Clinical trial NCT03560531
Conditions: Breast Cancer
Keywords: Estrogen receptor Hormone receptor Selective estrogen receptor degrader Hormone sensitive Phase 1 Dose Escalation Phase 2 Combination Phase 1 Dose Expansion Phase 2 Monotherapy
Sponsor: Zeno Alpha Inc.
Start date: 2018-11-30; Completion date: 2022-12-22
Enrollment: 181 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase 1/2, open-label, multicenter, dose-escalation and expansion study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of ZN-c5 administered orally in subjects with advanced estrogen receptor positive, human epidermal growth factor receptor 2 negative (ER+/HER2-) breast cancer. ZN-c5 will be evaluated both as monotherapy and in combination with palbociclib (IBRANCE®).

Detailed description:

Arms: arm 1: Dose escalation cohorts are planned to determine maximum tolerated dose(MTD) or recommended phase 2 dose (RP2D) of ZN-c5 as well as expansion cohorts and a Phase 2 cohort. arm 2: Dose escalation cohorts are planned to determine maximum tolerated dose(MTD) or recommended phase 2 dose (RP2D) of ZN-c5 in combination with palbociclib as well as a Phase 2 cohort.
Interventions: intervention 1: ZN-c5 intervention 2: Palbociclib
Intervention descriptions: intervention 1: ZN-c5 is a study drug intervention 2: Palbociclib (IBRANCE®) is an approved drug

Protocol documents:
Prot_000.pdf: 
Official Title: 
A PHASE 1/2 OPEN LABEL, MULTICENTER STUDY TO ASSESS 
THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND ANTI-
TUMOR ACTIVITY OF ZN-c5 ALONE AND IN COMBINATION 
WITH PALBOCICLIB IN SUBJECTS WITH ESTROGEN-RECEPTOR 
POSITIVE, HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR-
2 NEGATIVE ADVANCED BREAST CANCER 
NCT Number: 
NCT03560531 
Document Date: 
20-Apr-2021 
 


 
A PHASE 1/2 OPEN LABEL, MULTICENTER STUDY TO 
ASSESS THE SAFETY, TOLERABILITY, 
PHARMACOKINETICS, AND ANTI-TUMOR ACTIVITY OF 
ZN-c5 ALONE AND IN COMBINATION WITH 
PALBOCICLIB IN SUBJECTS WITH ESTROGEN-RECEPTOR 
POSITIVE, HUMAN EPIDERMAL GROWTH FACTOR 
RECEPTOR-2 NEGATIVE ADVANCED BREAST CANCER 
Protocol Number: ZN-c5-001 
EUDRACT Number: 2018-001364-27 
IND Sponsor: Zeno Alpha, Inc. 
Protocol Version: 6.0 
20 April 2021 
 
 
 
 
 
 
.. zeno 
... ALPHA . INC 


Phase 1/2 ZN-c5 + Palbociclib in ER+ HER2- advanced breast cancer 
Protocol Version 6.0 
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Table of Contents 
STATEMENT OF COMPLIANCE ...................................................................................................................... 6 
1 
PROTOCOL SUMMARY ....................................................................................................................... 7 
1.1 
Synopsis ................................................................................................................................... 7 
1.2 
Schema ................................................................................................................................... 11 
1.3 
Schedule of Activities ............................................................................................................. 12 
2 
INTRODUCTION ............................................................................................................................... 16 
2.1 
Study Rationale ...................................................................................................................... 16 
2.2 
Background ............................................................................................................................ 18 
2.3 
Risk/Benefit Assessment ........................................................................................................ 19 
2.3.1 
Known Potential Risks ......................................................................................................... 19 
2.3.2 
Known Potential Benefits .................................................................................................... 20 
2.3.3 
Assessment of Potential Risks and Benefits ........................................................................ 20 
3 
OBJECTIVES AND ENDPOINTS .......................................................................................................... 21 
4 
STUDY DESIGN ................................................................................................................................. 24 
4.1 
Overall Design ........................................................................................................................ 24 
4.2 
Scientific Rationale for Study Design ..................................................................................... 24 
4.3 
Justification for Dose ............................................................................................................. 24 
4.4 
End of Study Definition .......................................................................................................... 24 
5 
STUDY POPULATION ........................................................................................................................ 26 
5.1 
Inclusion Criteria .................................................................................................................... 26 
5.2 
Exclusion Criteria ................................................................................................................... 27 
5.3 
Lifestyle Considerations ......................................................................................................... 28 
5.4 
Screen Failures ....................................................................................................................... 28 
5.5 
Strategies for Recruitment and Retention ............................................................................. 29 
6 
STUDY INTERVENTION ..................................................................................................................... 30 
6.1 
Study Intervention(s) Administration .................................................................................... 30 
6.1.1 
Study Intervention Description ........................................................................................... 30 
6.1.2 
Dosing and Administration .................................................................................................. 30 
6.1.3 
Definition Of MTD and RP2D ............................................................................................... 31 
6.1.4 
Monotherapy Dose Escalation ............................................................................................ 31 
6.1.5 
Combination Dose Escalation .............................................................................................. 32 
6.1.6 
Monotherapy Expansion ..................................................................................................... 32 
6.1.7 
Monotherapy Phase 2 ......................................................................................................... 33 
6.1.8 
Combination Phase 2 ........................................................................................................... 33 
6.2 
Preparation/Handling/Storage/Accountability ..................................................................... 34 
6.2.1 
Acquisition and Accountability ............................................................................................ 34 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ........................................................... 34 
6.2.3 
Product Storage and Stability .............................................................................................. 35 
6.2.4 
Preparation .......................................................................................................................... 35 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................................... 35 
6.4 
Study Intervention Compliance ............................................................................................. 35 
6.5 
Concomitant Therapy ............................................................................................................ 35 
6.5.1 
Prophylactic medications and therapy ................................................................................ 35 
6.5.2 
Use of CYP3A4 and CYP2C9 inhibitors and inducers ........................................................... 36 
6.5.3 
Use of other inhibitors or inducers ..................................................................................... 36 
6.5.4 
Additional prohibited medications ...................................................................................... 36 


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6.5.5 
Rescue Medicine.................................................................................................................. 36 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL
 ......................................................................................................................................................... 37 
7.1 
Discontinuation of Study Intervention .................................................................................. 37 
7.2 
Participant Discontinuation/Withdrawal from TREATMENT AND FROM the Study ............. 37 
7.3 
Lost to Follow-Up ................................................................................................................... 38 
7.4 
End of Treatment Visit ........................................................................................................... 38 
7.5 
Safety Follow-up Visit ............................................................................................................ 38 
7.6 
Disease Assessment Follow-up Visits .................................................................................... 39 
7.7 
Survival Follow-up Visits ........................................................................................................ 39 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................................................... 40 
8.1 
Efficacy Assessments ............................................................................................................. 40 
8.1.1 
Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) ................................. 40 
8.2 
Safety and Other Assessments .............................................................................................. 40 
8.2.1 
Safety Assessments ............................................................................................................. 40 
8.2.2 
Pharmacokinetic, Pharmacodynamic, & Correlative Samples ............................................ 42 
8.3 
Adverse Events and Serious Adverse Events ......................................................................... 47 
8.3.1 
Definition of Adverse Events (AE)........................................................................................ 47 
8.3.2 
Definition of Serious Adverse Events (SAE) ......................................................................... 47 
8.3.3 
Classification of an Adverse Event ....................................................................................... 48 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up .................................... 49 
8.3.5 
Adverse Event Reporting ..................................................................................................... 50 
8.3.6 
Serious Adverse Event Reporting ........................................................................................ 50 
8.3.7 
Reporting Events to Participants ......................................................................................... 50 
8.3.8 
Special Situations Reports ................................................................................................... 51 
8.3.9 
Reporting of Pregnancy ....................................................................................................... 52 
8.4 
Dose-limiting Toxicities and Toxicity Management ............................................................... 52 
8.4.1 
Definition of Dose-Limiting Toxicity Monotherapy DOse Escalation .................................. 52 
8.4.2 
Definition of Dose-Limiting Toxicity – Combination Dose Escalation ................................. 53 
8.4.3 
Toxicity Management .......................................................................................................... 53 
8.5 
Unanticipated Problems ........................................................................................................ 55 
8.5.1 
Definition of Unanticipated Problems (UP) ......................................................................... 55 
8.5.2 
Unanticipated Problem Reporting ....................................................................................... 55 
8.5.3 
Reporting Unanticipated Problems to Participants ............................................................. 56 
9 
STATISTICAL CONSIDERATIONS ....................................................................................................... 57 
9.1 
Statistical Hypotheses ............................................................................................................ 57 
9.2 
Sample Size Determination .................................................................................................... 57 
9.2.1 
Monotherapy Dose Escalation and Combination Dose Escalation ..................................... 57 
9.2.2 
Monotherapy Expansion ..................................................................................................... 57 
9.2.3 
Monotherapy Phase 2 ......................................................................................................... 58 
9.2.4 
Combination Phase 2 ........................................................................................................... 58 
9.3 
Populations for Analyses ....................................................................................................... 59 
9.4 
Statistical Analyses ................................................................................................................. 59 
9.4.1 
General Approach ................................................................................................................ 59 
9.4.2 
Analysis of the Primary Endpoint(s) .................................................................................... 60 
9.4.3 
Analysis of the Secondary Endpoint(s) ................................................................................ 60 
9.4.4 
Safety Analyses .................................................................................................................... 60 
9.4.5 
Efficacy Analyses .................................................................................................................. 61 


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9.4.6 
Baseline Descriptive Statistics ............................................................................................. 63 
9.4.7 
Planned Interim Analyses .................................................................................................... 63 
9.4.8 
Sub-Group Analyses ............................................................................................................ 63 
9.4.9 
Tabulation of Individual Participant Data ............................................................................ 63 
9.4.10 
Exploratory Analyses ........................................................................................................... 63 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................................... 65 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ..................................................... 65 
10.1.1 
Informed Consent Process .................................................................................................. 65 
10.1.2 
Study Discontinuation and Closure ..................................................................................... 66 
10.1.3 
Confidentiality and Privacy .................................................................................................. 66 
10.1.4 
Future Use of Stored Specimens and Data .......................................................................... 67 
10.1.5 
Key Roles and Study Governance ........................................................................................ 68 
10.1.6 
Safety Oversight .................................................................................................................. 69 
10.1.7 
Clinical Monitoring .............................................................................................................. 69 
10.1.8 
Quality Assurance and Quality Control ............................................................................... 69 
10.1.9 
Data Handling and Record Keeping ..................................................................................... 70 
10.1.10 Protocol Deviations ............................................................................................................. 72 
10.1.11 Publication and Data Sharing Policy .................................................................................... 72 
10.1.12 Conflict of Interest Policy .................................................................................................... 72 
10.2 
Additional Considerations ..................................................................................................... 72 
10.3 
Abbreviations ......................................................................................................................... 73 
10.4 
Appendices ............................................................................................................................ 76 
10.4.1 
List of Drugs Known to Predispose to Torsade de Pointes .................................................. 76 
10.4.2 
Revised RECIST Guidelines (version 1.1) ............................................................................. 77 
10.4.3 
ECOG Performance Status ................................................................................................... 80 
10.4.4 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 ..................................... 81 
10.4.5 
Contraception and Maternal/Paternal Exposure ................................................................ 82 
10.4.6 
Potential Drug-Drug Interactions ........................................................................................ 84 
10.4.7 
Hy’s Law Definition .............................................................................................................. 85 
10.5 
Protocol Amendment History ................................................................................................ 86 
11 
REFERENCES ..................................................................................................................................... 87 
12 
SPONSOR SIGNATURE PAGE ............................................................................................................ 88 
13 
INVESTIGATOR SIGNATURE PAGE ................................................................................................... 89 
14 
REVISION HISTORY ........................................................................................................................... 90 
 
List of Tables 
Table 1: 
Study Procedures Table ....................................................................................................... 12 
Table 2: 
Dose Escalation Rules .......................................................................................................... 31 
Table 3: 
ZN-c5 Study Dose Levels ...................................................................................................... 32 
Table 4: 
Analytes ............................................................................................................................... 42 
Table 5: 
Pharmacokinetic Sampling per Study Component .............................................................. 43 
Table 6: 
Full Pharmacokinetic Sampling Time Points ........................................................................ 44 
Table 7: 
Abbreviated ZN-c5 Pharmacokinetic Sampling Time Points ............................................... 44 
Table 8: 
ZN-c5 Dose Levels for Treatment Modification in Monotherapy Expansion and 
Combination Phase 2 ........................................................................................................... 53 
Table 9: 
Dose Reduction Criteria ZN-c5: All Phases .......................................................................... 55 


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Table 10: 
Time Point Response: Patients with Target (± Non-target) Disease ................................... 78 
Table 11: 
Time Point Response: Patients with Non-target Disease Only ........................................... 79 
Table 12: 
Time Point Response: Best Overall Response ..................................................................... 79 
Table 13: 
ECOG Performance Status ................................................................................................... 80 
Table 14: 
Examples of CYP3A and CYP2C9 Inhibitors/Inducers .......................................................... 84 
 
List of Figures 
Figure 1 
ZN-c5-001 Phase 1 Monotherapy Dose Escalation, Expansion and Phase 2 ....................... 11 
Figure 2 
ZN-c5-001 Phase 1 Combination with Palbociclib Dose Escalation and Phase 2 ................ 11 
 
 
 


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STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), or with the laws and regulations of the country in which the research is conducted, 
whichever affords the greater protection to the study subject, and the following: 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) 
• 
European Clinical Trials Directive 2001/20/EC  
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB)/Independent Ethics Committee (IEC) for review and 
approval. Approval of both the protocol and the consent form must be obtained before any participant 
is enrolled. Any amendment to the protocol will require review and approval by the IRB/IEC before the 
changes are implemented to the study. In addition, all changes to the consent form will be 
IRB/IEC-approved; a determination will be made regarding whether a new consent needs to be obtained 
from participants who provided consent, using a previously approved consent form. 
 
 


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1 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
A Phase 1/2 Open Label, Multicenter Study to Assess the Safety, 
Tolerability, Pharmacokinetics, and Anti-Tumor Activity of ZN-c5 Alone and 
in Combination with Palbociclib in Subjects with Estrogen-Receptor Positive, 
Human Epidermal Growth Factor Receptor-2 Negative Advanced Breast 
Cancer 
Study Description: 
The study has 5 components: 
Phase 1 
• 
Monotherapy Dose Escalation 
• 
Monotherapy Expansion 
• 
Combination Dose Escalation 
Phase 2 
• 
Monotherapy Phase 2 
• 
Combination Phase 2 
Objectives: 
Primary Objectives: 
Phase 1 
• 
Monotherapy Dose Escalation: Determine a maximum tolerated 
dose (MTD) or recommended Phase 2 dose (RP2D) for ZN-c5 as a 
monotherapy 
• 
Monotherapy Expansion: Investigate the safety and tolerability of 
ZN-c5 as a monotherapy in subjects with Estrogen Receptor (ER) 
positive, Human Epidermal Growth Factor Receptor-2 (HER2) 
negative advanced breast cancer 
• 
Combination Dose Escalation:  Determine an MTD or RP2D for 
ZN-c5 when administered in combination with palbociclib  
Phase 2 
• 
Monotherapy Phase 2: Determine preliminary anti-tumor efficacy 
(Clinical Benefit Rate [CBR]) for ZN-c5 as a monotherapy 
• 
Combination Phase 2: Determine preliminary anti-tumor efficacy 
(CBR) for ZN-c5 when administered in combination with palbociclib 
Secondary Objectives: 
• 
Monotherapy Dose Escalation and Monotherapy Phase 2: 
Investigate the safety and tolerability of ZN-c5 as a monotherapy in 
subjects with ER positive, HER2 negative advanced breast cancer 
• 
Combination Dose Escalation and Combination Phase 2: Investigate 
the safety and tolerability of ZN-c5 in combination with palbociclib 
in subjects with ER positive, HER2 negative advanced breast cancer 


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• 
Monotherapy Expansion Phase 1: Investigate the preliminary 
anti-tumor efficacy (CBR) for ZN-c5 as a monotherapy 
• 
All Cohorts: Assess preliminary efficacy of ZN-c5 alone and in 
combination with palbociclib by Objective Response Rate (ORR), 
CBR, Duration of Response (DOR), Progression-Free Survival (PFS) 
and Overall Survival (OS) using Response Evaluation Criteria in Solid 
Tumors (RECIST v.1.1) as assessed by investigators 
• 
Monotherapy Dose Escalation and Monotherapy Expansion Phase 1 
and Monotherapy Phase 2: Characterize the pharmacokinetics (PK) 
of ZN-c5 (and its potential metabolites as applicable) when given as 
oral monotherapy 
• 
Combination Dose Escalation and Combination Phase 2: 
Characterize the PK of ZN-c5 (and its potential metabolites as 
applicable) when given in combination with palbociclib 
• 
Combination Dose Escalation and Combination Phase 2: 
Characterize the PK of palbociclib when given in combination with 
ZN-c5 
Tertiary/Exploratory Objectives (All Cohorts): 
• 
Evaluate pharmacodynamic and prognostic biomarkers associated 
with disease prognosis and/or likelihood of response to ZN-c5 
• 
Assess the effect of ZN-c5 on tumor’s ability to bind estradiol as 
measured by uptake of 18F-fluoroestradiol (FES) Positron Emission 
Tomography (PET) 
Endpoints: 
Primary Endpoints: 
• 
Monotherapy Dose Escalation and Combination Dose Escalation: 
Observed Dose Limiting Toxicities  
• 
Monotherapy Expansion: Safety and tolerability as measured by 
incidence of treatment-emergent adverse events (TEAEs) and lab 
abnormalities 
• 
Monotherapy Phase 2 and Combination Phase 2: CBR (CR [+ PR] + 
SD ≥ 24 weeks). PR will only be included for patients with 
measurable disease.  
Secondary Endpoints: 
• 
All Cohorts: Safety and tolerability as measured by incidence of 
treatment-emergent AEs and lab abnormalities 
• 
Monotherapy Expansion: CBR (CR [+ PR] + SD ≥ 24 weeks). PR will 
only be included for patients with measurable disease.  


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• 
All Cohorts: Tumor response including ORR, DOR, CBR, PFS using 
Response Evaluation Criteria in Solid Tumors (RECIST v.1.1) as 
assessed by Investigators, and OS 
• 
All Cohorts: ZN-c5 (and its potential metabolites as applicable) and 
palbociclib (if applicable) plasma pharmacokinetic (PK) parameters 
(including Cmax, Tmax, AUClast, t½ and Ctau, as applicable) 
Tertiary/Exploratory Endpoints (All Cohorts): 
• 
Pharmacodynamic or prognostic markers (including but not limited 
to estrogen receptor degradation, Ki-67, RNA-Seq, 
4βhydroxycholesterol/cholesterol and ESR1 mutations) 
• 
FES-PET Scan (18F-fluoroestradiol radiotracer) 
Study Population: 
Phase 1 Monotherapy Dose Escalation and Combination Dose Escalation: 
Adult subjects with advanced ER+/HER2-negative advanced breast cancer 
who are refractory to or intolerant of established therapy(ies) known to 
provide clinical benefit for their malignancy.  
Phase 1 Monotherapy Expansion: Adult subjects with advanced ER+/HER2-
negative advanced breast cancer who have received up to 2 prior lines of 
endocrine-based therapy for advanced/metastatic breast cancer. 
Phase 2 Monotherapy: Adult subjects with advanced ER+/HER2-negative 
breast cancer who have received 1 or 2 prior lines of endocrine-based 
therapy for advanced/metastatic breast cancer.   
Phase 2 Combination: Adult subjects with advanced ER+/HER2-negative 
breast cancer who have received up to 1 prior line of endocrine-based 
therapy for advanced/metastatic breast cancer.   
Phase: 
1/2 
Estimated No. of Sites: 
Approximately 60 centers globally, including the US  
Estimated No. of 
Subjects: 
Phase 1 Monotherapy Dose Escalation: Approximately 36 subjects 
Phase 1 Monotherapy Expansion: Approximately 45 subjects 
Phase 1 Combination Dose Escalation:  Approximately 40 subjects 
Phase 2 Monotherapy:  Approximately 225 subjects 
Phase 2 Combination: Approximately 112 subjects 
ESTIMATED TOTAL: Approximately 458 subjects 
Study Intervention: 
ZN-c5   
Palbociclib (IBRANCE®); Pfizer, Inc.  
Overall Study Design: 
Phase 1/2 trial of ZN-c5 both as monotherapy and in combination with 
palbociclib.  
The study consists of 5 components: 
Phase 1 Monotherapy Dose Escalation and Phase 1 Monotherapy 
Expansion: Single agent ZN-c5 will be evaluated at sequentially escalating 
doses starting with 50 mg and up to 1200 mg administered orally, once daily 


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(alternatively, this total daily dose may be divided by 2 and administered 
BID [every 12 hours]), using a 28-day cycle (Dose Escalation). During or on 
completion of the Dose Escalation, additional patients may be enrolled onto 
one or more dose levels for the Monotherapy Expansion portion of the 
study. The decision to expand will be based on the PK, safety and available 
biomarker data.  
Phase 2 Monotherapy:  ZN-c5 will be administered at the single agent RP2D 
and schedule. This Monotherapy Phase 2 portion will follow a randomized, 
parallel cohort, non-comparative (estimation) design and up to 3 dose levels 
of ZN-c5 will be assessed. 
Phase 1 Combination Dose Escalation and Phase 2 Combination: In 
Phase 1, ZN-c5, starting at a dose level deemed well-tolerated (as 
determined from the Monotherapy Dose Escalation) will be evaluated in 
combination with palbociclib in ascending dose cohorts to assess the safety 
and determine the MTD or RP2D. ZN-c5 will be administered orally once 
daily (alternatively, this total daily dose may be divided by 2 and 
administered BID [every 12 hours]), on a 28-day treatment cycle. In Phase 2 
Combination, ZN-c5 will be dosed at the RP2D and potentially at a lower 
dose level in combination with palbociclib. The lower ZN-c5 dose will be 
selected based on available safety, PK and biomarker data. The dose and 
schedule of palbociclib will be the Regulatory Authority’s approved dose of 
125 mg taken orally once daily for 21 consecutive days followed by 7 days 
off treatment (1 cycle of treatment = 28 days) for both the Phase 1 
Combination Dose Escalation and Phase 2 components of the study. During 
the Dose Escalation, additional patients may be enrolled onto one or more 
dose levels (backfill). The Combination Phase 2 will follow a randomized, 
parallel group, non-comparative design, assuming both the RP2D and the 
lower dose are investigated, or a single dose cohort design, if only the RP2D 
is investigated. Each dose cohort will follow a Simon 2-stage design. 
Study Duration: 
60 months 
Participant Duration: 
Treatment will continue in the absence of disease progression, 
unacceptable toxicity, withdrawal of consent, or other reason (specified in 
Section 7.2). 


