at least 1 nonmissing postbaseline PSA 
assessment or who discontinue study treatment due to 
disease progression or death. 
 
Radiographic Evaluable 
Population 
Patients who receive at least 1 dose of ZEN003694, have 
a nonmissing baseline and have at least 1 evaluable 
postbaseline radiographic assessment or who discontinue 
study treatment due to disease progression or death. 
 
Safety Population 
Patients who receive at least 1 dose of ZEN003694. 
 
CTC Evaluable 
Population 
Patients who receive at least 1 dose of ZEN003694, have 
a nonmissing baseline and at least 1 evaluable post-
baseline circulating tumor cell (CTC) collection.  
 
Serious AE 
An AE occurring at any dose that results in death; is a 
life-threatening experience; requires inpatient 
hospitalization or prolongation of an existing 
hospitalization; results in a persistent or significant 
disability/incapacity; or is a congenital anomaly/birth 
defect in the offspring of a patient who received study 
drug; is any other important medical event; other AEs, 
based on appropriate medical judgment, that may 
jeopardize the patient and may require medical or 
surgical intervention to prevent a serious outcome. 
 
Treatment-Emergent AE 
AEs with an onset time after the initial dose of 
ZEN003694. 
 
 


 
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Tumor Burden 
High tumor burden defined as 1 or more of: visceral 
metastases, sum of target lesions ≥30mm, ≥10 bone 
lesions. Low tumor burden is everyone else. 


 
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1. INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of data 
collected within the scope of Zenith Epigenetics Ltd. Protocol ZEN003694-002, “A Phase 1b 
Safety and Tolerability Study of ZEN003694 in Combination with Enzalutamide or Abiraterone 
in Patients with Metastatic Castration-Resistant Prostate Cancer.” The purpose of this plan is to 
provide specific guidelines from which the statistical analyses will proceed. Any deviations from 
this plan will be documented in the clinical study report (CSR). 
2. STUDY DOCUMENTS 
The following study documents were used for the preparation of the statistical analysis plan 
(SAP): 
x Protocol Version 10, 05NOV2018 
On 11APR2019, Zenith informed all study sites that they no longer plan to move forward 
with the abiraterone combination of the Zenith metastatic castration-resistant prostate 
cancer (mCRPC) study, ZEN003694-002, Part 2. Part 2 will be postponed indefinitely. 
Therefore, this SAP includes the statistical methods for Part 1 of the study only. 
x Annotated electronic case report form (eCRF) version 12, 14MAY2019 
x Data management plan version 1, 29APR2016 
3. STUDY OBJECTIVES 
3.1 Primary Objective 
x To determine the safety, tolerability, and maximum tolerated dose (MTD) of ZEN03694 
in combination with enzalutamide in patients with mCRPC who have progressed during 
prior treatment with enzalutamide or apalutamide (Cohort DE-A) or with abiraterone 
(Cohort DE-B) by Prostate Cancer Working Group 2 (PCWG2) criteria 2007 (Scher 
2008) (dose escalation). 
x To confirm the safety and tolerability of the MTD and recommended Phase 2 dose of 
ZEN003694 in combination with enzalutamide in the following two cohorts of patients 
with mCRPC (dose confirmation): 
o Cohort DC-A: Patients with prior progression on enzalutamide or apalutamide by 
PCWG2 criteria who are currently or will be receiving a stable dose of 
enzalutamide 
o Cohort DC-B: Patients who are enzalutamide-naïve and apalutamide-naïve with 
prior progression on abiraterone by PCWG2 criteria 


 
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3.2 Secondary Objective 
x To determine the pharmacokinetics (PK) of ZEN003694 and the PK of enzalutamide 
along with their primary active metabolites when administered in combination 
x To evaluate the preliminary clinical activity of ZEN003694 in combination with 
enzalutamide as applicable: 
o Prostate-specific antigen (PSA) response rate by PCWG2 criteria 
o Radiographic response rate by PCWG2 criteria 
o Median radiographic progression-free survival (rPFS) by PCWG2 criteria 
o Median progression-free survival (PFS) by PCWG2 criteria 
o Circulating tumor cell (CTC) response rate (dose confirmation only) 
3.3 Exploratory Objectives 
x To explore pharmacodynamics, prognostic and/or predictive biomarkers of ZEN003694 
in combination with enzalutamide in whole blood, plasma and tumor samples in the dose 
escalation phase and/or dose confirmation phase as follows: 
o Possible relationship of baseline tumor abnormalities (such as mutations, 
translocations, messenger ribonucleic acid (mRNA), protein expression and 
localization), in circulating tumor DNA (ctDNA), CTC and tumor biopsies and/or 
on-treatment changes with any observed antitumor activity 
x To explore the effects of ZEN003694 on immuno-oncology markers in tumor tissue and 
peripheral blood mononuclear cells 
4. STUDY DESIGN AND PLAN 
This study is an open-label, nonrandomized, Phase 1 dose-escalation/dose-confirmation study of 
ZEN003694 in combination with enzalutamide in patients with mCRPC. 
A standard 3+3 cohort design will be utilized. Cohorts of up to 6 patients will be enrolled at each 
dose level, and each patient will participate in only 1 cohort. Each cycle will be 28 days in 
duration. Up to 10 sites in the United States will be used to enroll patients. Approximately 40 
patients will be enrolled in the dose escalation phase and up to 40 patients will be enrolled in the 
dose confirmation phase for a total of 80 evaluable patients. 
Dose Escalation 
For patients who have progressed on abiraterone (Cohort DE-B), enzalutamide will be 
administered orally as a single agent daily for 14 days before the initiation of the combination 
therapy (Lead-in) to reach enzalutamide steady-state concentration (Css) during Cycle 1. After 
the Lead-in, if applicable, ZEN003694 will be administered orally in combination with daily 


 
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enzalutamide for 28-day cycles. Patients who are progressing on enzalutamide or apalutamide 
(Cohort DE-A, Sub-arm A1) and who are currently receiving a stable dose of enzalutamide will 
continue to receive enzalutamide in combination with ZEN003694, if eligibility criteria are met. 
Patients in Cohort DE-A who are currently receiving enzalutamide or apalutamide or are 
currently taking apalutamide (Cohort DE-A, Sub-arm A2) will be administered enzalutamide 
orally once daily for 14 days prior to the initiation of the combination therapy (Lead-in) to reach 
enzalutamide Css during Cycle 1. 
After the Lead-in, ZEN003694 will be administered orally in combination with daily 
enzalutamide for 28-day cycles. The first patient at each dose level will be treated with 
ZEN003694 for one week before the second patient at the same dose level is allowed to receive 
their first dose of ZEN003694. Patients at each dose level will be treated (for 28 days) and 
observed through the end of the first cycle before treatment of patients at the next higher dose 
level can begin. In unusual circumstances, (e.g., if there is 1 slot remaining to fill a cohort and 2 
prospective enrollees are being screened and qualify simultaneously) the sponsor may allow an 
extra subject to enter a cohort, although the same rules for determining MTD will apply.  
ZEN003694-related adverse events (AEs) for determination of DLTs will be assessed for each 
patient during the 28 days of Cycle 1. The most common AEs for enzalutamide are well-known. 
As such, the Investigator should to the best of his/her ability assess the relatedness of an AE 
observed as attributable to enzalutamide or ZEN003694 alone, or if unable to do so, as 
attributable to the combination of enzalutamide and ZEN003694. 
Dose escalation will continue after all patients enrolled within a cohort have completed the 28-
day Cycle 1 DLT observation period with either 0 of 3 patients, or no more than 1 out of 6 
patients in a cohort experiencing a DLT, with the proviso that dose escalation to MTD may be 
waived in Part 2. Dose escalation decisions will be made based on clinical safety and (when 
available) PK data (maximum or peak concentration [Cmax] and AUC) after review by the 
Cohort Review Committee (CRC), consisting of all Investigators and the Zenith Medical 
Monitor. If a DLT is observed in 1 of 3 patients in a cohort and confirmed by the CRC, 3 
additional patients will be enrolled into that cohort. If 1 of 6 patients in a cohort experiences a 
DLT, then dose escalation may continue in the next cohort or the MTD of the combination can 
be declared. If ≥2 of 3 to 6 patients experience DLTs within a cohort, then the MTD will be 
considered to have been exceeded and further dose escalation will cease. In this case, if fewer 
than 6 patients have been enrolled at the previous dose level, that cohort will be expanded to 6 
patients to confirm the MTD. Should the MTD of the combination be exceeded at Dose Level 1, 
a cohort may be explored with a reduced dose of ZEN003694 or enzalutamide at the discretion 
of the CRC. Cohort management is summarized below.  
Dose-limiting Toxicity and Cohort Management 
Number of Patients with 
Dose-limiting Toxicity 
Action 
1 of 1 
Add 5 more patients  
0 of 3 
Proceed to next dose level  


 
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1 of 3 
Add 3 more patients  
1 of 6 
Proceed to next dose level  
≥2 of 3 or ≥2 of 6 
Add 3 more patients in the next lower dose level if only 
3 patients were treated in the next lower dose. If 6 
patients were treated at the next lower dose level and no 
more than one patient had DLT, then the next lower  
 
Enzalutamide is a strong inducer of CYP3A4. Treatment with enzalutamide reduces the Cmax 
and AUC of the sensitive CYP3A4 substrate midazolam approximately 7- and 4-fold, 
respectively. ZEN003694 is also a CYP3A4 substrate and therefore the levels of ZEN003694 
may be substantially lower when administrated to patients treated with enzalutamide due to 
increased clearance of ZEN003694 compared to ZEN003694 treatment alone. Enrollment in this 
study with ZEN003694 in combination with enzalutamide will commence with 36 mg as the 
starting dose for ZEN003694 and 160 mg dose of enzalutamide (or at a lower stable dose for 
patients in DE-A or DC-A). The dose of enzalutamide will be held constant through Cycle 1 of 
the Dose Escalation. After Cycle 1, the dose of enzalutamide may be modified for toxicity per 
the XTANDI® Package Insert. Due to the possible higher clearance of ZEN003694 during co-
administration with enzalutamide, higher doses of ZEN003694 may be needed to achieve 
sufficient ZEN003694 exposure with the combination treatment than with ZEN003694 alone. If 
enzalutamide dose is reduced at any time after Cycle 1, PK samples are to be obtained 28 Days 
(±7 Days) following dose modification. Dose escalation of ZEN003694 in this study will 
proceed as follows unless intervening toxicity is observed. 
Dose Level  
ZEN003694 (mg)  
Fold Increase from  
Prior Dose Level  
1  
36  
--  
2  
48  
1.33  
3  
60  
1.25  
4  
72  
1.20  
5  
96  
1.33*  
Additional levels may be explored at the discretion of the CRC  
 
Dose escalation increments between cohorts will be determined by the CRC based on safety and 
available PK data (e.g., Cmax and AUC) based on the following schema:  
x Dose escalation up to 2-fold is allowed in Dose Level 2 and 3 unless one drug-related 
Grade 2 event is observed in Dose Level 1 and 2, respectively  
x Subsequent dose escalation up to 1.5-fold is allowed until a DLT is observed  
x Subsequent dose escalation up to 1.33-fold is allowed until MTD is established, or, in 
Part 2, if MTD is waived and RP2D is declared  




 
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Patients who miss more than 25% of ZEN003694 and/or enzalutamide or abiraterone doses or 
fail to begin Cycle 2 within 1 week of the scheduled start date for reasons other than 
ZEN003694-related toxicity  
x Patients who require enzalutamide or abiraterone dose hold or modification in Cycle 1, 
including during the 14-day Lead-in period for reasons other than ZEN003694-related 
toxicity  
x If a patient is unable to tolerate enzalutamide for any reason at dose of 160 mg during the 
14 day Lead-in prior to first dose of ZEN003694, then the patient should not receive 
ZEN003694, and be withdrawn from the study and replaced  
Dose Confirmation 
Once the MTD of ZEN003694 in combination with enzalutamide has been determined in the 
dose escalation portion of the study, up to 20 patients who meet the inclusion/exclusion criteria 
for Cohort DC-A and up to 20 patients who meet the inclusion/exclusion criteria for Cohort DC-
B of the dose confirmation phase will be enrolled for further evaluation of safety, PK, 
pharmacodynamics, and preliminary clinical activity. 
Enzalutamide-naive and apalutamide-naïve patients in Cohort DC-B will be administered 
enzalutamide (160 mg) orally once daily for 14 days prior to the initiation of the combination 
therapy (Lead-in) to reach enzalutamide Css during Cycle 1. After the Lead-in, ZEN003694 will 
be administered orally in combination with daily enzalutamide for 28-day cycles. Patients in 
Cohort DC-A who are currently receiving a stable dose of enzalutamide (Sub-arm A1) will 
continue to receive enzalutamide and will not participate in the Lead-in. Patients in Cohort DC-A 
who are not currently receiving enzalutamide or apalutamide or are currently taking apalutamide 
(Sub-arm A2) will be administered enzalutamide orally once daily for 14 days prior to the 
initiation of the combination therapy (Lead-in) to reach enzalutamide Css. After the Lead-in, 
ZEN003694 will be administered orally in combination with daily enzalutamide for 28-day 
cycles. 
When the 6th patient in each cohort in the dose confirmation phase has completed one cycle of 
therapy, or earlier if clinically indicated, the CRC will review the safety data. If ≥2 patients have 
experienced drug-related SAEs or DLT-equivalent events, the CRC may recommend a modification 
in the dose or regimen of ZEN003694 in combination with enzalutamide for the dose confirmation 
phase. 
5. DETERMINATION OF SAMPLE SIZE 
The sample size for this study was not based on any formal statistical considerations.   
6. GENERAL ANALYSIS CONSIDERATIONS 
The statistical analyses will be reported using summary tables, listings, and figures (TLFs). The 
International Council for Harmonisation (ICH) numbering convention will be used for all TLFs. 


 
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Continuous variables will be summarized with means, standard deviations, medians, minimums, 
and maximums and valid cases.  
Categorical variables will be summarized by counts and by percentage of patients in 
corresponding categories. Percentages for missing values are omitted and do not account for the 
percent calculation of other categories. Percentages are routinely based on the total category 
count excluding the missing category if not otherwise mentioned. Percentages showing a rate 
relative to the total number of patients in this group are given in special tables (e.g. adverse event 
[AE] tables). Footnotes will specify the percent basis. All summary tables will be presented by 
treatment group. Baseline summaries will also include a total summary column.  
Individual patient data obtained from the case report forms (CRFs), local clinical lab, and any 
derived data will be presented by patient in data listings. 
For AEs and concomitant medications, no imputation of partial or missing dates will be 
performed except for the determination for treatment emergence and prior and/or concomitant 
medications. The most conservative approach will be systematically considered for determining 
treatment emergence and prior and/or concomitant medications. If the AE onset date is missing 
or incomplete, it is assumed to have occurred during the study treatment phase (ie, considered a 
treatment-emergent adverse event [TEAE]) unless the partial onset date or other data, such as the 
stop date, indicates differently. Similarly, a medication with partial start and stop dates could be 
considered as both a prior and concomitant treatment. 
The analyses described in this plan are considered a priori, in that they have been defined prior to 
database lock. Post-hoc analyses will be labeled as such on the output and identified in the CSR. 
All analyses and tabulations will be performed using SAS£ Version 9.4 or higher. Tables, 
listings, and figures will be presented in RTF format. 
7. NOTATION OF TREATMENT GROUPS AND VISITS 
The following notation of treatment groups will be used throughout the report: 
 
Full notation (as used in the study protocol) 
Notation as used throughout all tables, 
listings and figures 
36 mg, Dose Escalation 
DE-A, 36mg 
36 mg, Dose Escalation 
DE-B, 36mg 
48 mg, Dose Escalation 
DE-A, 48mg 
48 mg, Dose Escalation 
DE-B, 48mg 
60 mg, Dose Escalation 
DE-A, 60mg 
60 mg, Dose Escalation 
DE-B, 60mg 
72 mg, Dose Escalation 
DE-A, 72mg 
72 mg, Dose Escalation 
DE-B, 72mg 
96 mg, Dose Escalation 
DE-A, 96mg 


 
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96 mg, Dose Escalation 
DE-B, 96mg 
120 mg, Dose Escalation 
DE-A, 120mg 
144 mg, Dose Escalation 
DE-A, 144mg 
48 mg, Dose Confirmation 
DC-A, 48mg 
48 mg, Dose Confirmation 
DC-B, 48mg 
96 mg, Dose Confirmation 
DC-A, 96mg 
96 mg, Dose Confirmation 
DC-B, 96mg 
Note: The table shells are created based on all treatment groups used in the protocol. However, 
actual table programming may/may not necessarily include all of these doses if they were not 
included in the study. 
The following visit terminology will be used throughout the report: 
Visit 
Notation as used throughout all tables, 
listings and figures 
Screening 
Screening 
Cycle X Day X 
CXDX, Baseline 
8. ANALYSIS POPULATIONS 
The following patient population will be used for demographic, baseline characteristics and 
primary endpoints:  
x Safety population   
The following patient populations may be used for primary and secondary endpoints:  
x Safety population 
x Safety population with radiographic progression or ongoing at study completion 
x PSA Evaluable Population, which will be used for PSA related endpoints. 
x Radiographic Evaluable Population, which will be used for overall tumor response rate. 
The following patient population will be used for PK analyses: 
x PK Population will include all patients who have adequate PK data. Pharmacokinetic 
analysis will be performed by an independent party and will be provided separately. 
Note, for all analyses, treatment group will be based on the treatment the patient was assigned to 
when enrolled in the study.


 
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9. STUDY POPULATION 
9.1 Patient Disposition 
Patient disposition information will be summarized for all patients by dose regimen. Summaries 
will include: the number of screened patients, the number of enrolled patients, the number of 
patients in each analysis population, the number of cycles a patient completed, and the primary 
reason for study completion/discontinuation. 
Information for screen failures will be described separately in the CSR. 
9.2 Protocol Deviations 
All protocol deviations will be presented by patient in a data listing and summarized in the 
following categories: 
x Major 
o Inclusion/exclusion criteria not met 
o Noncompliance with study protocol 
x Minor 
For major protocol deviations, noncompliance with study protocol includes any subject who met 
withdrawal criteria but was not withdrawn from the study treatment, received excluded or 
prohibited concomitant medication or treatment, and received the wrong study treatment or 
incorrect dose of study treatment. 
9.3 Demographic and Baseline Characteristics 
Demographic variables include: age, sex, ethnicity, race, height (cm), weight (kg), body mass 
index (BMI) (kg/m2). Age will be calculated in years relative to the informed consent date. 
Baseline characteristics include Eastern Cooperative Oncology Group (ECOG) performance 
status, PSA (ng/mL), tumor burden, pain (from external data), opioid use, metastatic location, 
alkaline phosphatase, lactic acid dehydrogenase, albumin, hemoglobin, number of prior 
chemotherapies, duration of prior androgen receptor signaling inhibitor (ARSI) therapy, and 
reason for prior enzalutamide/abiraterone discontinuation.  
Descriptive statistics will be presented for age, baseline age, height, weight, BMI, PSA, alkaline 
phosphatase, lactic acid dehydrogenase, albumin, hemoglobin, number of prior chemotherapies 
and duration prior ARSI therapy. Frequency counts and percentages will be presented for sex, 
ethnicity, race, medical history, opioid use, ECOG performance status, and reason for prior 
enzalutamide/abiraterone discontinuation. Demographic and baseline characteristics will be 
summarized for the Safety Population.  


 
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Prostate cancer history, PSA history and prior cancer therapy will be presented by patient in a 
data listing. Baseline medical history will be be summarized by primary system organ class and 
dictionary-derived term in a table.  
9.4 Prior Cancer Therapy, Chemotherapy Treatment, Surgical Treatment, and 
Radiotherapy Treatment 
Prior cancer therapy reported by prior systemic treatment (from the Prior Chemotherapy 
Treatment CRF page), prior surgical treatment and prior radiotherapy treatment are summarized 
by frequency counts by dose regimen. Prior chemotherapy treatment includes type of 
chemotherapy treatment (chemotherapy, biologic therapy, immunotherapy, hormonal therapy, or 
other), best overall response, route, and reason stopped. Prior surgical treatment includes intent 
(curative, palliative, and adjunctive). Prior radiotherapy treatment includes type of radiotherapy, 
site of treatment, total radiation dose (descriptive statistics), and best overall response. 
9.5 Prior and Concomitant Medications 
Prior and concomitant medication verbatim terms on CRFs will be mapped to Anatomical 
Therapeutic Chemical (ATC) class and preferred terms using the World Health Organization 
(WHO) Drug Dictionary Enhanced (version 01MAR2019). 
Prior medications are those medications taken prior to the initial dose of ZEN003694. 
Concomitant medications are those medications taken after the initial dose of ZEN003694 or 
medications started prior to initial dose of ZEN003694 and continued during the treatment 
period.  A medication can be classified as both prior and concomitant. If it cannot be determined 
whether the medication was a prior (or concomitant) medication due to a partial start or stop 
date, then it will be counted as both prior and concomitant.  
Prior and concomitant medications will be summarized for each treatment by WHO ATC class 
and preferred name. These summaries will present the number and percentage of patients using 
each medication. Patients may have more than 1 medication per ATC class and preferred name. 
At each level of patient summarization, a patient is counted once if he/she reported 1 or more 
medications at that level. Each summary will be ordered by descending order of incidence of 
ATC class and preferred name within each ATC class. 
10. CLINICAL ACTIVITY ANALYSES 
10.1 Clinical Activity Variables 
Tumor response, PSA response, and time-to-event analysis will be based on the Safety 
Population. The PK analysis will be based on the PK Population. The CTC response will be 
analyzed for CTC Population. 
Secondary endpoints 


 
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x Plasma concentrations of ZEN003694, the active metabolite ZEN003791 and 
enzalutamide and the active metabolite des-methyl enzalutamide.* The following PK 
parameters, at a minimum, will be calculated as appropriate: area under the curve, from 
time zero to last time point with a quantifiable level of drug (AUC0-last) and area under the 
curve, from time zero to infinity with a quantifiable level of drug (AUC0-inf), maximum 
plasma concentration (Cmax) and minimum or trough concentration (Cmin), dosing 
interval, and time to reach maxium plasma concentration (Tmax) and half-life (t1/2) 
x Overall response rate 
x PSA response rate by PCWG2 criteria 
x PFS by PCWG2 criteria 
o Overall PFS by PCWG2 criteria 
o rPFS by PCWG2 criteria 
o Time to PSA progression by PCWG2 criteria 
x CTC response* 
Exploratory endpoints* 
x Baseline and change from baseline post-treatment in bromodomain and extra-terminal 
domain (BET) gene expression in whole blood 
x Baseline and change from baseline post-treatment in quantification of androgen receptor 
splice variants in blood (dose confirmation) and post-treatment in tumor tissue and 
response (complete response [CR], partial response [PR], progressive disease [PD])  
x Baseline and change from baseline post-treatment in V-Myc avian myelocytomatosis 
viral oncogene homolog (MYC) expression in tumor tissue and response (CR, PR, PD) 
x Baseline and change from baseline post-treatment in glucocorticoid receptor expression 
in tumor tissue and response (CR, PR, PD) 
x Possible relationship of baseline tumor abnormalities (such as mutations, translocations, 
mRNA, protein expression and localization), in ctDNA, CTC and tumor biopsies and/or 
on-treatment changes with any observed antitumor activity 
x Baseline and change from baseline post-treatment in immune-oncology biomarkers, if 
observed 
x Correlation between ZEN003694, ZEN003791, enzalutamide and des-methyl 
enzalutamide plasma exposure levels and PD responses 
x Correlation between PSA and radiographic response (CR, PR, PD) 


 
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Note: *The analysis methodology for PK, exploratory endpoints and CTC response will be 
provided by the sponsor in a separate document. Further, the analyses will be performed by the 
sponsor and the analysis results will be provided in a separate document appended to the CSR. 
10.2 Baseline Values 
Unless otherwise noted, baseline is defined as the last non-missing value recorded prior to the 
first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B 
and DC-B, baseline is defined as the last non-missing value recorded prior to the first dose of 
enzalutamide.  If the date is the same as first dose of ZEN003694 (DE-A and DC-A) or 
enzalutamide (DE-B or DC-B), it will be baseline unless a time is collected then we compare it 
with dosing time. 
10.3 Adjustments for Covariates 
No adjustments for covariates are planned for the clinical activity analyses. 
10.4 Handling of Dropouts or Missing Data 
No imputations will be made for missing values except as described for missing start and stop 
dates for AEs and medications. Summaries will be based on observed data only. 
10.5 Interim Analysis and Data Monitoring 
There are no planned interim analyses for this study. 
10.6 Examination of Subgroups 
No subgroup analyses are planned. 
10.7 Multiple Comparison/Multiplicity 
No adjustments for multiplicity will be made in this study. 
10.8 Multicenter Studies 
No analyses by site are planned. 
11. DEFINITIONS OF CLINICAL ACTIVITY ENDPOINTS 
11.1 Radiographic Tumor Response (Overall Response Rate) by PCWG2 Criteria 
Tumor response will be evaluated using the PCWG2 criteria. Patients with measurable disease 
will be evaluated for clinical benefit as determined by tumor response using RECIST v1.1. 