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1.2 
SCHEMA 
Figure 1 
ZN-c5-001 Phase 1 Monotherapy Dose Escalation, Expansion and Phase 2 
 
 
Figure 2 
ZN-c5-001 Phase 1 Combination with Palbociclib Dose Escalation and 
Phase 2 
 
  
Dose Escalation Component 
Design: 3 + 3 
Population: ER+ Breast Cancer 
·l+tiiii 
.c.a,;;; 
rhi·l&J 
rli+Zii 
.MfiMI 
IM:i/1 
Dose Expansion Component 
Design: Futility Screening 
Population: 1'1/2 nd/3 rd Line Endocrine 
Therapy 
Phase 2 Component 
Design: Randomized, parallel cohort, 
non-comparative ( estimation) design 
Population : 2nd/3 rd Line Endocrine 
Therapy 
The dose in mg is the total dose/day 
Dose Escalation Component 
Design: 3 + 3 
Population: ER+ Breast Cancer 
N ~ 18 subjects 
rlWIIM===;;;;;;;a> 
r-
===> 
Phase 2 Component N ~ 112 subjects 
Design: Randomized, parallel group, non-comparative design 
Two cohorts: ZN-cS at combinat ion RP2D and ZN-cS at a lower dose 
2-Stage Simon Design per cohort, endpoint= CBR 
Population : 1'1/2nd Line Endocrine Therapy 
RP20 - Stage 1 
Futility Stage; N ~21 
RP2D - Stage 2 
Efficacy Stage: N -35 
* Decision on which ZN-cS dose to start the expansion wi ll depend on the PK profile, safety and any available biomarker data 
** More than 3 ZN-cS dose levels may be assessed based on the Monotherapy Dose Escalation 
Palbociclib is dosed at 125 mg/day taken orally once daily for 21 consecutive days, followed by 7 days off treatment to comprise a complete 
cycle of 28 days. 


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1.3 
SCHEDULE OF ACTIVITIES 
Table 1: 
Study Procedures Table 
Study Phase 
Screening 
Cycle 1 
(28-day cycle) 
Cycles ≥ 2 
(28-day cycle) 
EOT 
30-day 
Safety 
Follow-
up 
Disease 
Assess
ment 
Follow-
up21 
(every 
12 
weeks) 
Survival 
Follow-
up22 
(every 
12 
weeks) 
Cycle Day 
Day 
-28 
Day 
1 
Day 
2 
Day 
8 
Day 
15 
Day 
16 
Day 
1 
[Day 15* 
Cycle 2 
Combination 
only] 
 
 
 
 
Window 
(days) 
-28 to 
-1 
 
 
± 1 
± 2 
 
[± 423] 
[± 2] 
± 7 
± 7 
± 7 
± 14 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
Medication 
History1  
X 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination2 
X 
X 
 
X 
X 
 
X 
[X] 
X 
X 
 
 
ECOG 
Performance 
Status 
X 
X 
 
 
 
 
X 
[X] 
X 
X 
 
 
Vital Signs3 
X 
X 
 
X 
X 
 
X 
[X] 
X 
X 
 
 
Triplicate 12-
lead ECG4 
X 
X 
[X] 
 
X 
[X] 
[X] 
 
X 
 
 
 
Adverse 
events/ 
Concomitant 
medications5 
[X] 
X 
[X] 
X 
X 
[X] 
X 
[X] 
X 
X 
 
 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X7 
X 
 
X 
X 
 
X 
[X] 
X 
X 
 
 
Chemistry 
X7 
X 
 
X 
X 
 
X 
[X] 
X 
X 
 
 
Coagulation8 
X7 
 
 
 
 
 
 
 
X 
 
 
 
Full Lipid 
Panel9 
 
[X] 
 
 
 
 
[X] 
 
 
 
 
 
Urinalysis10  
X7 
 
 
 
 
 
 
 
X 
 
 
 
Pregnancy 
Test11 
X 
X 
 
 
 
 
X 
 
X 
X 
 
 
PK12 
 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
 
 
 
 
 


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Study Phase 
Screening 
Cycle 1 
(28-day cycle) 
Cycles ≥ 2 
(28-day cycle) 
EOT 
30-day 
Safety 
Follow-
up 
Disease 
Assess
ment 
Follow-
up21 
(every 
12 
weeks) 
Survival 
Follow-
up22 
(every 
12 
weeks) 
Cycle Day 
Day 
-28 
Day 
1 
Day 
2 
Day 
8 
Day 
15 
Day 
16 
Day 
1 
[Day 15* 
Cycle 2 
Combination 
only] 
 
 
 
 
Window 
(days) 
-28 to 
-1 
 
 
± 1 
± 2 
 
[± 423] 
[± 2] 
± 7 
± 7 
± 7 
± 14 
ZN-c5 
pharmaco-
dynamic and 
exploratory 
biomarkers in 
blood13 
 
X 
 
 
 
 
X 
 
[X] 
 
[X] 
 
Tumor 
Biopsy14 
[X] 
 
 
 
 
 
[X] 
 
[X] 
 
[X] 
 
ESR1 
Mutation15 
 
X 
 
 
 
 
X 
 
[X] 
 
[X] 
 
CT/MRI16 
X 
 
 
 
 
 
X 
 
X 
 
[X] 
 
4β-
hydroxycholest
erol / 
cholesterol17 
 
X 
 
 
X 
 
X 
 
 
 
 
 
FES-PET18 
[X] 
 
 
 
 
 
[X] 
 
 
 
 
 
ZN-c5 oral 
dosing19 
 
X 
 
 
 
 
Palbociclib oral 
dosing (Combo 
only)20 
 
[X] 
 
 
 
 
Subject Dosing 
Diary 
Accountability 
and/or 
Dispensing6 
 
X 
 
 
 
 
X 
 
X 
 
 
 
LTFU22 
 
 
 
 
 
 
 
 
 
 
 
[X] 
Notes: X = Required; [X] = Only applicable as per footnote as indicated by the Assessment 
Cycle 1 Day 1 safety lab samples, physical examination, ECOG status and pregnancy test may be assessed up to 3 days prior to 
the Day 1 visit. On subsequent visits throughout the study, these procedures/assessments are allowed to be performed within 
1 day prior to the planned visit.  
Cycle 1 Days 2 and 16 are only required for subjects participating in the Phase 1 parts of the protocol. 
*Cycle 2 Day 15 visit – only for subjects participating in Combination Therapy (Combination Dose Escalation and Phase 2) 
 
1. 
Medical history includes significant past medical events (e.g., prior hospitalizations or surgeries), a review of the disease 
under study, prior anti-cancer therapies, and any concurrent medical illnesses. 


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2. 
Screening and End of Treatment Physical Examinations (PE) will be a complete PE. Beginning at C1D1, a modified physical 
examination may be performed. Weight (without shoes) should be measured at each PE. Height (without shoes) is 
measured at Screening only. 
3. 
C1D1 Vital Signs will be taken within 15 min pre-ZN-c5 dose and 2 and 4 hours post-dose (Phase 1) or pre-dose and 2 hours 
post-dose (Phase 2); vital signs will be taken pre-dose only at all subsequent visits. Oxygen saturation will be tested with a 
pulse oximeter. 
4. 
Resting, semi recumbent triplicate ECGs will be collected at any time during Screening window, Day 1 of every other cycle 
(alternating cycles) starting with Cycle 2 (at pre-dose), and at EOT. In Phase 1, triplicate ECGs will be collected on C1D1 and 
C1D15 at pre-dose, 8 hours, and 24 hours post-dose (pre-dose on C1D2 and C1D16). In Phase 2, triplicate ECGs will be 
collected on C1D1 and C1D15 at pre-dose and 2 hours post-dose. ECGs should preferably be collected prior to PK (or any 
other blood draw) if they are to be collected at the same nominal time point.  ECGs should be collected over a 5-minute 
window at each time point. 
5. 
AEs will be assessed using NCI CTCAE (v 4.03) criteria. Subjects will also return to clinic at 30-days (± 7 days) post last IP 
dose (but prior to initiation of subsequent breast cancer therapy) to assess AEs and SAEs. At Screening, all medications 
taken up to 30 days prior to Screening will be documented in the eCRF. 
6. 
Subjects will be given a Subject Diary on which they will record dates/times of study drug administration. Compliance with 
study drug(s) will be assessed and reviewed during visits.  
7. 
Screening chemistry, hematology, coagulation, and urinalysis should be collected within 7 days of C1D1. 
8. 
Coagulation assessment includes PT/INR, aPTT. 
9. 
A non-fasting full lipid panel will be performed on C1D1, C3D1 (coinciding with the first on-study tumor assessment after 
8 weeks) and C7D1 (6 months into the study). This will not be collected in the Monotherapy Phase 2. 
10. Urinalysis assessment includes visual inspection, microscopic examination, and dipstick test for pH, protein, glucose, WBC, 
bilirubin, and blood. 
11. Serum pregnancy testing will be conducted at Screening (within ≤ 7 days of C1D1). Serum or urine pregnancy tests 
thereafter will be done on Day 1 of every cycle for all premenopausal and perimenopausal female subjects of childbearing 
potential, including EOT and the Safety Follow-up Visit. 
12. Plasma samples for PK analysis of ZN-c5 (having been administered without food [at least 1 hour before and 2 hours after 
a meal]) and of palbociclib (having been administered with food) will be collected relative to ingestion of each drug as per 
Table 6 and Table 7.  Regarding the PK sampling for ZN-c5 if administered twice daily (BID), a sample at 12 hours post 
morning dose and immediately preceding the second daily dose may also be collected (optional).  Note:  If the optional, 
On-Treatment tumor biopsy is performed, an additional PK sample should be collected at that time.   
13. Whole blood, serum and/or plasma will be collected for exploratory biomarkers at C1D1, C2D1, and at time of disease 
progression. 
14. Tumor biopsy:  At baseline, de novo biopsy of any amenable site of disease (at investigator’s discretion). Additional tumor 
biopsy at C2D1 or any time beyond may also be obtained. The on-treatment biopsy should be obtained 2 – 4 hours after 
the subject has taken the ZN-c5 dose that day. Subjects will also have the option to undergo a biopsy of a lesion at the 
time of disease progression. Samples will be collected, labelled, stored and shipped as detailed in the laboratory manual. 
Any residual tumor remaining after analysis may be used for exploratory research into factors that may influence 
development of breast cancer and/or response to ZN-c5. All tumor biopsies are optional for all subjects participating 
during the study.  Biopsies must not be taken from target lesions used to assess anti-tumor efficacy, if possible. If sufficient 
tumor material is available, part of the tumor biopsy at C2D1 will be used for determination of ZN-c5 tissue concentration.  
If a biopsy is obtained on C2D1 or beyond, a plasma PK sample should also be collected, as close as possible, within 2 hours 
prior to the biopsy. 
15.  A blood sample for the assessment of ESR1 mutations will be drawn at C1D1, C2D1, and at time of progression. 
16. Tumor evaluation by CT/MRI or applicable scan will be performed during Screening (within 28 days of Cycle 1 Day 1) and 
every 8 weeks (± 7 days) after C1D1 for the first 24 weeks. After 24 weeks, scans may be performed every 12 weeks 
(± 7 days). The same radiographic procedure used to define measurable lesions must be used throughout the study for 
each subject. Applicable scans to be done at EOT visit if not done within the previous 4 weeks. 
17. Plasma samples for 4β-hydroxycholesterol and cholesterol will be collected pre-dose on C1D1, C1D15, and pre-dose on 
Day 1 of Cycles 2-4 of the Monotherapy Dose Escalation and Expansion. 
18. A FES-PET scan (optional) should be conducted at Screening and at least after 1 month of treatment (preferably within the 
first 2 months, in Cycle 2). 
19. Beginning on C1D1, subjects will take ZN-c5 once daily (alternatively, this total daily dose may be divided by 2 and 
administered BID [every 12 hours]).  ZN-c5 dosing and administration as per assigned cohort (see Section 6.1.2.1). 
20. In Phase 1, beginning on C1D1, subjects in the combination treatment cohorts will take palbociclib at the label indicated 
dose of 125 mg orally once daily (2 hours after the ZN-c5 dose was taken) for 21 consecutive days followed by 7 days off 
treatment (1 cycle of treatment = 28 days) (see Section 6.1.2.2). In Phase 2, subjects in the combination treatment cohorts 
will take palbociclib at the label indicated dose of 125 mg orally once daily (at the same time the ZN-c5 dose is taken) for 


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21 consecutive days followed by 7 days off treatment (1 cycle of treatment = 28 days).21. 
Disease Assessment Follow-
up Visit: Subjects without progression of disease (PD) at the time of study drug discontinuation will continue to undergo 
disease evaluations every 12 weeks ± 7 days until confirmation of PD, initiation of the first subsequent cancer therapy, 
withdrawal of consent, death, loss to follow-up, or until the study is terminated.  Once a subject has confirmation of PD or 
has initiated subsequent cancer therapy, whichever occurs first, disease follow-up will discontinue. 
22. Long-term Follow-up (LTFU) – Subjects will be contacted every 3 months (phone or medical records) for survival status and 
collection of subsequent breast cancer treatments. 
23. In the Combination Dose Escalation and Combination Phase 2 with palbociclib, the window for the Day 1 visit for 
subsequent cycles is only + 4 days, since there must always be at least a full 7-day off treatment recovery period for 
palbociclib before starting the next 21-day dosing cycle. 
 
 
 


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2 
INTRODUCTION 
2.1 
STUDY RATIONALE 
Hormone receptor-positive, HER2-negative breast cancer is the most common subset of breast cancer, 
with the majority of patients diagnosed at an early stage and remaining relapse-free if treated with a 
prolonged course of endocrine therapy1. Unfortunately, not all patients respond to first-line endocrine 
therapy, and many patients who initially respond will relapse (acquired resistance). Approximately one-
third of all HR+/HER2-negative patients diagnosed with initial early stage disease experience disease 
recurrence2, resulting in the HR+/HER2-negative subset accounting for the majority of breast cancer 
related deaths. The estrogen receptor (ER) in these patients is a key driver of disease progression, and 
the primary reason for relapse in these patients is that endocrine therapies are only partially effective, 
typically causing cell cycle arrest rather than cell death. As a result, secondary resistance to endocrine 
therapy is a major clinical challenge. 
Most pre- or peri-menopausal women with HR+ breast cancer present with early stage disease and are 
treated with the anti-estrogen tamoxifen (with or without ovarian ablation by surgery, chemotherapy or 
luteinizing hormone-releasing hormone) in the adjuvant setting3. Upon initial presentation with 
metastatic disease during pre-menopause, the recommended approach is to suppress ovarian function 
(by ovarian ablation or luteinizing hormone-releasing hormone (LHRH) agonist therapy), and then follow 
post-menopausal treatment guidelines, switching treatment from tamoxifen to AIs or fulvestrant. Thus, 
in clinical practice so called “pre/peri-menopausal” patients with HR+ metastatic breast cancer will be 
rendered postmenopausal by the time of first line treatment for advanced disease. 
Upon disease progression on hormonal therapy, treatment options have historically been limited to 
a change in AIs (steroidal or nonsteroidal) or the use of the ER antagonists such as fulvestrant. Clinical 
trials in postmenopausal women with primary breast cancer have shown that fulvestrant significantly 
down-regulates ER protein in ER-positive tumors. While effective, more efficacious and safe therapeutic 
options are still needed, particularly in selected patient populations. Thus, HR+/HER2-negative breast 
cancer patients who have tumor progression following endocrine therapies for advanced/metastatic 
disease remains an important medical need. 
Fulvestrant is currently the only approved anti-estrogen drug that binds and selectively degrades the ER. 
Recent data with fulvestrant administered at the dose of 500 mg/monthly to patients with recurrent 
HR+/HER2-negative breast cancer indicate significant anti-tumor activity after both anti-estrogen and 
aromatase inhibitor (AI) failures. Fulvestrant is currently indicated for the treatment of postmenopausal 
women with metastatic HR+ breast cancer following the failure of antiestrogen therapy. Although it is 
effective, fulvestrant is limited by its poor pharmaceutical properties, which leads to sub-optimal 
exposure due to its administration via intramuscular injection, which also results in potential injection-
related adverse events such as hypersensitivity reactions, including urticaria and angioedema. In 
addition, as with other intramuscular injections, caution is advised when treating patients with bleeding 
disorders or thrombocytopenia, and those receiving treatment with anticoagulants such as warfarin. 
Therefore, efforts have been made to develop selective ER-receptor degraders that can be taken by 
mouth to avoid some potential complications of injection and increase the exposure. 


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Fulvestrant has also not been studied extensively in pre-or peri-menopausal women, although it is 
expected to also add benefit to the treatment of these patients (if given concurrently with ovarian 
suppression/ablation). Clinical experience demonstrates that medical or surgical ovarian ablation 
produces comparable outcomes to tamoxifen monotherapy and supports the use of goserelin (LHRH 
agonist) concurrently with fulvestrant in premenopausal women with metastatic breast cancer4. Clinical 
studies are currently underway evaluating the combination of fulvestrant with medical ovarian 
suppression in premenopausal women with breast cancer5. 
There is evidence to suggest that more complete estrogen receptor degradation may result in improved 
clinical outcomes. Therefore, this study will investigate the safety and potential efficacy of an oral 
selective estrogen receptor degrader in the hormone-therapy refractory ER+/HER2-negative patient 
population. 
The use of a selective estrogen receptor degrader (SERD) in combination with CDK4/6 inhibition was 
shown to be clinically beneficial in a large, multinational clinical trial PALOMA-3, which combined 
fulvestrant with palbociclib (IBRANCE®, Pfizer Inc.) in patients with HR-positive, HER2-negative advanced 
or metastatic breast cancer who had disease progression on or after prior adjuvant or metastatic 
endocrine therapy6. PALOMA-3 was an international, randomized, double-blind, parallel group, 
multicenter study of palbociclib (IBRANCE) plus fulvestrant versus placebo + fulvestrant conducted in 
women with HR-positive, HER2-negative advanced breast cancer, regardless of their menopausal status, 
whose disease progressed on or after prior endocrine therapy. A total of 521 pre/postmenopausal 
women were randomized 2:1 to palbociclib + fulvestrant or placebo + fulvestrant and stratified by 
documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre/peri versus 
postmenopausal), and presence of visceral metastases. Palbociclib was given orally at a dose of 125 mg 
daily for 21 consecutive days followed by 7 days off treatment. Pre/perimenopausal women were 
enrolled in the study and received the LHRH agonist goserelin for at least 4 weeks prior to and for the 
duration of study. Patients continued to receive assigned treatment until objective disease progression, 
symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred 
first. The major efficacy outcome of the study was investigator-assessed Progression-Free Survival (PFS) 
evaluated according to RECIST 1.1. 
Patients enrolled in the PALOMA-3 study had a median age of 57 years (range 29 to 88). The majority of 
patients on study were White (74%), all patients had an Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) of 0 or 1, and 80% were postmenopausal. All patients had received prior 
systemic therapy, and 75% of patients had received a previous chemotherapy regimen. Twenty-five 
percent of patients had received no prior therapy in the metastatic disease setting, 60% had visceral 
metastases, and 23% had bone only disease. 
The results from the Investigator-assessed PFS analysis showed a statistically significant improvement in 
PFS (9.5 months vs. 4.6 months) in favor of palbociclib + fulvestrant. Consistent results were observed 
across patient subgroups of disease site, sensitivity to prior hormonal therapy, and menopausal status. 
The Overall Survival (OS) data were not mature at the time of the final PFS analysis. These results 
suggest that the combination of a SERD and a CDK4/6 inhibitor are a clinically useful strategy for the 
treatment of ER+/HER2-negative advanced breast cancer patients after endocrine therapy failure. 


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2.2 
BACKGROUND 
ZN-c5 (also known as KP-868) binds potently to the estrogen receptors alpha and beta (ERα and ERβ) 
with Ki values of 3.4, 3.2 nM, respectively. Treatment of MCF-7 cells with ZN-c5 results in the 
degradation of ERα (EC50 = 0.19 nM) and inhibition of breast cancer cell growth (MCF-7, IC50 = 0.4 nM, 
MCF-7 LTED IC50 = 0.2 nM). ZN-c5 is orally bioavailable and shows improved activity over fulvestrant in 
human tumor xenograft models and shows activity in tumor models that are resistant to tamoxifen. In 
the MCF-7 orthotopic tumor xenograft model, ZN-c5 treatment at 5 mg/kg and 10 mg/kg, resulted in 
89% and 101% tumor growth inhibition (TGI), respectively, as a single agent. The 5 mg/kg dose resulted 
in 89% TGI and 9.35 µg*hr/m is considered the minimal efficacious exposure for ZN-c5. Combination of 
ZN-c5 with the CDK inhibitors palbociclib or abemaciclib, resulted in increased tumor growth inhibition 
and regression of large tumors. In the tamoxifen resistant (TAMR) MCF-7 orthotopic tumor model, 
treatment with ZN-c5 at 10 and 40 mg/kg resulted in 37% and 60% TGI, respectively. In rat uterine wet 
weight studies, ZN-c5 acted as an estrogen antagonist but not an agonist. Overall these studies show 
that ZN-c5 is a novel and potent SERD with oral bioavailability and strong activity in estrogen-dependent 
and tamoxifen-resistant tumor models. 
Nonclinical in vivo data indicate that ZN-c5 is rapidly absorbed with oral bioavailability typically 
exceeding 74% in all species. ZN-c5 plasma exposure was generally dose proportional with no major 
accumulation occurring in the 28-day and 13-week toxicology studies. Sex differences in ZN-c5 exposure 
in rats was observed, consistent with CYP3A and CYP2C metabolism of ZN-c5 as shown in an in vitro CYP 
phenotyping study. Free fraction of ZN-c5 was 0.241% in human plasma, ~0.5% in rodents and ~0.15% in 
dogs. ZN-c5 shows an efflux ratio of < 1 in Caco-2 cells and does not appear to be a P-gp or BCRP, 
substrate. 
ZN-c5 is metabolically stable in liver microsomes and hepatocytes of all species tested except monkeys. 
CYP isoforms that most efficiently metabolize ZN-c5 are CYP3A5, CYP2C9, and CYP3A4. The major 
metabolite was detected in liver microsomes and hepatocytes of all species tested except mice. ZN-c5 
inhibited CYP2C8 with an IC50 value of 0.152 µM. The IC50 values for the other CYP isoforms ranged from 
20.9 to > 50 µM. No time dependent inhibition of CYP3A was observed. ZN-c5 did not inhibit P-gp, 
whereas, the IC50 value for BCRP inhibition was 1.56 μM. IC50 values for SLC transporter inhibition ranged 
from 1.42 to > 30 μM with OATP1B1 and OATP1B3 being most potently inhibited (1.42 and 5.80 µM, 
respectively). IC50 value for BSEP inhibition was 20.2 μM. In a CYP induction experiment performed in 
hepatocytes from three human donors, there was no CYP1A2 and CYP2B6 induction but CYP3A4 
induction was observed in all three donors. Subsequently, PBPK modeling was performed with the 
objectives to develop a model for ZN-c5 using in vitro ADME, physicochemical and relevant clinical data 
to predict its Drug-Drug Interaction (DDI) liability with substrates of CYP3A4, CYP2C8, P-gp, BCRP and 
OATP1B1. Simulations predicted a moderate interaction with CYP3A4 substrates, a mild to moderate 
interaction with CYP2C8 substrates, a minimal interaction with either P-gp or OATP1B1 substrates and a 
potential for a moderate BCRP-mediated interaction (the latter considered exploratory). Overall, ZN-c5 
may alter clearance and exposure of concomitantly administered drugs that are substrates of CYP2C8, 
CYP3A4, and, potentially, BCRP. 


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The results of an excretion study conducted in female rats that received a single IV or oral dose of ZN-c5 
indicate that ZN-c5 is eliminated from the body by biliary excretion, and renal elimination is not 
substantial. 
The nonclinical safety profile of ZN-c5 has been well characterized through the conduct of single- and 
repeat-dose studies of up to 13 weeks in duration. The primary target organ effects in repeat dose 
studies were related to reproductive tissues and the liver. Microscopic findings in the bone marrow in 
high-dose treated dogs in the 28-day study consisted of decreased erythropoiesis which correlated with 
the hematology finding of decreased reticulocyte counts, secondary to inflammation.  These effects 
were not seen in the 13-week repeat dose dog study.  The liver effect in the 28-day dog study was 
associated with cholestasis leading to hyperbilirubinemia, most likely due to inhibition of the bile salt 
export pump (BSEP) in vitro, with an IC50 of 20.2 μM. These liver effects were not observed in the 13-
week dog study.  In the 14-day rat study, the liver effects were limited to microvesicular changes due to 
lipid deposition in hepatocytes as confirmed with oil--red--O staining. This effect in rats is most likely 
due to the anti-estrogenic effect of ZN-c5 given that estrogen plays an important role in lipid 
homeostasis within the liver. Effects of ZN-c5 on sex organs (decreased uterine weights, development of 
ovarian cysts, hypertrophy and hyperplasia of the mammary gland, prostate atrophy, testicular 
degeneration) are postulated to also be due to the pharmacological effect of the test article. This 
includes the effects seen in the male dog testes. The non-glandular stomach changes noted in the rat 
are not a risk to humans as humans lack a non-glandular stomach. The potential for reversibility of all 
adverse effects was established following a 1-month non-dosing period. All the adverse effects reversed 
or showed evidence of reversibility, except for the testicular effects in dogs that did not exhibit any signs 
of recovery. 
In the safety pharmacology endpoints captured during the repeat dose toxicology studies, ZN-c5 did not 
exhibit any adverse CNS effects based on the functional observation battery (FOB), and no respiratory 
findings in the repeat dose toxicology studies or in a stand-alone respiratory study. In addition, there 
were no cardiovascular effects based on monitoring of electrocardiogram (ECG) parameters in the 
28-day dog study or in a definitive cardiovascular study in dogs with telemetry implants. In addition, 
ZN-c5 was negative in the in vitro and in vivo genetic toxicology studies. 
The nonclinical safety findings related to ZN-c5 administration represent toxicities that can be 
monitored and are considered clinically manageable or acceptable risks in the intended patient 
population. The nonclinical safety profile of ZN-c5 has been adequately characterized to support 
progression into clinical trials in advanced cancer patients. 
Please refer to the ZN-c5 Investigator’s Brochure (IB) for additional information. 
2.3 
RISK/BENEFIT ASSESSMENT 
2.3.1 
KNOWN POTENTIAL RISKS 
Based on the nonclinical toxicology studies conducted with ZN-c5, the potential adverse effects will 
include alterations in sex organs, the potential for hepatic injury, and a potential decrease in 
erythropoiesis/reticulocytes.  The sex organ effects (including but not limited to development of ovarian 
cysts, atrophy of the uterus, and hypertrophy and hyperplasia of the mammary gland) are due to 


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decreases in estrogen as a result of ZN-c5 pharmacology.  Although specific nonclinical fertility studies 
have not been conducted with ZN-c5, based on the microscopic changes in the testes and ovaries, 
decreased fertility in both male and female patients taking ZN-c5 is possible.  The potential hepatic 
effects include cholestasis and hyperbilirubinemia leading to hepatocellular necrosis, as well as pruritus 
due to elevated bile salts. All changes, except for the changes in the testes, were noted to be reversible 
during a treatment-free recovery period. The adverse effect profile of fulvestrant is well-documented, 
and includes injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in 
extremities, hot flashes, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and 
constipation, as well as increased hepatic enzymes.  
The adverse effect profile of palbociclib (IBRANCE®, Pfizer Inc.) is well-documented across multiple 
international, multi-center trials.  Known adverse effects attributable to palbociclib include low blood 
cell counts (cytopenia), fatigue, nausea, diarrhea, vomiting, infections, stomatitis, alopecia, rash, 
decreased appetite, asthenia, and pyrexia, among other potential adverse effects.  The full product 
safety information is available in the most recent Prescribing Information for palbociclib from Pfizer. 
2.3.2 
KNOWN POTENTIAL BENEFITS 
Pre-clinical data suggests that treatment with ZN-c5 can result in anti-proliferative activity in ER+ tumor 
models, and clinical data has shown that the combination of a SERD and a CDK4/6 inhibitor is clinically 
beneficial in patients with ER+/HER2-negative advanced breast cancer who have progressed on or after 
endocrine therapy. 
For patients enrolled in the combination therapy portion of the trial, subjects will receive palbociclib 
(IBRANCE®, Pfizer Inc.), which has been approved by Regulatory Authorities for the treatment of HR+, 
HER2 negative advanced or metastatic breast cancer in combination with an AI or fulvestrant based on 
significant improvement in Progression-Free Survival (PFS). 
2.3.3 
ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
This study is a Phase 1/2 study with ZN-c5, an oral selective estrogen receptor degrader, alone and in 
combination with the CDK4/6 inhibitor palbociclib.  The selected starting dose for this study is within the 
range that is predicted to provide biological activity based upon nonclinical explant models, in 
accordance with the ICH S9 Nonclinical Evaluation for Anticancer Pharmaceuticals.  The toxicological 
profile of ZN-c5 has been evaluated in rats and dogs in studies of up to one month in duration.  The 
pre-clinical safety profile has not identified any risks that would preclude investigation in this setting.  
The study is designed to minimize potential risks, and close monitoring is in place for those risks deemed 
to be most likely or serious. 
The investigation of ZN-c5 alone and in combination with the approved agent palbociclib in this patient 
population appears reasonable, based upon the pre-clinical safety profile, preliminary signals of efficacy, 
the proven efficacy of mechanism of action, and the strength of the scientific hypothesis under 
evaluation.  Thus, the benefit/risk assessment for this first-in-human Phase 1/2 study supports the oral 
administration of ZN-c5 to subjects with advanced ER+/HER2-negative breast cancer alone and in 
combination with palbociclib, according to the proposed study design. 


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3 
OBJECTIVES AND ENDPOINTS  
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
Primary 
 
 
Phase 1 
 
 
• 
Monotherapy Dose Escalation: 
Determine a maximum tolerated 
dose (MTD) or recommended 
Phase 2 dose (RP2D) for ZN-c5 as a 
monotherapy 
• 
Monotherapy Expansion: 
Investigate the safety and 
tolerability of ZN-c5 as a 
monotherapy in subjects with 
Estrogen Receptor (ER) positive, 
Human Epidermal Growth Factor 
Receptor-2 (HER2) negative 
advanced breast cancer 
• 
Combination Dose Escalation:   
Determine an MTD or RP2D for 
ZN-c5 when administered in 
combination with palbociclib 
 
Observed Dose Limiting 
Toxicities 
 
 
Safety and tolerability as 
measured by incidence of 
treatment-emergent AEs and lab 
abnormalities 
 
 
 
Observed Dose Limiting 
Toxicities 
This is accepted 
methodology to evaluate 
safety and determine the 
doses for further evaluation. 
The incidence of treatment 
emergent AEs and lab 
abnormalities reflects the 
safety profile of ZN-c5. 
Phase 2 
• 
Monotherapy Phase 2: Determine 
preliminary anti-tumor efficacy 
(Clinical Benefit Rate [CBR]) for 
ZN-c5 as a monotherapy 
• 
Combination Phase 2: Determine 
preliminary anti-tumor efficacy 
(CBR) for ZN-c5 when administered 
in combination with palbociclib 
 
CBR (CR [+ PR] + SD ≥ 24 weeks). 
PR will only be included for 
patients with measurable 
disease. 
 
ZN-c5 is expected to have 
activity in the selected 
patient population, and 
standard measures of 
disease 
response/progression were 
chosen to evaluate potential 
efficacy. 
Secondary 
 
 
• 
Monotherapy Dose Escalation and 
Phase 2:  Investigate the safety and 
tolerability of ZN-c5 as a 
monotherapy in subjects with ER 
positive, HER2-negative advanced 
breast cancer  
• 
Combination Dose Escalation and 
Phase 2:  Investigate the safety and 
tolerability of ZN-c5 in combination 
with palbociclib in subjects with ER 
positive, HER2 negative advanced 
breast cancer 
All Cohorts: Safety and 
tolerability as measured by 
incidence of treatment-
emergent AEs and lab 
abnormalities 
The incidence of 
treatment-emergent AEs 
and lab abnormalities 
reflects the safety profile of 
ZN-c5 across all subjects in 
the study. 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
• 
Monotherapy Expansion Phase 1: 
Investigate the preliminary anti-
tumor efficacy (CBR) for ZN-c5 as a 
monotherapy  
 
• 
All Cohorts: Assess preliminary 
efficacy of ZN-c5 alone and in 
combination with palbociclib by 
Objective Response Rate (ORR), 
CBR, Duration of Response (DOR), 
Progression-Free Survival (PFS) and 
Overall Survival (OS) using Response 
Evaluation Criteria in Solid Tumors 
(RECIST v.1.1) as assessed by 
investigators 
CBR (CR [+ PR] + SD ≥ 24 weeks). 
PR will only be included for 
patients with measurable 
disease. 
 
Tumor response including ORR, 
DOR, CBR, PFS using Response 
Evaluation Criteria in Solid 
Tumors (RECIST v.1.1) as 
assessed by Investigators, and 
OS 
ZN-c5 is expected to have 
activity in the selected 
patient population, and 
standard measures of 
disease 
response/progression were 
chosen to evaluate potential 
efficacy. 
• 
Monotherapy Dose Escalation, 
Phase 2 and Expansion: 
Characterize the pharmacokinetics 
(PK) of ZN-c5 (and its potential 
metabolites as applicable) when 
given as oral monotherapy 
ZN-c5 (and its potential 
metabolites as applicable) and 
palbociclib (if applicable) plasma 
PK parameters (including Cmax, 
Tmax, AUClast, t½ and Ctau, as 
applicable) 
ZN-c5/palbociclib plasma 
pharmacokinetic 
parameters may allow for 
correlating exposure with 
toxicity or efficacy. 
• 
Combination Dose Escalation and 
Phase 2: Characterize the PK of 
ZN-c5 (and its potential metabolites 
as applicable) when given in 
combination with palbociclib 
 
 
• 
Combination Dose Escalation and 
Phase 2: Characterize the PK of 
palbociclib when given in 
combination with ZN-c5 
 
 
Tertiary/Exploratory (All Cohorts) 
 
 
• 
Evaluate pharmacodynamic and 
prognostic biomarkers associated 
with disease prognosis and/or 
likelihood of response to ZN-c5 
Pharmacodynamic or prognostic 
markers (including but not 
limited to estrogen receptor 
degradation, Ki67, RNA seq, 4β 
hydroxycholesterol/ cholesterol 
and ESR1 mutations 
Investigational 
pharmacodynamics may 
allow for correlation 
between response and 
biomarkers 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION 
• 
Assess the effect of ZN-c5 on 
tumor’s ability to bind estradiol as 
measured by uptake of 18F-
fluoroestradiol (FES) positron 
emission tomography (PET) 
FES-PET Scan (18F-fluoroestradiol 
radiotracer) 
PET scanning with FES 
correlates with ER 
expression.  It is performed 
to explore its potential as a 
predictive assay and 
method of assessing 
pharmacodynamic response 
to ZN-c5. 
 


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4 
STUDY DESIGN 
4.1 
OVERALL DESIGN 
This is a Phase 1/2, open-label, multicenter, dose-escalation and expansion study to evaluate the safety, 
tolerability, PK, and preliminary efficacy of ZN-c5 administered orally in subjects with advanced 
ER+/HER2-negative breast cancer, both as monotherapy and in combination with palbociclib (IBRANCE®, 
Pfizer Inc.). 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Open label dose escalation with a standard rule-based 3+3 design was chosen so as to accurately 
identify the MTD/RP2D as safely as possible, while minimizing the number of subjects exposed to lower 
(and potentially less efficacious) doses of study drug. For the combination portion of the study, dose 
escalation will start and will follow ZN-c5 dose levels that are deemed to be well-tolerated in the 
Monotherapy Dose Escalation. ZN-c5 will be evaluated in combination with the approved dose of 
palbociclib in ascending dose cohorts to assess the safety and determine the MTD or RP2D prior to 
initiation of the Phase 2 portion of the study. 
Screening (estimation) as well as Simon 2-stage designs are well established to evaluate anti-tumor 
efficacy in the uncontrolled proof of concept setting, considering that no previous clinical efficacy 
experience exists in this setting. It accounts for minimal subject exposure in the event of futile efficacy 
against historically established performance in a specific population setting. 
4.3 
JUSTIFICATION FOR DOSE 
The recommended clinical starting dose (50 mg) in advanced cancer patients is based on the 28-day 
repeat-dose toxicity study in dogs, with the highest non-severely toxic dose (HNSTD) at 10 mg/kg/day. 
Taking one-sixth the HNSTD dose as outlined in ICH S9, then correcting for body surface area, equates to 
a recommended starting dose of 0.93 mg/kg, or 55.6 mg for a 60 kg patient. Therefore, a 50 mg starting 
dose was suggested as the safe starting dose for the Phase 1 Monotherapy Dose Escalation study. 
In the ZN-c5 food effect Study ZN-c5-006, the ratio of AUC0-inf after a high-fat meal compared to fasting 
showed no effect. A small, <20%, decrease in Cmax was observed when ZN-c5 was administered after 
a high-fat meal. Although the Cmax change was statistically significant (lower 90% confidence bound 
< 0.8), the difference was small compared to the variability of the ZN-c5 exposure in cancer patients and 
therefore not considered clinically relevant. Based on these results (data on file), ZN-c5 is allowed to be 
dosed with or without food. This will be implemented only in the Phase 2 parts of the protocol. 
4.4 
END OF STUDY DEFINITION 
The end of the study is defined as when the last patient on study has completed their last study visit 
(i.e., last safety follow-up or last disease assessment follow-up, whichever is last). 
If the primary objectives of the study have been met or the Sponsor decides to stop the study early, the 
database may be locked for the purpose of analyzing and reporting data.  Subjects may continue to 
receive ZN-c5 per protocol beyond the data cut-off for database lock if the Investigator and the Sponsor 
agree that the patient’s best interests are served by remaining on study treatment. 


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Limited information including, but not limited to study drug administration, study drug accountability, 
and non-serious and serious adverse events will be collected in addition to any cases of pregnancy, 
overdose, or medication error.  Less frequent subject visits might be implemented as per institutional 
standard of care. 