 
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Patients with non-measurable bone disease will be evaluated for progression based on the 
presence of any new lesions by bone scans. Radiographic tumor evaluation will be performed at 
screening and every 3 cycles or more frequently as determined by the investigator. Evaluations 
include computed tomography of thorax, abdomen and pelvis, bone scan, or magnetic resonance 
imaging as indicated for assessment of measurable lesions. For each assessment, the overall 
tumor response to treatment will be one of the following: CR, PR, stable disease (SD), PD, 
symptomatic deterioration, and not evaluable (NE). Progressive disease and symptomatic 
deterioration are considered equivalent in terms of disease progression.  
A status of PR or CR must be confirmed by repeat evaluation at least 4 weeks (28 days) after the 
criteria for response are first met.  
Using the tumor response that is determined by the investigator, best overall response will be 
determined using RECIST v1.1. Best overall response is defined as the best response recorded 
from the start of treatment until disease progression or study exit. Each overall tumor response 
assessment collected at protocol-specified time points will be considered.  
The best responses for pairs of time point responses (when confirmation of CR and PR are 
required) are determined as shown below in Table 3. Table 3 is an extended version of Table 3 in 
the RECIST v1.1 guidance (Eisenhauer 2009). The additional discussions provided here clarify 
how best responses for individual pairs of overall responses, i.e., paired by sequential time 
points, are determined by the investigator.  All of these best responses, as determined by the 
investigator,  are then used to determine the best overall response. 
In the table below, the first and subsequent time points referenced in the column headers refer to 
an arbitrary pair of sequential time points. Also, as indicated in the table and in the table notes, 
special rules may apply when the first time point of the pair is the very first (post-treatment) 
assessment time point or when there is only 1 assessment. 
Table 3:  Best Response When Confirmation of CR and PR are Required 
 
Overall 
Response 
First 
Time Point 
Overall 
Response 
Subsequent 
Time Point 
Best Response for the Pair 
1 CR 
CR 
CR (if minimum criteria for CR duration is met), otherwise  
Best Response = NE. 
2 CR 
PR 
If the first time point is truly CR, any worsening at a subsequent 
time point—even disease meeting the PR criteria—makes the 
disease PD at that subsequent time point. Then Best Response = 
SD provided minimum criteria for SD duration is met at the first 
time point; otherwise Best Response = PD. 
However, sometimes ‘CR’ may still be claimed when subsequent 
scans suggest small lesions that were likely present and in fact the 
patient had PR, not CR, at the first time point. Under these 


 
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Overall 
Response 
First 
Time Point 
Overall 
Response 
Subsequent 
Time Point 
Best Response for the Pair 
circumstances, the original CR should be changed to PR; see Row 
6 for Best Response criteria. 
3 CR 
SD 
Best Response = SD provided minimum criteria for SD duration is 
met by the second time point; otherwise Best Response = PD. 
4 CR, PR, SD 
PD 
Best Response = SD provided minimum criteria for SD duration is 
met at the first time point; otherwise Best Response = PD. 
5 CR, PR 
NE 
Best Response = SD provided minimum criteria for SD duration is 
met at the first time point; otherwise Best Response = NE. 
6 PR 
CR, PR 
Best Response = PR provided minimum criteria for PR duration is 
met; otherwise, Best Response = SD provided minimum criteria 
for SD duration is met by the second time point; otherwise  
Best Response = NE. 
7 PR 
SD 
Best Response = SD provided minimum criteria for SD duration is 
met by the second time point; otherwise Best Response = NE. 
8 SD 
SD, CR, PR 
Best Response = SD provided minimum criteria for SD duration is 
met by the second time point; otherwise Best Response = NE. 
9 SD 
NE 
Best Response = SD provided minimum criteria for SD duration is 
met at the first time point; otherwise Best Response = NE. 
10 SD 
PD 
Best Response = SD provided minimum criteria for SD duration is 
met at the first time point; otherwise Best Response =PD. 
11 PD 
CR, PR, SD, 
PD, NE 
Best Response = PD. 
12 NE 
CR, PR, SD, NE Best Response = NE. 
13 NE 
PD 
Best Response = PD. 
14 CR, PR, SD 
No 2nd visit 
Best Response = SD provided minimum criteria for SD duration is 
met at first time point; otherwise Best Response = NE. 
15 PD 
No 2nd visit 
Best Response = PD. 
16 NE 
No 2nd visit 
Best Response = NE. 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease,  
NE = not evaluable. 
Note: If response = SD, CR, or PR at the initial post-treatment assessment then, in meeting the minimum 
criteria for SD duration (only SD, not CR or PR), duration is measured from the treatment start date 
rather than the date of the assessment. 
Note: In some situations, it may be necessary to check across more than two sequential time points in order 
to determine whether or not a minimum duration criteria has been met.  The same logic as used for the 
pairs of time points should be applied.  For example, for the triplet SD CR SD, duration is calculated 


 
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from the first assessment date (or from the treatment start date if these are  
the initial assessments) to the third assessment date, if needed, to determine whether the minimum 
criteria for SD duration has been met. 
Per the RECIST v1.1 guidance and as indicated in the first table note, for patients with SD at the 
first time point: in determining whether the minimum criteria for SD duration is met, duration is 
measured from the treatment start date to that first assessment date. Then, if the duration meets 
the minimum interval requirement for SD, Best Response = SD, otherwise Best Response = 
NE. Further, as indicated in the note, this same rule is also applied to patients with a response 
better than SD at the first time point.  
In some situations, it may be necessary to check across more than two sequential time points in 
order to determine whether or not a minimum duration criteria has been met.  The same logic 
used for the pairs of time points should be applied. For example, note the following examples. 
x For the triplet SD CR SD, duration is calculated from the first assessment date (or from 
the treatment start date if these are the initial assessments) to the third assessment date, if 
needed, to determine whether the minimum criteria for SD duration has been met. If it is 
met, then Best Response = SD. Otherwise, Best Response = NE. 
x For the triplet CR NE CR, if the minimum criteria for CR duration is met for the interval 
between the two CR assessments, then Best Response = CR. Otherwise  
Best Response = NE. 
x For the triplet PR NE PR, if the minimum interval criteria for PR is met for the interval 
between the two PR assessments, then Best Response = PR. Otherwise  
Best Response = NE. 
x For the triplet SD NE SD, Best Response = NE. 
The minimum interval of CR and PR to be considered for assessment of the best overall response 
is is 4 weeks (28 days). The minimum interval of SD to be considered for assessment of the best 
overall response is 12 weeks (84 days). 
A best response is determined by the investigator for each sequential pair of post-treatment time 
points (and in some cases, triplets of sequential time points) as indicated in the previous section. 
Then, the best overall response (when confirmation of CR and PR are required) for a patient 
equals the best of these best responses. 
Using the best overall response, overall response rate is defined as the proportion of patients with 
CR or PR. The start of the response is the date the patient first meets the criteria for CR or PR to 
the time of disease progression. 
11.2 PSA Response Rate by PCWG2 Criteria 
The PSA response rate will be evaluated using PCWG2 criteria and defined as the proportion of 
patients with a PSA decline of at least 50% in a table. Three categories of PSA decline will be 


 
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summarized - less than 30% decline, at least a 30% decline, and at least a 50% decline in PSA 
from baseline to study exit. Any change from baseline is confirmed by a second measurement at 
least 3 weeks later. Subjects can be included in both the ≥30% and ≥50% response categories 
PSA Response Rate will be evaluated using PCWG2 criteria and defined as following in figures 
x Percentage change from baseline in PSA to 12 weeks post ZEN-003694 dose. Only 
evaluate for patients with at least 12 weeks of treatment, the PSA assessment at 12 
weeks (84 days +/–3 days) will be used. 
x Maximum percent decrease in PSA from baseline that occurs at any point after 
treatment. Evalubale for all patients with post-baseline PSA. 
Note that safety follow-up PSA is 30 days after end of treatment and patient off treatment for 
significant time, therefore safety follow-up collection will not be used for PSA response rate 
calculation. 
Individual PSA response will be presented in a patient listing. 
11.3 Progression-Free Survival by PCWG2 Criteria 
Progression-free survival includes 3 separate analyses for median overall progression-free 
survival, median radiographic progression-free survival, and median time to PSA progression. 
Doses will be combined for patients in both the Dose Escaltion (DE) and Dose Confirmation 
(DC) groups. Kaplan-Meier Plots will be repeated for 3 patient groups: enzalutamide progressor 
in DE and DC, abiraterone progressor in DE and DC, and all patients.  
11.3.1  Overall Progression-Free Survival by PCWG2 Criteria 
Overall PFS is determined using the PCWG2 criteria. Overall progressive disease includes 
disease progression determined by radiographic assessments and clinical deterioration 
(development of an indication for radiotherapy while on treatment and global deterioration of 
health status requiring discontinuation of treatment without objective evidence of disease 
progression).  
Overall PFS is measured from baseline until the time that disease progression (radiographic 
progressive disease or clinical deterioration) or death is documented, whichever occurs first. 
Disease progression is documented in the tumor assessment CRF and study exit status CRF. If a 
patient has no reported disease progression from a tumor assessment but disease progression is 
reported in the study exit status CRF (i.e., clinical progression by PCWG2, radiographic 
progression by PCWG2, PSA progression with clinical progression by PCWG2, or PSA 
progression with radiographic progression by PCWG2 is marked as the primary reason for study 
completion/discontinuation), then the patient is considered to have progressed.  Radiographic 
progression is measured from baseline to the date of the first scan that shows the change.  If 
radiographic disease progression is identified at the first on-treatment radiographic assessment at 


 
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Cycle 3 Day 1 (8 weeks), radiographic progression must be confirmed by a second assessment 6 
or more weeks later. Clinical progression is measured from baseline to date of last dose of 
ZEN003694. 
Patients who did not progress overall or did not die prior to study exit are censored on the date of 
their last dose of ZEN003694. 
11.3.2  Radiographic Progression-Free Survival by PCWG2 Criteria 
Radiographic progression-free survival (rPFS) is determined using the PCWG2 criteria to assess 
both soft-tissue and bone assessments. 
The rPFS is measured from the baseline until the time that disease progression based on 
radiographic assessments or death is documented. Radiographic disease progression is 
documented in the tumor assessment CRF and study exit status CRF. If a patient has no reported 
disease progression from a tumor assessment but disease progression is reported in the study exit 
status CRF (i.e., radiographic progression by PCWG2 or PSA progression with radiographic 
progression by PCWG2 is marked as the primary reason for study completion/discontinuation), 
then the patient is considered to have progressed. rPFS is measured from baseline to the date of 
the first scan that shows the change.  rPFS is also measured from date of screening scan to the 
date of the first scan that shows the change. If radiographic disease progression is identified at 
the first on-treatment radiographic assessment at Cycle 3 Day 1 (8 weeks), radiographic 
progression must be confirmed by a second assessment 6 or more weeks later.  
Patients who do not progress radiographically or did not die prior to study exit are censored on 
the date of their last dose of ZEN003694. 
11.3.3  Time to PSA Progression by PCWG2 Criteria 
Time to PSA progression is determined using the PCWG2 criteria. Only subjects with at least 12 
weeks of treatment with ZEN003694 are evaluable for PSA progression. PSA progression occurs 
when the PSA has increased 25% or greater above nadir and an absolute increase of 2 ng/mL or 
more from the nadir is documented. When no decline is observed, PSA progression occurs when 
a 25% increase from baseline value along with an increase in absolute value of 2 ng/mL or more. 
Progression is confirmed by a second assessment 3 or more weeks after the initial documented 
PSA increase that meets the progression criteria. Time to PSA progression is measured from the 
start of treatment with ZEN003694 until the time that the PSA progression is first documented. 
PSA progression is documented in the serum PSA CRF and study exit status CRF. If a patient 
has no reported PSA progression from a serum PSA assessment but PSA progression is reported 
in the study exit status CRF (i.e., PSA progression with clinical progression by PCWG2 or PSA 
progression with radiographic progression by PCWG2 is marked as the primary reason for study 
completion/discontinuation), then the patient is considered to have progressed. 


 
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Patients who do not progress or who die are censored on the date of their last PSA assessment or, 
if they die, on their date of death. 
11.4 CTC Response 
As described in Section 10.1, the analysis methodology and results for CTC Response will be 
provided by the sponsor in a separate document appended to the CSR.   
11.5 Exploratory Analysis 
As described in Section 10.1, exploratory analyses include pharmacodynamic analysis (including 
BET inhibitor gene expression profiles, and exploratory biomarkers), and immuno-oncology 
biomarker analysis will be provided by the sponsor in a separate document appended to the CSR. 
12.  METHODS OF CLINICAL ACTIVITY ANALYSES 
12.1 Response Rate Endpoints 
The response rate endpoints include overall response rate and PSA response rate. Each response 
rate, along with its exact binomial 95% confidence interval, will be summarized by dose 
regimen.  
The best overall response and PSA response at each protocol-defined time point will also be 
summarized descriptively by dose regimen. 
Individual tumor and PSA response will be presented in patient listings.  
12.2 Time to Event Endpoints 
Time to event endpoints include overall PFS, rPFS, and time to PSA progression. Each endpoint 
will be summarized in a tabular summary that will include the number and percent of patients 
that progressed or died and the number and percent of patients that did not progress and are alive. 
Progression and timing of events is described in a previous section (Section 11.3). For all 
patients and non-censored patients, the minimum and maximum number of months a patient was 
progression-free will be included. The Kaplan-Meier quartile estimates for number of 
progression-free months and corresponding 95% confidence intervals will be reported (25th 
percentile, median, and 75th percentile) along with the Kaplan-Meier product limit estimates and 
number of patients at risk at 3 month intervals. Time to event endpoints will also be summarized 
by dose levels and progressor groups in Kaplan-Meier plots. 
Individual time to endpoints will be presented in patient listings. 


 
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13. PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
PK analyses will be described in a separate plan and performed by the sponsor. 
Pharmacodynamic analyses are outlined in Section 10.1. 
14. SAFETY ANALYSES 
All safety analyses will be based on the Safety population. 
14.1 Extent of Exposure 
Study drug exposure will be summarized for each ZEN003694 dose level using the actual 
number of doses taken, number of cycles, duration of treatment (days) and compliance.  
Study drug compliance over the study will be calculated as follows: 
Compliance [%] = 
୅ୡ୲୳ୟ୪୒୳୫ୠୣ୰୭୤ୈ୭ୱୣୱ
ୈ୳୰ୟ୲୧୭୬୭୤ୗ୲୳ୢ୷୘୰ୣୟ୲୫ୣ୬୲ሺୢୟ୷ୱሻൈͳͲͲΨ  
All in-clinic study drug administration is reported on the ZEN003694 Administration – Single 
Dose CRF and all out-clinic study drug administration is reported on the ZEN003694 
Administration Log CRF.  
In order to calculate the actual number of doses used, the number of administration days will be 
determined by adding each administration day from the ZEN003694 Single Dose CRF and the 
number of days of administration reported in the ZEN003694 Administration Log CRF. The 
number of days the dose was held or missed reported on the ZEN003694 Administration Log 
CRF will not be included in the calculation of actual number of doses used. Since the dose is 
taken once daily, it is assumed that 1 day is equal to 1 dose.  
Duration of study treatment is defined as the last dose date minus the first dose date plus 1. 
Individual enzalutamide exposure data will be presented in patient listings. 
14.2 Adverse Events 
All AE summaries will be restricted to TEAEs, which are defined as those AEs that occurred 
after dosing and those existing AEs that worsened during the study. In this study, only events 
that started after administration of study drug until 30 days after the last dose of study drug are 
considered AEs and recorded. Those that started before study drug administration were to be 
recorded on the Medical History CRF. If it cannot be determined whether the AE is treatment 
emergent due to a partial onset date then it will be counted as treatment emergent. Verbatim 
terms on CRFs will be mapped to preferred terms and system organ classes using the Medical 
Dictionary for Regulatory Activities (MedDRA) (version 19.0).  
Each AE summary will be displayed by treatment group. Summaries that are displayed by 
system organ class and preferred terms will be ordered by descending order of patient incidence 


 
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of system organ class and preferred term within each system organ class. Summaries of the 
following types will be presented: 
 
Overall summary of TEAEs which contain an overview of each item below. 
x Patient incidence of TEAEs and total number of unique TEAEs by MedDRA system 
organ class and preferred term.   
x Patient incidence of TEAEs by MedDRA system organ class, preferred term, and highest 
severity.  At each level of patient summarization a patient is classified according to the 
highest severity if the patient reported 1 or more events.  AEs with missing severity will 
be considered severe for this summary. 
x Patient incidence of TEAEs by MedDRA system organ class, preferred term, and closest 
relationship to study drug (Related/Not Related). Related AEs are those reported as 
“Related” and unrelated AEs are those reported as “Not Related.” At each level of patient 
summarization, a patient is classified according to the closest relationship if the patient 
reported 1 or more events.  Adverse events with a missing relationship will be considered 
related for this summary. 
x Patient incidence of serious TEAEs and total number of unique serious TEAEs by 
MedDRA system organ class and preferred term.  
x Patient incidence of serious TEAEs by MedDRA system organ class, preferred term, and 
highest severity.  At each level of patient summarization a patient is classified according 
to the highest severity if the patient reported 1 or more events.  AEs with missing severity 
will be considered severe for this summary. 
x Patient incidence of serious TEAEs by MedDRA system organ class, preferred term, and 
closest relationship to study drug (Related/Not Related). Related AEs are those reported 
as “Related” and unrelated AEs are those reported as “Not Related.” At each level of 
patient summarization a patient is classified according to the closest relationship if the 
patient reported 1 or more events.  Adverse events with a missing relationship will be 
considered related for this summary. 
x Patient incidence of TEAEs leading to death as an outcome by MedDRA system organ 
class and preferred term 
x Patient incidence of TEAEs leading to study discontinuation by MedDRA system organ 
class and preferred term. 
14.3 Clinical Laboratory Evaluation 
Laboratory parameters (serum chemistry, hematology, coagulation tests [international 
normalized ratio, prothrombin time, and partial thromboplastin time], serum troponin [troponin T 
and/or I proteins, based on local laboratory procedure], PSA, and urinalysis) will be collected at 
protocol-defined time points. Parameters will be summarized using descriptive statistics at 
baseline and at each post-baseline time point. Changes from baseline will also be summarized. 


 
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Serum troponin will be provided in the same listing as the 12-lead electrocardiogram (ECG) 
data. PSA values will be listed separately from other clinical assessments for the PCWG2 
Evaluable Population and for the Safety Population (if that population is different from the 
efficacy population). Serum testosterone (collected on the first day of each cycle will be included 
in the serum chemistry listing. The incidence of clinically significant laboratory results will be 
summarized by number of unique subjects per parameter at any post-baseline time point. 
In addition, shift tables (i.e., low-normal-high at baseline versus low-normal-high at follow-up in 
a 3-by-3 contingency table) will be provided to assess changes in laboratory values from baseline 
to follow-up.   
Select laboratory parameters will be graded according to National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 as specified in Appendix D. 
Select laboratory parameters include platelet counts, neutrophils, lymphocyte, white blood cells), 
creatinine, alanine aminotransferase, aspartate aminotransferase, total bilirubin, and glucose. 
Shift tables assessing changes from baseline in CTCAE grade will be presented.  
Urinalysis results will not be summarized but will be provided in a data listing.  
14.4 Vital Signs 
Vital signs will be summarized using descriptive statistics at baseline and at each post-baseline 
time point. Changes from baseline will also be summarized. Vital signs parameters include 
temperature, systolic and diastolic blood pressure, and heart rate. The position of the patient will 
also be reported. Height is only measured at screening while weight is measured at specific time 
points specified in the protocol. 
Vital signs will be reported in a patient data listing as well. 
14.5 Physical Examination 
Physical examination results will be included in data listings only.  
14.6 Echocardiogram or Multigated Acquisition (MUGA) Scan 
An echocardiogram or multigated acquisition (MUGA) scan with left ventricular ejection 
fraction will be obtained during the Screening period. Results will be included in patient data 
listings only. 
14.7 Electrocardiogram 
A triplicate 12-lead ECG will be performed at protocol-defined time points. Electrocardiogram 
parameters collected include interpretation and clinical significance, ventricular rate (bpm), RR 
interval (msec), PR interval (msec), QRS duration (msec), QT interval (msec), corrected QT 
interval according to Fridericia formula (QTcF) (msec), and average QTcF (msec). 


 
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The ECG data analysis will be conducted based on methodology recommended in the ICH E14 
Guidance, “The clinical evaluation of QT/corrected QT interval (QTc) interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs.” Descriptive statistics at baseline and at 
each post-baseline time point as well as changes from baseline will be summarized for each ECG 
parameter using the average result. Each individual QTcF measurement will be re-derived using 
the following equation: 
QTcF (msec)=QT/(RR0.33) 
 
In addition, categorical summaries of abnormal average QTcF values will be presented as 
follows: 
x Number of patients with QTcF values at each time point (>450 msec to <480 msec, >480 
msec to <500 msec, and >500 msec) 
x Number of patients with change from baseline values in QTcF at each post-baseline time 
point (>30 msec to <60 msec, >60 msec) 
14.8 Eastern Cooperative Oncology Group (ECOG) Performance Status 
ECOG performance status is classified on a 6-point (0 to 5) rating scale. 
x 0 = Fully active, able to carry on all pre-disease performance without restriction. 
x 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work 
of light or sedentary nature, e.g., light house work, office work. 
x 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
x 3 = Capable of only limited self-care , confined to bed or chair more than 50% of waking 
hours. 
x 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
x 5 = Dead. 
ECOG performance status will be summarized in a shift from baseline table and presented in a 
patient listing. 
14.9 Ophthalmology Assessments 
Ophthalmology assessments include: a detailed ophthalmic history, Snellen best corrected visual 
acuity (including refraction, if needed), color vision testing (using standard HRR 
pseudoisochromatic plates), pupillometry, confrontational visual field testing, intraocular 
pressure (using Goldmann tonometry or TonoPen tonometry), external eye and ocular motility 
exam and slit lamp biomicroscopy, indirect ophthalmoscopy, optical coherence tomography 


 
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(OCT) optic nerve and macula tests, fundus photography, and other exams are clinically 
indicated. 
Any clinically significant changes from baseline for each parameter (best-corrected visual acuity, 
color vision plates, relative afferent pupillary deficit, pupil diameter in bright light, pupil 
diameter in dim light, velocity of pupillary constriction, intraocular pressure, slit lamp exam, 
dilated fundoscopic exam, OCT of optic nerve, macular OCT, and fundus photographs of the 
posterior pole) will be summarized in a table for on-study examinations and presented in a listing 
by patient. 
Baseline and in-clinic qualitative exploration of visual symptoms will be summarized in a table 
and presented in a patient listing. In the tabular summary, all categorical parameters will be 
summarized using frequency counts and percentages while all continuous parameters will be 
summarized using descriptive statistics. Only known times for duration since dosing and start of 
symptoms will be summarized. For unknown times, the number of unknown times and reported 
time ranges will be displayed. 
15. CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
The primary purpose of this section is to modify and/or clarify items specified in the protocol  
(Version 05NOV2018 Amendment 10) as noted below: 
x On 11APR2019, Zenith informed all study sites that they no longer plan to move forward 
with the abiraterone combination of the Zenith mCRPC study, ZEN003694-002, Part 2. 
Part 2 will be postponed indefinitely.  
x A DLT Population was specified in the protocol as an analysis population but no analyses 
are planned that are specific to this population. Thus, this patient population is not 
defined in the SAP. Adverse events that qualify as a DLT will be marked as such in an 
AE listing. 
x A PK population was not explicitly defined in the protocol. In order to clarify the PK 
analyses, a definition of PK Population has been added to this SAP. 
x Patients in the Radiographic Evaluable Population are included in the tumor response, 
Overall PFS, and rPFS analyses. Patients in the PSA Evaluable Population are included 
in the PSA response rate and time to PSA progression endpoint analyses. 
x In order to capture all meaningful endpoints in PCWG2 criteria, 3 separate analyses are 
included in the SAP: median overall PFS, radiographic PFS, and median time to PSA 
progression. Only median PFS by PCWG2 criteria was pre-specified in the protocol. 
 
 
 
 


 
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17. REFERENCES 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
revised RECIST guideline (version 1.1). Eur. J Cancer. 2009;45(2):228-47. 
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients with 
progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate 
Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26(7):1148-59. 
US Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER). Guidance for industry. E14 The Clinical Evaluation 
of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-antiarrhythmic Drugs. 
October 2005. 


 
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18. APPENDICES 
Appendix A:  Presentation of Data and Programming Specifications 
 
General  
x Specialized text styles, such as bold, italics, borders, shading, superscripted and 
subscripted text will not be used in tables, figures, and data listings unless they add 
significant value to the table, figure, or data listing. 
x Only standard keyboard characters are to be used in tables and data listings. 
x Special characters, such as non-printable control characters, printer-specific, or font-
specific characters, will not be used on a table, figure, or data listing. 
x Hexadecimal character representations are allowed (e.g., μ, a, ß). 
x All footnotes will be left justified and at the bottom of a page. Footnotes should be used 
sparingly and must add value to the table, figure, or data listing. 
 
Tables 
x Formal organization of tabulations may be changed during programming if appropriate, 
e.g., tables for the different variables may be combined into a single table, or tables with 
more than 1 variable may be split into several tables. 
x Means and medians will be presented to 1 more decimal place than the raw data. 
Standard deviations will be presented to two more decimal places than the raw data. 
Minimums and maximums will be reported with the same number of decimal places as 
the raw data.  
x Percentages will be presented to the tenths place. 
x For frequency counts of categorical variables, categories whose counts are zero will be 
displayed for the sake of completeness. For example, if none of the subjects discontinue 
due to “lost to follow-up,” this reason will be included in the table with a count of 0. 
Categories with zero counts will not have zero percentages displayed. 
x Lower and upper confidence interval values should be presented to 1 decimal place more 
than the raw/derived data (i.e., to the same number of decimal places as the mean). 
x Percentiles (e.g., 25%, 75%) should be presented to 1 decimal place more than the 
raw/derived data. 
x For all inferential analyses, p-values will be rounded to four decimal places (or at the 
highest level of precision) with a leading zero (0.0001). P-values less than 0.0001 will be 
presented as “<0.0001”. 
x The last footnotes will be 
- “Source: xxx”, where xxx indicates the source table number(s) if applicable (in case 
aggregated results like mean or median are plotted) or the source listing(s) (in case 
individual responses are plotted) and/or source datatset(s) (eg, analysis data model 
[ADaM]). 


 
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Figures 
x Legends will be used for all figures with more than 1 variable or item displayed.  Dose 
regimen group sizes (n=xx) will be included, as appropriate. 
x Figures will be in black and white  but can be in color to add value to the clarity and 
readability of a figure. Lines should be wide enough to see the line after being copied. 
x The last footnotes will be 
- “Source: xxx”, where xxx indicates the source listing number(s) and/or source 
datatset(s) (eg, ADaM). 
- “PROGRAM SOURCE: ...\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN 
DATE: DDMMYY hh:mm”. 
where extraxt date is the datestamp of the data snapshot used. 
 
Listings 
x Formal organization of the listing may be changed during programming if appropriate, 
e.g., additional variables may be included, change in the column order, or the listing may 
be split into multiple parts due to space constraints, etc. 
x If not otherwise specified, all data listings will be sorted by sequence/treatment, center, 
patient number, visit, and date/time as appropriate.   
x All date values will be presented in a SAS date (e.g., 29AUG2001) format.  
x All observed time values will be presented using a 24-hour clock HH:MM:SS format 
(e.g., 01:35:45 or 11:26). Seconds will only be reported if they were measured as part of 
the study. 
x The last footnote will be 
- “PROGRAM SOURCE: ...\\xx.sas, DATA CUT OFF DATE: DDMMMYYYY, RUN 
DATE: DDMMYY hh:mm”.  
where extract date is the datestamp of the data snapshot used. 
 