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5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study: 
1) Male or female 
2) Age ≥ 18 years 
3) Menopausal Status [Female subjects]: 
Postmenopausal, as defined by at least one of the following 
a) Age ≥ 60 years; 
b) Age < 60 years and cessation of regular menses for at least 12 consecutive months with no 
alternative pathological or physiological cause; and serum estradiol and FSH level within 
the laboratory’s reference range for postmenopausal females; 
c) Documented bilateral oophorectomy; 
or 
Pre- or peri-menopausal, who must receive a gonadotropin-releasing hormone agonist 
beginning at least 4 weeks prior to first dose of study medication. 
4) Histologically or cytologically confirmed diagnosis of advanced adenocarcinoma of the breast, not 
amenable to any potential curative intervention 
5) Estrogen Receptor (ER) positive disease defined as follows documented by a local laboratory: 
a) [Monotherapy Escalation and Combination Dose Escalation Cohorts]: > 1% positive stained cells 
based on medical record, archival tumor biopsy, or de novo tumor biopsy 
b) [Monotherapy Expansion/Monotherapy Phase 2/Combination Phase 2 Cohorts]: > 10% positive 
stained cells  
6) Human Epidermal Growth Factor Receptor 2 (HER2) negative disease as documented by a local 
laboratory 
a) [Monotherapy Escalation and Combination Dose Escalation Cohorts]: Documentation by medical 
record or archival tumor tissue allowed 
b) [Monotherapy Expansion/Monotherapy Phase 2/Combination Phase 2 Cohorts]: Based on 
analysis of archival tumor biopsy or de novo biopsy with HER2-negativity defined as: 1) 
Immunohistochemistry score 0/1+ or 2) Negative by in situ hybridization (FISH/CISH/SISH) 
defined as a HER2/CEP17 ratio < 2, or for single probe assessment a HER2 copy number < 4 
7) [Monotherapy Escalation and Combination Dose Escalation Cohorts]: Refractory to or intolerant of 
established therapy(ies) known to provide clinical benefit for their malignancy 
8) Prior Hormonal Therapy: 
a) [Monotherapy Expansion Cohort]:  up to 2 prior lines of endocrine therapy for advanced or 
metastatic breast cancer 
b) [Monotherapy Phase 2]:  1 or 2 prior lines of endocrine therapy for advanced or metastatic 
breast cancer 
c) [Combination Phase 2]: up to 1 prior line of endocrine therapy for advanced or metastatic breast 
cancer 


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d) Subjects who will undergo a FES-PET must have discontinued all prior ER blocking therapy (e.g., 
tamoxifen or fulvestrant) for ≥ 60 days before the day of the examination at baseline. 
In counting lines of treatment for advanced/metastatic disease, any change in regimen due to PD or 
toxicity will be counted as a separate line of treatment. 
9) Documented prior response to endocrine therapy for advanced or metastatic disease (SD, PR, or CR) 
lasting > 6 months or disease recurrence after at least 24 months of adjuvant endocrine treatment. 
(not required for treatment naïve patients) 
10) Prior Chemotherapy: 
a) [Monotherapy Dose Escalation Cohort]:  Up to 2 prior lines of chemotherapy for the treatment 
of advanced breast cancer 
b) [Monotherapy Phase 2]:  No prior chemotherapeutic regimens for the treatment of advanced 
breast cancer 
c) [Monotherapy Expansion, Combination Dose Escalation and Combination Phase 2 Cohorts]: Up 
to 1 prior line of chemotherapy for the treatment of advanced breast cancer 
In counting lines of treatment for advanced/metastatic disease, any change in regimen due to PD or 
toxicity will be counted as a separate line of treatment. 
11) Prior treatment with a CDK4/6 inhibitor is allowed 
12) Evaluable or measurable disease per RECIST v1.1. 
13) Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 
14) All acute toxic effects of any prior anti-tumor therapy resolved to Grade ≤ 1 or baseline (with the 
exception of alopecia [any grade permitted]) 
15) Adequate organ function defined as follows: 
a) Hematologic: Platelets ≥ 100 × 109/L; Hemoglobin ≥ 9.0 g/dL; Absolute Neutrophil Count (ANC) 
≥ 1.5 × 109/L (without platelet transfusion or any growth factors within previous 7 days of the 
hematologic laboratory values obtained at Screening visit). 
b) Hepatic: Aspartate transaminase (AST) and Alanine transaminase (ALT) ≤ 2.5 × upper limit of 
normal (ULN) or ≤ 5 × ULN in case of liver metastases; Total or conjugated bilirubin ≤ 1.5 × ULN. 
c) Renal: Creatinine clearance (CrCl) ≥ 30 mL/min as calculated by the Cockcroft Gault method or 
serum creatinine ≤ 1.5 × ULN 
16) [Premenopausal and perimenopausal female subjects]: Negative serum pregnancy test 
17) Male and female subjects of childbearing potential or partners of subjects who engage in 
intercourse must agree to use protocol specified method(s) of contraception. 
5.2 
EXCLUSION CRITERIA 
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study: 
1) Any of the following within the specified window prior to the first dose of study drug: 
a) Tamoxifen, AI, fulvestrant or other anti-cancer endocrine therapy < 14 days 
b) Any chemotherapy < 28 days (or 5 half-lives, whichever is shorter) 
c) Any investigational drug therapy < 28 days or 5 half-lives (whichever is shorter) 


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d) Prior radiotherapy < 14 days (except for palliative radiotherapy to peripheral sites without 
residual toxicity) 
e) Major surgery < 28 days 
f) Minor surgery < 7 days (placement of central venous catheter, fine needle aspiration, or 
endoscopic biliary stent < 1 day is acceptable) 
2) Prior hematopoietic stem cell or bone marrow transplantation 
3) Prior radiotherapy to > 25% of bone marrow 
4) Brain metastases that require immediate treatment or are clinically or radiologically unstable (i.e., 
have been stable for < 1 month). If receiving steroids, subjects must be receiving a stable to 
decreasing corticosteroid dose during at least 1 week before enrollment.   
5) Leptomeningeal disease that requires or is anticipated to require immediate treatment. 
6) Presence of life-threatening metastatic visceral disease or symptomatic pulmonary lymphangitic 
spread 
7) Other known active cancer(s) likely to require treatment in the next year that would impact the 
assessment of any study endpoints 
8) [Female subjects]: Pregnant or breast-feeding 
9) Unexplained symptomatic endometrial disorders (including, but not limited to endometrial 
hyperplasia, dysfunctional uterine bleeding, or cysts) 
10) Uncontrolled symptomatic thyroid dysfunction 
11) Impairment of gastrointestinal (GI) absorption for oral medications  
12) Nausea, vomiting, or diarrhea > Grade 1 
13) Myocardial infarction, symptomatic congestive heart failure (NYHA > Class II), unstable angina, or 
serious uncontrolled cardiac arrhythmia within the last 6 months 
14) QTc interval > 480 msec (based on the mean value of the triplicate ECGs), family or personal history 
of long or short QT syndrome, Brugada syndrome or history of Torsade de Pointes 
15) Concurrent use of food or drugs known to be moderate or strong CYP3A or CYP2C9 inducers and 
moderate or strong CYP3A4 or CYP2C9 inhibitors.  In addition, for moderate or strong CYP3A or 
CYP2C9 inducers, there should be a wash-out of 14 days (or 5 half-lives, whichever is shorter) before 
the first administration of study drug (see Section 10.4.6). 
16) Any clinically significant disorder, condition, or disease that, in the opinion of the Investigator or 
Medical Monitor would pose a risk to subject safety or interfere with the study evaluations, 
procedures, or completion 
5.3 
LIFESTYLE CONSIDERATIONS 
Not applicable. 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently entered on study. A minimal set of information will be collected from these participants to 
ensure transparent reporting of screen failure participants, to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 


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authorities. The information collected will include demography, screen failure details, and eligibility 
criteria.  Subjects may be rescreened after discussion with the Sponsor. 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Not applicable. 


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6 
STUDY INTERVENTION 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
6.1.1 
STUDY INTERVENTION DESCRIPTION 
6.1.1.1 ZN-c5 
ZN-c5 is an oral selective estrogen degrader (SERD) that binds potently to the estrogen receptors alpha 
and beta (ERα and ERβ). ZN-c5 has not been tested in humans prior to this study. See Investigator’s 
Brochure (IB) for details of ZN-c5. 
6.1.1.2 PALBOCICLIB 
Palbociclib (IBRANCE®, Pfizer Inc.) is an orally active pyridopyrimidine that is a potent and highly 
selective reversible inhibitor of Cyclin-Dependent Kinases 4 and 6 (CDK 4/6). The compound prevents 
cellular DNA synthesis by prohibiting progression of the cell cycle from G1 into the S phase, as 
demonstrated both in laboratory models and in early clinical trials. There is a strong link between the 
action of estradiol on the G1-S phase transition, where it drives transcriptional activation of cyclin D1 
leading to formation of the cyclin D1-CDK4/6-Rb complex which facilitates the G1 to S phase transition. 
In nonclinical experiments, palbociclib synergizes with antiestrogen to cause tumor regression in in vitro 
ER+ advanced breast cancer cell lines. Based on the results of the PALOMA-2 study, palbociclib is 
approved by the US FDA and other Health Authorities for the treatment of for the treatment of HR+, 
HER2-negative advanced or metastatic breast cancer in combination with an AI as initial endocrine 
based therapy in postmenopausal women. Additionally, based on the results of the PALOMA-3 trial 
which showed a statistically significant improvement in PFS (9.5 months vs 4.6 months for placebo + 
fulvestrant), palbociclib is approved for the treatment of HR-positive, HER2-negative advanced or 
metastatic breast cancer in combination with fulvestrant in women with disease progression following 
endocrine therapy. 
6.1.2 
DOSING AND ADMINISTRATION 
6.1.2.1 DOSING AND ADMINISTRATION OF ZN-c5 
ZN-c5 capsules (25 and 100 mg) will be provided by Zeno Alpha. 
Regardless of cohort, subjects should take ZN-c5 once daily at approximately 24-hour intervals 
(alternatively, this total daily dose may be divided by 2 and administered BID [every 12 hours]). 
In the Phase 1 parts of the study, subjects should take ZN-c5 at least 1 hour before or 2 hours after a 
meal. 
In the Phase 2 parts of the study, ZN-c5 can be taken with or without food.   
If the subject vomits or misses a dose, an additional dose should not be taken. The subject should wait 
and take the next dose at the regularly scheduled time. Subjects should not take more than 1 dose of 
ZN-c5 at a time. Capsules should be swallowed whole (do not chew, crush, or open them prior to 
swallowing). Capsules should not be ingested if they are broken, cracked, or otherwise not intact. 


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6.1.2.2 DOSING AND ADMINISTRATION OF PALBOCICLIB 
Palbociclib (IBRANCE®, Pfizer Inc.) at a dose of 125 mg should be taken orally once daily for 
21 consecutive days, followed by 7 days off treatment to comprise a complete cycle of 28 days, per the 
most recent local or US Full Prescribing Information for palbociclib. Subjects should take palbociclib at 
approximately 24-hour intervals at approximately the same time each day. 
On days that PK samples are drawn, palbociclib should be taken with food 2 hours after the ZN-c5 dose. 
If a subject vomits or misses a dose, an additional dose should not be taken. The next prescribed dose 
should be taken at the usual time. Palbociclib should be swallowed whole (do not chew, crush, or open 
them prior to swallowing). Palbociclib should not be ingested if the medication is broken, cracked, or 
otherwise not intact. 
6.1.3 
DEFINITION OF MTD AND RP2D 
During both the Monotherapy and Combination Dose Escalation cohorts of the study, dose limiting 
toxicity (DLT) will be assessed during Cycle 1. A cohort will be expanded from 3 to 6 subjects if one of the 
initial 3 subjects demonstrates DLT. Cohort expansion or dose escalation will follow the rules outlined in 
Table 2.  Subjects who do not receive at least 24/28 doses of ZN-c5 or at least 18/21 doses of palbociclib 
in Cycle 1 for reasons other than DLT will be replaced. 
Table 2: 
Dose Escalation Rules 
If DLT was observed in: 
Then: 
0 in 3 subjects 
Proceed with enrollment in next cohort 
1 of 3 subjects 
Enroll 3 additional subjects in current cohort 
1 of 6 subjects 
Proceed with enrollment in next cohort 
≥ 2 subjects in a cohort 
Do not escalate; enroll 3 additional subjects in previous 
cohort or new intermediate dose level 
The MTD is defined as the highest dose level with ≤ 1 DLT in a cohort of 6 subjects. The RP2D may be 
lower but will not be higher than the MTD. The MTD/RP2D for monotherapy treatment may be different 
than the MTD/RP2D for combination therapy. 
6.1.4 
MONOTHERAPY DOSE ESCALATION 
In order to define an MTD or the RP2D for ZN-c5 as a single agent, this study will follow a standard 3+3 
design. At least 3 and up to 6 evaluable subjects will be enrolled for each dose cohort. ZN-c5 will be 
administered orally once daily (alternatively, this total daily dose may be divided by 2 and administered 
BID [every 12 hours]), on a 28-day cycle (continuous dosing). The total number of patients will depend 
upon the number of dose escalations necessary, but it is estimated to be approximately 36 subjects. 
Dose levels and dosing frequency may be adjusted during the study on the basis of emerging safety and 
PK data. Intermediate dose levels may be evaluated. 
Additional subjects can be enrolled at a lower dose level already deemed well-tolerated; these patients 
will be part of the Monotherapy Expansion (Section 6.1.6). 
At least 6 subjects will be treated at the MTD/RP2D. 


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The dose levels for the study are shown in Table 3. 
Table 3: 
ZN-c5 Study Dose Levels 
Dose Level* 
ZN-c5* (once daily)** 
1 
50 mg 
2 
75 mg 
3 
100 mg 
4 
150 mg 
5 
300 mg 
6 
600 mg 
7 
900 mg 
8 
1200 mg 
*Dose Levels may be modified, and intermittent dose levels may be implemented based on emerging 
safety and PK results. 
** Alternatively, this total daily dose may be divided by 2 and administered BID (every 12 hours).  
6.1.5 
COMBINATION DOSE ESCALATION 
Dose escalation in combination with palbociclib will be initiated at a ZN-c5 dose that is deemed 
well-tolerated in the Monotherapy Dose Escalation and will proceed with higher ZN-c5 doses, as 
tolerated in the Monotherapy Dose Escalation, based on standard rules of 3+3 design in order to define 
an MTD/RP2D for ZN-c5 in combination with palbociclib (Section 6.1.3). The total number of patients 
will depend upon the number of dose escalations necessary, but it is estimated to be approximately 
40 subjects (including alternate dosing schedules, e.g., BID, and possible backfill). 
Dose levels and schedule will follow the dose levels and schedule per the Monotherapy Dose Escalation. 
Additional subjects can be enrolled at a lower dose level already deemed tolerated (backfill).  At least 
6 subjects will be treated at the MTD/RP2D. 
The subjects treated in the Combination Dose Escalation can possibly count towards the futility 
assessment stage accrual (Section 9.2.4, Combination Phase 2). 
The dose of palbociclib used in the combination phases of the study will be the Regulatory Authority 
approved dose and schedule (125 mg PO QD × 21 days, followed by 7 days off treatment). 
6.1.6 
MONOTHERAPY EXPANSION 
To further assess the safety, tolerability, and preliminary efficacy of ZN-c5, the dose expansion with 
monotherapy will be initiated at a dose selected based on PK, safety and available biomarker data from 
the Monotherapy Dose Escalation. Expansion at a specific dose level will continue until a higher dose has 
been deemed well-tolerated (no DLTs in 3 subjects or at most 1 DLT in 6 subjects), at which point 
expansion accrual will shift to the higher dose level.  
Efficacy in the Monotherapy Expansion will be determined by CBR. 
The Monotherapy Expansion overall will target balanced accrual between the 3 lines of therapy (1st, 2nd 
and 3rd hormonal therapy line) across all dose levels. 


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The total cohort size necessary for futility has been estimated based on futility screening criteria 
targeting at least 10 evaluable subjects for each line cohort across all dose levels where anti-tumor 
activity is demonstrated and providing an acceptable false negative risk of concluding that there is no 
activity if the true CBR is at least 40%.  The total number subjects will depend upon the number of dose 
escalations, but it is not estimated to exceed approximately 45 subjects. 
Futility screening 
Patients are evaluable for assessment of anti-tumor efficacy (based on CBR) if they were dosed and had 
at least 1 post-baseline disease/tumor assessment (Section 9.3). CBR as measured using RECIST v.1.1 will 
be assessed to provide a preliminary, anti-tumor activity evaluation. 
6.1.7 
MONOTHERAPY PHASE 2 
To establish the appropriate dose for further development of ZN-c5, additional subjects will be enrolled 
to further assess the safety, tolerability, and preliminary efficacy of up to 3 dose levels of single agent 
ZN-c5 (which can include QD or BID dosing). The ZN-c5 dose levels will be selected based on available 
safety, PK, anti-tumor activity and biomarker data. 
Up to 75 subjects will be enrolled per dose level using a randomized (if 2 or more doses), parallel cohort, 
non-comparative (estimation) design.  Efficacy in the Monotherapy Phase 2 will be determined by CBR 
and results will be combined with those from subjects with similar treatment characteristics (2nd/3rd Line 
therapy) and treated at the same dose level of ZN-c5 in the Monotherapy Expansion arm (Section 9.2.3). 
Therefore, the targeted total N (Phase 2 and same population/dose subjects in the Monotherapy 
Expansion combined) is 75 subjects per dose level to estimate the CBR rate with certain confidence 
before proceeding with a larger confirmatory study. 
6.1.8 
COMBINATION PHASE 2 
Following the determination of the MTD/RP2D for ZN-c5 in combination with palbociclib, additional 
subjects will be enrolled to further assess the safety, tolerability, and preliminary efficacy of ZN-c5 in 
combination with palbociclib. 
ZN-c5 will be administered at the combination RP2D and potentially at a lower dose in combination with 
palbociclib.  The lower ZN-c5 dose will be selected based on available safety, PK and biomarker data. 
Efficacy in the Combination Phase 2 will be determined by CBR. The Combination Phase 2 will target 
balanced accrual between the 2 lines of therapy (1st and 2nd hormonal therapy line) across dose levels. 
The Combination Phase 2 portion will follow a randomized, parallel group, non-comparative design, 
assuming both the RP2D and the lower dose are investigated, or a single dose cohort, if only the RP2D is 
investigated. Each dose cohort will follow a Simon 2-stage design. 
Approximately 56 subjects will be enrolled in each dose cohort. Subjects treated in the Combination 
Dose Escalation at a demonstrated well-tolerated lower combination dose (no DLTs in 3 subjects or at 
most 1 DLT in 6 subjects) may also count towards the futility stage accrual, assuming the subjects are 
evaluable (dosed subjects with at least 1 post baseline disease/tumor assessment [Section 9.3]). The two 
dose cohorts evaluated in Phase 2 will not use the same subjects from lower dose cohorts in the Phase 1 


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Combination Dose Escalation phase; for example ZN-c5 50 mg Combination Dose Escalation subjects 
may count for the 100 mg futility cohort in Phase 2, if that is selected as the lower dose cohort for the 
Phase 2 component, but will not also count for the RP2D futility cohort, if a higher dose is selected as 
the RP2D.  
Futility (Stage 1) and Efficacy (Stage 2) 
Within each dose cohort, 51 evaluable subjects will be enrolled in 2 stages, with 19 subjects in the 
Futility Stage (Stage 1) and 32 subjects in the Efficacy Stage (Stage 2). 
Second stage accrual at each cohort will be completed, assuming that Stage 1 futility criteria are 
exceeded, with at least 11 subjects with CBR in the first 19 evaluable subjects. An approximate 10% loss 
for CBR evaluability has been assumed resulting in a total sample size for each dose cohort of 
approximately 56 subjects or a total sample size of 112 subjects for the Combination Phase 2. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 
ACQUISITION AND ACCOUNTABILITY 
The investigator is responsible for ensuring adequate accountability of all study drug. 
Accountability records will be provided to each study site or sites may utilize their own accountability 
records in order to: 
• 
Record the date received and quantity of study drug kits 
• 
Record the date, subject number, subject initials, the study drug kit number dispensed 
• 
Record the date, quantity of used and unused study drug returned, along with the initials of the 
person recording the information 
• 
Study drug should be retrieved from each subject at the end of each dispensing interval. The 
quantity of study drug and the date returned by the subject should be reconciled against the 
Subject Dosing Diaries and recorded in the study drug accountability records. All study drug 
returned by the subject should be retained for review by the study site monitor prior to 
destruction. 
Unused study drug may be destroyed at the site if the site has the appropriate standard operating 
procedure (SOP) in place. The study monitor will evaluate each study center’s study drug disposal 
procedures and provide appropriate instruction for destruction of unused study drug supplies, as 
needed. If the site is unable to destroy unused study drug on site, the Sponsor will provide instruction 
for the return of the study drug for disposal/destruction. 
6.2.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
ZN-c5 will be supplied (and labeled per local regulation) as plain-faced capsules containing 25 mg (white 
size 4 capsules) or 100 mg (opaque white size 0) of ZN-c5.  Please see the Pharmacy Manual for 
additional details. 
Palbociclib (IBRANCE®, Pfizer Inc.) will be supplied (and labeled per local regulation) for the study. 