Missing or incomplete dates (i.e., AEs and concomitant medications) 
The most conservative approach will be systematically considered. If the AE onset date is 
missing / incomplete, it is assumed to have occurred during the study treatment phase (i.e., 
considered a TEAE) except if the partial onset date or other data such as the stop date, indicates 
differently. Similarly, a medication with partial start and stop dates could be considered as both a 
prior and concomitant treatment. 
 
The following algorithms will be applied to missing and incomplete start and stop dates: 
 
Start Dates 
x If the day portion of the start date is missing, then the start date will be estimated to be 
equal to the date of first dose of study drug, provided the start month and year are the 


 
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same as the first dose of study drug and the stop date is either after the first dose of study 
drug or completely missing. Otherwise, the missing day portion will be estimated as ‘01’. 
x If both the day and month portions of the start date are missing, then the start date will be 
estimated to be equal to the date of first dose of study drug, provided the start year is the 
same as the first dose of study drug and the stop date is either after the first dose of study 
drug or completely missing. Otherwise, the event will be assumed to start on the first day 
of the given year (e.g., ??-???-2013 is estimated as 01-JAN-2013). 
x If the start date is completely missing and the stop date is either after the dose of study 
drug or completely missing, the start date will be estimated to be the day of study drug 
dosing. Otherwise, the start date will be estimated to be the first day of the same year as 
the stop date. All other non-AE and non-concomitant medication day calculations where 
only partial dates are available will be handled as follows: the first day of the month will 
be used in the calculations if the day part of a start date is missing while January 1 will be 
employed if both the month and day parts of a start date are missing. 
 
Stop Dates 
x If only the day of resolution is unknown, the day will be assumed to the last of the month 
(e.g., ??-JAN-2013 will be treated as 31-JAN-2013).  
x If both the day and month of resolution are unknown, the event will be assumed to have 
ceased on the last day of the year (e.g., ??-???-2013 will be treated as 31-DEC-2013).  
x If the stop date is completely missing or the event is continuing, the event will be 
assumed to be after first dose of study drug and will be imputed using the last known date 
on the study. 
 
Standard Calculations 
Variables requiring calculation will be derived using the following formulas: 
 
x Days – A duration expressed in days between 1 date (date1) and another later date (date2) is 
calculated using the formulas noted below: 
duration in days = date2 – date1 + 1, where date1 ≥first dose date 
duration in days = date2 – date1, where date1 <first dose date 
x Months – A duration expressed in months is calculated as the number days divided by 
365.25/12 (~30.4).  
x Years – A duration expressed in years between 1 date (date1) and another later date (date2) 
is calculated using the formula noted below: 
duration in years = (date2-date1+1)/365.25  
x Age –Age is calculated as the number of years from the date of birth (DOB) to the date of 
informed consent (DOIC).  If the month of DOIC <month of DOB or the month of 
DOIC=DOB and the day of DOIC <day of DOB, then the following formula is used: 


 
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age (years) = year of DOIC – year of DOB – 1. 
Otherwise, the following formula is used: 
age (years) = year of DOIC – year of DOB. 
x Height – Height entries made in inches (in) are converted to centimeters (cm) using the 
following formula: 
height (cm) = height (in) * 2.54 
x Weight – Weight entries made in pounds (lb) are converted to kilograms (kg) using the 
following formula: 
weight (kg) = weight (lb) / 2.2046 
x Temperature – Temperature entries in degrees Fahrenheit are converted to degrees 
centigrade using the following formula: 
temp (degrees centigrade) = 5/9 * [temp (degrees Fahrenheit) - 32] 
x Body Mass Index (BMI) – BMI is calculated using height (cm) and weight (kg) using the 
following formula: 
BMI (kg/m2) = weight (kg) / [[height (cm)/100]2] 
x Change from baseline – Change from baseline will be calculated as: 
Change = post baseline value – baseline value 
x Percent change from baseline – Change from baseline will be calculated as: 
Percent change from baseline = post baseline value – baseline value / baseline value  
× 100 


 
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Appendix B: SAS programming QC requirements  
SDTM/TDM:  
 
1. Program Review 
1.1. Program name follows standard naming conventions and is consistent with other 
study program names. 
1.2. Program header uses standard template with all relevant information completed. This 
includes the SDTMIG Version and SDTM controlled terminology version (i.e., date). 
1.3. Program flow is logical (i.e., header → initialization code → macro variable 
definitions → format definitions → main body). 
1.4. Programmer comments are included throughout program to describe purpose of 
individual sections or macros and provide understanding of specific code, if necessary. 
All comments are clear and up-to-date. 
1.5. Hard coding, if any, is implemented correctly and documented in program header 
with: date, reason, and reference to sponsor approval. A comment is also inserted at the 
location of the hard coding. 
1.6. SAP Derivation rules, if any, are followed.  Significant deviations from mock table or 
SAP text are documented in the SAS Program Header. 
1.7. Permanent intermediate datasets utilized as source data have either been fully 
validated elsewhere or are fully validated within the scope of this QC.  
1.8. Program runs properly and output dataset is generated as intended. 
 
2. SAS Log Review 
2.1. Scan of entire log confirming that each data step and procedure completed properly.  
2.2. Critical messages such as: errors, warnings, merge notes, or uninitialized variables are 
not found in log. Unavoidable critical messages are verified to not adversely affect the 
output and the reasons why they are unavoidable are documented. 
2.3. Other messages such as “PUT” or “INFO” messages (e.g., overwritten variables 
following merge) are handled appropriately, if they are found in log. 
 
3. Dataset Structure 
3.1. Output dataset name follows standard naming conventions and is consistent with 
other study dataset file names. 
3.2. Number of records is as expected (e.g., all expected records from source data are 
kept). 
3.3. Dataset label is assigned according to specifications/SDTMIG.  
3.4. Variable attributes meet the specifications/SDTMIG as defined (e.g., name, length, 
and label).  
3.5. Variable lengths are appropriate and are not arbitrarily set to a large value and do not 
exceed 200 characters. 
3.6. Sorting order is based on the defined sort key variables and creates unique records. 


 
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3.7. All SDTMIG “Required” variables have been created and are populated following 
SDTMIG requirements. 
3.8. All SDTMIG “Expected” variables have been created and are populated, where 
source data content allows, following SDTMIG requirements. 
3.9. All SDTMIG “Permissible” variables that may be needed based on the source data 
content and/or analysis needs, have been created following SDTMIG requirements. 
3.10. SDTMIG labels have been used.  User-defined labels follow the SDTMIG and are 40 
characters or less in length. 
3.11. SDTMIG variable names have been used.  User-defined variable names follow the 
SDTMIG and are 8 characters or less in length. 
3.12. No formats or informats are attached to variables. 
3.13. Supplemental datasets are created, if source data warrants, following SDTMIG 
guidelines. 
3.14. Dataset size is no larger than 1 gb.  
3.15. OpenCDISC validator is run.  Any findings that result are updated or explained. 
 
4. Verification of Data  
4.1. TDM Programmer 
x Each TDM is opened and data are reviewed for consistency with the protocol, SAP, 
and/or CRF (no programming is necessary). 
4.2. TDM Validator 
x Full validation is performed against the protocol, SAP, and/or CRF without utilizing 
the dataset specifications document.  This may be done programmatically or through a 
manual review. The Trial Summary (TS) domain should be validated by the Study 
Statistician or Biostatistics Project Lead, and may require input from the sponsor or a 
Clinical Operations team member. 
4.3. SDTM Programmer 
x All data fields are spot-checked for at least 3 subjects. 
4.4. SDTM Validator uses one of the following methods. The choice of QC method must 
be approved by the Biostatistics Project Lead. 
x Independent program to confirm all content from all data fields. 
x Independent program to confirm all content from derived data fields and a spot-check 
of source data against the output dataset is performed on at least 3 subjects for non-
derived fields. 
x Study specific alternative method (if applicable) that is agreed upon by the sponsor 
and defined prospectively in a study specific document (e.g., Validation Plan, SAP or 
a modified QC requirement template TMP-SOP-0205-003). 
5. Documentation 
5.1. The Programmer and Validator must document completion of QC (e.g., date of QC and 
method used) in TMP-SOP-0205-002 Program Status Document. 


 
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5.2. Validator findings and/or comments may be tracked in the Program Status Document 
along with a description of how the finding was resolved and resolution date. 
5.3. The following must be retained electronically within the study folder by the 
Programmer as supporting documentation for SDTM and TDM datasets:  
x OpenCDISC report generated at time of QC including comments explaining findings. 
5.4. The following must be retained electronically within the study folder by the Validator 
as supporting documentation:  
x PROC CONTENTS of permanent dataset. 
x Confirmatory output (See Section 4.4). 
x If a spot-check of subject data is performed, output that clearly identifies the subjects 
that are checked (See Section 4.4). 
x OpenCDISC report generated at time of QC including comments explaining findings. 
 
ADaM: 
 
1. Program Review 
1.1. Program name follows standard naming conventions and is consistent with other 
study program names. 
1.2. Program header uses standard template with all relevant information completed. 
This includes the ADaMIG Version and ADaM controlled terminology version 
(i.e., date). 
1.3. Program flow is logical (i.e., header → initialization code → macro variable 
definitions → format definitions → main body).  
1.4. Programmer comments are included throughout program to describe purpose of 
individual sections or macros and provide understanding of specific code, if 
necessary. All comments are clear and up-to-date. 
1.5. Hard coding, if any, is implemented correctly and documented in program header 
with: date, reason, and reference to sponsor approval. A comment is also inserted at 
the location of the hard coding. 
1.6. SAP Derivation rules, if any, are followed.  Significant deviations from mock table 
or SAP text are documented in the SAS Program Header. 
1.7. Permanent intermediate datasets utilized as source data have either been fully 
validated elsewhere or are fully validated within the scope of this QC.  
1.8. Program runs properly and output dataset is generated as intended. 
 
2. SAS Log Review 
2.1. Scan of entire log confirming that each data step and procedure completed 
properly.  
2.2. Critical messages such as: errors, warnings, merge notes, or uninitialized variables 
are not found in log. Unavoidable critical messages are verified to not adversely 
affect the output and the reasons why they are unavoidable are documented. 


 
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2.3. Other messages such as “PUT” or “INFO” messages (e.g., overwritten variables 
following merge) are handled appropriately, if they are found in log. 
 
3. ADaM and ADaM-Like Dataset Structure 
3.1. Output dataset name follows standard naming conventions and is consistent with 
other study dataset file names. 
3.2. Number of records is as expected (e.g., all records for non-screen failures). 
3.3. Dataset label is assigned according to specifications. 
3.4. Variable attributes meet the specifications as defined (e.g., name, length, and 
label).  
3.5. Variable lengths are appropriate and are not arbitrarily set to a large value and do 
not exceed 200 characters. 
3.6. Sorting order is based on the defined sort key variables and creates unique 
records. 
 
4. ADaM Requirements 
4.1. Appropriate ADaM structure is followed as specified in the ADaMIG and 
supplemental documents (e.g., ADSL, Basic Data Structure, ADAE, etc.). 
4.2. All ADaMIG “Required” variables have been created and are populated 
following ADaMIG requirements. 
4.3. All ADaMIG “Conditional” variables that are needed based on the trial design 
and/or analysis have been created and are populated following ADaMIG 
requirements. 
4.4. All ADaMIG “Permissible” variables that may be needed based on the analysis 
needs have been created and are populated following ADaMIG requirements. 
4.5. Core variables, as specified in ADSL, are included in non-ADSL datasets. 
4.6. Variables from SDTM keeping the same name are unchanged (i.e., have the same 
values, meaning, and attributes as found in the source SDTM domain). 
4.7. No further derivations are required to generate analysis (e.g., manipulation of 
AVAL).  Separate procedures for different sections of an output (e.g., numerators 
and denominators) are expected. 
4.8. ADaM IG variable names are used for ADaM-defined variables.  User-defined 
variable names are 8 characters or less in length.  
4.9. ADaM IG labels have been used for ADaM-defined variables.  User-defined 
variable labels are 40 characters or less in length.  
4.10. No formats or informats are attached to variables except for date, time and 
date/time variables. 
4.11. ADSL source data are SDTM datasets. 
4.12. ADaM dataset source data are ADSL, other ADaM datasets and SDTM datasets. 
No circular logic is used. 
4.13. OpenCDISC validator is run.  Any findings that result are updated or explained. 
  


 
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5. Verification of Data 
5.1. Validator uses one of the following methods. The choice of QC method must be 
approved by the Biostatistics Project Lead.  
x Independent program to confirm all content from all data fields. 
x Independent program to confirm all content from derived data fields and a spot-
check of source data against the output dataset is performed on at least 3 subjects 
for non-derived fields. 
x Study specific alternative method (if applicable) that is agreed upon by the sponsor 
and defined prospectively in a study specific document (e.g., Validation Plan, SAP 
or a modified QC requirement template TMP-SOP-0205-003). 
 
6. Documentation 
6.1. The Programmer and Validator must document completion of QC (e.g. date of QC 
and method used) in TMP-SOP-0205-002 Program Status Document. 
6.2. Validator findings and/or comments may be tracked in the Program Status 
Document along with a description of how the finding was resolved and resolution 
date. 
6.3. The following must be retained electronically within the study folder by the 
Programmer as supporting documentation 
x If following ADaM standards, OpenCDISC report generated at time of QC 
including comments explaining findings. 
6.4. The following must be retained electronically within the study folder by the 
Validator as supporting documentation 
x PROC CONTENTS of permanent dataset. 
x Confirmatory output that displays results of programmatic dataset comparison 
(e.g., PROC COMPARE output) (See Section 5.1). 
x If a spot-check of subject data is performed, output that clearly identifies the 
subjects that are checked (See Section 5.1). 
x If following ADaM standards, OpenCDISC report generated at time of QC 
including comments explaining findings. 
 
Tables:  
 
1. Program Review 
1.1. Program name follows standard naming conventions and is consistent with other 
study program names. 
1.2. Program header uses standard template with all relevant information completed. 
1.3. Program flow is logical (i.e., header → initialization code → macro variable 
definitions → format definitions → main body). 


 
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1.4. Programmer comments are included throughout program to describe purpose of 
individual sections or macros and provide understanding of specific code, if necessary. 
All comments are clear and up-to-date. 
1.5. Hard coding, if any, is implemented correctly and documented in program header 
with: date, reason, and reference to sponsor approval. A comment is also inserted at the 
location of the hard coding. 
1.6. SAP Derivation rules, if any, are followed.  Significant deviations from mock table or 
SAP text are documented in the SAS Program Header. 
1.7. Endpoints are generally derived in source datasets and not within the program itself. 
1.8. Program runs properly and output file is generated as intended. 
 
2. SAS Log Review 
2.1. Scan of entire log confirming that each data step and procedure completed properly.  
2.2. Critical messages such as: errors, warnings, merge notes, or uninitialized variables are 
not found in log. Unavoidable critical messages are verified to not adversely affect the 
output and the reasons why they are unavoidable are documented. 
2.3. Other messages such as “PUT” or “INFO” messages (e.g., overwritten variables 
following merge) are handled appropriately, if they are found in log. 
 
3. Output Review 
3.1. Output file name follows standard naming conventions and is consistent with other 
study output file names. 
3.2. Titles and footnotes are verified against mock table (if available). Discrepancies, 
including footnotes added for clarification, are noted and verified.  
3.3. Column/row header text is verified against mock table and/or CRF.  
3.4. Format and sorting order are correct relative to mock table and/or CRF.  
3.5. Pages breaks are as intended throughout the document. 
3.6. Significant digits are appropriate for summary results (e.g., mean is 1 more digit than 
collected on the CRF, etc.). 
3.7. Analysis population totals are verified as correct based on SAP definitions and are 
consistent with other tables using the same population(s). 
3.8. Inappropriate data: checked for outliers, invalid numbers, missing results, etc. 
 
4. Verification/Review of Results 
Results are either verified as described in Section 4.1 or are reviewed as described in 
Section 4.2. A study specific alternative method may also be used if agreed upon by the 
sponsor and defined prospectively in a study specific document (e.g., Validation Plan, 
SAP or a modified QC requirement template TMP-SOP-0205-003). An abbreviated 
review of results (Section 4.2) is only allowed when the program uses standard 
validated macros to produce summary statistics and generate the output.  Verification 
of results (Section 4.1) is required for primary efficacy analysis output regardless of the 


 
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method used to produce the output. The choice of QC method must be approved by the 
Biostatistics Project Lead. 
4.1. Verification of results can be performed using one of the following methods 
4.1.1. Independent confirmatory program is written to match output results. 
4.1.2. Manual calculations (if feasible based on small Ns or frequency counts). 
4.2. Abbreviated review - Please see Section 5.2 of “QC Requirements #08: Abbreviated 
QC Requirements”. 
 
5. Documentation 
5.1. The Programmer and Validator must document completion of QC (e.g., date of QC 
completion and method used) in TMP-SOP-0205-002 Program Status Document. 
5.2. Validator findings and/or comments may be tracked in the Program Status Document 
along with a description of how the finding was resolved and resolution date. 
5.3. The following must be retained electronically within the study folder by the Validator 
to document the method of QC performed: 
x Table output generated at time of QC completion.  
x If independent confirmatory program is created, a portion of the resulting output that 
verifies results (Section 4.1.1). 
x If manual calculations are performed, insert a comment into the output file to indicate 
verification of results (Section 4.1.2). 
 
Listings:  
 
1. Program Review 
1.1. Program name follows standard naming conventions and is consistent with other 
study program names. 
1.2. Program header uses standard template with all relevant information completed. 
1.3. Program flow is logical (i.e., header → initialization code → macro variable 
definitions → format definitions → main body).  
1.4. Programmer comments are included throughout program to describe purpose of 
individual sections or macros and provide understanding of specific code, if necessary. 
All comments are clear and up-to-date. 
1.5. Hard coding, if any, is implemented correctly and documented in program header 
with: date, reason, and reference to sponsor approval. A comment is also inserted at the 
location of the hard coding. 
1.6. SAP Derivation rules, if any, are followed.  Significant deviations from mock table or 
SAP text are documented in the SAS Program Header. 
1.7. Endpoints are generally derived in source datasets and not within the program itself. 
1.8. Program runs properly and output file is generated as intended. 
 
2. SAS Log Review 


 
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2.1. Scan of entire log confirming that each data step and procedure completed properly.  
2.2. Critical messages such as: errors, warnings, merge notes, or uninitialized variables are 
not found in log. Unavoidable critical messages are verified to not adversely affect the 
output and the reasons why they are unavoidable are documented. 
2.3. Other messages such as “PUT” or “INFO” messages (e.g., overwritten variables 
following merge) are handled appropriately, if they are found in log. 
2.4. Number of records is as expected based on source data. 
 
3. Output Review 
3.1. Output file name follows standard naming conventions and is consistent with other 
study output file names. 
3.2. Titles and footnotes are verified against mock listing (if available) or SAP list of 
listings. Discrepancies, including footnotes added for clarification or to match 
corresponding table, are noted and verified.  
3.3. Column header text is verified against mock listing and/or CRF. Verify that all 
corresponding CRF fields are included or document reason why a field is excluded. 
3.4. Format and sorting order of rows and columns are correct relative to mock listing 
and/or CRF.  
3.5. Pages breaks are as intended throughout the document. 
3.6. Inappropriate data: checked for outliers, invalid numbers, missing results, etc. 
 
4. Verification/Review of Results 
4.1. Listing content is as expected (e.g., listing includes all enrolled subjects, all expected 
visits, etc.) 
4.2. Variables directly from source dataset are spot-checked for accuracy and 
completeness. 
4.3. Derived or calculated variables are confirmed through independent confirmatory 
program or compared to corresponding source data for at least 3 subjects. 
4.4. Study specific alternative method (if applicable) that is agreed upon by the sponsor 
and defined prospectively in a study specific document (e.g., Validation Plan, SAP or a 
modified QC requirement template TMP-SOP-0205-003). 
 
5. Documentation 
5.1. The Programmer and Validator must document completion of QC (e.g., date of QC 
completion and method used) in TMP-SOP-0205-002 Program Status Document. 
5.2. Validator findings and/or comments may be tracked in the Program Status Document 
along with a description of how the finding was resolved and resolution date. 
5.3. The following must be retained electronically within the study folder by the Validator 
to document the method of QC performed: 
x Listing output generated at time of QC completion. 
x If independent confirmatory program is created, a portion of the resulting output that 
verifies results (Section 4.3). 


 
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If a spot-check of subject data is performed, output that clearly identifies the subjects that are 
checked (Section 4.3). 
 
Figures:  
 
1. Program Review 
1.1. Program name follows standard naming conventions and is consistent with other 
study program names. 
1.2. Program header uses standard template with all relevant information completed. 
1.3. Program flow is logical (i.e., header → initialization code → macro variable 
definitions → format definitions → main body).  
1.4. Programmer comments are included throughout program to describe purpose of 
individual sections or macros and provide understanding of specific code, if necessary. 
All comments are clear and up-to-date. 
1.5. Hard coding, if any, is implemented correctly and documented in program header 
with: date, reason, and reference to sponsor approval. A comment is also inserted at the 
location of the hard coding. 
1.6. SAP Derivation rules, if any, are followed.  Significant deviations from mock table or 
SAP text are documented in the SAS Program Header. 
1.7. Endpoints are generally derived in source datasets and not within the program itself. 
1.8. Program runs properly and output file is generated as intended. 
 
2. SAS Log Review 
2.1. Scan of entire log confirming that each data step and procedure completed properly.  
2.2. Critical messages such as: errors, warnings, merge notes, or uninitialized variables are 
not found in log. Unavoidable critical messages are verified to not adversely affect the 
output and the reasons why they are unavoidable are documented. 
2.3. Other messages such as “PUT” or “INFO” messages (e.g., overwritten variables 
following merge) are handled appropriately, if they are found in log. 
 
3. Output Review 
3.1. Output file name follows standard naming conventions and is consistent with other 
study output file names. 
3.2. Titles and footnotes are verified against mock figure (if available), corresponding 
table and/or SAP list of figures. Discrepancies, including footnotes added for 
clarification or to match corresponding table, are noted and verified.  
3.3. Axis/legend labels are verified against mock figure and/or corresponding table.  
3.4. Axis ranges capture all available data and, if required, are consistent across other 
figures.  Tick marks are spaced appropriately.  
3.5. Pages breaks are as intended throughout the document. 
3.6. Inappropriate data: checked for outliers, invalid numbers, missing results, etc. 


 
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4. Verification of Results 
Verification of results may be performed using one of the following methods. The choice of QC 
method must be approved by the Biostatistics Project Lead. 
4.1. Manual comparison to the corresponding table, where the table is validated and all data 
points on the figure are compared to the corresponding value on the table. 
4.2. Independent confirmatory program is written to match output results. 
4.3. Manual calculations (if feasible based on small Ns or frequency counts). 
4.4. Manual comparison and program review, where the related table, if produced, is 
validated and a subset of data points are compared to the table. Program code and logs 
are reviewed to confirm the intended data is used appropriately throughout the 
program. 
4.5. Study specific alternative method (if applicable) that is agreed upon by the sponsor and 
defined prospectively in a study specific document (e.g., Validation Plan, SAP or a 
modified QC requirement template TMP-SOP-0205-003). 
 
5   Documentation 
5.1. The Programmer and Validator must document completion of QC (e.g., date of QC 
completion and method used) in TMP-SOP-0205-002 Program Status Document. 
5.2. Validator findings and/or comments may be tracked in the Program Status Document 
along with a description of how the finding was resolved and resolution date. 
5.3. The following must be retained electronically within the study folder by the Validator 
to document the method of QC performed:  
x Figure output generated at time of QC completion. 
x If comparison to corresponding validated table is performed, the corresponding table 
output that verifies results (Section 4.1). 
x If independent confirmatory program is created, a portion of the resulting output that 
verifies results (Section 4.2). 
x If manual calculations are performed, insert a comment into the output file to indicate 
verification of results (Section 4.3). 
 
Senior Level Review:  
 
1. Output Package  
1.1. All analysis tables, listings and figures, as outlined in the SAP are contained in the 
package.  If any are missing, the reason is documented appropriately. 
1.2. Dates and times of electronic output files are consistent with each other and with the 
corresponding dates of the source data sets. 
1.3. Output files are sorted in a user-friendly format such as by table, listing, and figure 
number. Table of Contents document is included to decode file names, or TLF number 
is included in the filename itself. 
 


 
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2. Database and Documentation 
2.1. File dates of datasets within the clinical database, SDTM datasets, and analysis 
datasets are consistent.  All clinical database datasets were updated together at the 
appropriate time, SDTM datasets (if any) were updated following the update of the 
clinical database, and analysis datasets were updated following the update of the 
clinical source datasets and SDTM datasets (if any).  
2.2. QC of all programs has been completed by both the Programmer and Validator, as 
confirmed by TMP-SOP-0205-002 Program Status Document. 
2.3. All datasets, SAS programs, and SAS program logs have been saved and are ready 
for archival. 
2.4. The randomization assignments have been verified to be accurate in all datasets at 
the time of the final batch run of programs.   
 
3. Output Review 
3.1. Titles are appropriate and match the corresponding mocks and Table of Contents (if 
available). Title format and numbering is consistent across all TLFs. 
3.2. Footnotes are appropriate and match the corresponding mocks and Table of Contents 
(if available). Reference numbers are consistent in format and correspond to the body 
of the output. Version of output is represented accordingly (e.g., DRAFT designation is 
removed, if final). 
3.3. Formatting is consistent across all analysis tables, listings, and figures (i.e., 
case/punctuation in column and row headers, underlining of column headers, page 
breaks, etc.). 
3.4. Invalid data such as blatant data point errors, outliers, missing data are scanned for in 
the outputs.   
3.5. Population denominators are consistent across summary tables and figures. 
3.6. Potential discrepancies, if any, found during review have been corrected and/or 
handled appropriately. 
 
 
4. Statistical Review 
4.1. The primary efficacy analysis and any key secondary efficacy or safety analyses are 
carefully reviewed for consistency and plausibility. Any potential issues are 
investigated and discussed with the Programmer and/or Biostatistician. 
 
 
 
 
 
 


 
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Appendix C:  Prostate Cancer Working Group 2 (PCWG2) Criteria 
The PCWG2 criteria establishes disease progression as the following: 
 
Soft-tissue Lesions 
Objective response criteria for target, non-target, and new lesions follow RECIST v1.1 criteria: 
Target Lesions 
 
Non-Target Lesions 
 
New Lesions 
Response 
Definition 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short 
axis to <10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. The appearance of 1 or more 
new lesions is also considered progression. 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease, taking as reference 
the smallest sum diameters while on study. 
Response 
Definition 
Complete Response (CR) 
Disappearance of all non-target lesions and 
normalization of tumour marker level. All lymph 
nodes must be non-pathological in size (<10 mm short 
axis). 
Non-CR/Non-Progressive Disease 
(Non-PD) 
Persistence of 1 or more non-target lesion(s) and/or 
maintenance of tumour marker level above the normal 
limits. 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions. 
The appearance of 1 or more new lesions is also 
considered progression.