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6.2.3 
PRODUCT STORAGE AND STABILITY 
ZN-c5 capsules should be stored under refrigeration (2°-8°C or 36°-46°F) and protected from light. 
Storage conditions are specified on the label. The study center will be required to maintain a log of 
regular temperature readings in the storage area for the duration of the study. 
Palbociclib capsules should be stored at controlled room temperature (15–30°C, 59–86°F) in their 
original container. Please see the most recent local or US Full Prescribing Information for additional 
information. 
Until dispensed to the subjects, all bottles of study drug should be stored in a securely locked area, 
accessible only to authorized site personnel. To ensure the stability and proper identification, the drug 
product should not be stored in a container other than the container in which it was supplied. 
Appropriate precautions should be followed to avoid direct eye contact or exposure through inhalation 
when handling ZN-c5 capsules. 
6.2.4 
PREPARATION 
Not applicable. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Not applicable. 
6.4 
STUDY INTERVENTION COMPLIANCE 
The investigator is responsible for ensuring the study is conducted in accordance with the procedures 
and evaluations described in this protocol. 
Compliance will be described by dose level in terms of the proportion of study drug actually taken based 
on returned pill count relative to the amount that was dispensed (taking into account physician-
prescribed modification and interruptions). 
6.5 
CONCOMITANT THERAPY 
At Screening, all medications taken up to 30 days prior to the screening visit will be recorded on the 
eCRF. In addition, supportive therapies given during the course of the study (e.g. blood transfusion, 
growth factor) should be collected and recorded on the eCRF. 
At each study visit, the site will capture any and all medications taken by the subject since the last visit 
or during the visit (as applicable). 
6.5.1 
PROPHYLACTIC MEDICATIONS AND THERAPY 
Premenopausal and perimenopausal women must receive a gonadotropin-releasing hormone agonist 
starting at least 4 weeks prior to enrollment and repeated, as per the prescribing information of the 
product administered, for the duration of study treatment. 
The use of the following is prohibited during Cycle 1 in dose escalation cohorts: 
• 
Prophylactic hematopoietic growth factors (e.g., G-CSF, erythropoietin) 


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• 
Prophylactic blood product transfusions 
After Cycle 1, use of these treatments should be dictated by clinical situation and discussed with the 
Sponsor prior to initiation (when possible). 
6.5.2 
USE OF CYP3A4 AND CYP2C9 INHIBITORS AND INDUCERS 
The following are prohibited at any time during the study: 
• 
Moderate and strong CYP3A4 and CYP2C9 inhibitors 
The following are prohibited at any time during the study and for 2 weeks (or 5 half-lives, whichever is 
shorter) prior to study drug administration: 
• 
Moderate and strong CYP3A4 and CYP2C9 inducers 
Examples of moderate and strong CYP3A4 and CYP2C9 inhibitors and inducers are provided in 
Section 10.4.6. 
6.5.3 
USE OF OTHER INHIBITORS OR INDUCERS 
The following are allowed but should be avoided if possible. If required, doses of these agents may be 
modified as outlined in the appropriate product insert 
• 
Substrates of CYP2C8 and BCRP 
• 
Substrates of CYP3A 
Subjects receiving palbociclib should avoid grapefruit or grapefruit juice. In addition, subject who require 
coadministration of a strong CYP3A inhibitor may require a reduced dose of palbociclib (see the most 
recent local or US Full Prescribing Information for palbociclib). 
6.5.4 
ADDITIONAL PROHIBITED MEDICATIONS 
In addition, the following treatments are prohibited during the duration of the time that subjects are on 
active therapy during the study period: 
• 
Hormone replacement therapy, topical estrogens, megestrol acetate, and selective estrogen 
receptor modulators 
• 
Drugs known to cause QT interval prolongation (see Section 10.4.1) 
6.5.5 
RESCUE MEDICINE 
Medications required to treat study drug related adverse events may be used as appropriate at the 
discretion of the investigator. Unless required urgently for patient care, the investigator should discuss 
such medications with the study monitor prior to use. 


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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from investigational treatment does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol (unless withdrawal 
of consent by the subject). 
Subjects should have an End of Treatment Administration Visit as soon as possible (within 7 days) after 
the decision is made to discontinue study treatment (Section 7.4). 
Subjects will return or will be contacted for a Safety Follow-up Visit 30 days (± 7 days) after the last dose 
of ZN-c5 taken (Section 7.5). 
Subjects without PD at the time of study drug discontinuation will continue to undergo a Disease 
Assessment Follow-up Visit every 12 weeks (± 7 days) (Section 7.6). 
Subjects will be followed for survival and subsequent breast cancer therapies. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM TREATMENT AND FROM THE 
STUDY 
Subjects may be discontinued from the investigational treatment in the following situations: 
• 
Documented progression of disease or clinical progression 
• 
Death 
• 
Investigator discretion 
• 
Non-compliance with study drug or protocol 
• 
Important protocol deviation 
• 
Pregnancy  
• 
Patient discretion  
• 
Withdrawal of consent (subjects are free to withdraw participation at any time) 
• 
Lost to follow-up 
• 
Subjects incorrectly initiated on study treatment 
• 
Intercurrent illness that would, in the judgment of the investigator, affect assessments of clinical 
status to a significant degree 
• 
Unacceptable toxicity 
• 
Liver testing abnormalities meeting Hy’s Law criteria (See Section 10.4.7) 
• 
Study termination by the Sponsor 
Subjects who are withdrawn from the study but are evaluable will not be replaced. Any subject who is 
withdrawn and is not evaluable may be replaced to ensure a minimum number of evaluable patients. 
Subjects may withdraw from any aspect of the voluntary exploratory research at any time, without 
prejudice to further treatment and independent of any decision concerning participation in other 
aspects of the study. 


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If there is strong evidence of clinical benefit and reasons to justify continuation of the study drug, even 
though treatment discontinuation criteria have been met, this decision must be reviewed with the 
Sponsor, and continuation of therapy may be allowed assuming all other treatment resumption criteria 
have been met. 
Subjects will be discontinued from the study in the following situations: 
• 
Death 
• 
Lost to follow-up 
• 
Withdrawal of consent 
• 
Study end per protocol 
• 
Early study termination by Sponsor 
7.3 
LOST TO FOLLOW-UP 
A participant may be considered lost to follow-up if they fail to return for 2 consecutive scheduled visits 
and is unable to be contacted by the study site staff. 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
Attempt to contact the participant and reschedule the missed visit 
• 
Counsel the participant on the importance of maintaining the assigned visit schedule 
• 
Ascertain if the participant wishes to and/or should continue in the study. 
Prior to determining that a participant is lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (e.g., at least 3 telephone calls and, if necessary, a certified 
letter to the participant’s last known mailing address). Contact attempts should be documented in the 
participant’s medical record or study file. 
Participants who are unreachable based on the attempts outlined above will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
If study drug is discontinued due to subject decision, the subject may elect to continue with treatment 
discontinuation assessments, safety follow-up and additional follow-up, if applicable. 
7.4 
END OF TREATMENT VISIT 
At this visit, every effort should be made to perform the procedures listed in the Schedule of Activities 
for each study phase (Section 1.3). 
7.5 
SAFETY FOLLOW-UP VISIT 
A Safety Follow-up Visit will be conducted 30 ± 7 days after the last administration of ZN-c5.  If the 
subject begins a new anticancer treatment within 30 days of the last administration of study drug, the 
Safety Follow-up Visit should be performed prior to initiation of the new anticancer treatment, if 
possible 
At this visit, every effort should be made to perform the procedures listed in the Schedule of Activities 
for each study phase (Section 1.3). 


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If the subject is unable to return to the study site, a follow-up phone call can be made by the study site 
to collect any new safety information that occurred during the Safety Follow-up Period. 
7.6 
DISEASE ASSESSMENT FOLLOW-UP VISITS 
Subjects without PD at the time of study drug discontinuation will continue to undergo disease 
evaluations every 12 weeks ± 7 days until confirmation of PD, initiation of the first subsequent cancer 
therapy, withdrawal of consent, death, loss to follow-up, or until the study is terminated. 
Once a subject has confirmation of PD or has initiated subsequent cancer therapy, whichever occurs 
first, follow-up will discontinue. 
7.7 
SURVIVAL FOLLOW-UP VISITS 
Once disease progression is confirmed or the first subsequent new breast cancer therapy is initiated, 
whichever occurs first, the survival follow-up period begins.  During this period, the patient or family 
should be contacted for survival follow-up every 12 weeks (± 14 days) until withdrawal of consent, 
death, loss to follow up, the end of study (Section 4.4) or the study is terminated earlier by the Sponsor.  
In addition, all subsequent breast cancer treatments will be recorded. 


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8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
EFFICACY ASSESSMENTS 
The study procedures to be conducted for each subject enrolled in the study are presented in tabular 
form in Section 1.3 and described in the text below. Additional information is provided in the study 
manual. 
8.1.1 
COMPUTED TOMOGRAPHY (CT) OR MAGNETIC RESONANCE IMAGING (MRI) 
Subjects will be assessed by scans (CT or MRI) or other modalities as appropriate. The same modality of 
assessment (CT or MRI) and specification (e.g., contrast agent, slice thickness) should be used 
throughout the study for a given subject. 
Imaging will be performed at Screening (within 28 days prior to Cycle 1 Day 1) and every 8 weeks 
(± 7 days) for 24 weeks. After 24 weeks, scans may be performed every 12 weeks (± 7 days). Additional 
scans may be performed as clinically indicated to assess tumor progression. 
Response assessments will be performed according to the RECIST v1.1 Criteria. 
8.2 
SAFETY AND OTHER ASSESSMENTS 
The study procedures to be conducted for each subject enrolled in the study are presented in tabular 
form in Section 1.3 and described in the text below. Additional information is provided in the study 
manual. 
8.2.1 
SAFETY ASSESSMENTS 
Safety and tolerability assessments will include regular monitoring of AEs, changes from baseline in 
laboratory variables, physical examinations, vital signs, and special safety assessments such as ECGs. 
8.2.1.1 PHYSICAL EXAMINATION 
The Investigator or qualified designee will perform a complete physical examination at Screening and at 
the End of Treatment visit. Pre-dose abnormal findings will be reported on the medical history page of 
the eCRF. Any changes from the pre-dose baseline physical examination that represent a clinically 
significant deterioration will be documented on the AE page of the eCRF. 
Weight (without shoes) should be measured with each physical examination. 
Height (without shoes) should be measured at Screening only. 
Beginning at C1D1, a modified physical examination will be performed to monitor for any changes and 
will also include weight and assessment of disease-related clinical signs and symptoms. 
8.2.1.2 VITAL SIGNS 
Vital signs will include blood pressure, respiratory rate, pulse, oxygen saturation and temperature. Any 
abnormal measurements may be repeated and reported as AEs if appropriate. 


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8.2.1.3 ELECTROCARDIOGRAM (ECG) 
Resting, semi recumbent triplicate 12-lead ECGs (reporting ventricular rate, PR interval, QRS complex, 
QT, and QTc intervals) will be obtained over a 5-minute window at the applicable study visits. 
ECGs should be collected prior to PK (or any other blood draw) if collected at the same nominal time 
point. All efforts should be made to perform the EKG within 10% of the nominal time relative to dosing, 
however, a protocol deviation applies only if it is missed. 
The Investigator or qualified designee will review all ECGs. 
8.2.1.4 ECOG PERFORMANCE STATUS 
The ECOG Performance Status will be scored using the scale in Section 10.4.3. 
8.2.1.5 ADVERSE EVENTS 
Subjects will be assessed for adverse events (AEs) per guidelines in the National Cancer Institute (NCI) 
CTCAE (Version 4.03) at the time points outlined in Section 1.3. Any non-serious AEs reported after 
initiation of ZN-c5 treatment on Cycle 1 Day 1 and throughout the study will be recorded on the eCRF 
with appropriate source documentation. The subject will be assessed for AEs until 30 days after the last 
dose of study drug, but prior to initiation of subsequent breast cancer therapy. Please refer to 
Section 10.4.4 for CTCAE grading criteria. 
Please refer to Section 8.3.5 for additional information on AE reporting. 
8.2.1.6 LABORATORY ASSESSMENTS 
Screening laboratory samples should be obtained within 7 days prior to Cycle 1 Day 1. Eligibility will be 
based on local laboratory assessments. 
Local laboratory assessments may be collected as required for dose adjustments throughout the study. 
Local laboratory assessments resulting in a dose change will be reported on the eCRF. 
Each site laboratory will be responsible for chemistry, hematology, coagulation, and urinalysis testing 
per Table 4 and storage of other study samples. Other tests listed in Table 4 will be performed by 
Sponsor or a designated laboratory. Specific instructions for processing, labeling, and shipping samples 
will be provided in the appropriate laboratory manual. The date and time of sample collection will be 
recorded in the subject’s source documentation.  
Study Day 1 (Cycle 1 Day 1) pre-dose samples may be drawn up to 2 days prior to the visit. Pre-dose 
samples may be drawn within 1 day of subsequent visits. 


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Table 4: 
Analytes 
Serum Chemistry 
Hematology 
Other 
Sodium 
Potassium 
Chloride 
Glucose 
BUN 
Creatinine 
Creatinine Clearancea 
ALT (SGPT) 
AST (SGOT) 
Alkaline phosphatasec 
Total bilirubinb 
Gamma-GTc 
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphate 
Full Lipid Paneld 
White Blood Cell (WBC) Count 
Hemoglobin 
Hematocrit 
Platelet Count 
Neutrophils (ANC) 
Lymphocytes 
Monocytes 
Basophils 
Eosinophils 
ZN-c5 concentration 
Concentrations of ZN-c5 
metabolite(s) as 
applicable, may be 
determined 
 
Tumor Biopsy 
 
Serum and Plasma for 
Pharmacodynamic and 
Exploratory Biomarkers  
 
Plasma 4β-
hydroxycholesterol and 
cholesterol as applicable 
 
 
Coagulation 
PT/INR 
aPTT 
Urine 
Urinalysis (visual inspection, microscopic 
examination, and dipstick test for pH, 
protein, glucose, WBC, bilirubin, and blood) 
a 
Cockcroft-Gault using Actual Body Weight: CRCL (mL/min) = [(140-age(years)) × weight(kg) × [0.85 if Female]] / 
(serum creatinine (mg/dL) ×72) 
b 
Includes direct bilirubin 
c 
If ≥ Grade 3 Alkaline Phosphatase or Gamma-GT, perform a bile acid panel assay (if available locally) 
d 
A full lipid panel, regardless of fasting status, will be performed on C1D1, C3D1 (coinciding with the first on-
study tumor assessment after 8 weeks) and C7D1 (6 months into the study).  This will not be assessed in the 
Monotherapy Phase 2 part of the study. 
8.2.2 
PHARMACOKINETIC, PHARMACODYNAMIC, & CORRELATIVE SAMPLES 
8.2.2.1 PHARMACOKINETIC SAMPLES 
Details of sample preparation and procedures for transfer of samples to the central laboratory are 
provided in the Laboratory Manual. 
Plasma samples for ZN-c5 (and its potential metabolites as applicable) (± palbociclib) will be collected as 
described in Table 5.  


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Table 5: 
Pharmacokinetic Sampling per Study Component 
Study Component 
N subjects and type of PK 
PK Time Points 
Monotherapy Dose Escalation 
Full ZN-c5 PK in all subjects 
Table 6 
(Monotherapy)  
Monotherapy Expansion – at each 
dose level assessed 
Full ZN-c5 PK in approximately 6 – 12 subjects in 
total, subjects from the Monotherapy Dose 
Escalation treated at the same dose level and 
with evaluable PK data included 
Table 6 
(Monotherapy) 
Abbreviated ZN-c5 PK schedule for the 
remaining subjects (optional) 
Table 7 
Monotherapy Phase 2 
Abbreviated ZN-c5 PK schedule in all subjects 
(optional) 
Table 7 
Combination Dose Escalation 
Full ZN-c5 + palbociclib PK in all subjects 
Table 6 (Combination 
Therapy) 
Combination Phase 2 – Stage 1 – at 
each dose level assessed 
Full ZN-c5 + palbociclib PK in approximately 6 – 
12 subjects in total, subjects from the 
Combination Dose Escalation treated at the 
same dose level and with evaluable PK data 
included 
Table 6 (Combination 
Therapy) 
Abbreviated ZN-c5 + palbociclib PK schedule for 
the remaining subjects (optional) 
Table 7 
Combination Phase 2 – Stage 2 
Abbreviated ZN-c5 + palbociclib PK schedule in 
all subjects (optional) 
Table 7 
The decision to switch from a full PK schedule to an abbreviated PK schedule (population PK) will 
depend on the variability of the ZN-c5 PK parameters observed in the subjects with full PK.  If required, 
more subjects in the Monotherapy Phase 2 or in the Combination Phase 2 (Stage 2) will continue to be 
assessed with full PK. 
In the combination cohorts, on PK days, palbociclib should be taken with food 2 hours after the ZN-c5 
dose. 


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Table 6: 
Full Pharmacokinetic Sampling Time Points 
Day on Study 
Time (hr) 
Monotherapy 
Combination Therapy 
ZN-c5 
ZN-c5 
Palbociclib 
Cycle 1  
Day 1 and 15 
T=0 
PK (pre-dose, within 
0.5 hrs) 
PK (pre-dose, within 
0.5 hrs) 
NA 
Dose 
(fasted) 
Dose 
(fasted) 
NA 
0.5 
PK 
PK 
NA 
1  
PK 
PK 
NA 
2  
PK 
PK 
(prior to Palbociclib 
dosing) 
PK  
(pre-dose, within 
0.5 hrs) 
Dose 
(with food) 
2.5  
NA 
NA 
PK (0.5-hr) 
3  
NA 
NA 
PK    (1-hr) 
4  
PK 
PK 
PK    (2-hr) 
6  
PK 
PK 
PK    (4-hr) 
8  
PK 
PK 
PK    (6-hr) 
10  
NA 
NA 
PK    (8-hr) 
Cycle 1  
Day 2 and 16 
24  
PK 
PK 
NA 
26  
NA 
NA 
PK (24-hr) 
Cycle 1 Day 8 
 
PK (pre-dose, within 
0.5 hrs) 
PK (pre-dose, within 
0.5 hrs) 
PK 
Cycle 2 Day 1 
 
PK (pre-dose, within 
0.5 hrs) 
PK (pre-dose, within 
0.5 hrs) 
NA 
Cycle 3 Day 1 
 
PK (pre-dose, within 
0.5 hrs) 
PK (pre-dose, within 
0.5 hrs) 
NA 
Cycle 4 Day 1 
 
PK (pre-dose, within 
0.5 hrs) 
PK (pre-dose, within 
0.5 hrs) 
NA 
 NA= not applicable 
In case the dosing schedule is changed to BID dosing, an additional PK time point at 12 hours post ZN-c5 
dosing will be drawn (optional). 
Table 7: 
Abbreviated Pharmacokinetic Sampling Time Points 
Day of Study 
Collection Time Points (and Allowable Windows)  
ZN-c5 
Palbociclib* 
Cycle 1 Day 
15 
Pre-dose (within 0.5 hour prior to ZN-c5 administration) 
X 
X 
2-hours (± 10 min) post ZN-c5 administration 
X 
X 
4-hours (± 1 hour) post ZN-c5 administration 
X 
X 
*in the combination parts of the study 
All efforts will be made to obtain the PK samples at the exact nominal time relative to dosing, however, 
samples obtained within 10% of nominal time from dosing are acceptable for up to and including the 


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12-hour time points. The 24-hour time points should be drawn within ± 1 hour. A protocol deviation only 
applies if a PK time point is missed. 
If the optional On-Treatment tumor biopsy is performed, an additional PK sample should be collected at 
that time, regardless if tissue was obtained for ZN-c5 tissue concentration. 
8.2.2.2 CORRELATIVE (4Β-HYDROXYCHOLESTEROL & CHOLESTEROL) SAMPLES 
Plasma will be collected (from the same blood draw as for PK) for analysis of 4β-hydroxycholesterol and 
cholesterol at the following time points of the Monotherapy Dose Escalation and Expansion cohorts: 
• 
[Cycle 1 Day 1] pre-dose (0 hr) 
• 
[Cycle 1 Day 15] pre-dose (0 hr) 
• 
[Cycles 2, 3 and 4 Day 1] pre-dose (0 hour) 
No samples will be collected in the Monotherapy Phase 2. 
See Lab Manual for sample collection details. 
8.2.2.3 ESR1 MUTATION TESTING 
A blood sample will be collected for the detection of ESR1 mutations as described in the Schedule of 
Assessments. 
See Lab Manual for sample collection details. 
8.2.2.4 
BIOMARKER TESTING 
Whole blood, plasma and serum biomarkers will be collected at C1D1, C2D1 and at time of disease 
progression (Section 1.3) and will be used to evaluate the association of exploratory systemic specific 
biomarkers with study drug response, including efficacy and/or AEs and to increase knowledge and 
understanding of the biology of breast cancer or related diseases. Biomarker specimens will be collected 
from all subjects. In addition, sampling time points may be modified during the study based upon 
emerging data. 
For sampling procedures, storage conditions, and shipment instructions, see the Lab Manual. 
Remaining plasma samples obtained to measure ZN-c5 levels may also be used to measure the 
exploratory pharmacodynamic biomarkers. 
8.2.2.5 
TUMOR BIOPSY TISSUE 
Subjects in all portions of the study will have the option to undergo paired biopsies of a lesion. The first 
biopsy will be obtained after consent and before the first dose of study drug. The second biopsy will be 
obtained on C2D1 or thereafter.   Subjects will also have the option to undergo biopsy of a lesion at the 
time of disease progression. The biopsy will be used to evaluate for the presence of exploratory 
biomarker analyses. The Informed Consent Form will address participation in this optional research. 