 
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The unequivocal appearance of new malignant lesions denotes disease progression.  
 
Additional PCWG2 criteria for evaluation of objective response: 
x Only changes in lymph nodes that were ≥2 cm in diameter at baseline should be reported 
x Favorable change is confirmed with a second scan 
x Progression at first assessment must be confirmed by a second scan 6 or more weeks later 
 
Bone Lesions 
Response criteria for bone lesions are reported as new lesions or no new lesions. If new lesions 
are observed, a confirmatory scan 6 or more weeks later is required. If new lesions are observed 
in the subsequent reassessment, then it is considered progression. For progression, the 
appearance of ≥2 new lesions, and, for the first reassessment only, a confirmatory scan 
performed 6 or more weeks later that shows a minimum of 2 or more additional new lesions. The 
date of progression is the date of the first scan that shows the change. 
 
PSA 
PCWG2 criteria recognizes that effects on PSA may be delayed for 12 weeks or more and early 
rises (prior to 2 weeks) should be ignored in determining PSA response. Percent change from 
baseline at 12 weeks and the maximal change at any time should be reported.  
 
PSA progression is defined as the date that a 25% or greater increase and an absolute increase of 
2 ng/mL or more from the nadir is documented, which is confirmed by a second value obtained 3 
or more weeks later. Where no decline from baseline is documented, PCWG2 defines PSA 
progression as a 25% increase from the baseline value along with an increase in absolute value of 
2 ng/mL or more after 12 weeks of treatments. 
 
 
 
 
 
 
 
 


 
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Appendix D: NCI CTCAE v4.03 Toxicity Grades for Clinical Laboratory Abnormalities 
Laboratory 
Category 
Analyte 
SI 
 Unit 
Directional 
Change 
CTCAE Toxicity Grades 
Hematology 
Platelet Count 
109/L 
Decrease 
Grade 1: < LLN to 75.0 x 109/L 
 
 
 
 
Grade 2: < 75.0 to 50.0 x 109/L 
 
 
 
 
Grade 3: <50.0 to 25.0 x 109/L 
 
 
 
 
Grade 4: < 25.0 x 109/L 
 
 
 
 
Grade 5: Not defined 
 
 
 
 
 
 
Neutrophils 
109/L 
Decrease 
Grade 1: < LLN to 1.5 x 109/L 
 
 
 
 
Grade 2: < 1.5 to 1.0 x 109/L 
 
 
 
 
Grade 3: < 1.0 to 0.5 x 109/L 
 
 
 
 
Grade 4: < 0.5 x 109/L 
 
 
 
 
Grade 5: Not defined 
 
 
 
 
 
 
Lymphocytes 
109/L 
Decrease 
Grade 1: < LLN to 0.8 x 109/L 
 
 
 
 
Grade 2: < 0.8 to 0.5 x 109/L 
 
 
 
 
Grade 3: < 0.5 to 0.2 x 109/L 
 
 
 
 
Grade 4: < 0.2 x 109/L 
 
 
 
 
Grade 5: Not defined 
 
 
 
 
 
 
White Blood Cells 
(WBC) 
109/L 
Decrease 
Grade 1: < LLN to 3.0 x 109/L 
 
 
 
 
Grade 2: < 3.0 to 2.0 x 109/L 
 
 
 
 
Grade 3: < 2.0 to 1.0 x 109/L 
 
 
 
 
Grade 4: < 1.0 x 109/L 
 
 
 
 
Grade 5: Not defined 
 
 
 
 
 
Serum 
Chemistry 
Creatinine 
 
umol/L 
Increase 
Grade 1: > 1 to 1.5 x baseline or > ULN to 1.5 x 
ULN 
 
 
Grade 2: > 1.5 to 3 x baseline or 1>1.5 to 3.0 x 
ULN 
 
 
 
 
Grade 3: > 3.0 x baseline or > 3.0 to 6.0 x ULN 
 
 
 
 
Grade 4: > 6.0 x ULN 
 
 
 
 
Grade 5: Not defined 
 
 
 
 
 
 
Bilirubin (total) 
umol/L 
Increase 
Grade 1: > ULN to 1.5 x ULN 
 
 
 
 
Grade 2: > 1.5 to 3.0 x ULN 
 
 
 
 
Grade 3: > 3.0 to to 10.0 x ULN 
 
 
 
 
Grade 4: > 10.0 x ULN 
 
 
 
 
Grade 5: Not defined 
 
 
 
 
 
 
AST (SGOT) 
U/L 
Increase 
Grade 1: > ULN to 3.0 x ULN 
 
 
 
 
Grade 2: > 3.0 to 5.0 x ULN 
 
 
 
 
Grade 3: > 5.0 to to 20.0 x ULN 
 
 
 
 
Grade 4: > 20.0 x ULN 
 
 
 
 
Grade 5: Not defined 
 
 
 
 
 


 
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NCI CTCAE v4.03 Toxicity Grades for Clinical Laboratory Abnormalities (continued) 
 
Laboratory 
Category 
Analyte 
Standard 
Unit 
Directional 
Change 
CTCAE Toxicity Grades 
Serum 
Chemistry 
ALT 
(SGPT) 
U/L 
Increase 
Grade 1: > ULN to 3.0 x ULN 
 
 
 
 
Grade 2: > 3.0 to 5.0 x ULN 
 
 
 
 
Grade 3: > 5.0 to to 20.0 x ULN 
 
 
 
 
Grade 4: > 20.0 x ULN 
 
 
 
 
Grade 5: Not defined 
 
 
 
 
 
 
Glucose 
mmol/L 
Decrease 
Grade 1: < LLN to 3.0 mmol/L 
 
 
 
 
Grade 2: < 3.0 to 2.2 mmol/L 
 
 
 
 
Grade 3: < 2.2 to 1.7 mmol/L 
 
 
 
 
Grade 4: < 1.7 mmol/L 
 
 
 
 
Grade 5: Not defined 
 
 
 
 
 
 
Glucose 
mmol/L 
Increase 
Grade 1: > ULN to 8.9 mmol/L 
 
 
 
 
Grade 2: > 8.9-13.9 mmol/L 
 
 
 
 
Grade 3: > 13.9-27.8 mmol/L 
 
 
 
 
Grade 4: > 27.8 mmol/L 
 
 
 
 
Grade 5: Not defined 
 
 
 
 
 
 


 
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Appendix E:  List of Tables, Figures, and Listings 
The following TLF numbering is completed according to ICH guidelines.  The ICH heading number and description are in bold. 
Minor changes from this planned index do not need to be amended in the SAP.    
 
Formal organization of tabulations may be changed during programming if appropriate, e.g., tables for the different variables may be 
combined into a single table, or tables with more than 1 variable may be split into several tables. 
 
List of Tables 
 
 
Table 
Number 
 
Table Title 
 
14 
TABLES, FIGURES, AND GRAPHS REFERRED TO BUT NOT INCLUDED IN 
THE TEXT 
 
14.1 
DEMOGRAPHIC DATA 
 
14.1.1 
Patient Disposition 
 
14.1.2 
Protocol Deviations 
 
14.1.3.1 
Demographic (Safety Population) 
 
14.1.3.2 
Baseline Characteristics (Safety Population) 
 
14.1.4 
Medical History at Baseline (Safety Population) 
 
14.1.5 
Prior Cancer Therapy (Safety Population) 
 
14.1.6 
Prior and Concomitant Medications (Safety Population) 
 
14.2 
EFFICACY DATA 
 
14.2.1.1 
Overall Response Rate (Radiographic Evaluable Population) 
 
14.2.1.2 
Overall Response Rate (Safety Population) 
 
14.2.2 
PSA Response Rate by PCWG2 Criteria (PSA Evaluable Population) 
 
14.2.3.1 
Serum PSA Change from Baseline (PSA Evaluable Population) 


 
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Table 
Number 
 
Table Title 
 
14.2.4 
Overall Progression-Free Survival by PCWG2 Criteria (Safety Population) 
 
14.2.5.1 
Radiographic Progression-Free Survival by PCWG2 Criteria – Measured from Baseline 
(Safety Population) 
 
14.2.5.2 
Radiographic Progression-Free Survival by PCWG2 Criteria – Measured from Baseline 
(Safety Population with Radiographic Progression or Ongoing at Study Completion) 
 
14.2.5.3 
Radiographic Progression-Free Survival by PCWG2 Criteria – Measured form Screening 
Scan (Safety Population) 
 
14.2.6 
Time to PSA Progression by PCWG2 Criteria  (PSA Evaluable Population with at least 
12 weeks of treatment) 
14.3 
 
SAFETY DATA 
 
14.3.1 
Study Drug Exposure (Safety Population) 
14.3.1 
 
Displays of Adverse Events 
 
14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events (Safety Population) 
 
14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term (Safety 
Population) 
 
14.3.1.3 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Maximum Severity (Safety Population) 
 
14.3.1.4 
Treatment-Emergent Related Adverse Events by System Organ Class and Preferred Term 
(Safety Population) 
 
14.3.1.5 
Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred Term 
(Safety Population) 
 
14.3.1.6 
Treatment-Emergent Serious Adverse Events by System Organ Class, Preferred Term, 
and Maximum Severity (Safety Population) 
 
14.3.1.7 
Treatment-Emergent Related Serious Adverse Events by System Organ Class and 
Preferred Term (Safety Population) 


 
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Table 
Number 
 
Table Title 
 
14.3.1.8 
Treatment-Emergent Adverse Events Leading to Death by System Organ Class and 
Preferred Term (Safety Population) 
 
14.3.1.9 
Treatment-Emergent Adverse Events Leading to Study Discontinuation by System Organ 
Class and Preferred Term (Safety Population) 
 
14.3.2.1 
Serious Adverse Events 
 
14.3.2.2 
Treatment-Emergent Adverse Events Leading to Study Discontinuation  
 
14.3.2.3 
Treatment-Emergent Adverse Events Leading to Death 
 
14.3.2.4 
Death Details 
14.3.4 
 
Abnormal Laboratory Value Listing (Each Patient)  
 
14.3.4.1 
Hematology (Safety Population) 
 
14.3.4.2 
Hematology - Shift from Baseline (Safety Population) 
 
14.3.4.3 
Select Hematology Parameters – CTCAE Shift from Baseline (Safety Population) 
 
14.3.4.4 
Coagulation (Safety Population) 
 
14.3.4.5 
Coagulation - Shift from Baseline (Safety Population) 
 
14.3.4.6 
Serum Chemistry (Safety Population) 
 
14.3.4.7 
Serum Chemistry - Shift from Baseline (Safety Population) 
 
14.3.4.8 
Select Serum Chemistry - CTCAE Shift from Baseline (Safety Population) 
 
14.3.4.9 
Serum Troponin (Safety Population) 
 
14.3.4.10 
Incidence of Clinically Significant Laboratory Abnormalities (Safety Population) 
 
14.3.4.11 
ECOG Performance Status – Shift from Baseline (Safety Population) 
 
14.3.4.12 
Vital Signs (Safety Population) 
 
14.3.4.13 
12-Lead Electrocardiogram (Safety Population) 
 
14.3.4.14 
12-Lead Electrocardiogram QTcF Abnormalities (Safety Population) 
 
14.3.4.15 
Ophthalmology Assessments (On-Study Examination) – Clinically Significant Changes 
from Baseline (Safety Population) 


 
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Table 
Number 
 
Table Title 
 
14.3.4.16 
Ophthalmology Assessments (Qualitative Exploration of Visual Symptoms) (Safety 
Population) 


 
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List of Figures 
 
ICH 
Heading 
Figure 
Number 
 
Figure Description 
14.2 
 
EFFICACY DATA 
 
14.2.1 
Mean Percent Change From Baseline in PSA Over Time (Safety Population by Dose Level) 
 
14.2.2.1 
Kaplan-Meier Plot for Overall Progression-Free Survival (Safety Population by Dose Level)
 
14.2.2.2 
Kaplan-Meier Plot for Overall Progression-Free Survival (Safety Population by Progressor) 
 
14.2.3.1 
Kaplan-Meier Plot for Radiographic Progression-Free Survival (Safety Population by Dose 
Level) 
 
14.2.3.2 
Kaplan-Meier Plot for Radiographic Progression-Free Survival (Safety Population by Dose 
Group) 
 
14.2.3.3.1 
Kaplan-Meier Plot for Radiographic Progression-Free Survival Measured from Baseline 
(Safety Population by Progressor) 
 
14.2.3.3.2 
Kaplan-Meier Plot for Radiographic Progression-Free Survival Measured from Baseline 
(Safety Population with Radiographic Progression or Ongoing at Study Completion by 
Progressor) 
 
14.2.3.3.3 
Kaplan-Meier Plot for Radiographic Progression-Free Survival Measured from Screening 
Scan (Safety Population by Progressor) 
 
14.2.4.1 
Kaplan-Meier Plot for Time to PSA Progression (PSA Evaluable Population by Dose Level) 
 
14.2.4.2 
Kaplan-Meier Plot for Time to PSA Progression (PSA Evaluable Population by Progressor) 
 
14.2.5 
Waterfall Plot for Percent Change from Baseline in PSA at 12 Weeks of Treatment (PSA 
Evaluable Population with at least 12 weeks of treatment) 
 
14.2.6 
Waterfall Plot for Maximum Change from Baseline in PSA (PSA Evaluable Population) 
 
 
 


 
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List of Data Listings 
 
ICH 
Heading 
Listing 
Number 
 
Listing Description 
16.2 
 
PATIENT DATA LISTINGS 
16.2.1 
 
Discontinued patients 
 
16.2.1.1 
Patient Disposition 
16.2.2 
 
Protocol deviations 
 
16.2.2.1 
Protocol Deviations  
 
16.2.2.2 
Informed Consent and Inclusion/Exclusion Criteria 
16.2.4 
 
Demographic data 
 
16.2.4.1 
Demographics and Baseline Characteristics 
 
16.2.4.2 
Medical History 
 
16.2.4.3 
Prostate Cancer History 
 
16.2.4.4 
Prostate-Specific Antigen History 
 
16.2.4.5 
Prior Cancer Therapy 
 
16.2.4.6 
Prior and Concomitant Medications 
16.2.5 
 
Compliance and/or drug concentration data  
 
16.2.5.1 
Study Drug Compliance 
 
16.2.5.2 
ZEN003694 Administration – Single Dose 
 
16.2.5.3 
ZEN003694 Administration Log 
 
16.2.5.4 
Enzalutamide Administration – Single Dose 
 
16.2.5.5 
Enzalutamide Administration Log 
16.2.6 
 
Individual efficacy response data 
 
16.2.6.1 
Tumor Evaluation – Target Lesions 
 
16.2.6.2 
Tumor Evaluation – Non-Target Lesions 
 
16.2.6.3 
Tumor Evaluation – New Lesions 
 
16.2.6.4 
Overall Tumor Response Assessment 


 
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ICH 
Heading 
Listing 
Number 
 
Listing Description 
 
16.2.6.5 
Derived Clinical Activity Data 
 
16.2.6.6 
Fresh and Archival Tumor Tissue Collection  
16.2.7 
 
Adverse events listings 
 
16.2.7.1 
Adverse Events 
16.2.8 
 
Listing of Individual Laboratory Measurements by Patient and Other Safety 
Assessments 
 
16.2.8.1 
Hematology (Safety Population) 
 
16.2.8.2 
Coagulation (Safety Population) 
 
16.2.8.3 
Serum Chemistry (Safety Population) 
 
16.2.8.4 
Urinalysis (Safety Population) 
 
16.2.8.5 
Serum PSA  (Safety Population) 
 
16.2.8.6 
Physical Examination (Safety Population) 
 
16.2.8.7 
Echocardiogram or MUGA Scan (Safety Population) 
 
16.2.8.8 
Vital Signs (Safety Population) 
 
16.2.8.9 
12-Lead Electrocardiogram (Safety Population) 
 
16.2.8.10 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
16.2.8.11 
Ophthalmology Examination (Baseline and On-Study) (Safety Population) 
 
16.2.8.12 
Qualitative Exploration of Visual Symptoms (Baseline and In-Clinic) (Safety 
Population) 
 
 
 
 
 


 
 
 
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Appendix F:  Table Layouts 
 
 
 


 
 
 
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General Table Format Display 
Below header applies to all safety analysis tables 
 
Dose Escalation 
 
Dose Confirmation 
 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
 
36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 Total 
(N=) 
 
Note: DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
 
 
Below header applies to all efficacy analysis tables (14.2.1.1–14.2.6) 
 
Enzalutamide Progressor 
 
 
Abiraterone Progressor 
 
36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
120 mg 
 (N=) 
144 mg  
 (N=) 
Total 
(N=) 
 36 mg 
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
Total 
(N=) 
 
Note: 48mg and 96mg dose levels are pooled from Dose Escalation and Dose Comfirmation. 
 
 
Programmer note:  All tables should follow the same column/format display. Tables may/may not necessarily include all of these doses if they were not included in the study. Even 
if the table shell shows a different structure this general table format display takes precedence. If table cannot fit in one page, please separate to Part 1, Par 2, etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Zenith Epigenetics Ltd. 
 
 
 
 
 
 
 
 
 
 
 
 
 
             Page 1 of x 
ZEN003694-002 
Table 14.1.1 
Patient Disposition 
All Patients 
 
Dose Escalation 
 
Dose Confirmation 
 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
 
36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg 
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
120 mg  
 (N=) 
144 mg 
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients Enrolled 
n 
n 
n 
n 
n 
n 
n 
 
n 
n 
n 
n 
n 
 
n 
n 
 
n 
n 
 
n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Population [1] 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
Radiographic Evaluable 
Population [2] 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
PSA Evaluable Population 
[3] 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
PSA Evaluable Population 
with at least 12 weeks of 
treatment 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Cycles 
Completed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  ≤ 1 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
  ≤ 3 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
  ≤ 6 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
  ≤ 12 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
  > 12 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary Reason for Study 
Completion/Discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Completed study 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
   Clinical progression by 
PCWG2 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
   Radiographic progression 
by PCWG2 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
   PSA progression with 
clinical progression by 
PCWG2 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 


 
 
 
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   PSA progression with 
radiographic progression by 
PCWG2 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
   Adverse Event 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
   Treatment with or need 
for prohibited concomitant 
medication 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
   Withdrawal by Subject 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
   Withdrawal by Physician n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
   Non-Compliance, 
Specify 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
   Lost to Follow-up 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
   Death 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
   Termination of study by 
sponsor 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
   Other, Specify 
n (%) 
n (%) n (%) n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%)  n (%) 
n (%)  n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: Percentages are based on the N of each dose regimen. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor.  
[1] Patients who received any least one dose of ZEN003694. 
[2] Patients who receive at least one dose of ZEN003694, have a non-missing baseline and at least one evaluable post-baseline radiographic assessment or discontinues study 
treatment due to disease progression or death. 
 [3] Patients who receive at least one dose of ZEN003694, have a non-missing baseline PSA and at least one non-missing post-baseline PSA assessment or discontinues study 
treatment due to disease progression or death. 
 
path\t_program.sas date 
time   
 
Programmer note: Include all applicable dose escalation and dose confirmation cohorts.  


 
 
 
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Table 14.1.2 
Protocol Deviation 
 
 
Dose Escalation 
 
Dose Confirmation 
 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Protocol Deviations 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Major Protocol Deviations [1] 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Inclusion/Exclusion Criteria Not 
Met 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Non-Compliance with Study 
Protocol [2] 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Minor Protocol Deviations 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
Source: xxx 
Note: Percentage is calculated by dividing the number of protocol deviations (n) by the total number of protocol deviations per cohort. DE-A and DC-A indicate enzalutamide 
progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Patients may be included in more than one protocol deviation category. 
[2] Non-compliance with study protocol includes any subject who met withdrawal criteria but was not withdrawn from the study treatment, received excluded or prohibited 
concomitant medication or treatment, and received the wrong study treatment or incorrect dose of study treatment. 
 
path\t_program.sas date 
time   


 
 
 
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Table 14.1.3.1 
Demographics  
Safety Population 
 
Dose Escalation 
 
Dose Confirmation 
 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 Total 
(N=) 
Age (years) [1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx)
   Median 
xx x 
xx x 
… 
xx x 
xx x 
 
xx x 
xx x 
… 
xx x 
 
xx.x 
xx x 
 
xx x 
xx x 
 
xx x 
   Min, Max 
xx, xx 
xx, xx 
… 
xx, xx 
xx, xx  xx, xx 
xx, xx 
… 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
Sex 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Male 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Female 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethnicity 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Hispanic or Latino 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Not Hispanic or Latino 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   American Indian or Alaska Native 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Asian  
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Black or African American 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Native Hawaiian or Other Pacific 
Islander 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   White 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Multiple Races Checked [2] 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height (in) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx)
   Median 
xx x 
xx x 
… 
xx x 
xx x 
 
xx x 
xx x 
… 
xx x 
 
xx.x 
xx x 
 
xx x 
xx x 
 
xx x 
   Min, Max 
xx, xx 
xx, xx 
… 
xx, xx 
xx, xx  xx, xx 
xx, xx 
… 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 xx, xx 
 
 
 
` 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Weight (kg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx)
   Median 
xx x 
xx x 
… 
xx x 
xx x 
 
xx x 
xx x 
… 
xx x 
 
xx.x 
xx x 
 
xx x 
xx x 
 
xx x 
   Min, Max 
xx, xx 
xx, xx 
… 
xx, xx 
xx, xx  xx, xx 
xx, xx 
… 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI (kg/m2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx)
   Median 
xx x 
xx x 
… 
xx x 
xx x 
 
xx x 
xx x 
… 
xx x 
 
xx.x 
xx x 
 
xx x 
xx x 
 
xx x 
   Min, Max 
xx, xx 
xx, xx 
… 
xx, xx 
xx, xx  xx, xx 
xx, xx 
… 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: Percentages are based on the N of each dose regimen. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Relative to informed consent date. 
[2] Subjects with multiple races may not add to the total number of each treatment. 
 
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time   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.1.3.2 
Baseline[1] Characteristics  
Safety Population 
 
Dose Escalation 
 
Dose Confirmation 
 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSA (ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx)
   Median 
xx x 
xx x 
… 
xx x 
xx x 
 
xx x 
xx x 
… 
xx x 
 
xx.x 
xx x 
 
xx x 
xx x 
 
xx x 
   Min, Max 
xx, xx 
xx, xx 
… 
xx, xx 
xx, xx  xx, xx 
xx, xx 
… 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor Burden 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   High 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Low 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   0 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pain 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Opioid Use 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Metastatic Location 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Bone +/- other sites 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Bone only 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Lymphatic +/- other sites 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Visceral 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Soft tissue 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline ALP 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx)


 
 
 
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   Median 
xx x 
xx x 
… 
xx x 
xx x 
 
xx x 
xx x 
… 
xx x 
 
xx.x 
xx x 
 
xx x 
xx x 
 
xx x 
   Min, Max 
xx, xx 
xx, xx 
… 
xx, xx 
xx, xx  xx, xx 
xx, xx 
… 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline LDH 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx)
   Median 
xx x 
xx x 
… 
xx x 
xx x 
 
xx x 
xx x 
… 
xx x 
 
xx.x 
xx x 
 
xx x 
xx x 
 
xx x 
   Min, Max 
xx, xx 
xx, xx 
… 
xx, xx 
xx, xx  xx, xx 
xx, xx 
… 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Albumin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx)
   Median 
xx x 
xx x 
… 
xx x 
xx x 
 
xx x 
xx x 
… 
xx x 
 
xx.x 
xx x 
 
xx x 
xx x 
 
xx x 
   Min, Max 
xx, xx 
xx, xx 
… 
xx, xx 
xx, xx  xx, xx 
xx, xx 
… 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline Hemoglobin 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx)
   Median 
xx x 
xx x 
… 
xx x 
xx x 
 
xx x 
xx x 
… 
xx x 
 
xx.x 
xx x 
 
xx x 
xx x 
 
xx x 
   Min, Max 
xx, xx 
xx, xx 
… 
xx, xx 
xx, xx  xx, xx 
xx, xx 
… 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Prior Chemotherapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx)
   Median 
xx x 
xx x 
… 
xx x 
xx x 
 
xx x 
xx x 
… 
xx x 
 
xx.x 
xx x 
 
xx x 
xx x 
 
xx x 
   Min, Max 
xx, xx 
xx, xx 
… 
xx, xx 
xx, xx  xx, xx 
xx, xx 
… 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Duration prior ARSI therapy [2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx)
   Median 
xx x 
xx x 
… 
xx x 
xx x 
 
xx x 
xx x 
… 
xx x 
 
xx.x 
xx x 
 
xx x 
xx x 
 
xx x 
   Min, Max 
xx, xx 
xx, xx 
… 
xx, xx 
xx, xx  xx, xx 
xx, xx 
… 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reason for Prior 
Enzalutamide/Abiraterone 
Discontinuation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   rPD 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)


 
 
 
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   rPD + PSA 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   cPD + PSA 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   PSA 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: Percentages are based on the N of each dose regimen. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
[2] Prior ARSI therapy includes prior Enzalutamide, prior Apalutamide, prior Abiraterone and prior Ena + Abiraterone if used both. 
 
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Table 14.1.4 
Medical History at Baseline 
Safety Population 
 
Dose Escalation 
 
Dose Confirmation 
 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
 
Primary System Organ Class /  
 Dictionary-Derived Term 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Resolved Medical History at 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary System Organ Class #1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Dictionary-Derived Term 1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Dictionary-Derived Term 2 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
 
 
 
 
 
 
 
 
 
 
 
Primary System Organ Class #2 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Dictionary-Derived Term 1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Dictionary-Derived Term 2 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ongoing Medical History at Baseline 
 
  
 
 
 
 
 
 
Primary System Organ Class #1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Dictionary-Derived Term 1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Dictionary-Derived Term 2 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
  
 
 
 
 
 
 
Primary System Organ Class #2 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Dictionary-Derived Term 1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
   Dictionary-Derived Term 2 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%)
 
 
Source: xxx 
Note: Percentages are based on the N of each dose regimen. At each level of summation (overall, primary system organ class, dictionary-derived term), patients reporting more 
than one event are counted only once. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
 
path\t_program.sas date 
time   
 
 
 


 
 
 
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             Page 1 of x 
ZEN003694-002 
Table 14.1.5 
Prior Cancer Therapy 
Safety Population 
 
Dose Escalation 
 
Dose Confirmation 
 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Systemic Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Type 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Chemotherapy 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Biologic Therapy 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Immunotherapy 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Hormonal Therapy 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Other 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Best Overall Response 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CR 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   PR 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   SD 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   PD 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Unknown 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Not Applicable 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Route 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   IV 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   PO 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
  Topical 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
  Other 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reason Stopped 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Completed Scheduled Regimen 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Progressive Disease 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Toxicity 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Achieved Disease Control 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Other 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
 


 
 
 
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Table 14.1.5 
Prior Cancer Therapy (continued) 
Safety Population  
 
Dose Escalation 
 
Dose Confirmation 
 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Surgical Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Curative 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Palliative 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Adjunctive 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
Prior Radiotherapy Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Type of Radiotherapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Internal 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   External 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site of Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Adrenal Glands 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Bladder 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Other Organ 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total Radiation Dose (cGY) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx)
   Median 
xx x 
xx x 
… 
xx x 
xx x 
 
xx x 
xx x 
… 
xx x 
 
xx.x 
xx x 
 
xx x 
xx x 
 
xx x 
   Min, Max 
xx, xx 
xx, xx 
… 
xx, xx 
xx, xx  xx, xx 
xx, xx 
… 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 xx, xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Best Overall Response 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   CR 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   PR 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   SD 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 


 
 
 
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   PD 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Unknown 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Not Applicable 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
 
 
Source: xxx 
Note: CR=Complete Response; PR=Partial Response; SD=Stable Disease; PD=Progressive Disease. 
Note: DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
 
path\t_program.sas date 
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            Page 1 of x 
ZEN003694-002 
Table 14.1.6 
Prior and Concomitant Medications 
Safety Population 
Part 1 of 2 
 
 
Dose Escalation 
 
Dose Confirmation 
 
 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
 
ATC Class /  
   Preferred Name 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients Receiving any Prior Medications [1] 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATC Class 1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%) 
    Preferred Name 1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%) 
    Preferred Name 2 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATC Class 2 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%) 
    Preferred Name 1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%) 
    Preferred Name 2 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 n (%) 
 
Table 14.1.6 
Prior and Concomitant Medications 
Safety Population 
Part 2 of 2 
 
 
Dose Escalation 
 
Dose Confirmation 
 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
ATC Class /  
   Preferred Name 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 
48 mg  
 (N=) 
96 mg  
 (N=) 
 Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients Receiving any Concomitant 
Medications [2] 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%)
n (%) 
 n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATC Class 1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%)
n (%) 
 n (%) 
    Preferred Name 1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%)
n (%) 
 n (%) 
    Preferred Name 2 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%)
n (%) 
 n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATC Class 2 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%)
n (%) 
 n (%) 
    Preferred Name 1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%)
n (%) 
 n (%) 


 
 
 
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    Preferred Name 2 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%)
n (%) 
 n (%) 
 
 
Source: xxx 
Note: Percentages are based on the N of each dose regimen. At each level of summation (overall, ATC class, preferred name), patients reporting more than one medication are 
counted only once. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Prior medications are those medications taken within 21 days prior to enrollment in the study. 
[2] Concomitant medications are those medications taken after the initial dose of ZEN003694. 
 
path\t_program.sas date 
time   
 


 
 
 
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Table 14.2.1.1 
Overall Response Rate 
 Radiographic Evaluable Population  
 
Enzalutamide Progressor 
 
 
Abiraterone Progressor 
 
36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
120 mg 
 (N=) 
144 mg  
 (N=) 
Total 
(N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Best Overall Response (confirmed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Complete Response (CR) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Partial Response (PR) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Stable Disease (SD) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Progressive Disease (PD) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Not Evaluable (NE) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall Response Rate [95% Confidence 
Interval] [1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   Confirmed CR + PR 
n (%) 
[xx x %, 
xx x %] 
n (%) 
[xx x %, 
xx x %] 
n (%) 
[xx x %, 
xx x %] 
n (%) 
[xx x %, 
xx.x %] 
n (%) 
[xx.x %, 
xx x %] 
n (%) 
[xx x %, 
xx x %] 
n (%) 
[xx x %, 
xx.x %] 
n (%) 
[xx x %, 
xx x %] 
 n (%) 
[xx.x %, 
xx x %] 
n (%) 
[xx.x %, 
xx x %] 
n (%) 
[xx x %, 
xx x %] 
n (%) 
[xx x %, 
xx x %] 
n (%) 
[xx x %, 
xx x %] 
n (%) 
[xx x %, 
xx.x %] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: Percentages are based on the N of each dose regimen. 48mg and 96mg dose levels are pooled from Dose Escalation and Dose Comfirmation. 
[1] Binomial exact 95% confidence interval. 
 
path\t_program.sas date 
time   
 
 
Programmer note: repeat for table 14.2.1.2 Overall Response Rate (Safety Population) 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.2.2 
PSA Response Rate by PCWG2 Criteria 
 PSA Evaluable Population 
 
Enzalutamide Progressor 
 
 
Abiraterone Progressor 
 
36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
120 mg 
 (N=) 
144 mg 
 (N=) 
Total 
(N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSA Decline  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  < 30% Decline 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   >= 30% Decline 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   >= 50% Decline 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PSA Response Rate [95% 
Confidence Interval] [1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    >= 50% Decline 
n (%) 
[xx x %, 
xx x %] 
n (%) 
[xx x %, 
xx x %] 
n (%) 
[xx x %, 
xx.x %] 
n (%) 
[xx x %, 
xx x %] 
n (%) 
[xx x %, 
xx x %] 
n (%) 
[xx x %, 
xx.x %] 
n (%) 
[xx.x %, 
xx x %] 
n (%) 
[xx x %, 
xx.x %] 
 n (%) 
[xx.x %, 
xx x %] 
n (%) 
[xx x %, 
xx x %] 
n (%) 
[xx x %, 
xx x %] 
n (%) 
[xx x %, 
xx.x %] 
n (%) 
[xx x %, 
xx x %] 
n (%) 
[xx x %, 
xx x %] 
 
 
Source: xxx 
Note: Percentages are based on the N of each dose regimen. 48mg and 96mg dose levels are pooled from Dose Escalation and Dose Comfirmation.  
[1] Binomial exact 95% confidence interval. 
 
path\t_program.sas date 
time 
 
 
Programming note: safety follow-up PSA is 30 days after end of treatment and patient off treatment for significant time, therefore this SFU collection should not be used for PSA 
response rate calculations 
 


 
 
 
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ZEN003694-002 
Table 14.2.3.1 
Serum PSA Change from Baseline 
 PSA Evaluable Population 
 
Enzalutamide Progressor 
 
 
Abiraterone Progressor 
 
36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
120 mg 
 (N=) 
144 mg  
 (N=) 
Total 
(N=) 
 36 mg 
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline [1] (ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
n 
n 
n 
n 
n 
n 
 
n 
n 
n 
n 
n 
n 
   Mean (SD) 
x x 
(x xx) 
x.x 
(x xx) 
x x 
(x xx) 
x.x 
(x xx) 
x x 
(x xx) 
x x 
(x xx) 
x.x 
(x.xx) 
x.x 
(x xx) 
 x.x 
(x.xx) 
x x 
(x.xx) 
x x 
(x xx) 
x.x 
(x.xx) 
x x 
(x xx) 
x x 
(x xx) 
   Median 
x x 
x.x 
x x 
x.x 
x x 
x x 
x.x 
x.x 
 x x 
x x 
x x 
x x 
x x 
x x 
   Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 Day 1 (ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
n 
n 
n 
n 
n 
n 
 
n 
n 
n 
n 
n 
n 
   Mean (SD) 
x x 
(x xx) 
x.x 
(x xx) 
x x 
(x xx) 
x.x 
(x xx) 
x x 
(x xx) 
x x 
(x xx) 
x.x 
(x.xx) 
x.x 
(x xx) 
 x.x 
(x.xx) 
x x 
(x.xx) 
x x 
(x xx) 
x.x 
(x.xx) 
x x 
(x xx) 
x x 
(x xx) 
   Median 
x x 
x.x 
x x 
x.x 
x x 
x x 
x.x 
x.x 
 x x 
x x 
x x 
x x 
x x 
x x 
   Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Change from Baseline to Cycle 2 Day 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
n 
n 
n 
n 
n 
n 
 
n 
n 
n 
n 
n 
n 
   Mean (SD) 
x x 
(x xx) 
x.x 
(x xx) 
x x 
(x xx) 
x.x 
(x xx) 
x x 
(x xx) 
x x 
(x xx) 
x.x 
(x.xx) 
x.x 
(x xx) 
 x.x 
(x.xx) 
x x 
(x.xx) 
x x 
(x xx) 
x.x 
(x.xx) 
x x 
(x xx) 
x x 
(x xx) 
   Median 
x x 
x.x 
x x 
x.x 
x x 
x x 
x.x 
x.x 
 x x 
x x 
x x 
x x 
x x 
x x 
   Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Percent Change from Baseline to Cycle 2 
Day 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
n 
n 
n 
n 
n 
n 
 
n 
n 
n 
n 
n 
n 
   Mean (SD) 
x x 
(x xx) 
x.x 
(x xx) 
x x 
(x xx) 
x.x 
(x xx) 
x x 
(x xx) 
x x 
(x xx) 
x.x 
(x.xx) 
x.x 
(x xx) 
 x.x 
(x.xx) 
x x 
(x.xx) 
x x 
(x xx) 
x.x 
(x.xx) 
x x 
(x xx) 
x x 
(x xx) 
   Median 
x x 
x.x 
x x 
x.x 
x x 
x x 
x.x 
x.x 
 x x 
x x 
x x 
x x 
x x 
x x 
   Min, Max 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 x, x 
x, x 
x, x 
x, x 
x, x 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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                                                                                                                                          27 January 2020 
 
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Source: xxx 
Note: 48mg and 96mg dose levels are pooled from Dose Escalation and Dose Comfirmation. 
[1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
path\t_program.sas date 
time   


 
 
 
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                                                                                                                                          27 January 2020 
 
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Table 14.2.4 
Overall Progression-Free Survival by PCWG2 Criteria  
 Safety Population  
 
Enzalutamide Progressor 
 
 
Abiraterone Progressor 
 
Survival Estimates 
36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
120 mg  
 (N=) 
144 mg  
 (N=) 
Total 
(N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number (%) of Patients that Progressed 
or Died 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Number (%) of Patients that Did Not 
Progress and are Alive 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Min, Max (months patient was 
progression-free for all patients) 
xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx  xxx, xxx 
xxx, 
xxx 
xxx, xxx xxx, xxx xxx, xxx xxx, xxx 
Min, Max for Non-Censored Patients 
(months patient was progression-free 
for patients that progressed or died) 
xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx  xxx, xxx 
xxx, 
xxx 
xxx, xxx xxx, xxx xxx, xxx xxx, xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kaplan-Meier Quartile Estimates [95% 
CI] (months progression-free) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   25th Percentile 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
   Median 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
   75th Percentile  
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kaplan-Meier Product Limit Estimates 
(# of patients at risk)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   3 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
   6 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
   9 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
   12 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 


 
 
 
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ZEN003694-002 
                                                                                                                                          27 January 2020 
 
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   18 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
   24 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
 
 
Source: xxx 
Note: Percentages are based on the N of each dose regimen. For patients who progressed (radiographic progression or clinical deterioration) or died, their time to event is 
calculated as [(date of progression or death) – (treatment start date +1)]/30.44. Patients who did not progress are censored on the date of their last tumor assessment. Their time to 
event is calculated as [(date of last tumor assessment) – (treatment start date +1)]/30.44. 
Note: 48mg and 96mg dose levels are pooled from Dose Escalation and Dose Comfirmation. 
 
path\t_program.sas date 
time   


 
 
 
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                                                                                                                                          27 January 2020 
 
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Table 14.2.5.1 
Radiographic Progression-Free Survival by PCWG2 Criteria  
– Measured from Baseline 
 Safety Population 
 
Enzalutamide Progressor 
 
 
Abiraterone Progressor 
 
Survival Estimates 
36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
120 mg  
 (N=) 
144 mg  
 (N=) 
Total 
(N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number (%) of Patients that Progressed 
or Died 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Number (%) of Patients that Did Not 
Progress and are Alive 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Min, Max (months patient was 
progression-free for all patients) 
xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx  xxx, xxx 
xxx, 
xxx 
xxx, xxx xxx, xxx xxx, xxx xxx, xxx 
Min, Max for Non-Censored Patients 
(months patient was progression-free 
for patients that progressed or died) 
xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx  xxx, xxx 
xxx, 
xxx 
xxx, xxx xxx, xxx xxx, xxx xxx, xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kaplan-Meier Quartile Estimates [95% 
CI] (months progression-free) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   25th Percentile 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
   Median 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
   75th Percentile  
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kaplan-Meier Product Limit Estimates 
(# of patients at risk)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   3 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
   6 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
   9 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
   12 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 


 
 
 
Zenith Epigenetics Ltd.   
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ZEN003694-002 
                                                                                                                                          27 January 2020 
 
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   18 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
   24 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
 
 
Source: xxx 
Note: Percentages are based on the N of each dose regimen. For patients who progressed or died, their time to event is calculated as [(date of progression or death) – (treatment 
start date +1)]/30.44. Patients who did not progress are censored on the date of their last tumor assessment. Their time to event is calculated as [(date of last tumor assessment) – 
(treatment start date +1)]/30.44. 
Note: 48mg and 96mg dose levels are pooled from Dose Escalation and Dose Comfirmation. 
 
path\t_program.sas date 
time   
 
Programmer note: Repeat for table 14.2.5.2 Radiographic Progression-Free Survival by PCWG2 Criteria – Measured from Baseline (Safety Population with Radiographic Progression or 
Ongoing at Study Completion) 
 
Programmer note: Repeat for table 14.2.5.3 Radiographic Progression-Free Survival by PCWG2 Criteria – Measured from Screening Scan (Safety Population) 
Update Note: Percentages are based on the N of each dose regimen. For patients who progressed or died, their time to event is calculated as [(date of progression or death) – 
(date of screening scan +1)]/30.44. Patients who did not progress are censored on the date of their last tumor assessment. Their time to event is calculated as [(date of last tumor 
assessment) – (date of screening scan +1)]/30.44. 
 


 
 
 
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Table 14.2.6 
Time to PSA Progression by PCWG2 Criteria  
PSA Evaluable Population with at least 12 weeks of treatment 
 
Enzalutamide Progressor 
 
 
Abiraterone Progressor 
 
Survival Estimates 
36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
120 mg  
 (N=) 
144 mg  
 (N=) 
Total 
(N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
60 mg  
 (N=) 
72 mg  
 (N=) 
96 mg  
 (N=) 
Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number (%) of Patients with PSA 
Progression 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Number (%) of Patients that Did Not 
Progress or Died 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Min, Max (months patient was 
progression-free for all patients) 
xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx  xxx, xxx 
xxx, 
xxx 
xxx, xxx xxx, xxx xxx, xxx xxx, xxx 
Min, Max for Non-Censored Patients 
(months patient was progression-free 
for patients that progressed) 
xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx xxx, xxx  xxx, xxx 
xxx, 
xxx 
xxx, xxx xxx, xxx xxx, xxx xxx, xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kaplan-Meier Quartile Estimates [95% 
CI] (months progression-free) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   25th Percentile 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
   Median 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
   75th Percentile  
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
xx 
 [xx, xx] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kaplan-Meier Product Limit Estimates 
(# of patients at risk)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   3 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
   6 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
   9 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
   12 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 


 
 
 
Zenith Epigenetics Ltd.   
                                                                                                  Statistical Analysis Plan 
ZEN003694-002 
                                                                                                                                          27 January 2020 
 
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   18 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
   24 Months 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x xxx 
(xxx) 
x.xxx 
(xxx) 
x.xxx 
(xxx) 
 
 
Source: xxx 
Note: Percentages are based on the N of each dose regimen. For patients with PSA progression, their time to event is calculated as [(date of PSA progression) – (treatment start 
date +1)]/30.44. Patients who did not progress or died at time of study exit are censored on the date of their last PSA assessment or date of death. Their time to event is calculated 
as [(date of last PSA assessment or death) – (treatment start date +1)]/30.44. 
Note: 48mg and 96mg dose levels are pooled from Dose Escalation and Dose Comfirmation. 
 
path\t_program.sas date 
time   


 
 
 
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ZEN003694-002 
                                                                                                                                          27 January 2020 
 
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             Page 1 of x 
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Table 14.3.1 
Study Drug Exposure 
Safety Population 
 
Dose Escalation 
 
Dose Confirmation 
 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 
48 mg  
 (N=) 
96 mg  
 (N=) 
 
Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total Number of Doses Taken 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x.x (x xx) x x (x xx) … 
x x (x.xx) x x (x xx)  x x (x xx) x x (x.xx) 
… x x (x.xx)  x x (x xx) x x (x xx)  x.x (x xx) x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
… 
x x 
x x 
 
x x 
x x 
… 
x x 
 
x x 
x x 
 
x.x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Cycles 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x.x (x xx) x x (x xx) … 
x x (x.xx) x x (x xx)  x x (x xx) x x (x.xx) 
… x x (x.xx)  x x (x xx) x x (x xx)  x.x (x xx) x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
… 
x x 
x x 
 
x x 
x x 
… 
x x 
 
x x 
x x 
 
x.x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Duration of Treatment (weeks) [1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x.x (x xx) x x (x xx) … 
x x (x.xx) x x (x xx)  x x (x xx) x x (x.xx) 
… x x (x.xx)  x x (x xx) x x (x xx)  x.x (x xx) x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
… 
x x 
x x 
 
x x 
x x 
… 
x x 
 
x x 
x x 
 
x.x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Compliance [2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   >100% 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   >90 – 100% 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   >80 – 90% 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   >70 – 80% 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   <70% 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
Source: xxx 
Note: Percentages are based on the N of each dose regimen. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Duration of treatment is defined as the last dose date minus the first dose date plus 1 divided by 7. 
[2]  Compliance is calculated using the following equation: Compliance (%)=(Actual number of used doses in total)/(Number of days from treatment start date to treatment end) 
×100%.  


 
 
 
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time   
 
Programmer Note: Compliance can be further broken down by visits as appropriate.


 
 
 
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Table 14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events  
Safety Population 
 
Dose Escalation 
 
Dose Confirmation 
 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg  
 (N=) 
 48 mg  
 (N=) 
96 mg  
 (N=) 
 
48 mg  
 (N=) 
96 mg  
 (N=) 
 
Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients Reporting at Least One 
TEAE 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
Patients Reporting at Least One 
TEAE Related to ZEN003694[2] 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
Patients Reporting at Least One 
TEAE Related to Enzalutamide[2] 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
Patients Reporting at Least One 
Serious TEAE 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
Patients Reporting at Least One 
Serious TEAE Related to 
ZEN003694[2] 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
Patients Reporting at Least One 
Serious TEAE Related to 
Enzalutamide[2] 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
Patients Reporting at Least One 
TEAE Leading to Death 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
Patients Reporting at Least One 
TEAE Leading to Study 
Discontinuation 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum Severity of TEAEs by 
CTCAE Grade[1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Grade 1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Grade 2 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Grade 3 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Grade 4 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Grade 5 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maximum Severity of Serious 
TEAEs by CTCAE Grade[1] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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  Grade 1 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Grade 2 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Grade 3 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Grade 4 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Grade 5 
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Closest Relationship to ZEN003694 
[2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Related[3]  
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Not Related[4]  
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Closest Relationship to 
Enzalutamide[2] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Related[3]  
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Not Related[4]  
n (%) 
n (%) 
… 
n (%) 
n (%) 
 
n (%) 
n (%) 
… 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: Percentages are based on the N of each dose regimen. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Patients reporting more than one adverse event are counted only once using the highest severity.  
[2] Patients reporting more than one adverse event are counted only once using the closest relationship to study drug.  
[3] Includes all events reported as "Related" or missing relationship to study drug. 
[4] Includes all events reported as "Not Related" relationship to study drug. 
 
path\t_program.sas date 
time   
 


 
 
 
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Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Safety Population 
Part 1 of 3 
 
Dose Escalation 
DE-A 
System Organ Class /  
  Preferred Term 
36 mg 
(N=   ) 
48 mg 
(N=   ) 
… 
120 mg 
(N=   ) 
144mg 
(N=   ) 
Patients [1] 
Events Patients [1] Events 
 
Patients [1] Events 
Patients [1] Events 
 
 
 
 
 
 
 
 
 
Patients Reporting at Least One Adverse Event 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
 
 
 
 
 
 
 
 
System Organ Class 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
Preferred Term 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
Preferred Term 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
. 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
Preferred Term 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
Preferred Term 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
 
 
 
 
 
 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Safety Population 
Part 2 of 3 
 
Dose Escalation 
DE-B 
System Organ Class /  
  Preferred Term 
36 mg 
(N=   ) 
48 mg 
(N=   ) 
… 
72 mg 
(N=   ) 
96mg 
(N=   ) 
Patients [1] 
Events Patients [1] Events 
 
Patients [1] Events 
Patients [1] Events 
 
 
 
 
 
 
 
 
 
Patients Reporting at Least One Adverse Event 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
 
 
 
 
 
 
 
 
System Organ Class 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
Preferred Term 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 


 
 
 
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Preferred Term 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
. 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
Preferred Term 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
Preferred Term 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
 
 
 
 
 
 
Table 14.3.1.2 
Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
Safety Population 
Part 3 of 3 
 
Dose Confirmation 
 
 
DC-A 
 
DC-B 
 
 
System Organ Class /  
  Preferred Term 
36 mg 
(N=   ) 
48 mg 
(N=   ) 
 
72 mg 
(N=   ) 
96mg 
(N=   ) 
 
Total 
(N=   ) 
Patients [1] Events Patients [1] Events  Patients [1] Events Patients [1] Events  Patients [1] Events 
 
 
 
 
 
 
 
 
 
 
 
 
Patients Reporting at Least One 
Adverse Event 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
n (%) 
n 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
n (%) 
n 
Preferred Term 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
n (%) 
n 
Preferred Term 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
n (%) 
n 
. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
n (%) 
n 
Preferred Term 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
n (%) 
n 
Preferred Term 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
n (%) 
n 
 
 
  
 
 
 
Source: xxx 
Note: DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
 [1] Percentages are based on the N of each dose regimen. At each level of summation (overall, system organ class, preferred term), patients reporting more than one adverse event 
are counted only once. 
 
path\t_program.sas date 
time   
 


 
 
 
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Repeat format for the following tables: 
14.3.1.5 “Treatment-Emergent Serious Adverse Events by System Organ Class and Preferred Term (Safety Population)” Update first row label to “Patients Reporting at Least 
One Serious Adverse Event” 
14.3.1.8 “Treatment-Emergent Adverse Events Leading to Death by System Organ Class and Preferred Term (Safety Population)” Update first row label to “Patients 
Reporting at Least One Adverse Event Leading to Death” 
14.3.1.9 “Treatment-Emergent Adverse Events Leading to Study Discontinuation by System Organ Class and Preferred Term (Safety Population)” Update first row label to 
“Patients Reporting at Least One Adverse Event Leading to Study Discontinuation” 


 
 
 
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                                                                                                  Statistical Analysis Plan 
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Table 14.3.1.3 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and Maximum Severity 
Safety Population 
Part 1 of 4 
 
Dose Escalation 
DE-A 
System Organ Class /  
  Preferred Term 
36 mg 
(N=   ) 
… 
144 mg 
(N=  ) 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
 
 
 
 
 
 
 
 
 
 
Patients Reporting at Least One 
Adverse Event 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
Table 14.3.1.3 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and Maximum Severity 
Safety Population 
Part 2 of 4 
 
Dose Escalation 
DE-B 
System Organ Class /  
  Preferred Term 
36 mg 
(N=   ) 
… 
96 mg 
(N=  ) 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
 
 
 
 
 
 
 
 
 
 
Patients Reporting at Least One 
Adverse Event 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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System Organ Class 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
Table 14.3.1.3 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and Maximum Severity 
Safety Population 
Part 3 of 4 
 
Dose Confirmation 
DC-A 
System Organ Class /  
  Preferred Term 
36 mg 
(N=   ) 
96 mg 
(N=  ) 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
 
 
 
 
 
 
 
 
 
Patients Reporting at Least One Adverse Event 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
System Organ Class 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.3.1.3 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and Maximum Severity 
Safety Population 
Part 4 of 4 
 
Dose Confirmation 
 
 
DC-A 
 
 
System Organ Class /  
  Preferred Term 
36 mg 
(N=   ) 
96 mg 
(N=  ) 
Total 
(N=  ) 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Grade 1 Grade 2 Grade 3 Grade 4 Grade 5  Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patients Reporting at 
Least One Adverse Event 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
Source: xxx 
Note: Percentages are based on the N of each dose regimen. At each level of summation (overall, system organ class, preferred term), patients reporting more than one adverse 
event are counted only once using the highest severity. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
 
path\t_program.sas date 
time   
 
Repeat format for the following tables: 
14.3.1.6 “Serious Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and Maximum Severity (Safety Population)” Update first row label to 
“Patients Reporting at Least One Serious Adverse Event” 
 


 
 
 
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             Page 1 of x 
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Table 14.3.1.4 
Treatment-Emergent Related[1] Adverse Events by System Organ Class and Preferred Term 
Safety Population 
Part 1 of 3 
 
Dose Escalation 
DE-A 
System Organ Class /  
  Preferred Term 
36 mg 
(N=   ) 
48 mg 
(N=   ) 
… 
120 mg 
(N=   ) 
144mg 
(N=   ) 
Patients [2] Events Patients [2] 
Events 
 
Patients [2] Events Patients [2] Events 
 
 
 
 
 
 
 
 
 
Patients Reporting at Least One Related [1] Adverse Event 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
 
 
 
 
 
 
 
 
System Organ Class 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
Preferred Term 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
Preferred Term 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
. 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
Preferred Term 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
Preferred Term 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
 
 
 
 
 
 
Table 14.3.1.4 
Treatment-Emergent Related[1] Adverse Events by System Organ Class and Preferred Term 
Safety Population 
Part 2 of 3 
 
Dose Escalation 
DE-B 
System Organ Class /  
  Preferred Term 
36 mg 
(N=   ) 
48 mg 
(N=   ) 
… 
72 mg 
(N=   ) 
96mg 
(N=   ) 
Patients [2] 
Events Patients [2] Events 
 
Patients [2] Events Patients [2] Events 
 
 
 
 
 
 
 
 
 
Patients Reporting at Least One Related [1] Adverse Event 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
 
 
 
 
 
 
 
 
System Organ Class 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 


 
 
 
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Preferred Term 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
Preferred Term 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
. 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
Preferred Term 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
Preferred Term 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
 
 
 
 
 
 
Table 14.3.1.4 
Treatment-Emergent Related[1] Adverse Events by System Organ Class and Preferred Term 
Safety Population 
Part 3 of 3 
 
Dose Confirmation 
 
 
DC-A 
 
DC-B 
 
 
System Organ Class /  
  Preferred Term 
36 mg 
(N=   ) 
48 mg 
(N=   ) 
 
72 mg 
(N=   ) 
96mg 
(N=   ) 
 
Total 
(N=   ) 
Patients [2] Events Patients [2] Events  Patients [2] Events Patients [2] Events  Patients [2] Events 
 
 
 
 
 
 
 
 
 
 
 
 
Patients Reporting at Least One Related [1] Adverse Event 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
n (%) 
n 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
n (%) 
n 
Preferred Term 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
n (%) 
n 
Preferred Term 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
n (%) 
n 
. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
n (%) 
n 
Preferred Term 1 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
n (%) 
n 
Preferred Term 2 
n (%) 
n (%) 
n 
n 
 
n (%) 
n 
n (%) 
n 
 
n (%) 
n 
 
 
 
  
 
 
 
Source: xxx 
Note: DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Includes all events reported as "Related" or missing relationship to ZEN003694.  
[2] Percentages are based on the N of each dose regimen. At each level of summation (overall, system organ class, preferred term), patients reporting more than one related adverse 
event are counted only once. 
 