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Analyses can include, but are not limited to: 
• 
Estrogen and progesterone receptor expression 
• 
Ki-67 
• 
RNA seq 
Biopsies must not be taken from target lesions used to assess anti-tumor efficacy, if possible. 
If the optional, On-Treatment tumor biopsy is performed, an additional PK sample should be collected at 
that time (Section 8.2.2.1). This plasma PK sample should be collected as close as possible, within 
2 hours prior to the biopsy.  If sufficient tumor material is available, part of the C2D1 tumor biopsy will 
be used for determination of ZN-c5 tissue concentration (see Section 8.2.2.6). 
See Lab Manual for sample collection details. 
8.2.2.6 
ZN-c5 TUMOR TISSUE CONCENTRATION 
A tumor sample from the C2D1 tumor biopsy will be collected to determine ZN-c5 concentrations and 
concentrations of ZN-c5 metabolite(s), as applicable.  The tissue PK sample will be collected unless 
harvesting of a fresh tumor sample will not leave enough tumor specimen for the 
immunohistochemistry analyses per Section 8.2.2.5, which have priority. 
If tumor tissue is collected for ZN-c5 concentrations, a plasma PK sample should be collected at that 
time (Section 8.2.2.1). 
8.2.2.7 
PK AND BIOMARKER SAMPLES FOR OPTIONAL FUTURE RESEARCH 
Subjects will be requested to allow the use of any remaining samples to be used for future research. 
The Informed Consent Form will contain a separate section that addresses participation in the optional 
future research. Subjects who decline to participate will check a “no” box in the appropriate section and 
will not provide a separate signature. Subjects are not required to consent for optional future research 
in order to participate in this study and have the right to withdraw their consent for optional future 
research at any time and for any reason. If a subject wishes to withdraw consent to the testing of his or 
her specimens, the investigator must inform the Sponsor. 
8.2.2.8 
FES-PET 
For exploratory purposes, to assess the effect of ZN-c5 on tumor cell proliferation and to measure 
regional estrogen binding, an optional positron emission tomography (PET) scan with 18F-fluoroestradiol 
(FES) will be performed as described in the Schedule of Assessments. 
Subjects who will undergo this procedure must have discontinued all prior ER blocking therapy (e.g., 
tamoxifen or fulvestrant) for ≥ 60 days before the day of the examination at baseline. 
The detailed endpoints and analytical methods will be specified in the Statistical Analysis Plan (SAP). 


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8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
8.3.1 
DEFINITION OF ADVERSE EVENTS (AE) 
An adverse event (AE) is any untoward medical occurrence in a clinical study subject administered a 
medicinal product, which does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and/or unintended sign, symptom, or disease temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal product. AEs may 
also include pre- or post-treatment complications that occur as a result of protocol specified procedures, 
lack of efficacy, overdose, drug abuse/misuse reports, or occupational exposure. Preexisting events that 
increase in severity or change in nature during or as a consequence of participation in the clinical study 
will also be considered AEs. 
An AE does not include the following: 
• 
Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and transfusion. 
The condition that led to the procedure may be an AE and must be reported. 
• 
Pre-existing diseases, conditions, or laboratory abnormalities present or detected before the 
screening visit that do not worsen 
• 
Situations where an untoward medical occurrence has not occurred (e.g., hospitalization for 
elective surgery, social and/or convenience admissions) 
• 
Any medical condition or clinically significant laboratory abnormality with an onset date before 
Cycle 1 Day 1 and not related to a protocol-associated procedure is not an AE. It is considered to 
be pre-existing and should be documented on the medical history CRF. 
8.3.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
A serious adverse event (SAE) or serious adverse drug reaction (SADR) is defined as an event that, at any 
dose, results in the following: 
• 
Death 
• 
Life-threatening (Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death if it were more severe.) 
• 
In-patient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant disability/incapacity 
• 
A congenital anomaly/birth defect 
• 
A medically important event or reaction: such events may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the subject or may require intervention 
to prevent one of the other outcomes constituting SAEs. Medical and scientific judgment must 
be exercised to determine whether such an event is reportable under expedited reporting rules. 
Examples of medically important events include intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; and development of drug dependency or drug abuse. For the avoidance of 


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doubt, infections resulting from contaminated medicinal product will be considered a medically 
important event and subject to expedited reporting requirements. 
Clarification of Serious Adverse Events: 
• 
Death is an outcome of an AE, and not an AE in itself 
• 
An SAE may occur even if the subject was not on study drug at the time of occurrence of the 
event. Dosing may have been given as treatment cycles or interrupted temporarily before the 
onset of the SAE 
• 
“Life-threatening” means that the subject was at immediate risk of death from the event as it 
occurred. This does not include an event that might have led to death if it had occurred with 
greater severity 
• 
Complications that occur during hospitalizations are AEs. If a complication prolongs the 
hospitalization, it is an SAE 
• 
“In-patient hospitalization” means the subject is formally admitted to a hospital for medical 
reasons, for any length of time. This may or may not be overnight. It does not include 
presentation and care within an emergency department 
• 
The investigator should attempt to establish a diagnosis of the event on the basis of signs, 
symptoms and/or other clinical information. In such cases, the diagnosis should be documented 
as the AE and/or SAE and not the individual signs/symptoms 
Given the endpoints of the study, in order to maintain the integrity of the study, the following events 
that are assessed as unrelated to study drug will not be considered SAEs: 
• 
Progression of underlying disease (breast cancer) 
• 
Death related to progression of underlying disease (breast cancer) 
Disease progression and death from disease progression should be reported as SAEs by the investigator 
only if it is assessed that the study drug caused or contributed to the disease progression (i.e., by a 
means other than lack of effect). Unrelated disease progression should be captured on the eCRF. 
Cases of overdose should also be reported on an SAE form within 24 hours of the Investigator becoming 
aware of the situation (see Section 8.3.8).  
The investigator or qualified sub-investigator is responsible for assessing AEs and SAEs for causality and 
severity, and for final review and confirmation of accuracy of event information and assessments. 
8.3.3 
CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
The severity of AEs will be graded using NCI CTCAE, v4.03 (See Section 10.4.4). 
For each episode, the highest severity grade attained should be reported. 
The distinction between the seriousness and the severity of an AE should be noted. Severe is a measure 
of intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a headache may 
be severe in intensity, but would not be classified as serious unless it met one of the criteria for serious 
events listed in Section 8.3.2. 


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The investigator or qualified sub-investigator is responsible for final review and confirmation of accuracy 
of event information and assessments. 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
The investigator or qualified sub-investigator is responsible for assessing the relationship to study drug 
therapy using clinical judgment and the following considerations: 
• 
No: Evidence exists that the AE has an etiology other than the study drug. For SAEs, an 
alternative causality must be provided (e.g., pre-existing condition, underlying disease, 
intercurrent illness, or concomitant medication). 
• 
Yes: There is reasonable possibility that the event may have been caused by the study drug. 
It should be emphasized that ineffective treatment should not be considered as causally related in the 
context of AE reporting. 
The relationship to study procedures (e.g., invasive procedures such as venipuncture or biopsy) should 
be assessed using the following considerations: 
• 
No: Evidence exists that the AE has an etiology other than the study procedure. 
• 
Yes: The AE occurred as a result of protocol procedures, (e.g., venipuncture) 
8.3.3.3 EXPECTEDNESS 
The Sponsor will be responsible for determining whether an AE is expected or unexpected. An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study intervention. 
Assessment of expectedness for SAEs will be determined by the Sponsor using reference safety 
information specified in the Investigator’s Brochure (IB) or relevant local label as applicable. 
8.3.4 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits, 
interviews of a study participant presenting for medical care, or upon review by a study monitor. 
 The AE Reporting Period begins at the initiation of study medication (C1D1) and ends after the 
30-Day Safety Follow-up Visit.  All AEs should be followed up until resolution or until the AE is 
stable, if possible. Sponsor may request that certain AEs be followed beyond the protocol 
defined follow-up period. 
 The SAE Reporting Period begins at the time a study participant signed an Informed Consent 
Form and ends after the 30-day Safety Follow-up Visit.  Investigators are not obligated to 
actively seek SAEs after the 30-day period. However, if the investigator learns of any SAEs that 
occur after study participation has concluded and the event is deemed related to the use of 
study drug, he/she should promptly document and report the event to the study Sponsor.  All 
SAEs will be followed until satisfactory resolution or until the site investigator deems the event 
to be chronic or the participant is stable. Other supporting documentation of the event may be 


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requested by the study Sponsor or designee (contract research organization [CRO]) and should 
be provided as soon as possible. 
Note: Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study after Cycle 1 Day 1, it will be recorded as an AE. 
All other untoward medical occurrences observed during the Screening period, including exacerbation 
or changes in medical history are to be captured on the medical history eCRF. 
8.3.5 
ADVERSE EVENT REPORTING 
All AEs (including SAEs) will be recorded in the eCRF database within the timelines outlined in the eCRF 
completion guideline. 
Information to be collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study product (assessed only by those with the training and authority to make 
a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while on study must be 
documented appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
8.3.6 
SERIOUS ADVERSE EVENT REPORTING 
The study clinician will immediately (within 24 hours of identification by the site) report to the Sponsor 
any SAE, whether or not considered study intervention related, including those listed in the protocol or 
Investigator’s Brochure.  The SAE Report must include an assessment of whether there is a reasonable 
possibility that the study intervention caused the event.     
To report a Safety Event, please contact the main Safety Management phone/fax/email (or via the 
applicable country-specific toll-free numbers located in your study binder). 
For fatal or life-threatening events, copies of hospital case reports, autopsy reports, and other 
documents are also to be submitted by e-mail or fax when requested and applicable. Transmission of 
such documents should occur without personal subject identification, maintaining the traceability of 
a document to the subject identifiers. 
Additional information may be requested to ensure the timely completion of accurate safety reports. 
Any medications necessary for treatment of the SAE must be recorded onto the concomitant medication 
section of the subject’s eCRF and the event description section of the SAE form. 
8.3.7 
REPORTING EVENTS TO PARTICIPANTS  
Not applicable. 


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8.3.8 
SPECIAL SITUATIONS REPORTS  
Special situation reports include all reports of medication error, abuse, misuse, overdose, reports of AEs 
associated with product complaints, and pregnancy reports regardless of an associated AE. Reports of 
adverse reactions in infants following exposure from breastfeeding, and reports of adverse reactions 
associated with product complaints and reports arising from occupational exposure are also considered 
special situation reports. 
• 
A pregnancy report is used to report any pregnancy in female partners of male subjects on study 
• 
Medication error is any unintentional error in the prescribing, dispensing, or administration of 
a medicinal product while in the control of the health care provider, subject, or consumer 
• 
Abuse is defined as persistent or sporadic intentional excessive use of a medicinal product by 
a subject 
• 
Misuse is defined as any intentional or inappropriate use of a medicinal product that is not in 
accordance with the protocol instructions or the local prescribing information 
• 
An overdose is defined as an accidental or intentional administration of a quantity of a medicinal 
product given per administration or cumulatively which is above the maximum recommended 
dose as per protocol or in the product labelling (as it applies to the daily dose of the subject in 
question). In cases of a discrepancy in drug accountability, overdose will be established only 
when it is clear that the subject has taken the excess dose(s). Overdose cannot be established 
when the subject cannot account for the discrepancy except in cases in which the investigator 
has reason to suspect that the subject has taken the additional dose(s) 
• 
Product complaint is defined as complaints arising from potential deviations in the manufacture, 
packaging, or distribution of the medicinal product 
All special situation reports must be reported on the special situations report form and forwarded to 
Sponsor within 24 hours of the investigator becoming aware of the situation. These reports must consist 
of situations that involve study drug, but do not apply to non-Sponsor concomitant medications. Cases 
of overdose should also be reported on an SAE form within 24 hours of the Investigator becoming aware 
of the situation. 
Special situations involving non-Sponsor concomitant medications do not need to be reported on the 
special situations report form; however, for special situations that result in AEs due to a non-Sponsor 
concomitant medication, the AE should be reported on the AE form. 
Any inappropriate use of concomitant medications prohibited by this protocol should be appropriately 
documented as a protocol deviation. 
Refer to the eCRF completion guidelines for full instructions on the mechanism of special situations 
reporting. 
All clinical sequelae in relation to these special situation reports will be reported as AEs or SAEs at the 
same time using the AE eCRF and/or the SAE report form. Details of the symptoms and signs, clinical 
management, and outcome will be reported, when available. 


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8.3.9 
REPORTING OF PREGNANCY 
Pregnancies of subjects exposed to ZN-c5 must be reported and relevant information should be 
submitted to Sponsor using the pregnancy and pregnancy outcome forms within 24 hours. Monitoring 
should continue until the conclusion of the pregnancy. If the end of the pregnancy occurs after the study 
has been completed, the outcome should be reported directly to Sponsor. 
To report a pregnancy, please contact the main Safety Management phone/fax/email (or via the 
applicable country-specific toll-free numbers) located in your study binder. 
Refer to Section 10.4.5 for Contraceptive Requirements and Maternal and Paternal Exposure. 
8.4 
DOSE-LIMITING TOXICITIES AND TOXICITY MANAGEMENT 
8.4.1 
DEFINITION OF DOSE-LIMITING TOXICITY MONOTHERAPY DOSE ESCALATION 
A dose-limiting toxicity (DLT) is a toxicity as defined below, excluding toxicities clearly related to disease 
progression or intercurrent illness, which occurs during the DLT evaluation period (Cycle 1) in each 
cohort: 
• 
Grade ≥ 3 hematologic toxicity present for more than 7 days 
• 
Grade ≥ 3 neutropenia (ANC < 1000/mm3) with fever (a single temperature of > 38.3°C or 
a sustained temperature of ≥ 38°C for more than one hour) 
• 
Grade 3 thrombocytopenia with bleeding 
• 
Grade ≥ 3 or higher non-hematologic toxicity, except: 
o Grade 3 nausea or emesis with maximum duration of 48 hours on adequate medical 
therapy 
o Grade 3 diarrhea which persists for < 72 hours in the absence of maximal medical 
therapy 
• 
Grade ≥ 2 non-hematologic treatment-emergent adverse event (TEAE) that in the opinion of the 
investigator is of potential clinical significance such that further dose escalation would expose 
subjects to unacceptable risk 
• 
Treatment interruption of ≥ 4 days due to drug-related toxicity 
• 
Liver enzyme and bilirubin abnormalities meeting Hy’s Law criteria (See Section 10.4.7) 
• 
Any death not clearly due to the underlying disease or extraneous cause 
For certain toxicities, such as laboratory assessments without a clear clinical correlate, a discussion 
between the investigator and Medical Monitor may take place to determine if this adverse event (AE) 
should be assessed as a DLT necessitating dose reduction. In addition, any toxicity which occurs during 
the DLT evaluation period meeting the protocol-defined stopping criteria (Section 7.1) will be considered 
a DLT. 
During the DLT evaluation period (Cycle 1), subjects not completing at least 24 days of scheduled daily 
dosing of ZN-c5 for reasons other than drug-related toxicity (e.g., withdrawal of consent, rapid disease 
progression, etc.) may be replaced based on the discretion of the Safety Review Committee. 


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8.4.2 
DEFINITION OF DOSE-LIMITING TOXICITY – COMBINATION DOSE ESCALATION 
A DLT is a toxicity as defined below, excluding toxicities clearly related to disease progression or 
intercurrent illness, which occurs during the DLT evaluation period (Cycle 1) in each cohort: 
• 
Hematologic: 
o Grade 4 neutropenia  
o Febrile neutropenia (defined as neutropenia Grade ≥ 3 [ANC < 1000 cells/mm3] and 
a body temperature ≥ 38.5°C) requiring antibiotic or antifungal treatment 
o Any Grade 4 thrombocytopenia (< 25,000/mm3 or <25.0 x 109/L) 
• 
Nonhematologic:  
o Grade ≥ 3 toxicities despite adequate treatment (e.g., nausea, vomiting, diarrhea) 
• 
Other:  
o Any palbociclib treatment delay of greater than 7 days to start Cycle 2 
Subjects who do not receive at least 24/28 doses of ZN-c5 and/or at least 85% of palbociclib doses in 
Cycle 1 for reasons other than DLT will be replaced. 
8.4.3 
TOXICITY MANAGEMENT 
Whether or not considered treatment related, all subjects experiencing AEs must be monitored 
periodically until symptoms subside, any abnormal laboratory values have resolved or returned to 
baseline levels or they are considered irreversible, or until there is a satisfactory explanation for the 
changes observed. 
In the combination cohorts, in cases where a toxicity cannot be clearly attributed to either drug (ZN-c5 
or palbociclib), ZN-c5 should be modified or discontinued first. 
8.4.3.1 DOSE LEVELS FOR TREATMENT MODIFICATION 
ZN-c5 
ZN-c5 dose levels for intra-subject treatment modification in the Monotherapy and Combination Dose 
Escalation will become available as dose levels are being assessed. 
ZN-c5 dose levels for treatment modification in the Monotherapy Expansion and Combination Phase 2 
are provided in Table 8. 
Table 8: 
ZN-c5 Dose Levels for Treatment Modification in Monotherapy 
Expansion and Combination Phase 2 
Dose Level 
Dose of ZN-c5 
1 
RP2D and schedule from the Monotherapy and Combination Dose Escalation a 
- 1 
-25%, further to be determined based on the Dose Escalation data 
- 2 
-50%, further to be determined based on the Dose Escalation data 
RP2D = recommended Phase 2 dose 
a 
Dose Level 1 will be the RP2D or a lower dose from the Monotherapy and Combination Dose Escalation 
according to the information including the safety, PK, pharmacodynamic and/or preliminary efficacy data. 


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Subjects who are unable to tolerate ZN-c5 at the lowest dose level should be permanently discontinued 
from study drug, unless the Investigator considers continuation of treatment at a lower dose to be in the 
best interest of the subject and the Sponsor’s Medical Monitor or designee approves further dose 
reduction. 
Palbociclib 
Please follow safety guidelines in the most recent local or US Full Prescribing Information for palbociclib 
(IBRANCE®, Pfizer Inc.). 
8.4.3.2 DOSE ADJUSTMENT OF PALBOCICLIB 
For subjects participating in the combination therapy portion of the study with toxicity potentially 
attributable to palbociclib, please follow safety and toxicity guidelines in the most recent local or US Full 
Prescribing Information for palbociclib (IBRANCE®, Pfizer Inc.). 
Dose holds for reasons other than toxicity (e.g., scheduled surgery) are allowed for up to 21 days. Dose 
holds for reasons other than toxicity that last more than 21 days require that the subject be removed 
from study unless deemed in the best interest of the patient to continue and after discussion between 
the Investigator and the Sponsor’s Medical Monitor (Section 7.2). 
Unmanageable AEs attributed to palbociclib alone may result in continuation of single agent ZN-c5 
therapy as long as none of the treatment discontinuation criteria are met (Section 7.2). 
If treatment with ZN-c5 is discontinued, on-study treatment with palbociclib can be continued per 
protocol unless palbociclib is commercially available and treatment is reimbursed for the patient, then 
the patient can come off study treatment. 
8.4.3.3 DOSE ADJUSTMENT OF ZN-C5 
ZN-c5 will be held for any ZN-c5 related Grade ≥ 3 adverse event or any DLT. 
ZN-c5 dosing may be restarted if the AE that resulted in the dose hold resolves to ≤ Grade 1 (or baseline) 
within 21 days. If the toxicity does not resolve to ≤ Grade 1 or baseline within 21 days, ZN-c5 will be 
permanently discontinued, unless deemed in the best interest of the patient to continue and after 
discussion between the Investigator and the Sponsor’s Medical Monitor (Section 7.2). 
Dose holds for reasons other than toxicity (e.g., scheduled surgery) are allowed for up to 21 days. Dose 
holds for reasons other than toxicity that last more than 21 days require that the subject be removed 
from study unless deemed in the best interest of the patient to continue and after discussion between 
the Investigator and the Sponsor’s Medical Monitor (Section 7.2). 
Doses withheld during a cycle will not be made up. When a dose reduction is required because of 
AEs/DLTs, no dose re-escalation will be permitted for the duration of study treatment unless mutually 
agreed upon by the Investigator and Sponsor.  
For dose modifications based on the occurrence of ZN-c5 related AEs, see Table 9. Up to 2 dose 
reductions are allowed. 


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Table 9: 
Dose Reduction Criteria ZN-c5: All Phases 
Dose Reduction Criteria 
Dose Adjustment 
Grade 4 (< 0.5 × 109/L) neutropenia lasting ≥ 8 days 
Reduce 1 dose level or discontinue treatment if 
occurring at the lowest dose level possible (which 
is 50 mg/day in the Dose Escalation Cohorts or 
Dose Level -2 in the Monotherapy 
Expansion/Phase 2 and Combination Phase 2)b   
Febrile neutropenia requiring antibiotics 
Grade 4 (< 25 × 109/L) thrombocytopenia  
or  
Grade 3 (≥ 25 to < 50 × 109/L) thrombocytopenia associated 
with Grade ≥ 3 bleeding and/or requiring platelet 
transfusions 
Any non-hematologic Grade 3 toxicity a, c 
Any non-hematologic Grade 4 toxicity c 
Discontinue treatment b  
a 
Grade 3 nausea, vomiting, diarrhea, or constipation for < 48 hours do not require a dose reduction. 
b 
If it is in the best interest of the subject to continue treatment in the opinion of the Investigator and after 
discussion with the Sponsor, the subject can continue treatment at a (further) reduced dose level. 
c 
Includes laboratory values deemed clinically significant by the Investigator 
If the ZN-c5 dose is reduced, the dose will not be increased again. If a benefit/risk assessment favors the 
increase of dose up to the initial starting dose after dose reduction, an agreement with the Sponsor’s 
Medical Monitor is required prior to the dose increase. 
8.5 
UNANTICIPATED PROBLEMS 
8.5.1 
DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the IRB/IEC approved research protocol 
and informed consent document; and (b) the characteristics of the participant population being 
studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is 
a reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
8.5.2 
UNANTICIPATED PROBLEM REPORTING 
The investigator will report unanticipated problems (UPs) to the reviewing IRB/IEC and the Sponsor. The 
UP report will include the following information: 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB/IEC project 
number; 
• 
A detailed description of the event, incident, experience, or outcome; 


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• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP; 
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline: 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB/IEC and to the study 
sponsor within the timelines for SAE reporting outlined in Section 8.3.6. 
• 
Any other UP will be reported to the IRB/IEC and to sponsor within 15 business days of the 
investigator becoming aware of the problem. 
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 15 business days of the IRB/IEC’s receipt of the 
report of the problem from the investigator. 
8.5.3 
REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
Not applicable. 


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9 
STATISTICAL CONSIDERATIONS 
9.1 
STATISTICAL HYPOTHESES 
For this study, all statistical analyses will be descriptive. No formal hypothesis testing will be performed. 
For the Monotherapy and Combination Dose Escalation, statistical methodology will be applied towards 
identification of the MTD and for the Monotherapy and Combination Phase 2 setting towards estimation 
of anti-tumor activity. 
Additional details on the planned statistical analyses may be found in the trial SAP. 
9.2 
SAMPLE SIZE DETERMINATION 
9.2.1 
MONOTHERAPY DOSE ESCALATION AND COMBINATION DOSE ESCALATION 
The primary objective of this part of the study is to identify the MTD, if possible, or the RP2D of ZN-c5 as 
monotherapy and in combination with palbociclib, and to recommend dose(s) for evaluation in future 
clinical studies. Hence, the number of patients in the cohorts has been based on the desire to obtain 
adequate tolerability, safety and pharmacokinetic and pharmacodynamic data while exposing as few 
patients as possible to the investigational product and procedures. 
For the Monotherapy Dose Escalation phase of the study, cohorts of 3-6 evaluable patients will be 
required. The total number of patients will depend upon the number of dose escalations necessary, but 
it is estimated to be approximately 36 subjects. 
The Combination Dose Escalation with palbociclib will be initiated at a dose deemed well-tolerated in 
the Monotherapy Dose Escalation and proceed with higher ZN-c5 doses, as tolerated, based again on 
standard rules of a 3+3 design (Section 6.1.4). The total number of patients will depend upon the 
number of dose escalations necessary, but it is estimated to be approximately 40 subjects (including 
alternate dosing schedules, e.g., BID, and possible backfill). The subjects in the Combination Dose 
Escalation might also count towards the futility assessment stage accrual in the Combination Phase 2 
(Section 6.1.7, Combination Phase 2). 
9.2.2 
MONOTHERAPY EXPANSION 
The Monotherapy Expansion will be initiated at a dose selected based on PK, safety and any available 
biomarker data from the ZN-c5 Monotherapy Dose Escalation at a specific dose level will continue until 
a higher dose has been deemed to be well-tolerated (no DLTs in 3 subjects or at most 1 DLT in 6 subjects 
in the Monotherapy Dose Escalation), at which point expansion accrual might shift to the higher dose 
level. 
The CBR as measured using RECIST v.1.1 will be assessed to provide preliminary anti-tumor activity 
evaluation in a patient population thought most likely to respond to ZN-c5. 
The Monotherapy Expansion overall will target balanced accrual between the 3 lines of therapy (1st, 2nd 
and 3rd hormonal therapy line) across dose levels. The total cohort size necessary for futility has been 
estimated based on futility screening criteria targeting 10 evaluable subjects per line cohort at dose 


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levels where any anti-tumor activity is demonstrated and providing an acceptable false negative risk of 
concluding that there is no activity if the true clinical benefit rate is at least 40%. 
Subjects are evaluable for the CBR if they have at least 1 post baseline disease/tumor assessment 
(Section 9.3). CBR as measured using RECIST v.1.1 will be assessed to provide preliminary anti-tumor 
activity evaluation in a patient population thought most likely to respond to ZN-c5.  Data from these 
cohorts will provide a preliminary assessment of anti-tumor activity based on CBR. 
The total number of patients in all expansion cohorts will depend upon the number of dose escalations, 
but it is not estimated to exceed 45 subjects. 
9.2.3 
MONOTHERAPY PHASE 2 
Up to 3 dose levels with up to 75 subjects per dose level will be enrolled using a randomized (if 2 or 
more doses), parallel cohort, non-comparative (estimation) design.   
Efficacy in the Monotherapy Phase 2 will be assessed as in the Monotherapy Expansion and CBR 
outcomes in the Monotherapy Phase 2 will be combined with those from subjects in the Monotherapy 
Expansion arm who were treated with ZN-c5 as 2nd/3rd Line of treatment and dosed at the same ZN-c5 
dose in the Monotherapy Expansion. The sample size is determined in order to estimate the CBR at each 
dose level with certain confidence before proceeding with a larger confirmatory study. Based on the 
targeted sample size, the precision for a 95% exact confidence interval around a hypothesized 40 – 50% 
CBR rate is ± 12% at each dose level studied.  
Historical estimates for the CBR rate specific to 2nd/3rd Line patients (either post CDK4/6 inhibitor or not) 
are not readily available.  The CBR range was estimated based on two studies, reporting a CBR rate for 
fulvestrant alone of 40% in 2nd Line or higher (PALOMA-3) and 56% CBR in 1st or 2nd Line (MONARCH-2). 
The targeted precision will be adequately achieved within the specified range and it will increase further 
outside of the range, if the true CBR rate is further (higher or lower) from 50%.     
9.2.4 
COMBINATION PHASE 2 
The Combination Phase 2 portion follows a randomized, parallel group, non-comparative design, 
assuming both the RP2D and the lower dose are investigated, or a single dose cohort, if only the RP2D is 
investigated. Each dose cohort is independently powered (non-comparative) and follows a Simon 
2-stage design. 
Approximately 56 subjects will be enrolled in each dose cohort. Subjects treated in the Combination 
Dose Escalation at lower doses can possibly also count towards the futility stage accrual, assuming the 
subjects are evaluable. The two dose cohorts evaluated in Phase 2 will not use the same subjects from 
lower dose cohorts in the Phase 1 Combination Dose Escalation phase; for example, ZN-c5 50 mg 
Combination Dose Escalation subjects may count for the 100 mg futility cohort in Phase 2, if that is 
selected as the lower dose cohort for the Phase 2 component but will not also count for the RP2D futility 
cohort, if a higher dose is selected as the RP2D.  


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CBR as measured using RECIST v.1.1 will be assessed to provide preliminary anti-tumor activity 
evaluation in a patient population thought most likely to respond to ZN-c5.  Subjects are evaluable for 
CBR if they have at least 1 post baseline disease/tumor assessment (Section 9.3). 
Sample size for each dose cohort is based on a Simon 2-stage design with 80% power at the 1-sided 
2.5% alpha level to differentiate between 50% CBR (poor performance) and 70% CBR (promising 
performance). Fifty-one (51) evaluable subjects will be enrolled in two stages, with 19 subjects in 
Stage 1 and 32 subjects in Stage 2. The probability of early stopping is 68%. The Combination Phase 2 
will target balanced accrual between the 2 lines of prior hormonal therapy (1stand 2nd hormonal therapy 
line) across dose levels. 
Second stage accrual will be completed, assuming that Stage 1 futility criteria are exceeded with at least 
11 subjects with CBR in the first 19 evaluable subjects. An approximate 10% loss for CBR evaluability has 
been assumed resulting in a sample size of approximately 56 subjects for each cohort, resulting in a total 
sample size of approximately 112 subjects for this trial stage. 
9.3 
POPULATIONS FOR ANALYSES 
Full Analysis Set (FAS) 
The FAS includes all subjects who receive ≥ 1 dose of study drug. This analysis set will be used for subject 
characteristics and efficacy endpoints. 
Safety Analysis Set 
The Safety Analysis Set for this study will be the same as FAS as this study is not randomized. This 
analysis set will be used for safety endpoints, study treatment administration and post-study therapy. 
DLT-Evaluable Analysis Set 
The DLT-Evaluable Analysis Set includes all subjects in the Safety Analysis Set who take 
≥ 24/28 scheduled Cycle 1 doses of ZN-c5 and/or the cumulative dose of palbociclib was ≥ 85% in Cycle 1 
(or less, if for reasons due to DLTs) and underwent all treatment and safety procedures through Day 28 
or experienced a DLT prior to Day 28. Determination of the MTD will be in the DLT-Evaluable Analysis 
Set. 
Pharmacodynamic and Pharmacokinetic Analysis Sets 
The Pharmacodynamic and PK Analysis Sets consist of all subjects in the FAS who have the necessary 
baseline and on-study measurements to provide interpretable results for the specific parameters of 
interest. 
9.4 
STATISTICAL ANALYSES 
9.4.1 
GENERAL APPROACH 
All data will be listed individually by subject. For quantitative parameters, descriptive statistics will 
include the mean, standard deviation, minimum, median, and maximum. For qualitative parameters, 
descriptive statistics will include the frequency and percentage. Data collected from this study will be 
analyzed by a designated biostatistician. 


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9.4.2 
ANALYSIS OF THE PRIMARY ENDPOINT(S) 
Monotherapy Dose Escalation and Combination Dose Escalation 
The primary endpoint is DLTs, as described in Section 8.4. 
Monotherapy Expansion 
The primary endpoint is safety and tolerability, as described in Section 9.4.4. 
Monotherapy and Combination Phase 2  
The primary endpoint is CBR, as described in Section 9.4.5.2. 
9.4.3 
ANALYSIS OF THE SECONDARY ENDPOINT(S) 
The secondary endpoints are the following: 
• 
Safety (Section 9.4.4). 
• 
Efficacy:  ORR, DOR, CBR, PFS and OS (Section 9.4.5). 
• 
PK parameters (Section 9.4.10.1) 
9.4.4 
SAFETY ANALYSES  
All safety data collected on or after the date that study drug was first dispensed up to the date of last 
dose of study drug plus 30 days will be summarized by dose level. Data for the pretreatment will be 
included in data listings. 
9.4.4.1 EXTENT OF EXPOSURE 
Descriptive information will be provided by dose level regarding the number of doses of study drug 
prescribed, the total number of doses taken, the percent of expected doses taken, the number of days 
of study drug, and the number and timing of prescribed dose modification and interruptions. 
9.4.4.2 ADVERSE EVENTS 
All AEs will be listed. The focus of AE summary will be on treatment-emergent AEs. A treatment-
emergent AE is defined as an AE that occurs or worsens in the period from the first dose of study drug to 
30 days after the last dose of study drug. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA 
https://www.meddra.org/) with descriptions by System Organ Class (SOC), High Level Group Term, 
High-Level Term, Preferred Term, and Lower-Level Term. The severity of AEs will be graded by the 
investigator according to the CTCAE, Version 4.03.  The relationship of the AE to the IP will be 
categorized as related or unrelated. 
TEAEs will be summarized by dose level. Summary tables will be presented to show the number of 
subjects reporting treatment-emergent AEs by severity grade and corresponding percentages. A subject 
who reports multiple treatment-emergent AEs within the same Preferred Term (or SOC) is counted only 
once for that Preferred Term (or SOC) using the worst severity grade. AE descriptions will be presented 


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by decreasing frequency for a given SOC and Preferred Term. Separate listings and summaries will be 
prepared for the following types of treatment-emergent AEs: 
• 
Study drug-related AEs 
• 
AEs that are Grade ≥ 3 in severity 
• 
AEs leading to study drug interruption and/or dose modification 
• 
AEs leading to study drug discontinuation 
• 
SAEs 
9.4.4.3 LABORATORY EVALUATIONS 
All laboratory data will be listed. Summaries of laboratory data will be based on observed data. The 
focus of laboratory data summarization will be on treatment-emergent laboratory abnormalities. 
A treatment-emergent laboratory abnormality is defined as an abnormality that, compared to baseline, 
worsens by ≥ 1 grade in the period from the first dose of study drug to 30 days after the last dose of 
study drug. If baseline data are missing, then any graded abnormality (i.e., an abnormality that is 
Grade ≥ 1 in severity) will be considered treatment-emergent. 
Hematological, serum biochemistry, and urine data will be programmatically graded according to CTCAE 
severity grade, when applicable. For parameters for which a CTCAE scale does not exist, reference 
ranges from the local laboratory will be used to determine programmatically if a laboratory parameter is 
below, within, or above the normal range for the subject’s age, sex, etc. Hematological and serum 
biochemistry and their changes from baseline will be summarized by dose level, by visit. Summary tables 
will be presented for each relevant assay to show the number of subjects by CTCAE severity grade with 
corresponding percentages. For parameters for which a CTCAE scale does not exist, the frequency of 
subjects with values below, within, and above the normal ranges will be summarized. Subjects will be 
characterized only once for a given assay, based on their worst severity grade observed during a period 
of interest (e.g., during the study or from baseline to a particular visit). 
Shift tables for hematology and serum biochemistry will also be presented by showing change in CTCAE 
severity grade from baseline to the worst grade post-baseline. For parameters for which a CTCAE scale 
does not exist, shift tables will be presented showing change in results from baseline to the worst grade 
post baseline. Separate listings and summaries will be prepared for laboratory abnormalities that are 
Grade ≥ 3 in severity. 
9.4.5 
EFFICACY ANALYSES 
9.4.5.1 OBJECTIVE RESPONSE RATE 
Objective Response Rate is defined as the percentage of subjects with measurable disease who have at 
least one confirmed response of CR or PR prior to any evidence of progression (as defined by RECIST 
v1.1). 
A confirmed response of CR/PR means that a response of CR/PR is recorded at one visit and confirmed 
by repeat imaging at least 4 weeks later with no evidence of progression between confirmation visits. 


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In the case of stable disease, measurements should have met the stable disease criteria for a minimum 
interval of 8 weeks (8 weeks minus the 7-day visit window) following the start of treatment. 
When the investigator is in doubt as to whether progression of disease has occurred and therefore 
reassesses the subject at a later date, the date of the initial scan should be declared as the date of 
progression if the repeat scans confirm progression. 
Data obtained up until progression, or last evaluable assessment in the absence of progression, will be 
included in the assessment of ORR. However, any complete response or partial response which occurred 
after a further anticancer therapy was received will not be included in numerator of the ORR calculation. 
The ORR estimates and associated exact 95% CIs using Clopper Pearson methodology will be presented. 
9.4.5.2 CLINICAL BENEFIT RATE 
The CBR is defined as the percentage of patients who have at least one confirmed response of CR, PR 
(only if subject has measurable disease), or SD lasting at least for 24 weeks prior to any evidence of 
progression (as defined by RECIST v1.1). 
The CBR estimates and associated exact 95% CIs using Clopper Pearson methodology will be presented. 
9.4.5.3 DURATION OF RESPONSE 
Duration of Response will be defined as the time from the date of first documented response (that is 
subsequently confirmed per RECIST v1.1) until date of documented progression or death in the absence 
of disease progression. The end of response should coincide with the date of progression or death from 
any cause used for the PFS endpoint. The time of the initial response will be defined as the latest of the 
dates contributing towards the first visit response of PR or CR. 
If a subject does not progress following a response, then their Duration of Response will use the PFS 
censoring time. 
9.4.5.4 PROGRESSION-FREE SURVIVAL 
The PFS is defined as the time from date of first dosing until the date of objective disease progression as 
defined by RECIST v1.1 or death (by any cause in the absence of progression). 
Subjects who have not progressed or died at the time of analysis will be censored at the time of the 
latest date of assessment from their last evaluable RECIST assessment. If the subject has no evaluable 
visits or does not have baseline data, they will be censored at Day 1 unless they die within two visits of 
baseline. 
If a subject discontinues treatment prior to progression, then these subjects will continue to be followed 
until evidence of objective disease progression as defined by RECIST v1.1 and their PFS time will be 
derived as defined above. 
If a subject receives a subsequent therapy prior to progression, then these subjects will be censored at 
the time of the subsequent therapy. 
The PFS estimate will be presented using Kaplan-Meier methodology. 


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9.4.5.5 OVERALL SURVIVAL 
The OS is defined as the time from date of first dosing until the date of death.  Subjects alive at the time 
of analysis will be censored at the time of the latest date of survival status assessment. 
The OS will be summarized using Kaplan-Meier methodology. 
9.4.6 
BASELINE DESCRIPTIVE STATISTICS 
The baseline value will be the last (most recent) pre-treatment value. Data from all sites will be pooled 
for all analyses. Analyses will be based upon the observed data unless methods for handling missing 
data are specified. If there is a significant degree of non-normality, analyses may be performed on 
log-transformed data or nonparametric tests may be applied, as appropriate. 
9.4.7 
PLANNED INTERIM ANALYSES 
An interim futility analysis will be conducted after Stage 1 accrual for each dose cohort in the 
Combination Phase 2 and necessary minimum follow-up is complete.  The guiding futility criteria are 
presented in Section 9.2, Sample Size Determination. 
9.4.8 
SUB-GROUP ANALYSES 
Subgroups of interest for efficacy and safety analyses will be defined in the SAP. 
9.4.9 
TABULATION OF INDIVIDUAL PARTICIPANT DATA 
Individual subject data may be listed in tabular form or plotted over time, including Duration of 
Response, listing of AEs, exposure data, or other endpoint-related data. 
9.4.10 
EXPLORATORY ANALYSES 
Analyses of PK and biomarker parameters are discussed below. 
9.4.10.1 PHARMACOKINETIC ANALYSIS 
The plasma concentrations of ZN-c5 (and its potential metabolites as applicable) and palbociclib will be 
summarized for monotherapy and the combination therapy cohorts separately by dose level and 
nominal sampling time using descriptive statistics. Plasma PK parameters (Cmax, Ctau, AUClast, t1/2, and 
Tmax, as applicable) will be listed and summarized using descriptive statistics (e.g., sample size, arithmetic 
mean, geometric mean, coefficient of variation (%) StD, median, minimum, and maximum). Plasma 
concentrations over time will be plotted in semi-logarithmic and linear formats as mean ± StD, and 
median (Q1, Q3) if applicable. 
9.4.10.2 BIOMARKER ANALYSIS 
Descriptive statistics of baseline and change in biomarkers will be provided at each sampling time for all 
subjects, and by dose. 
Exploratory analyses may be performed to evaluate the association of each biomarker or combination of 
biomarkers with clinical outcomes, and the modulation of biomarkers related to mechanism of action 
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Exploratory biomarkers analyses that may enhance the understanding of the biological effects, the 
mechanism of action, or safety, may be performed. Biomarker objectives may be further described and 
updated based on evolving scientific knowledge of ZN-c5 activity. If an exploratory biomarker analysis is 
to be performed, a biomarker analysis plan, with details on objectives and analysis methods, will be 
issued prior to the actual data analysis. 


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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 
INFORMED CONSENT PROCESS 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to study participation. The 
following consent materials are submitted with this protocol: 
• 
Study Participation Informed Consent 
• 
Optional tumor biopsy informed consent 
• 
Optional future research informed consent 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be 
IRB/IEC -approved, and the participant will be asked to read, review, and sign the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants. 
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. 
The investigator is responsible for obtaining written informed consent from each individual participating 
in this study after adequate explanation of the aims, methods, objectives, and potential hazards of the 
study and before undertaking any study-related procedures. The investigator must use the most current 
IRB/IEC-approved consent form for documenting written informed consent. Each informed consent will 
be appropriately signed and dated by the subject or the subject’s legally authorized representative and 
the person conducting the consent discussion, and also by an impartial witness if required by local 
requirements. The consent form will inform subjects about genomic testing and sample retention, and 
their right to receive clinically relevant genomic analysis results. 


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All subjects must sign and date the most recent IRB/IEC-approved Informed Consent Form before any 
study procedures are performed. 
The Informed Consent Form will contain a separate section that addresses participation in the optional 
future research. The investigator or authorized designee will explain to each patient the objectives, 
methods, and potential hazards of participation in the optional future research. Subjects who decline to 
participate will check a “no” box in the appropriate section and will not provide a separate signature. 
Subjects are not required to consent for optional future research in order to participate in this study and 
have the right to withdraw their consent for optional future research at any time and for any reason. If 
a subject wishes to withdraw consent to the testing of his or her specimens, the investigator must 
inform the sponsor. 
10.1.2 
STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly 
inform study participants, the IRB/IEC, and sponsor and will provide the reason(s) for the termination or 
suspension. Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping 
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB/IEC and/or Regulatory Authorities). 
Both the sponsor and the investigator reserve the right to terminate the study at any time. Should this 
be necessary, both parties will arrange discontinuation procedures and notify the appropriate regulatory 
authority(ies), IRBs, and IECs. In terminating the study, Sponsor and the investigator will assure that 
adequate consideration is given to the protection of the subjects’ interests. 
10.1.3 
CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor. 
All research activities will be conducted in as private a setting as possible. 