 
 
 
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Repeat format for the following tables: 
14.3.1.7 “Treatment-Emergent Related[1] Serious Adverse Events by System Organ Class and Preferred Term (Safety Population)” Update first row label to “Patients 
Reporting at Least One Serious Related[1] Adverse Event”  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.3.2.1 
Serious Adverse Events 
 
Dose 
Regimen 
Cohort 
Subject 
ID 
AE 
# 
Verbatim Term// 
MedDRA Preferred 
Term// 
System Organ Class 
Onset 
Date 
(Study 
Day) 
End Date 
(Study Day) 
Severity 
(CTCAE 
Toxicity 
Grade) 
DLT 
Relationship 
to 
ZEN003694 
 
Relationship 
to 
Enzalutamide 
Action Taken 
with 
ZEN003694 
 
Action Taken 
with  
Enzalutamide 
Treatment 
of Event 
Final 
Outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-
xxx 
xx xxxxxx 
date9. 
date9. 
grade Yes/No/NA relationship relationship action taken action taken treatment outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-
xxx 
xx xxxxxx 
date9. 
date9. 
grade Yes/No/NA relationship relationship action taken action taken treatment outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: NA=Not Applicable.  
* indicates onset of Adverse Event was prior to first Dose. 
 
path\l_program.sas date 
time   
 
Programmer note: sort by onset date and resolution date within each patient 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.3.2.2 
Treatment-Emergent Adverse Events Leading to Study Discontinuation 
 
Dose 
Regimen 
Cohort 
Subject 
ID 
AE 
# 
Verbatim Term// 
MedDRA Preferred 
Term// 
System Organ Class 
Onset 
Date 
(Study 
Day) 
End Date 
(Study Day) 
Severity 
(CTCAE 
Toxicity 
Grade) 
DLT 
Serious 
Relationship
to 
ZEN003694 
 
Relationship 
to 
Enzalutamide
Action 
Taken  
with 
ZEN003694 
 
Action Taken 
with  
Enzalutamide 
Treatment
of Event
Final 
Outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-
xxx 
xx xxxxxx 
date9. 
date9. 
grade Yes/No/NA Yes/No relationship relationship action taken action taken treatment outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-
xxx 
xx xxxxxx 
date9. 
date9. 
grade Yes/No/NA Yes/No relationship relationship action taken action taken treatment outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: NA=Not Applicable. 
 
path\l_program.sas date 
time   
 
Programmer note: sort by onset date and resolution date within each patient  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.3.2.3 
Treatment-Emergent Adverse Events Leading to Death 
Safety Population 
 
Dose 
Regimen 
Cohort 
Subject 
ID 
AE 
# 
Verbatim Term// 
MedDRA Preferred 
Term// 
System Organ Class 
Onset 
Date 
(Study 
Day) 
End Date 
(Study Day) 
Severity 
(CTCAE 
Toxicity 
Grade) 
DLT 
Serious 
Relationship
to 
ZEN003694 
 
Relationship 
to 
Enzalutamide
Action 
Taken  
with 
ZEN003694 
 
Action Taken 
with  
Enzalutamide 
Treatment
of Event
Final 
Outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-
xxx 
xx xxxxxx 
date9. 
date9. 
grade Yes/No/NA Yes/No relationship relationship action taken action taken treatment outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-
xxx 
xx xxxxxx 
date9. 
date9. 
grade Yes/No/NA Yes/No relationship relationship action taken action taken treatment outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: NA=Not Applicable. 
 
path\l_program.sas date 
time   
 
Programmer note: sort by onset date and resolution date within each patient 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.3.2.4 
Death Details 
 
Dose Regimen 
Cohort 
Subject ID 
Date of Death 
Cause of Death 
Comments 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
date9. 
Progressive Disease/Unknown/ 
Other, specify 
comments 
 
 
 
 
. 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
date9. 
Progressive Disease/Unknown/ 
Other, specify 
comments 
 
 
 
 
 
path\l_program.sas date 
time   
 
 
 
 
 


 
 
 
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Table 14.3.4.1 
Hematology 
Safety Population 
Part 1 of 2 
 
Dose Escalation 
 
DE-A 
 
DE-B 
 
Laboratory Parameter 
Time Point 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg 
 (N=) 
 
 
 
 
 
 
 
 
 
 
 
 
WBC (109 /L) 
Baseline [1] 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 8 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
Change from Baseline to C1D8 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutrophils (109 /L) 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.3.4.1 
Hematology 
Safety Population 
Part 2 of 2 
 
Dose Confirmation 
 
DC-A 
 
DC-B 
 
 
Laboratory Parameter 
Time Point 
48 mg 
(N=) 
96 mg 
(N=) 
 
48 mg 
(N=) 
96 mg 
(N=) 
 
Total 
(N=) 
 
 
 
 
 
 
 
WBC (109 /L) 
Baseline [1] 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
Cycle 1 Day 8 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
Change from Baseline to C1D8 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutrophils (109 /L) 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
 [1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
path\t_program.sas date 
time   
Programmer note: Table will include the following hematology parameters: WBC (109 /L), Neutrophils (109 /L), Lymphocytes (109 /L), etc. 


 
 
 
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Table 14.3.4.2 
Hematology – Shift from Baseline 
Safety Population 
Part 1 of 3 
 
Dose Escalation  
DE-A 
36 mg 
(N=   ) 
Baseline [1] 
 
… 
120 mg 
(N=   )  
Baseline [1] 
 
144 mg 
(N=   )  
Baseline [1] 
Laboratory Parameter 
Time Point 
Low 
Normal 
High 
 
 
Low 
Normal 
High 
 
Low 
Normal 
High 
 
 
 
 
 
 
 
 
 
 
 
 
WBC 
Cycle 1 Day 8 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutrophils 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.2 
Hematology – Shift from Baseline 
Safety Population 
Part 2 of 3 
 
Dose Escalation  
DE-B 
36 mg 
(N=   ) 
Baseline [1] 
 
… 
72 mg 
(N=   )  
Baseline [1] 
 
96 mg 
(N=   )  
Baseline [1] 


 
 
 
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Laboratory Parameter 
Time Point 
Low 
Normal 
High 
 
 
Low 
Normal 
High 
 
Low 
Normal 
High 
 
 
 
 
 
 
 
 
 
 
 
 
WBC 
Cycle 1 Day 8 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutrophils 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.2 
Hematology – Shift from Baseline 
Safety Population 
Part 3 of 3 
 
Dose Confirmation 
 
DC-A 
 
DC-B 
 
48 mg 
(N=   ) 
Baseline [1] 
 
96 mg 
(N=   )  
Baseline [1] 
 
48 mg 
(N=   )  
Baseline [1] 
 
48 mg 
(N=   )  
Baseline [1] 
 
Total 
(N=  ) 
Laboratory Parameter Time Point 
Low 
Normal 
High 
 
Low 
Normal 
High 
 
Low 
Normal 
High 
 
Low 
Normal 
High 
Low 
Normal 
High 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
WBC 
Cycle 1 Day 8 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neutrophils 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: Percentages are based on the n of each dose regimen by time point. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
 [1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
 
 
path\t_program.sas date 
time   
 
 
Programmer note: Table will include the following hematology parameters: WBC, Neutrophils, Lymphocyte, etc. 


 
 
 
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Table 14.3.4.3 
Select Hematology Parameters – CTCAE Shift from Baseline 
Safety Population 
Part 1 of 4 
 
Dose Escalation 
DE-A 
Laboratory Parameter 
Time Point 
36 mg 
(N=   ) 
… 
144 mg 
(N=  ) 
Baseline [1] 
 
Baseline [1] 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
 
 
 
 
 
 
 
 
 
 
Platelets 
Cycle 1 Day 8 
 
 
(n =   ) 
 
 
 
 
 
(n =   ) 
 
 
   Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
 
(n =   ) 
 
 
 
 
 
(n =   ) 
 
 
 
Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.3 
Select Hematology Parameters – CTCAE Shift from Baseline 
Safety Population 
Part 2 of 4 
 
Dose Escalation 


 
 
 
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DE-B 
Laboratory Parameter 
Time Point 
36 mg 
(N=   ) 
… 
96 mg 
(N=  ) 
Baseline [1] 
 
Baseline [1] 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
 
 
 
 
 
 
 
 
 
 
Platelets 
Cycle 1 Day 8 
 
 
(n =   ) 
 
 
 
 
 
(n =   ) 
 
 
   Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
 
(n =   ) 
 
 
 
 
 
(n =   ) 
 
 
 
Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.3 
Select Hematology Parameters – CTCAE Shift from Baseline 
Safety Population 
Part 3 of 4 
 
Dose Confirmation 
DC-A 
Laboratory Parameter 
Time Point 
36 mg 
(N=   ) 
96 mg 
(N=  ) 
Baseline [1] 
Baseline [1] 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
 
 
 
 
 
 
 
 
 
Platelets 
Cycle 1 Day 8 
 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 


 
 
 
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   Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.3 
Select Hematology Parameters – CTCAE Shift from Baseline 
Safety Population 
Part 4 of 4 
 
Dose Confirmation 
 
 
DC-A 
 
 
Laboratory 
Parameter 
Time Point 
36 mg 
(N=   ) 
96 mg 
(N=  ) 
Total 
(N=  ) 
Baseline [1] 
Baseline [1] 
Baseline [1] 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Grade 1 Grade 2 Grade 3 Grade 4 Grade 5  Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Platelets 
Cycle 1 Day 8 
 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
 
 
(n =   ) 
 
 
   Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
 
 
(n =   ) 
 
 


 
 
 
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Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: Percentages are based on the n of each dose regimen by time point. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
 
path\t_program.sas date 
time   
 
 
Programmer note: Table will include the following hematology parameters: Platelets, WBC, Neutrophils, and Lymphocyte. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.3.4.4 
Coagulation 
Safety Population 
Part 1 of 2 
 
Dose Escalation 
 
DE-A 
 
DE-B 
 
Laboratory Parameter 
Time Point 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg 
 (N=) 
 
 
 
 
 
 
 
 
 
 
 
 
PT (sec) 
Baseline [1] 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
Change from Baseline to C1D15 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INR 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.4 
Coagulation 
Safety Population 
Part 2 of 2 


 
 
 
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Dose Confirmation 
 
DC-A 
 
DC-B 
 
 
Laboratory Parameter 
Time Point 
48 mg 
(N=) 
96 mg 
(N=) 
 
48 mg 
(N=) 
96 mg 
(N=) 
 
Total 
(N=) 
 
 
 
 
 
 
 
PT (sec) 
Baseline [1] 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
Change from Baseline to C1D15 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INR 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
Source: xxx 
Note: PT=Prothrombin Time; INR=International Normalized Ratio; PTT= Partial Thromboplastin Time. Note: DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-
B indicate abiraterone progressor. 
[1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
 
path\t_program.sas date 
time   
Programmer note: Table will include the following coagulation parameters: PT (sec), INR, and PTT (sec) 


 
 
 
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Table 14.3.4.5 
Coagulation – Shift from Baseline 
Safety Population 
Part 1 of 3 
 
Dose Escalation  
DE-A 
36 mg 
(N=   ) 
Baseline [1] 
 
… 
120 mg 
(N=   )  
Baseline [1] 
 
144 mg 
(N=   )  
Baseline [1] 
Laboratory Parameter 
Time Point 
Low 
Normal 
High 
 
 
Low 
Normal 
High 
 
Low 
Normal 
High 
 
 
 
 
 
 
 
 
 
 
 
 
PTT 
Cycle 1 Day 15 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 Day 1 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INR 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.5 
Coagulation – Shift from Baseline 
Safety Population 
Part 2 of 3 
 
Dose Escalation  
DE-B 


 
 
 
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36 mg 
(N=   ) 
Baseline [1] 
 
… 
72 mg 
(N=   )  
Baseline [1] 
 
96 mg 
(N=   )  
Baseline [1] 
Laboratory Parameter 
Time Point 
Low 
Normal 
High 
 
 
Low 
Normal 
High 
 
Low 
Normal 
High 
 
 
 
 
 
 
 
 
 
 
 
 
PTT 
Cycle 1 Day 15 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 Day 1 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INR 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.5 
Coagulation – Shift from Baseline 
Safety Population 
Part 3 of 3 
 
Dose Confirmation 
 
DC-A 
 
DC-B 
 
48 mg 
(N=   ) 
Baseline [1] 
 
96 mg 
(N=   )  
Baseline [1] 
 
48 mg 
(N=   )  
Baseline [1] 
 
48 mg 
(N=   )  
Baseline [1] 
 
Total 
(N=  ) 
Laboratory Parameter Time Point 
Low 
Normal 
High 
 
Low 
Normal 
High 
 
Low 
Normal 
High 
 
Low 
Normal 
High 
Low 
Normal 
High 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PTT 
Cycle 1 Day 15 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 Day 1 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 


 
 
 
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Normal 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INR 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: Percentages are based on the n of each dose regimen by time point. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
 
path\t_program.sas date 
time   
 
 
Programmer note: Table will include the following coagulation parameters: PT, INR, and PTT. 
 
 


 
 
 
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Table 14.3.4.6 
Serum Chemistry 
Safety Population 
Part 1 of 2 
 
Dose Escalation 
 
DE-A 
 
DE-B 
 
Laboratory Parameter 
Time Point 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg 
 (N=) 
 
 
 
 
 
 
 
 
 
 
 
 
ALT (SGPT) (U/L) 
Baseline [1] 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Baseline 1 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
Change from Baseline to PB 1 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST (SGOT) (U/L) 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.3.4.6 
Serum Chemistry 
Safety Population 
Part 2 of 2 
 
Dose Confirmation 
 
DC-A 
 
DC-B 
 
 
Laboratory Parameter 
Time Point 
48 mg 
(N=) 
96 mg 
(N=) 
 
48 mg 
(N=) 
96 mg 
(N=) 
 
Total 
(N=) 
 
 
 
 
 
 
 
ALT (SGPT) (U/L) 
Baseline [1] 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
Post-Baseline 1 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
Change from Baseline to PB 1 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST (SGOT) (U/L) 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
 


 
 
 
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time   
Programmer note: Table will include the following serum chemistry parameters: ALT (SGPT) (U/L), AST (SGOT) (U/L), Alkaline Phosphatase (U/L), Amylase (U/L), Albumin 
(g/L), Total Bilirubin (umol/L), Blood Urea Nitrogen (BUN) (mmol/L), Creatinine (umol/L), Sodium (mmol/L), Potassium (mmol/L), Chloride (mmol/L), Bicarbonate (mmol/L), 
Phosphorous (mmol/L), Calcium (mmol/L), Glucose (mmol/L), Magnesium (mmol/L), LDH (U/L), Lipase (U/L), and Serum Testosterone (nmol/L). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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ZEN003694-002 
 
Table 14.3.4.7 
Serum Chemistry – Shift from Baseline 
Safety Population 
Part 1 of 3 
 
Dose Escalation  
DE-A 
36 mg 
(N=   ) 
Baseline [1] 
 
… 
120 mg 
(N=   )  
Baseline [1] 
 
144 mg 
(N=   )  
Baseline [1] 
Laboratory Parameter 
Time Point 
Low 
Normal 
High 
 
 
Low 
Normal 
High 
 
Low 
Normal 
High 
 
 
 
 
 
 
 
 
 
 
 
 
ALT (SGPT) 
Post-Baseline 1 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Baseline 2 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST (SGOT) 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.7 
Serum Chemistry – Shift from Baseline 
Safety Population 
Part 2 of 3 
 
Dose Escalation  
DE-B 


 
 
 
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36 mg 
(N=   ) 
Baseline [1] 
 
… 
72 mg 
(N=   )  
Baseline [1] 
 
96 mg 
(N=   )  
Baseline [1] 
Laboratory Parameter 
Time Point 
Low 
Normal 
High 
 
 
Low 
Normal 
High 
 
Low 
Normal 
High 
 
 
 
 
 
 
 
 
 
 
 
 
ALT (SGPT) 
Post-Baseline 1 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Baseline 2 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST (SGOT) 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.7 
Serum Chemistry – Shift from Baseline 
Safety Population 
Part 3 of 3 
 
Dose Confirmation 
 
DC-A 
 
DC-B 
 
48 mg 
(N=   ) 
Baseline [1] 
 
96 mg 
(N=   )  
Baseline [1] 
 
48 mg 
(N=   )  
Baseline [1] 
 
48 mg 
(N=   )  
Baseline [1] 
 
Total 
(N=  ) 
Laboratory Parameter Time Point 
Low 
Normal 
High 
 
Low 
Normal 
High 
 
Low 
Normal 
High 
 
Low 
Normal 
High 
Low 
Normal 
High 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT (SGPT) 
Post-Baseline 1 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
Normal 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Baseline 2 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
 
(n =   ) 
 
 
(n =   ) 
 
Low 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 


 
 
 
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Normal 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
High 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%)
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AST (SGOT) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: Percentages are based on the n of each dose regimen by time point. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
 
path\t_program.sas date 
time   
 
 
Programmer note: Table will include the following serum chemistry parameters: ALT (SGPT), AST (SGOT), Alkaline Phosphatase, etc. 


 
 
 
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Table 14.3.4.8 
Select Serum Chemistry Parameters– CTCAE Shift from Baseline 
Safety Population 
Part 1 of 4 
 
Dose Escalation 
DE-A 
Laboratory Parameter 
Time Point 
36 mg 
(N=   ) 
… 
144 mg 
(N=  ) 
Baseline [1] 
 
Baseline [1] 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
 
 
 
 
 
 
 
 
 
 
ALT (SGPT) 
Cycle 1 Day 8 
 
 
(n =   ) 
 
 
 
 
 
(n =   ) 
 
 
   Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
 
(n =   ) 
 
 
 
 
 
(n =   ) 
 
 
 
Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.8 
Select Serum Chemistry Parameters– CTCAE Shift from Baseline 
Safety Population 
Part 2 of 4 
 


 
 
 
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Dose Escalation 
DE-B 
Laboratory Parameter 
Time Point 
36 mg 
(N=   ) 
… 
96 mg 
(N=  ) 
Baseline [1] 
 
Baseline [1] 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
 
 
 
 
 
 
 
 
 
 
ALT (SGPT) 
Cycle 1 Day 8 
 
 
(n =   ) 
 
 
 
 
 
(n =   ) 
 
 
   Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
 
(n =   ) 
 
 
 
 
 
(n =   ) 
 
 
 
Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.8 
Select Serum Chemistry Parameters– CTCAE Shift from Baseline 
Safety Population 
Part 3 of 4 
 
Dose Confirmation 
DC-A 
Laboratory Parameter 
Time Point 
36 mg 
(N=   ) 
96 mg 
(N=  ) 
Baseline [1] 
Baseline [1] 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
 
 
 
 
 
 
 
 
 


 
 
 
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ALT (SGPT) 
Cycle 1 Day 8 
 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
   Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.8 
Select Serum Chemistry Parameters– CTCAE Shift from Baseline 
Safety Population 
Part 4 of 4 
 
Dose Confirmation 
 
 
DC-A 
 
 
Laboratory 
Parameter 
Time Point 
36 mg 
(N=   ) 
96 mg 
(N=  ) 
Total 
(N=  ) 
Baseline [1] 
Baseline [1] 
Baseline [1] 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Grade 1 Grade 2 Grade 3 Grade 4 Grade 5  Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALT (SGPT) 
Cycle 1 Day 8 
 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
 
 
(n =   ) 
 
 
   Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Cycle 1 Day 15 
 
 
(n =   ) 
 
 
 
 
(n =   ) 
 
 
 
 
 
(n =   ) 
 
 
 
Grade 0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
Grade 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
   Grade 4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Source: xxx 
Note: Percentages are based on the n of each dose regimen by time point. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
 
path\t_program.sas date 
time   
 
Programmer note: Table will include the following serum chemistry parameters: ALT (SGPT), AST (SGOT), Total Bilirubin, Creatinine, and Glucose  


 
 
 
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Table 14.3.4.9 
Serum Troponin 
Safety Population 
Part 1 of 2 
 
Dose Escalation 
 
DE-A 
 
DE-B 
 
Laboratory Parameter 
Time Point 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg 
 (N=) 
 
 
 
 
 
 
 
 
 
 
 
 
Troponin I (ng/mL) 
Baseline [1] 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Baseline 1 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
Change from Baseline to PB 1 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.3.4.9 
Serum Troponin 
Safety Population 
Part 2 of 2 
 
Dose Confirmation 
 
DC-A 
 
DC-B 
 
 
Laboratory Parameter 
Time Point 
48 mg 
(N=) 
96 mg 
(N=) 
 
48 mg 
(N=) 
96 mg 
(N=) 
 
Total 
(N=) 
 
 
 
 
 
 
 
Troponin I (ng/mL) 
Baseline [1] 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
Post-Baseline 1 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
Change from Baseline to PB 1 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
 
path\t_program.sas date 
time  Programmer note: Table will include all applicable dose escalation cohorts, and time points. If Troponin T records are available, add 
Troponin T summaries by visit as well. 


 
 
 
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Table 14.3.4.10 
Incidence of Clinically Significant Laboratory Abnormalities 
Safety Population 
 
Dose Escalation 
 
Dose Confirmation 
 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
 
Any Post-Baseline  
Clinically Significant 
Abnormalities? 
 
36 mg  
 (N=) 
 
48 mg  
 (N=) 
 
… 
 
120 mg  
 (N=) 
 
144 mg  
 (N=) 
 
 
36 mg  
 (N=) 
 
48 mg  
 (N=) 
 
…  
  
 
96 mg  
 (N=) 
 
 
48 mg  
 (N=) 
 
96 mg  
 (N=) 
 
 
48 mg  
 (N=) 
 
96 mg  
 (N=) 
 
 
Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   WBC 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   Neutrophils 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   ALT (SGPT) 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   AST (SGOT) 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   . 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: Percentages are based on the N of each dose regimen. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
 
 
path\t_program.sas date 
time   


 
 
 
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Table 14.3.4.11 
Eastern Cooperative Oncology Group (ECOG) Performance Status – Shift from Baseline 
Safety Population 
Part 1 of 4 
 
Dose Escalation 
DE-A 
36 mg 
(N= ) 
 
48 mg 
(N= ) 
 
… 
144 mg 
(N=   ) 
Baseline[1] 
 
Baseline[1] 
 
Baseline[1] 
Time Point 
 
0 
1 
2 
3 
4 
5 
 
 
0 
1 
2 
3 
4 
5 
 
 
0 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 8 
 
 
(n =   ) 
 
 
 
 
 
 
(n =   ) 
 
 
 
 
 
 
(n =   ) 
 
 
 
0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
5 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
 
(n =   ) 
 
 
 
 
 
 
(n =   ) 
 
 
 
 
 
 
(n =   ) 
 
 
 
0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
5 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.11 
Eastern Cooperative Oncology Group (ECOG) Performance Status – Shift from Baseline 
Safety Population 
Part 2 of 4 
 
Dose Escalation 
DE-B 


 
 
 
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36 mg 
(N= ) 
 
48 mg 
(N= ) 
 
… 
96 mg 
(N=   ) 
Baseline[1] 
 
Baseline[1] 
 
Baseline[1] 
Time Point 
 
0 
1 
2 
3 
4 
5 
 
 
0 
1 
2 
3 
4 
5 
 
 
0 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 8 
 
 
(n =   ) 
 
 
 
 
 
 
(n =   ) 
 
 
 
 
 
 
(n =   ) 
 
 
 
0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
5 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
 
(n =   ) 
 
 
 
 
 
 
(n =   ) 
 
 
 
 
 
 
(n =   ) 
 
 
 
0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
5 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.11 
Eastern Cooperative Oncology Group (ECOG) Performance Status – Shift from Baseline 
Safety Population 
Part 3 of 4 
 
Dose Confirmation 
DC-A 
48 mg 
(N= ) 
 
96 mg 
(N= ) 
Baseline[1] 
 
Baseline[1] 
Time Point 
 
0 
1 
2 
3 
4 
5 
 
 
0 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 8 
 
 
(n =   ) 
 
 
 
 
 
 
(n =   ) 
 
 
 
0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
    2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
    3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 


 
 
 
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    4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
    5 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
 
(n =   ) 
 
 
 
 
 
 
(n =   ) 
 
 
 
0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
    2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
    3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
    4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
    5 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.11 
Eastern Cooperative Oncology Group (ECOG) Performance Status – Shift from Baseline 
Safety Population 
Part 4 of 4 
 
Dose Confirmation 
 
DC-B 
 
48 mg 
(N= ) 
 
96 mg 
(N= ) 
Total 
(N=   ) 
Baseline[1] 
 
Baseline[1] 
Baseline[1] 
Time Point 
 
0 
1 
2 
3 
4 
5 
 
 
0 
1 
2 
3 
4 
5 
 
0 
1 
2 
3 
4 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 8 
 
 
(n =   ) 
 
 
 
 
 
 
(n =   ) 
 
 
 
 
 
(n =   ) 
 
 
 
0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
    2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
    3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
    4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
    5 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 1 Day 15 
 
 
(n =   ) 
 
 
 
 
 
 
(n =   ) 
 
 
 
 
 
(n =   ) 
 
 
 
0 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
    2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
    3 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
    4 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
    5 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Source: xxx 
Note: Percentages are based on the n of each dose regimen by time point. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
 
path\t_program.sas date 
time  
 
Programmer note: Table will include all applicable dose escalation cohorts, and time points. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.3.4.12 
Vital Signs 
Safety Population 
Part 1 of 2 
 
Dose Escalation 
 
DE-A 
 
DE-B 
 
Vital Sign 
Time Point 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg 
 (N=) 
 
 
 
 
 
 
 
 
 
 
 
 
Systolic Blood Pressure (mmHg) 
Baseline [1] 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Baseline 1 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
Change from Baseline to PB 1 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
Diastolic Blood Pressure (mmHg) 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.3.4.12 
Vital Signs 
Safety Population 
Part 2 of 2 
 
Dose Confirmation 
 
DC-A 
 
DC-B 
 
 
Vital Sign 
Time Point 
48 mg 
(N=) 
96 mg 
(N=) 
 
48 mg 
(N=) 
96 mg 
(N=) 
 
Total 
(N=) 
 
 
 
 
 
 
 
Systolic Blood Pressure (mmHg) 
Baseline [1] 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
Post-Baseline 1 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
Change from Baseline to PB 1 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
Diastolic Blood Pressure (mmHg) 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
 
path\t_program.sas date 
time   
Programmer note: Table will include the following vital signs: systolic BP (mmHg), diastolic BP (mmHg), etc. 


 
 
 
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                                                                                                                                                                                                                             Page 1 of x 
ZEN003694-002 
 
Table 14.3.4.13 
12-Lead Electrocardiogram  
Safety Population 
Part 1 of 2 
 
Dose Escalation 
 
DE-A 
 
DE-B 
 
ECG Parameter 
Time Point 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg 
 (N=) 
 
 
 
 
 
 
 
 
 
 
 
 
Ventricular Rate (bpm) 
Baseline [1] 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Baseline 1 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
Change from Baseline to PB 1 
 
 
 
 
 
 
 
 
 
 
 
   n 
n 
n 
… 
n 
n 
 
n 
n 
… 
n 
 
   Mean (SD) 
x x (x xx) x x (x.xx) … 
x x (x.xx) x x (x.xx)  x.x (x xx) x.x (x xx) 
… x.x (x xx)  
   Median 
x x 
x x 
… 
x x 
x x 
 
x.x 
x.x 
… 
x.x 
 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RR Interval (msec) 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.3.4.13 
12-Lead Electrocardiogram  
Safety Population 
Part 2 of 2 
 
Dose Confirmation 
 
DC-A 
 
DC-B 
 
 
ECG Parameter 
Time Point 
48 mg 
(N=) 
96 mg 
(N=) 
 
48 mg 
(N=) 
96 mg 
(N=) 
 
Total 
(N=) 
 
 
 
 
 
 
 
Ventricular Rate (bpm) 
Baseline [1] 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
Post-Baseline 1 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
Change from Baseline to PB 1 
 
 
 
 
 
 
 
   n 
n 
n 
 
n 
n 
 
n 
   Mean (SD) 
x x (x xx) 
x x (x xx) 
 x x (x xx) 
x x (x xx)  x x (x xx) 
   Median 
x x 
x x 
 
x x 
x x 
 
x x 
   Min, Max 
x, x 
x, x 
 
x, x 
x, x 
 
x, x 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RR Interval (msec) 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
Source: xxx 
Note: All descriptive statistics for each ECG parameters are based on the averaged triplicate measurements at each time point. DE-A and DC-A indicate enzalutamide progressor. 
DE-B and DC-B indicate abiraterone progressor. 
[1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
 
path\t_program.sas date 
time   


 
 
 
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                                                                                                  Statistical Analysis Plan 
ZEN003694-002 
                                                                                                                                          27 January 2020 
 
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Programmer note: Table will include the following ECG parameters: Ventricular rate (bpm RR Interval (msec), PR Interval (msec), QRS Duration (msec), QT Interval (msec), and 
QTcF (Fridericia's Method) (msec). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Zenith Epigenetics Ltd. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 14.3.4.14 
12-Lead Electrocardiogram – QTc Abnormalities  
Safety Population 
Part 1 of 2 
 
Dose Escalation 
 
DE-A 
 
DE-B 
 
ECG Parameter 
Time Point 
36 mg  
 (N=) 
48 mg  
 (N=) 
… 
120 mg  
 (N=) 
144 mg  
 (N=) 
 36 mg  
 (N=) 
48 mg  
 (N=) 
…  
  
96 mg 
 (N=) 
 
 
 
 
 
 
 
 
 
 
 
 
QTcF (Fridericia's Method) 
Baseline [1] 
(n =   ) 
(n =   ) 
 
(n =   ) 
(n =   )  (n =   ) 
(n =   ) 
 
(n =   )  
   > 450 msec and < 480 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
   > 480 msec and < 500 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
   > 500 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Any Post-Baseline 
 
 
 
 
 
 
 
 
 
 
 
   > 450 msec and < 480 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
   > 480 msec and < 500 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
   > 500 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Change from Baseline to Any PB 
 
 
 
 
 
 
 
 
 
 
 
   > 30 msec and < 60 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
   > 60 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Post-Baseline 1 
(n =   ) 
(n =   ) 
 
(n =   ) 
(n =   )  (n =   ) 
(n =   ) 
 
(n =   )  
   > 450 msec and < 480 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
   > 480 msec and < 500 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
   > 500 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
Change from Baseline to PB 1 
(n =   ) 
(n =   ) 
 
(n =   ) 
(n =   )  (n =   ) 
(n =   ) 
 
(n =   )  
   > 30 msec and < 60 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
   > 60 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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                                                                                                  Statistical Analysis Plan 
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                                                                                                                                          27 January 2020 
 
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Table 14.3.4.14 
12-Lead Electrocardiogram – QTc Abnormalities  
Safety Population 
Part 2 of 2 
 
Dose Confirmation 
 
DC-A 
 
DC-B 
 
 
ECG Parameter 
Time Point 
48 mg 
(N=) 
96 mg 
(N=) 
 
48 mg 
(N=) 
96 mg 
(N=) 
 
Total 
(N=) 
 
 
 
 
 
 
 
QTcF (Fridericia's Method) 
Baseline [1] 
(n =   ) 
(n =   ) 
 
(n =   ) 
(n =   ) 
 
(n =   ) 
   > 450 msec and < 480 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   > 480 msec and < 500 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   > 500 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
Any Post-Baseline 
 
 
 
 
 
 
 
   > 450 msec and < 480 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   > 480 msec and < 500 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   > 500 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
Change from Baseline to Any PB 
 
 
 
 
 
 
 
   > 30 msec and < 60 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   > 60 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
Post-Baseline 1 
(n =   ) 
(n =   ) 
 
(n =   ) 
(n =   ) 
 
(n =   ) 
   > 450 msec and < 480 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   > 480 msec and < 500 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   > 500 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
Change from Baseline to PB 1 
(n =   ) 
(n =   ) 
 
(n =   ) 
(n =   ) 
 
(n =   ) 
   > 30 msec and < 60 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   > 60 msec 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
. 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
Source: xxx 
Note: Percentages are based on the n of each dose regimen by time point. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
 
path\t_program.sas date 
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Table 14.3.4.15 
Ophthalmology Assessments (On-Study Examination) – Clinically Significant Changes from Baseline 
Safety Population 
 
 
Dose Escalation 
 
Dose Confirmation 
 
 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
 
Time Point 
 
 
Eye 
 
36 mg  
 (N=) 
 
48 mg  
 (N=) 
 
… 
 
120 mg  
 (N=) 
 
144 mg  
 (N=) 
 
 
36 mg  
 (N=) 
 
48 mg  
 (N=) 
 
…  
  
 
96 mg  
 (N=) 
 
 
48 mg  
 (N=) 
 
96 mg  
 (N=) 
 
 
48 mg  
 (N=) 
 
96 mg  
 (N=) 
 
 
Total 
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 Day 1 
Left/Right 
(n =   ) 
(n =   ) 
 
(n =   ) 
(n =   )  (n =   ) 
(n =   ) 
 
(n =   ) 
 (n =   ) 
(n =   )  (n =   ) 
(n =   ) 
 
(n =   ) 
New clinically significant changes 
from baseline 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Consistent with Drug Effect 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Not Consistent with Drug Effect 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
      Unknown 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      BCVA 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
      Color Vision Plates 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
      RAPD 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
      Pupil diameter in bright light 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
      Pupil diameter in dim light 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
      Velocity of pupillary 
constriction 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
      Intraocular Pressure 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
      Slip lamp exam 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
      Dilated fundoscopic exam 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
      OCT of the optic nerve 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
      Macular OCT 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
      Fundus photographs of the 
posterior pole 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 6 Day 1 
Left/Right 
(n =   ) 
(n =   ) 
 
(n =   ) 
(n =   )  (n =   ) 
(n =   ) 
 
(n =   ) 
 (n =   ) 
(n =   )  (n =   ) 
(n =   ) 
 
(n =   ) 
   . 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   . 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   . 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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                                                                                                  Statistical Analysis Plan 
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                                                                                                                                          27 January 2020 
 
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Source: xxx 
Note: Percentages are based on the n of each dose regimen by time point. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
 
path\t_program.sas date 
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Programmer note: Table will include all applicable dose escalation cohorts and time points. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Table 14.3.4.16 
Ophthalmology Assessments (Qualitative Exploration of Visual Symptoms)  
Safety Population 
 
Dose Escalation 
 
Dose Confirmation 
 
DE-A 
 
DE-B 
 
DC-A 
 
DC-B 
 
Time Point 
 
36 mg  
 (N=) 
 
48 mg  
 (N=) 
 
… 
 
120 mg  
 (N=) 
 
144 mg  
 (N=) 
 
 
36 mg  
 (N=) 
 
48 mg  
 (N=) 
 
…  
  
 
96 mg  
 (N=) 
 
 
48 mg  
 (N=) 
 
96 mg  
 (N=) 
 
 
48 mg  
 (N=) 
 
96 mg  
 (N=) 
 
 
Total
(N=) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline [1] 
(n =   ) 
(n =   ) 
 
(n =   ) 
(n =   )  (n =   ) 
(n =   ) 
 
(n =   )  (n =   ) 
(n =   )  (n =   ) 
(n =   )  
(n =   ) 
  Abnormal color vision 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Perception of light appearing 
brighter than normal 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Pain or discomfort when in 
bright environments or looking at  
bright lights 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Perception of flashing lights 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Trouble navigating or seeing in 
dimly lit environments 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle 2 Day 1 
(n =   ) 
(n =   ) 
 
(n =   ) 
(n =   )  (n =   ) 
(n =   ) 
 
(n =   )  (n =   ) 
(n =   )  (n =   ) 
(n =   )  
(n =   ) 
  Abnormal color vision 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Perception of light appearing 
brighter than normal 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Pain or discomfort when in 
bright environments or looking at  
bright lights 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Perception of flashing lights 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
  Trouble navigating or seeing in 
dimly lit environments 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Frequency of Symptoms 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     After every dose 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
     1-2 days/week 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
     3-4 days/week 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
     5-7 days/week 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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  Time after Dosing to Onset of 
Symptoms (mins) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    n    
x 
x 
 
x 
x 
 
x 
x 
 
x 
 
x 
x 
 
x 
x 
 
x 
    Mean (SD) 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx.x 
(xx xx) 
 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx.xx) 
xx x 
(xx xx) 
 
xx x 
(xx.xx) 
    Median 
xx x 
xx x 
 
xx x 
xx x 
 
xx x 
xx.x 
 
xx x 
 
xx x 
xx x 
 
xx x 
xx x 
 
xx x 
    Min, Max 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
    Unknown 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Time Until Resolution of 
Symptoms (mins) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    n    
x 
x 
 
x 
x 
 
x 
x 
 
x 
 
x 
x 
 
x 
x 
 
x 
    Mean (SD) 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx xx) 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx.x 
(xx xx) 
 
xx x 
(xx xx) 
 
xx x 
(xx xx) 
xx x 
(xx.xx) 
 
xx x 
(xx.xx) 
xx x 
(xx xx) 
 
xx x 
(xx.xx) 
    Median 
xx x 
xx x 
 
xx x 
xx x 
 
xx x 
xx.x 
 
xx x 
 
xx x 
xx x 
 
xx x 
xx x 
 
xx x 
    Min, Max 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
xx, xx 
    Unknown 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
    Symptoms Constant   
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Behaviors that lessen visual 
symptoms 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Change of symptoms over time 
while on study 
(n =   ) 
(n =   ) 
 
(n =   ) 
(n =   )  (n =   ) 
(n =   ) 
 
(n =   )  (n =   ) 
(n =   )  (n =   ) 
(n =   )  
(n =   ) 
     Yes, they are lessening 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
     Yes, they are worsening 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
     No, they remain about the 
same 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
     Not clear, the symptoms 
fluctuate too much to tell 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
n (%) 
 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Source: xxx 
Note: Percentages are based on the n of each dose regimen by time point. DE-A and DC-A indicate enzalutamide progressor. DE-B and DC-B indicate abiraterone progressor. 
[1] Baseline is defined as the last non-missing value recorded prior to the first dose of ZEN003694 for patients in Cohorts DE-A and DC-A. For patients in Cohorts DE-B and DC-
B, baseline is defined as the last non-missing value recorded prior to the first dose of enzalutamide. 
 
path\t_program.sas date 
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Programmer note: Table will include all applicable dose escalation cohorts and time points. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Appendix G:  Figure Layouts 
 
 
 
 




























 
 
 
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Appendix H:  Listing Layouts 


 
 
 
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Listing 16.2.1.1 
Patient Disposition 
 
Dose Regimen 
 
 
Cohort 
 
Subject 
ID 
 
Safety 
Population [1] 
 
PSA Evaluable 
Population [2] 
PSA Evaluable 
Population (12 Weeks 
of Treatment) 
Radiographic 
Evaluable 
Population [3] 
 
Date of  
First Dose 
 
Date of  
Last Dose 
 
Date of  
Study Exit 
Primary Reason for Study 
Completion/Discontinuation 
xx mg, Dose Escalation 
1 
xxx-xxx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
date9. 
date9. 
date9. 
reason 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
date9. 
date9. 
date9. 
reason 
 
[1] Patients who receive at least one dose of ZEN003694. 
[2] Patients who receive at least one dose of ZEN003694, have a non-missing baseline prostate-specific antigen (PSA), and have at least one non-missing postbaseline PSA 
assessment or who discontinue study treatment due to disease progression or death. 
[3] Patients who receive at least one dose of ZEN003694, have a non-missing baseline and have at least one evaluable postbaseline radiographic assessment or who discontinue 
study treatment due to disease progression or death. 
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Listing 16.2.2.1 
Protocol Deviations 
 
Dose Regimen 
 
Cohort 
Subject ID 
Deviation Type 
 
Protocol Deviation Category 
 
Description of Protocol Deviation 
xx mg, Dose Escalation 
1 
xxx-xxx 
Major/Minor 
category 
description 
 
 
 
 
. 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
Major/Minor 
category 
description 
 
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Listing 16.2.4.1 
Demographics and Baseline Characteristics 
 
Dose Regimen 
Cohort 
Subject 
ID 
Date 
Informed 
Consent 
Signed 
Birth  
Date 
Age on 
Consent Date 
(Years) 
Sex 
Race 
Ethnicity 
Height 
(cm) 
Weight 
(kg)
BMI 
(kg/m2) 
ECOG 
Score 
PSA 
(ng/mL)
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
date9. 
date9. 
xx 
Male/Female 
xxxxx 
Hispanic or Latino /  
Not Hispanic or Latino 
 xx x 
 xx x 
 xx x 
   x 
xx xxx 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
date9. 
date9. 
xx 
Male/Female 
xxxxx 
Hispanic or Latino /  
Not Hispanic or Latino 
 xx.x 
 xx x 
xx.x
   x 
xx xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Listing 16.2.4.2 
Medical History 
 
 
 
 
 
 
 
Dose Regimen 
Cohort 
Subject 
ID 
Primary System Organ Class 
Condition // Dictionary-Derived Term 
Onset 
Date 
Ongoing/ 
Resolved? 
Resolution Date 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx Primary System Organ Class 
condition // Dictionary-Derived Term 
date9./ 
Unknown 
Ongoing/ 
Resolved 
date9./ 
Unknown 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx Primary System Organ Class 
condition // Dictionary-Derived Term 
date9./ 
Unknown 
Ongoing/ 
Resolved 
date9./ 
Unknown 
 
 
 
 
 
 
 
Note: A blank onset or resolution date indicates the date is unknown.  
 
path\l_program.sas date 
time   
 
Programmer note: sort by onset date within each patient. 


 
 
 
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Listing 16.2.4.3 
Prostate Cancer History 
Part 1 of 4 
 
 
 
Initial Diagnosis 
 
Metastatic Disease 
Dose Regimen 
Cohort 
Subject 
ID 
Date 
Method 
Result 
Stage 
Date of Initial 
Metastatic 
Diagnosis 
 
Status 
Current 
Stage  
Current Metastatic 
Sites 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
date9. 
 
method 
Adenocarcinoma/
Other, specify 
stage 
date9. 
 
 Histologically Confirmed/Not 
Histologically Confirmed 
stage 
sites 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
date9. 
 
method 
Adenocarcinoma/
Other, specify 
stage 
date9. 
 
 Histologically Confirmed/Not 
Histologically Confirmed 
stage 
sites 
 
path\l_program.sas date 
time   
 
Listing 16.2.4.3 
Prostate Cancer History 
Part 2 of 4 
 
 
 
 
 
 
 
 
If yes, mark all that apply 
Dose Regimen 
Cohort 
Subject 
ID 
Last Date of Anti-
androgen Therapy 
Date of Progression Relative 
to Anti-androgen Therapy 
Disease 
Progression?[1] 
If Yes, Date of 
Qualifying Event 
20% increase in 
sum of diameter[2] 
Growth of existing 
bone lesions 
Growth of existing 
visceral lesions 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
date9. 
 
date9. 
 
Yes/No/NA 
stage 
Yes/No 
 
Yes/No 
 
Yes/No 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
date9. 
 
date9. 
 
Yes/No/NA 
stage 
Yes/No 
 
Yes/No 
 
Yes/No 
 
 
 
 
 
 
 
 
 
 
Note: NA=Not Applicable 
[1] Protocol-defined disease progression per RECIST criteria in a subject with “measureable disease”? 
[2] At least 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started. 
path\l_program.sas date 
time   


 
 
 
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Listing 16.2.4.3 
Prostate Cancer History 
Part 3 of 4 
 
 
 
 
 
If yes, mark all that apply 
 
If yes, mark all that apply 
Dose Regimen 
Cohort 
Subject 
ID 
New non-bone 
scan lesions or 
2+ bone scan 
lesions?[3] 
 
 
 
New bone 
lesions 
 
 
 
New visceral 
lesions 
 
 
Was there 
clinical 
progression? 
 
 
Unconfirmed 
new bone 
lesions 
 
 
Unconfirmed 
new visceral 
lesions 
 
Unconfirmed 
growth of 
existing bone 
lesions 
Unconfirmed 
growth of 
existing 
visceral 
lesions 
 
 
Clinical 
status/deterior
ation 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: NA=Not Applicable 
[3] The appearance of one or more new non-bone scan lesions or two or more bone scan lesions. 
 
Listing 16.2.4.3 
Prostate Cancer History 
Part 4 of 4 
 
 
 
 
 
Reference PSA 
 
Qualifying PSA 
 
Most Recent PSA  
(Qualifying PSA #2) 
Dose Regimen 
Cohort 
Subject 
ID 
PSA  
progression?[4] 
Date 
Result 
(ng/mL) 
 
Date 
Result 
(ng/mL) 
 
Date 
Result 
(ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
Yes/No/NA  
date9. 
 
xx xxx 
 
date9. 
 
xx xxx 
 
date9. 
 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
Yes/No/NA  
date9. 
 
xx xxx 
 
date9. 
 
xx xxx 
 
date9. 
 
xx.xxx 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Note: NA=Not Applicable 
 [4] Protocol-specific PSA progression in a subject with “non-measurable disease”? 
 
path\l_program.sas date 
time   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Listing 16.2.4.4 
Prostate-Specific Antigen History 
 
Dose Regimen 
Cohort 
Subject 
ID 
AR Inhibitor 
Therapy 
Result Number 
PSA Date of Collection 
PSA result 
(ng/mL) 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
Abiraterone/ 
Enzalutamide 
xxx 
 
date9. 
 
xxx 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
Abiraterone/ 
Enzalutamide  
xxx 
 
date9. 
 
xxx 
 
 
 
 
 
 
 
 
 
path\l_program.sas date 
time   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Listing 16.2.4.5 
Prior Cancer Therapy 
Part 1 of 3 – Prior Chemotherapy Treatment 
 
Dose Regimen 
Cohort 
Subject 
ID 
Regimen 
Treatment Type 
Best 
Overall 
Response 
Drug Name 
Start 
Date 
End 
Date 
Route 
Reason 
Stopped 
Subject 
progress 
following 
treatment?[1] 
Date of 
Disease 
Progression[2] 
Any 
additional 
regimen?[3] 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
regimen 
 
type 
CR/PR/SD/PD/
Unknown/NA 
drug name 
date9. 
 
date9. 
 
route 
reason 
Yes/No 
date9.
 
Yes/No 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
regimen 
 
type 
CR/PR/SD/PD/
Unknown/NA 
drug name 
date9. 
 
date9. 
 
route 
reason 
Yes/No 
date9.
 
Yes/No 
 
Note: NA=Not Applicable; CR=Complete Response; PR=Partial Response; SD=Stable Disease; PD=Progressive Disease. 
Note: Listing only includes subjects with reported prior chemotherapy treatment. 
 [1] Did the subject progress following treatment regimen? 
[2] If Yes, Date of Disease Progression following Treatment Regimen. 
[3] Are there any additional regimen(s) to be reported? 
 
path\l_program.sas date 
time   
Listing 16.2.4.5 
Prior Cancer Therapy 
Part 2 of 3 – Prior Surgical Treatment 
 
Dose Regimen 
Cohort 
Subject 
ID 
Procedure 
Date of Procedure 
Intent 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
procedure 
 
date9. 
 
intent 
. 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
procedure 
date9. 
 
intent 
Note: Listing only includes subjects with reported prior surgical treatment. 
 
path\l_program.sas  date       time  
 


 
 
 
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Listing 16.2.4.5 
Prior Cancer Therapy 
Part 3 of 3 – Prior Radiotherapy Treatment 
 
Dose Regimen 
Cohort 
Subject 
ID 
Type of 
Radiotherapy 
Site Treatment 
Total cGY 
Best Overall 
Response 
Start Date 
End Date 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
Internal/External 
 
site 
xxx/Unknown 
 
CR/PR/SD/PD/
Unknown/NA 
date9. 
 
xx xxx 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
Internal/External 
 
site 
xxx/Unknown 
 
CR/PR/SD/PD/
Unknown/NA 
date9. 
 
xx xxx 
 
 
 
 
 
 
 
 
 
Note: NA=Not Applicable; CR=Complete Response; PR=Partial Response; SD=Stable Disease; PD=Progressive Disease. 
Note: Listing only includes subjects with reported prior radiotherapy treatment. 
 
path\l_program.sas date 
time   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Listing 16.2.4.6 
Prior and Concomitant Medications 
 
Dose Regimen 
Cohort 
Subject 
ID 
CM 
# 
Verbatim Term // Preferred Name 
Start Date 
(Study Day) 
Stop Date 
(Study Day) 
Dose (Units) 
Form 
Route 
Frequency 
Indication 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xx 
Verbatim term // Preferred Name 
date9. (xx) 
date9. (xx)/ 
Ongoing 
dose (units) 
form 
route 
frequency 
MH: term / AE: 
term1, term2, 
term3 / Other: 
specify 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xx 
Verbatim term // Preferred Name 
date9. (xx) 
date9. (xx)/ 
Ongoing 
dose (units) 
form 
route 
frequency 
MH: term / AE: 
term1, term2, 
term3 / Other: 
specify 
 
 
 
 
 
 
 
 
 
 
 
 
Note: “*” indicates that a medication is a prior medication. 
 
path\l_program.sas date 
time   
 
Programmer note: sort by start date and stop date within each patient. 
 
 
 


 
 
 
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Listing 16.2.5.1 
Study Drug Compliance 
 
Dose Regimen 
Cohort 
Subject ID 
Date of First 
Dose 
Start Time 
Date of Last 
Dose 
# of Doses 
Taken 
Number of 
Cycles 
Duration of 
Treatment 
(weeks) 
Compliance(%)[1] 
xx mg, Dose Escalation 
1 
xxx-xxx 
date9. 
time5. 
date9. 
xx 
xx 
xx 
xx x 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
date9. 
time5. 
date9. 
xx 
xx 
xx 
xx x 
 
 
[1] Compliance is calculated using the following equation: Compliance (%)=(Actual number of used doses in total)/(Number of days from treatment start date to treatment end date) 
×100%. 
 
path\l_program.sas date 
time   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Listing 16.2.5.2 
ZEN003694 Administration - Single Dose 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Was dose 
taken? 
If No, Reason 
Dose Not 
Taken 
Primary 
AE [1] 
Strength 
of Dose 
Taken 
(mg) 
Treatment 
Date 
(Study 
Day) 
Treatment 
Time 
Prior 
after 
Eating [2] 
If No, 
Estimate 
Time 
Subject Ate 
Was dose 
modified since 
last visit? 
Reason for 
Dose 
Modification[3] 
Primary 
AE[3] 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
visit 
Yes, with no 
Issue/Yes, 
with 
Issues/No 
xxxxx 
xx 
xx 
date9. 
time5. 
Yes/No 
time5./ 
Unknown 
Yes, dose 
increased/Yes, 
dose 
decreased/No 
xxxxx 
xx 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
visit 
Yes, with no 
Issue/Yes, 
with 
Issues/No 
xxxxx 
xx 
xx 
date9. 
time5. 
Yes/No 
time5./ 
Unknown 
Yes, dose 
increased/Yes, 
dose 
decreased/No 
xxxxx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] If dose was not taken due to an Adverse Event, provide primary Adverse Event. 
[2] Did the subject take their dose at least 1 hour prior to the morning meal or at least 2 hours after eating?  
[3] If dose was modified since last visit, specify reason for dose modification. If dose was modified due to an Adverse Event, provide primary Adverse Event. 
 
path\l_program.sas date 
time   
 
 
 
 


 
 
 
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Listing 16.2.5.3 
ZEN003694 Administration Log 
 
 
 
 
 
 
 
Dose Taken 
 
Dose Not Taken 
Dose Regimen 
Cohort 
Subject 
ID 
Start 
Date 
(Study 
Day) 
End Date 
(Study 
Day) 
Frequency
Dose  
Taken 
[1] 
Specify 
Dose 
(mg) 
Dose 
Modified, 
Specify 
Reason[2] 
Dose 
Modified, 
Specify 
Primary 
AE[3] 
Dose 
Taken in 
the 
Morning[4]
If No, 
Number of 
Dose Not 
Taken in the 
Morning[5]  
Dose Held 
or 
Missed[6] 
If Dose 
Was 
Held, 
Specify 
Reason 
If Dose 
Was 
Missed, 
Specify 
Reason 
Primary 
AE[7] 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx date9.  
(xx) 
date9. 
(xx) 
xx 
xx 
xx 
xx 
xx 
Yes/No/ 
Unknown 
xx 
 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx date9.  
(xx) 
date9. 
(xx) 
xx 
xx 
xx 
xx 
xx 
Yes/No/ 
Unknown 
xx 
 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Was dose/were all doses taken in this time period? 
[2] If dose was modified since last entry, specify reason: 
[3] If dose was modified due to an Adverse Event, specify Primary AE: 
[4] Were all doses in this time period taken in the morning? 
[5] If No, how many doses were not taken in the morning based on the dosing diary and accountability? 
[6] Was dose held or missed at the time of the Start Date in this time period? 
[7] If dose was held or missed due to an Adverse Event, provide primary Adverse Event. 
 
path\l_program.sas date 
time   
 
 
 
 
 
 
 
 
 


 
 
 
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Listing 16.2.5.4 
Enzalautamide Administration - Single Dose 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Was dose 
taken? 
If No, Reason 
Dose Not 
Taken 
Primary 
AE [1] 
Strength 
of Dose 
Taken 
(mg) 
Treatment 
Date 
(Study 
Day) 
Treatment 
Time 
Was dose 
modified since 
last visit? 
Reason for 
Dose 
Modification[2] 
Primary 
AE[2]
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
visit 
Yes, with no 
Issues/Yes, 
with 
Issues/No 
xxxxx 
xx 
xx 
date9. 
time5. 
Yes, dose 
increased/Yes, 
dose 
decreased/No 
xxxxx 
xx 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
visit 
Yes, with no 
Issues/Yes, 
with 
Issues/No 
xxxxx 
xx 
xx 
date9. 
time5. 
Yes, dose 
increased/Yes, 
dose 
decreased/No 
xxxxx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] If dose was not taken due to an Adverse Event, provide primary Adverse Event. 
 [2] If dose was modified since last visit, specify reason for dose modification. If dose was modified due to an Adverse Event, provide primary Adverse Event. 
 
path\l_program.sas date 
time   
 
 
 
 


 
 
 
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Listing 16.2.5.5 
Enzalutamide Administration Log 
 
 
 
 
 
 
 
Dose Taken 
 
Dose Not Taken 
Dose Regimen 
Cohort 
Subject 
ID 
Start 
Date 
(Study 
Day) 
End Date 
(Study 
Day) 
Frequency
Dose  
Taken 
[1] 
Specify 
Dose 
(mg) 
Dose 
Modified, 
Specify 
Reason[2] 
Dose 
Modified, 
Specify 
Primary 
AE[3] 
Dose 
Taken in 
the 
Morning[4]
If No, 
Number of 
Dose Not 
Taken in the 
Morning[5]  
Dose Held 
or 
Missed[6] 
If Dose 
Was 
Held, 
Specify 
Reason 
If Dose 
Was 
Missed, 
Specify 
Reason 
Primary 
AE[7] 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx date9.  
(xx) 
date9. 
(xx) 
xx 
xx 
xx 
xx 
xx 
Yes/No/ 
Unknown 
xx 
 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx date9.  
(xx) 
date9. 
(xx) 
xx 
xx 
xx 
xx 
xx 
Yes/No/ 
Unknown 
xx 
 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Was dose/were all doses taken in this time period? 
[2] If dose was modified since last entry, specify reason: 
[3] If dose was modified due to an Adverse Event, specify Primary AE: 
[4] Were all doses in this time period taken in the morning? 
[5] If No, how many doses were not taken in the morning based on the dosing diary and accountability? 
[6] Was dose held or missed at the time of the Start Date in this time period? 
[7] If dose was held or missed due to an Adverse Event, provide primary Adverse Event. 
 
path\l_program.sas date 
time 
 
 
 
 
 
 
 
 
 


 
 
 
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Listing 16.2.6.1 
Tumor Evaluation – Target Lesions 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Was Radiographic 
Evaluation 
performed? 
Assessment  
Date 
Lesion 
# 
Location 
Technique 
Used 
Longest 
Diameter 
(mm) 
Sum of Longest 
Diameters 
(mm) 
Target Lesion 
Response to 
Treatment 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
visit 
Yes/No/No Target 
Lesions 
date9. 
xx 
xxx 
xxx 
xx x/ 
UNM 
xx x 
CR/PR/SD/PD/NE 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
visit 
Yes/No/No Target 
Lesions 
date9. 
xx 
xxx 
xxx 
xx x/ 
UNM 
xx x 
CR/PR/SD/PD/NE 
 
 
 
 
 
 
 
 
 
 
 
 
Note: UNM=Unable to Measure; NA=Not Applicable. 
Note: CR=Complete Response; PR=Partial Response; SD=Stable Disease; PD=Progressive Disease; NE=Not Evaluable. 
 
path\l_program.sas date 
time   
 
 


 
 
 
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Listing 16.2.6.2 
Tumor Evaluation – Non-Target Lesions 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Was Radiographic 
Evaluation 
performed? 
Assessment  
Date 
Lesion 
# 
Location 
Technique 
Used 
Non-Target 
Lesion 
Status 
Measurement 
(mm) 
Non-Target Lesion 
Response to 
Treatment 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
visit 
Yes/No/No Non-
Target Lesions 
date9. 
xx 
xxx 
xxx 
xxxx 
xx x 
CR/IR/SD/PD/NE 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
visit 
Yes/No/No Non-
Target Lesions 
date9. 
xx 
xxx 
xxx 
xx.x 
 
xx x 
CR/IR/SD/PD/NE 
 
 
 
 
 
 
 
 
 
 
 
 
Note: UP=Unequivocally Progressed; UNE=Unable to Evaluate. 
Note: CR=Complete Response; IR/SD=Incomplete Response/Stable Disease; PD=Progressive Disease; NE=Not Evaluable. 
 
path\l_program.sas date 
time   
 
 


 
 
 
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Listing 16.2.6.3 
Tumor Evaluation – New Lesions 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Are there any new 
lesions for this 
subject? 
Assessment  
Date 
Lesion 
# 
Location 
Technique 
Used 
Longest 
Diameter 
(mm) 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
visit 
Yes/No 
date9. 
xx 
xxx 
xxx 
xx x/ 
UNM 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
visit 
Yes/No 
date9. 
xx 
xxx 
xxx 
xx x/ 
UNM 
 
 
 
 
 
 
 
 
 
Note: UNM=Unable to Measure. 
 
path\l_program.sas date 
time   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Listing 16.2.6.4 
Overall Tumor Response Assessment 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Was the Overall Tumor Response 
Assessment performed? 
Assessment Date 
Overall Tumor Response to 
Treatment 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
visit 
Yes/No 
date9. 
CR/PR/SD/PD/SYMD/NE 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
visit 
Yes/No 
date9. 
CR/PR/SD/PD/SYMD/NE 
 
 
 
 
 
 
 
Note: CR=Complete Response; PR=Partial Response; SD= Stable Disease; PD=Progressive Disease; SYMD=Symptomatic Deterioration; NE=Not Evaluable. 
 
path\l_program.sas date 
time   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 




 
 
 
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Listing 16.2.6.6 
Fresh and Archival Tumor Tissue Collection  
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Was a 
tissue 
sample 
collected? 
Type of 
Biopsy 
Sample 
Collection 
Date 
Sample 
Collection 
Time 
Stage of 
Disease 
when the 
Tissue was 
Taken 
# Tissue 
Cores 
Collected
Tissue 
Anatomical 
Location 
Detailed Description 
of Tissue Location 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
visit 
Yes/No: 
reason not 
done 
Archival 
Tumor 
Tissue/Fresh 
Tumor Tissue 
date9. 
time5./ 
Unknown 
stage 
xx 
xxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
visit 
Yes/No: 
reason not 
done 
Archival 
Tumor 
Tissue/Fresh 
Tumor Tissue 
date9. 
time5./ 
Unknown 
stage 
xx 
xxxxx 
xxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
path\l_program.sas date 
time   
 
Note: If Type of Biopsy is blank, the tumor tissue was collected on the Fresh Tumor Tissue Collection CRF. 
 
Programmer note: sort by date, visit, and type of biopsy. Both an archival and fresh tumor tissue sample can be collected at the same time. In these cases, make sure to output both 
sample information for that visit. 
 
 
 
 
 
 
 


 
 
 
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Listing 16.2.7.1 
Adverse Events 
Dose 
Regimen 
 
 
 
 
 
 
Cohort 
Subject 
ID 
AE 
# 
Verbatim Term// 
MedDRA Preferred 
Term// 
System Organ Class 
Onset Date 
(Study Day) 
Resolution 
Date 
(Study Day) 
 
 
 
Severity 
(CTCAE 
Toxicity 
Grade) 
DLT 
Severity 
Relationship 
to ZEN003694 
 
 
 
 
Relationship to 
Enzalutamide / 
Abiraterone 
Action Taken 
with 
ZEN003694 
 
 
 
Action Taken 
with 
Enzalutamide / 
Abiraterone 
Treatment 
of Event Outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xx 
xxxxxx 
date9. 
date9. 
grade 
Yes/No/
NA 
Yes/No 
relationship 
relationship 
action taken 
action taken 
treatment outcome 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
1 
xxx-xxx 
xx 
xxxxxx 
date9. 
date9. 
grade 
Yes/No/
NA 
Yes/No 
relationship 
relationship 
action taken 
action taken 
treatment outcome 
 
Note: NA=Not Applicable. 
Note: * indicates onset of Adverse Event was prior to first dose. 
 
path\l_program.sas date 
time   
 
Programmer note: sort by onset date and resolution date within each patient 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Listing 16.2.8.1 
Hematology 
Safety Population 
Part 1 of 2 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Collection 
Date 
(Study Day) 
Collection 
Time 
WBC 
(109 /L) 
Absolute 
Neutrophils 
(109 /L) 
Absolute 
Lymphocytes 
(109 /L) 
Absolute 
Monocytes 
(109 /L) 
Absolute 
Eosinophils 
(109 /L) 
Absolute 
Basophils 
(109 /L) 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xx xx 
xx xx 
xx xx 
xx xx 
xx xx 
xx xx
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xx xx 
xx xx 
xx xx 
xx xx 
xx xx 
xx xx
 
Listing 16.2.8.1 
Hematology 
Safety Population 
Part 2 of 2 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Collection 
Date 
(Study Day) 
Collection 
Time 
RBC 
(1012 /L) 
Platelets 
 (109 /L) 
Hemoglobin 
(g/L) 
Hematocrit 
MCV 
(fL) 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xx.xx 
xx xx 
xx xx 
xx xx 
xx.xx 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xx.xx 
xx xx 
xx xx 
xx xx 
xx.xx 
 
Note: L=Low and H=High with respect to laboratory reference ranges. CS=Clinically Significant, NCS=Not Clinically Significant. CTCAE V4.03 grades are in brackets, where 
applicable. 


 
 
 
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time   
 
Zenith Epigenetics Ltd. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Listing 16.2.8.2 
Coagulation 
Safety Population 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Collection 
Date 
(Study Day) 
Collection 
Time 
PT 
(sec) 
INR 
PTT 
(sec) 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xx.xx 
xx xx 
xx xx 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xx.xx 
xx xx 
xx xx 
 
 
 
 
 
 
 
 
 
 
 
Note: L=Low and H=High with respect to laboratory reference ranges. CS=Clinically Significant, NCS=Not Clinically Significant. 
 
path\l_program.sas date 
time   
 
  
 
 


 
 
 
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Listing 16.2.8.3 
Serum Chemistry 
Safety Population 
Part 1 of 3 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Collection 
Date 
(Study Day) 
Collection 
Time 
ALT (SGPT) 
(U/L) 
AST (SGOT) 
(U/L) 
Alkaline 
Phosphatase 
(U/L) 
Amylase 
(U/L) 
Albumin 
(g/L) 
Total 
Bilirubin 
(umol/L) 
Blood Urea 
Nitrogen  
(BUN) 
(mmol/L) 
Creatinine 
(umol/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xx xx 
xx.xx 
xx xx 
xx xx 
xx xx 
xx xx 
xx xx 
xx xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xx xx 
xx.xx 
xx xx 
xx xx 
xx xx 
xx xx 
xx xx 
xx xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.8.3 
Serum Chemistry 
Safety Population 
Part 2 of 3 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Collection 
Date 
(Study Day) 
Collection 
Time 
Sodium 
(mmol/L) 
Potassium 
(mmol/L) 
Chloride 
(mmol/L) 
Bicarbonate 
(mmol/L) 
Phosphorus
(mmol/L) 
Calcium 
(mmol/L) 
Glucose 
(mmol/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xx xx 
xx xx 
xx xx 
xx xx 
xx xx 
xx xx 
xx xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xx xx 
xx xx 
xx xx 
xx xx 
xx xx 
xx xx 
xx xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Listing 16.2.8.3 
Serum Chemistry 
Safety Population 
Part 3 of 3 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Collection 
Date 
(Study Day) 
Collection 
Time 
Magnesium 
(mmol/L) 
LDH 
(U/L) 
Lipase 
(U/L) 
Serum 
Testosterone 
(nmol/L) 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xx xx 
xx xx 
xx xx 
xx xx 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xx xx 
xx xx 
xx xx 
xx xx 
 
 
 
 
 
 
 
 
 
 
Note: L=Low and H=High with respect to laboratory reference ranges. CS=Clinically Significant, NCS=Not Clinically Significant. CTCAE V4.03 grades are in brackets, where 
applicable. 
 
path\l_program.sas date 
time   
 
 


 
 
 
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Listing 16.2.8.4 
Urinalysis 
Safety Population 
Part 1 of 2 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Collection 
Date 
(Study Day) 
Collection 
Time 
Appearance 
Color 
Protein 
Glucose 
Ketones 
Occult Blood 
Bilirubin 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xxxx 
xxxx 
xxxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xxxx 
xxxx 
xxxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.8.4 
Urinalysis 
Safety Population 
Part 2 of 2 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Collection 
Date 
(Study Day) 
Collection 
Time 
Was a 
microscopic 
exam 
performed? 
Bacteria 
Casts 
Crystals 
RBC 
(/HPF) 
WBC 
(/HPF) 
pH 
Specific 
Gravity 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
Yes/No 
xxxx 
xxxx 
xxx 
xx.xx 
xx xx 
xx xx 
xx.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
xxxx 
date9. (xx) 
time5. 
xxxx 
xxxx 
xxxx 
xxx 
xx.xx 
xx xx 
xx xx 
xx.xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: L=Low and H=High with respect to laboratory reference ranges. CS=Clinically Significant, NCS=Not Clinically Significant. CTCAE V4.0 grades are in brackets, where 
applicable. 
 
path\l_program.sas date 
time   


 
 
 
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Programmer note: “Other” urinalysis test is collected on the CRF. Is other urinalysis test is collected, add a column for this test after Crystals. Column header will be “Other Test 
Name (unit)”. 


 
 
 
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Listing 16.2.8.5 
Serum PSA 
Safety Population 
 
Dose Regimen 
Cohort 
Subject 
ID 
Was a Serum 
PSA sample 
collected? 
Visit 
Collection 
Date 
(Study Day) 
Collection 
Time 
PSA 
(ug/L) 
Has the subject 
completed 12 weeks of 
treatment? 
If Yes, has the PSA 
result increased >25% 
and at least 2 ng/mL 
above nadir or baseline, 
per PCWG2 criteria? 
 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
Yes/No 
xxxx 
date9. (xx) 
time5. 
xx xx 
Yes/No 
Yes/No 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
Yes/No 
xxxx 
date9. (xx) 
time5. 
xx xx 
Yes/No 
Yes/No 
 
 
 
 
 
 
 
 
 
 
 
Note: L=Low and H=High with respect to laboratory reference ranges. CS=Clinically Significant; NCS=Not Clinically Significant.  
 
path\l_program.sas date 
time   
 
 


 
 
 
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Listing 16.2.8.6 
Physical Examination 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Date of 
Examination 
Were there any abnormal findings on the physical examination? 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
visit 
date9./Not Done Yes/No 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Confirmation 
x 
xxx-xxx 
visit 
date9./Not Done Yes/No 
 
 
 
 
 
 
path\l_program.sas date 
time   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Listing 16.2.8.7 
Echocardiogram or MUGA Scan 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Was an echocardiogram or 
MUGA scan performed? 
Date of 
Assessment 
 
Type 
LVEF 
(%) 
If abnormal, specify: 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xxxxx 
Yes/No 
date9. 
Echocardiogram/ 
MUGA Scan 
xxx 
xxxx 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxxxx 
Yes/No 
date9. 
Echocardiogram/ 
MUGA Scan 
xxx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: LVEF=Left Ventricular Ejection Fraction. 
 
path\l_program.sas date 
time   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Listing 16.2.8.8 
Vital Signs 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Were vital 
signs 
collected? 
Date of 
Measurements 
Time of 
Measurements 
Height 
(cm) 
Weight 
(kg) 
Temperature 
(°F) 
Heart Rate 
(bpm) 
Systolic Blood 
Pressure 
(mmHg) 
Diastolic Blood 
Pressure 
(mmHg) 
Position of 
Subject
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xxxxx 
Yes/No 
date9. 
time5. 
xx x 
xx x 
xx x 
xxx 
xxx 
xxx 
position 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxxxx 
Yes/No 
date9. 
time5. 
xx x 
xx x 
xx x 
xxx 
xxx 
xxx 
position 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: ND=Not Done. 
 
path\l_program.sas date 
time   
  
 
 
 


 
 
 
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Listing 16.2.8.9 
12-Lead Electrocardiogram 
Part 1 of 2 – Interpretation and Clinically Significant Findings 
 
Dose Regimen 
 
Cohort 
Subject 
ID 
Visit 
Was ECG 
performed? 
Visit 
Date 
Reading 
No. 
Time 
Interpretation 
Comments Regarding Clinically 
Significant Findings 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xxx 
Yes/No 
date9. 
1 
Time5./ 
ND 
Normal/Abnormal 
NCS/Abnormal 
CS 
comments 
 
 
 
 
 
2 
Time5./ 
ND 
Normal/Abnormal 
NCS/Abnormal 
CS 
comments 
 
 
 
 
 
3 
Time5./ 
ND 
Normal/Abnormal 
NCS/Abnormal 
CS 
comments 
 
 
 
 
 
Average[1]
. 
. 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxx 
Yes/No 
date9. 
1 
Time5./ 
ND 
Normal/Abnormal 
NCS/Abnormal 
CS 
comments 
 
 
 
 
 
2 
Time5./ 
ND 
Normal/Abnormal 
NCS/Abnormal 
CS 
comments 
 
 
 
 
 
3 
Time5./ 
ND 
Normal/Abnormal 
NCS/Abnormal 
CS 
comments 
 
 
 
 
 
Average[1 
. 
. 
 
 
Note: ND=Not Done; NCS=Not Clinically Significant; CS=Clinically Significant. 
 
path\l_program.sas date 
time   
 
 
 
 


 
 
 
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Listing 16.2.8.9 
12-Lead Electrocardiogram 
Part 2 of 2 – Quantitative Results 
 
Dose Regimen 
 
Cohort 
Subject 
ID 
Visit 
Was ECG 
performed? 
Visit 
Date 
Reading 
No. 
Time 
Ventricular
Rate 
(bpm) 
RR 
Interval 
(msec) 
PR 
Interval 
(msec) 
QRS 
Duration 
(msec) 
QT 
Interval 
(msec) 
QTc Interval 
Fridericia 
(msec) [2] 
Serum 
Troponin 
(ug/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xxx 
Yes/No 
date9. 
1 
Time5./ 
ND 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
2 
Time5./ 
ND 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
3 
Time5./ 
ND 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
Average[1] 
. 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxx 
Yes/No 
date9. 
1 
Time5./ 
ND 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
2 
Time5./ 
ND 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
3 
Time5./ 
ND 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
 
Average[1 
. 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Note: ND=Not Done; NCS=Not Clinically Significant; CS=Clinically Significant. 
Note: ‘*’ indicates that the Serum Troponin assay used was Troponin T. 
[1] Average readings are derived by taking the average measurement of the triplicate measurements (i.e., readings 1-3). 
[2] Each individual QTcF result is re-calculated using the following equation: QTcF (msec)=QT/(RR^0.33). The average QTcF result re-derived using the re-calculated individual 
QTcF results. 
 
 
path\l_program.sas date 
time   
 
 
 


 
 
 
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Listing 16.2.8.10 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Was ECOG 
assessment 
performed? 
Date of 
Assessment Score 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
xxxxx 
Yes/No 
date9. 
X - Full score description 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxxxx 
Yes/No 
date9. 
X - Full score description 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
path\l_program.sas date 
time   
 
Programmer note: Display full score description as shown on the actual CRF –  
 
0 – Fully active, able to carry on all pre-disease performance without restriction. 
1 – Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 – Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 
3 – Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 – Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 – Dead. 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Listing 16.2.8.11 
Ophthalmology Examination (Baseline and On-Study) 
Safety Population 
Part 1 of 2 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Was eye  
exam 
performed? 
Date of 
Exam 
Eye 
BCVA 
worse than 
20/400? 
Color 
Vision 
Plates 
RAPD 
present? 
Pupil 
diameter 
in bright 
light 
(mm) 
Pupil 
diameter 
in dim 
light 
(mm) 
Velocity of 
pupillary 
constriction
Intraocular 
Pressure 
(mmHg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose Escalation 
1 
xxx-xxx 
xxxxx 
Yes/ 
No: reason 
date9. Left/ 
Right 
Yes: xx/ 
No: xx 
xx/xx 
Yes/No 
xx xx 
xx xx 
xxxx
xx xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxxxx 
Yes/ 
No: reason 
date9. Left/ 
Right 
Yes: xx/ 
No: xx 
xx/xx 
Yes/No 
xx xx 
xx xx 
xxxx
xx xx 
 
Note: BCVA=Best-corrected Visual Acuity. CF=Count Fingers, HM=Hand Motions, LP=Light Perception, and NLP=No Light Perception. RAPD=Relative Afferent Pupillary 
Deficit. 
Note: ‘*’ indicates a clinically significant change from baseline. 
 
path\l_program.sas date 
time   
 
Programmer note: For “Best-Corrected Visual Acuity worse than 20/400?” column, if result is No, include reported Best-corrected visual acuity in Snellen Notation (e.g., 20/20, 
20/40, etc.). If result is yes, include level of visual function present (e.g., CF, HM, LP, NLP). 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Listing 16.2.8.11 
Ophthalmology Examination (Baseline and On-Study) 
Safety Population 
Part 2 of 2 
 
 
 
 
 
 
Clinically significant abnormalities on: 
 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Was eye 
exam 
performed?
Date of 
Exam 
Slight 
Lamp 
Exam? 
Dilated 
Funduscopic 
Exam? 
OCT of 
the optic 
nerve? 
Macular 
OCT? 
Fundus 
photographs of 
the posterior 
pole? 
Any new clinically 
significant changes 
since baseline? 
If changes were 
detected, were 
changes consistent 
with drug effect? 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xxxxx 
Yes/ 
No: reason 
date9. Yes/No 
Yes/No 
Yes/No/ 
ND 
Yes/No/
ND 
Yes/No/ 
ND 
Yes/No 
Yes/No/Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxxxx 
Yes/ 
No: reason 
date9. Yes/No 
Yes/No 
Yes/No/ 
ND 
Yes/No/
ND 
Yes/No/ 
ND 
Yes/No 
Yes/No/Unknown 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: ND=Not Done. 
Note: ‘*’ indicates a clinically significant change from baseline. 
 
path\l_program.sas date 
time   
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
Zenith Epigenetics Ltd.   
                                                                                                  Statistical Analysis Plan 
ZEN003694-002 
                                                                                                                                          27 January 2020 
 
Page 196/197 
CONFIDENTIAL 
Zenith_ZEN003694-002_SAP_Final_v2 (clean) 
 
Zenith Epigenetics Ltd. 
 
 
 
 
 
 
 
 
 
 
 
 
 
             Page 1 of x 
ZEN003694-002 
Listing 16.2.8.12 
Qualitative Exploration of Visual Symptoms (Baseline and In-Clinic) 
Safety Population 
Part 1 of 2 
 
 
 
 
 
 
 
Have you had any of the following symptoms? 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Was visual 
symptom 
assessment 
performed?
Date 
of 
Exam 
Have you 
experienced 
any visual 
symptoms 
of concern 
in the past? 
Abnormal 
color 
vision 
Perception of 
light 
appearing 
brighter than 
normal 
Pain or discomfort 
when in bright 
environments or 
looking at bright 
lights 
Perception 
of 
flashing 
lights 
Trouble navigating 
or seeing in dimly lit 
environments 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xxxxx 
Yes/ 
No: reason 
date9. 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxxxx 
Yes/ 
No: reason 
date9. 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
path\l_program.sas date 
time   
 
 
Listing 16.2.8.12 
Qualitative Exploration of Visual Symptoms (Baseline and In-Clinic) 
Safety Population 
Part 2 of 2 
 
Dose Regimen 
Cohort 
Subject 
ID 
Visit 
Was visual 
symptom 
assessment 
performed? 
Date 
of 
Exam 
Symptoms 
occur after 
ever dose? 
How long 
after dosing 
do these 
symptoms 
start? 
(mins) 
Are 
symptoms 
constant?  
If no, how long after 
the symptoms start 
does it take for them 
to resolve? 
(mins) 
Are there 
certain 
behaviors that 
lessen these 
visual 
symptoms? 
Are visual 
symptoms 
changing over the 
time that you have 
been on the study? 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Escalation 
1 
xxx-xxx 
xxxxx 
Yes/ 
No: reason 
date9. 
Yes/No: 
frequency 
xx or range 
Yes/No 
xx or range 
Yes/No 
xxx 


 
 
 
Zenith Epigenetics Ltd.   
                                                                                                  Statistical Analysis Plan 
ZEN003694-002 
                                                                                                                                          27 January 2020 
 
Page 197/197 
CONFIDENTIAL 
Zenith_ZEN003694-002_SAP_Final_v2 (clean) 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xx mg, Dose 
Confirmation 
x 
xxx-xxx 
xxxxx 
Yes/ 
No: reason 
date9. 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
xxxx 
 
path\l_program.sas date 
time