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The study monitor, other authorized representatives of the sponsor, representatives of the IRB/IEC, 
regulatory agencies or pharmaceutical company supplying study product may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site 
will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB/IEC, Institutional policies, or sponsor requirements. 
The investigator must assure that subjects’ anonymity will be strictly maintained and that their identities 
are protected from unauthorized parties. Only subject initials, date of birth, another unique identifier (as 
allowed by local law) and an identification code will be recorded on any form or biological sample 
submitted to the sponsor, IRB/IEC, or laboratory. Laboratory specimens must be labeled in such a way as 
to protect subject identity while allowing the results to be recorded to the proper subject. Refer to 
specific laboratory instructions. NOTE: The investigator must keep a screening log showing codes and 
appropriate subject identifiers for all subjects screened and for all subjects enrolled in the trial. Subject 
data will be processed in accordance with all applicable regulations. 
The investigator agrees that all information received from the study Sponsor, including but not limited 
to the Investigator’s Brochure, this protocol, CRF/eCRF, the study drug, and any other study information, 
remain the sole and exclusive property of the Sponsor during the conduct of the study and thereafter. 
This information is not to be disclosed to any third party (except employees or agents directly involved 
in the conduct of the study or as required by law) without prior written consent from Sponsor. The 
investigator further agrees to take all reasonable precautions to prevent the disclosure by any employee 
or agent of the study site to any third party or otherwise into the public domain. 
10.1.4 
FUTURE USE OF STORED SPECIMENS AND DATA 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed. 
The biomarker samples will be destroyed no later than 10 years after the end of study unless the subject 
gives specific consent for the remainder of the samples to be stored for optional future research. If the 
subject provides consent for optional future research, the samples will be destroyed no later than 
10 years after the end of the study. 
The specimens consented for optional future research, including body fluids, solid tissues, and 
derivatives thereof (e.g., RNA, proteins, peptides) will be destroyed no later than 10 years after the end 
of study. The specimen storage period will be in accordance with the IRB/IEC approved Informed 
Consent Form and applicable laws (e.g., health authority requirements). 
A subject’s withdrawal from the study does not, by itself, constitute withdrawal of specimens from the 
optional genomic research. Likewise, a subject’s withdrawal from the optional genomic research does 
not constitute withdrawal from the study. 


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In the event of a subject’s death or loss of competence, the subject’s specimens and data will continue 
to be used as part of the optional future research. 
10.1.5 
KEY ROLES AND STUDY GOVERNANCE 
The Sponsor is responsible for all aspects of study management and governance.  Refer to the study 
binder for contact information for the Medical Monitor, Clinical Monitor, and other key study personnel 
and parties. 
10.1.5.1 INVESTIGATOR RESPONSIBILITIES 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
Declaration of Helsinki (as amended in Edinburgh, Tokyo, Venice, Hong Kong, and South Africa), ICH 
guidelines, or with the laws and regulations of the country in which the research is conducted, 
whichever affords the greater protection to the study subject. These standards are consistent with the 
European Union Clinical Trials Directive 2001/20/EC and Good Clinical Practice (GCP) Directive 
2005/28/EC. 
The investigator will ensure adherence to the basic principles of GCP, as outlined in 21 CFR 312, subpart 
D, “Responsibilities of Sponsors and Investigators,” 21 CFR, part 50, 1998, and 21 CFR, part 56, 1998. 
The investigator and all applicable sub-investigators will comply with 21 CFR, Part 54, 1998, providing 
documentation of their financial interest or arrangements with Sponsor, or proprietary interests in the 
investigational drug under study. This documentation must be provided prior to the investigator’s (and 
any sub-investigator’s) participation in the study. The investigator and sub-investigator agree to notify 
Sponsor of any change in reportable interests during the study and for 1 year following completion of 
the study. Study completion is defined as the date when the last subject completes the protocol-defined 
activities. 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) Review and Approval 
The investigator (or sponsor as appropriate according to local regulations) will submit this protocol, 
Informed Consent Form, and any accompanying material to be provided to the subject (such as 
advertisements, subject information sheets, or descriptions of the study used to obtain informed 
consent) to an IRB/IEC. The investigator will not begin any study subject activities until approval from 
the IRB/IEC has been documented and provided as a letter to the investigator. 
Before implementation, the investigator will submit to and receive documented approval from the 
IRB/IEC on any modifications made to the protocol or any accompanying material to be provided to the 
subject after initial approval, with the exception of those necessary to reduce immediate risk to study 
subjects. 


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10.1.5.2 SPONSOR RESPONSIBILITIES – PROTOCOL MODIFICATIONS 
Protocol modifications, except those intended to reduce immediate risk to study subjects, may be made 
only by the study Sponsor. The investigator must submit all protocol modifications to the in accordance 
with local requirements and receive documented approval before modifications can be implemented. 
10.1.6 
SAFETY OVERSIGHT 
In the Phase 1 Monotherapy and Combination Dose Escalation, the safety and tolerability of each dose 
level will be assessed by a Safety Review Committee after all subjects in the cohort have been followed 
for at least 28 days after the first dose of ZN-c5. The Safety Review Committee will consist of the Study 
Team Physician/Medical monitor (or delegate) who will serve as chair of the committee and the 
Principal Investigator or delegate from each investigational site (or delegate). Others may be invited on 
an ad hoc basis, including (but not limited to) project team manager, preclinical team lead, study 
statistician, or others. Other internal or external experts may be consulted as needed. Frequent safety 
assessments will be conducted throughout Phase 1 (Monotherapy Expansion) and Phase 2 
(Monotherapy and Combination). 
10.1.7 
CLINICAL MONITORING 
In accordance with regulations and guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the accuracy of the data recorded in the eCRF. 
The monitor is responsible for routine review of the eCRF at regular intervals throughout the study to 
verify adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered on them. The monitor should have access to any subject records needed to verify the entries in 
the eCRF. The investigator agrees to cooperate with the monitor to ensure that any problems detected 
through any type of monitoring (central, on site) are resolved. 
Representatives of regulatory authorities or of the study Sponsor may conduct inspections or audits of 
the clinical study. If the investigator is notified of an inspection by a regulatory authority the investigator 
agrees to notify the Sponsor immediately. The investigator agrees to provide to representatives of 
a regulatory agency or Sponsor access to records, facilities, and personnel for the effective conduct of 
any inspection or audit. 
10.1.8 
QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. 
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
Following written SOPs, the monitors will verify that the clinical trial is conducted and data are 
generated and biological specimens are collected, documented (recorded), and reported in compliance 
with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and 


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applicable regulatory requirements (e.g., Good Laboratory Practices [GLP], Good Manufacturing 
Practices [GMP]). 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
The investigator will make available all source documents and other records for this trial to Sponsor’s 
appointed study monitors, to IRBs/IECs, or to regulatory authority or health authority inspectors. 
10.1.9 
DATA HANDLING AND RECORD KEEPING 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data. 
Data recorded in the electronic case report form (eCRF) derived from source documents should be 
consistent with the data recorded on the source documents. 
For each subject consented, an eCRF will be completed by an authorized study staff member whose 
training for this function is documented according to study procedures. Electronic CRFs should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring of safety 
data. The Eligibility Criteria eCRF should be completed only after all data related to eligibility have been 
received. Subsequent to data entry, a study monitor will perform source data verification within the 
Electronic Data Capture (EDC) system. Original entries as well as any changes to data fields will be stored 
in the audit trail of the system. Prior to database lock (or any interim time points as described in the 
clinical data management plan), the investigator will use his/her log in credentials to confirm that the 
forms have been reviewed, that the entries accurately reflect the information in the source documents, 
and the eCRF captures the data required per the protocol schedule of events and procedures. System-
generated or manual queries will be issued to the investigative site staff as data discrepancies are 
identified by the monitor, contract research organization (CRO) or internal Sponsor staff, who routinely 
review the data for completeness, correctness, and consistency. The site coordinator is responsible for 
responding to the queries in a timely manner, within the system, either by confirming the data as 
correct or updating the original entry, and providing the reason for the update (e.g., data entry error). At 
the conclusion of the trial, Sponsor will provide the site with a read-only archive copy of the data 
entered by that site. This archive must be stored in accordance with the records retention requirements 
outlined in Section 10.1.9.2. 
10.1.9.2 STUDY RECORDS RETENTION 
The investigator must maintain adequate and accurate records to enable the conduct of the study to be 
fully documented and the study data to be subsequently verified. These documents should be classified 


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into at least the following two categories: (1) investigator’s study file, and (2) subject clinical source 
documents. 
The investigator’s study file will contain the protocol/amendments, CRF and query forms, and 
governmental approval with correspondence, informed consent, drug records, staff curriculum vitae and 
authorization forms, and other appropriate documents and correspondence. 
The required source data should include sequential notes containing at least the following information 
for each subject: 
• 
Subject identification (name, date of birth, gender) 
• 
Documentation that subject meets eligibility criteria, i.e., history, physical examination, and 
confirmation of diagnosis (to support inclusion and exclusion criteria) 
• 
Documentation of the reason(s) a consented subject is not enrolled 
• 
Participation in study (including study number) 
• 
Study discussed and date of informed consent 
• 
Dates of all visits 
• 
Documentation that protocol specific procedures were performed 
• 
Results of efficacy parameters, as required by the protocol 
• 
Start and end date (including dose regimen) of study drug, including dates of dispensing and 
return 
• 
Record of all AEs and other safety parameters (start and end date, and including causality and 
severity) 
• 
Concomitant medication (including start and end date, dose if relevant; dose changes) 
• 
Date of study completion and reason for early discontinuation, if it occurs. 
All clinical study documents must be retained by the investigator until at least 2 years or according to 
local laws, whichever is longer, after the last approval of a marketing application in an ICH region (i.e., 
US, Europe, or Japan) and until there are no pending or planned marketing applications in an ICH region; 
or, if no application is filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and regulatory authorities have been notified. Investigators may be 
required to retain documents longer if specified by regulatory requirements, by local regulations, or by 
an agreement with Sponsor. The investigator must notify Sponsor before destroying any clinical study 
records. 
Should the investigator wish to assign the study records to another party or move them to another 
location, the Sponsor must be notified in advance. 
If the investigator cannot provide for this archiving requirement at the study site for any or all of the 
documents, special arrangements must be made between the investigator and Sponsor to store these 
records securely away from the site so that they can be returned sealed to the investigator in case of an 
inspection. When source documents are required for the continued care of the subject, appropriate 
copies should be made for storage away from the site. 


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10.1.10 
PROTOCOL DEVIATIONS 
Refer to the Study Manual for handling of protocol deviations. 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
A clinical study report will be prepared and provided to the regulatory agency. Sponsor will ensure that 
the report meets the standards set out in the ICH Guideline for Structure and Content of Clinical Study 
Reports (ICH E3). Note that an abbreviated report may be prepared in certain cases. 
Investigators in this study may communicate, orally present, or publish in scientific journals or other 
scholarly media only after the following conditions have been met: 
• 
The results of the study in their entirety have been publicly disclosed by or with the consent of 
Sponsor in an abstract, manuscript, or presentation form or the study has been completed at all 
study sites for at least 2 years. 
• 
The investigator will submit to Sponsor any proposed publication or presentation along with the 
respective scientific journal or presentation forum at least 30 days before submission of the 
publication or presentation. 
• 
No such communication, presentation, or publication will include Sponsor’s confidential 
information (see Section 10.1.3). 
• 
The investigator will comply with Sponsor’s request to delete references to its confidential 
information (other than the study results) in any paper or presentation and agrees to withhold 
publication or presentation for an additional 60 days in order to obtain patent protection if 
deemed necessary. 
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in 
a way that is appropriate to their participation in the design and conduct of this trial. 
Investigators and their study staff may be asked to provide services performed under this protocol, e.g., 
attendance at Investigator’s Meetings. If required under the applicable statutory and regulatory 
requirements, Sponsor will capture and disclose to Federal and State agencies any expenses paid or 
reimbursed for such services, including any clinical trial payments, meal, travel expenses or 
reimbursements, consulting fees, and any other transfer of value. 
10.2 
ADDITIONAL CONSIDERATIONS 
Not applicable. 
 
 


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10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
AI 
Aromatase Inhibitor 
ALT 
Alanine Aminotransferase 
ANC 
Absolute Neutrophil Count 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
AUClast 
Area Under the Curve Up to the Last Measurable Concentration 
BID 
Twice daily 
BSEP 
Bile Salt Export Pump 
BUN 
Blood Urea Nitrogen 
°C 
Degrees Celsius 
C1D1 
Cycle 1 Day 1 
CBR 
Clinical Benefit Rate 
CDK 
Cyclin-Dependent Kinase 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
Cmax 
Maximum concentration 
CNS 
Central Nervous System 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
Complete Response 
CrCl 
Creatinine Clearance 
CRO 
Contract Research Organization 
CT 
Computed Tomography (scan) 
Ctau 
Trough Concentration 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P450 
DILI 
Drug-Induced Liver Injury 
dL 
Deciliter 
DLT 
Dose-Limiting Toxicity 
DOR 
Duration of Response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOT 
End of Treatment 
ER 
Estrogen Receptor 
°F 
Degrees Fahrenheit 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FES 
18F-fluoroestradiol 
FOB 
Functional Observational Battery 
FSH 
Follicle-Stimulating Hormone 
g 
Gram 


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GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HER2 
Human Epidermal Growth Factor Receptor 2 
HIV 
Human Immunodeficiency Virus 
HR 
Hormone Receptor 
hr 
Hour 
HNSTD 
Highest Non-Severely Toxic Dose 
IB 
Investigator’s Brochure 
IC50 
Half-maximal Inhibition 
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
INR 
International Normalized Ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
kg 
Kilogram 
L 
Liter 
LD 
Longest Diameter 
LHRH 
Luteinizing Hormone-Releasing Hormone 
LTFU 
Long-term Follow-up 
m 
Meter 
µg 
Microgram 
µM 
Micromolar 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
min 
Minute 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
nM 
Nanomolar 
NYHA 
New York Heart Association 
OHRP 
Office for Human Research Protections 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PD 
Progression of Disease  
PE 
Physical Examination 
PET 
Positron Emission Tomography 
PFS 
Progression-Free Survival 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PR 
Partial Response 


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PS 
Performance Status 
PT 
Prothrombin Time 
QC 
Quality Control 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 Dose 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable Disease 
SERD 
Selective Estrogen Degrader 
SLD 
Sum of the Longest Diameters 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
StD 
Standard Deviation 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Half Life 
TAMR 
Tamoxifen-Resistant 
TBL 
Total Bilirubin 
TEAE 
Treatment-Emergent Adverse Event 
TGI 
Tumor Growth Inhibition 
Tmax 
Time at which maximum concentration seen 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problem 
US 
United States 
 
 
 


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10.4 APPENDICES 
10.4.1 
LIST OF DRUGS KNOWN TO PREDISPOSE TO TORSADE DE POINTES 
Please follow the guidelines for classification per the following website: 
https://www.crediblemeds.org/pdftemp/pdf/CombinedList.pdf 
Subjects must not be enrolled if they are taking medications classified as having a Known Risk of Torsade 
de Pointes (TdP) (KR). 
 
 


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10.4.2 
REVISED RECIST GUIDELINES (VERSION 1.1) 
Please see reference (E.A. Eisenhauer, et al. New response evaluation criteria in solid tumours: Revised 
RECIST guideline (version 1.1) European Journal of Cancer 45(2009) 228-247.) for full RECIST guidelines. 
Measurable Lesions: 
• 
Tumor ≥ 10 mm in longest diameter (LD) on an axial image on CT or MRI with ≤ 5 mm 
reconstruction interval If slice thickness > 5 mm, LD must be at least 2 times the thickness 
• 
Tumor ≥ 20 mm LD by chest x-ray (if clearly defined & surrounded by aerated lung); CT is 
preferred (even without contrast) 
• 
Tumor ≥ 10 mm LD on clinical evaluation (photo) with electronic calipers; skin photos should 
include ruler Lesions which cannot be accurately measured with calipers should be recorded as 
non-measurable 
• 
Lymph nodes ≥ 15 mm in short axis on CT (CT slice thickness no more than 5 mm) 
• 
Ultrasound cannot be used to measure lesions 
Non-Measurable Lesions: 
• 
All other definite tumor lesions 
o Masses < 10 mm 
o Lymph nodes 10–14 mm in short axis 
o Leptomeningeal disease 
o Ascites, pleural or pericardial effusion 
o Inflammatory breast disease 
o Lymphangitic involvement of skin or lung 
o Abdominal masses or organomegaly identified by physical exam which cannot be 
measured by reproducible imaging techniques 
• 
Benign findings are NEVER included. Also, do not include equivocal (“cannot exclude”) findings 
Target Lesions: 
• 
Choose up to 5 lesions (up to two (2) per organ) 
• 
Add up longest diameters (LD) of non-nodal lesions (axial plane) 
• 
Add short axis diameters of nodes 
• 
This is the “sum of the longest diameters” (SLD) 


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Table 10: 
Time Point Response: Patients with Target (± Non-target) Disease 
Target lesions 
Non-Target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
SD 
SD 
Non-PD or not all evaluated 
No 
NE 
Not all 
evaluated 
Non-PD 
No 
PD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and NE = 
unevaluable. 


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Table 11: 
Time Point Response: Patients with Non-target Disease Only 
Non-target lesions 
New lesions 
Overall response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/Non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PD = progressive disease, and NE = unevaluable. 
a 
“Non-CR/non-PD’ is preferred over “stable disease’ for non-target disease since SD is increasingly used as 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured 
is not advised. 
Table 12: 
Time Point Response: Best Overall Response 
Overall 
response 
First time point 
Overall response 
Subsequent time 
point 
BEST overall response 
CR 
CR 
CR 
PR 
CR 
SD, PD or PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
CR 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, PD 
PR 
NE 
SD provided minimum criteria for SD duration met, otherwise NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = unevaluable. 
a 
If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting 
PR criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after 
CR). Best response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ 
may be claimed when subsequent scans suggest small lesions were likely still present and in fact the patient 
had PR, not CR at the first time point. Under these circumstances, the original CR should be changed to PR and 
the best response is PR. 
http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1) E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, 
R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. 
Verweij 


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10.4.3 
ECOG PERFORMANCE STATUS 
Table 13: 
ECOG Performance Status 
Grade 
ECOG Performance Status - Description 
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 
Reference for ECOG Performance Status: Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the 
Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982 Dec; 5(6):649-55 
 
 


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10.4.4 
COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) V4.03 
NCI CTCAE v 4.03 can be accessed from the link below: 
http://www.hrc.govt.nz/sites/default/files/CTCAE%20manual%20-%20DMCC.pdf 
 
 


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10.4.5 
CONTRACEPTION AND MATERNAL/PATERNAL EXPOSURE 
Contraceptive Requirements for Females 
Female subjects of childbearing potential must agree to use protocol specified highly effective 
method(s) of contraception from the screening visit throughout the study period, 90 days following the 
last dose of study drug ZN-c5 (and 21 days after the last dose of palbociclib, if applicable) unless the 
subject chooses continuous heterosexual abstinence as a lifestyle choice. The investigator should 
counsel subjects on the protocol specified method(s) for avoiding pregnancy during the study. See the 
listed below for the protocol specified contraceptive methods. 
Lactating females must discontinue nursing before study drug administration. 
Protocol specified contraceptive methods: 
• 
Complete abstinence from intercourse. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) is not permitted. 
Or 
• 
Consistent and correct use of 1 of the following methods of birth control listed below, in 
addition to a male partner who correctly uses a condom from the date of Screening until 
90 days after last dose of ZN-c5 (and 21 days after the last dose of palbociclib, if applicable): 
o intrauterine device with a failure rate of < 1% per year 
o female barrier method: cervical cap or diaphragm with spermicidal agent 
o tubal sterilization 
o vasectomy in male partner 
Female subjects must agree to refrain from egg donation or egg harvesting for the purpose of 
fertilization during the course of the study for at least 90 days after the last dose of study drug. 
Contraceptive Requirements for Males 
Male subjects must agree to use condoms and avoid sperm donation from the screening visit 
throughout the study period, and for at least 90 days after administration of the last dose of study drug. 
Maternal exposure 
If a subject becomes pregnant during the course of the study, investigational product should be 
discontinued immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and handled 
as SAEs. Elective abortions without complications should not be handled as AEs. The outcome of 
a pregnancy should be followed up and documented even if the subject was withdrawn from the study. 
If a pregnancy occurs during exposure to investigational product or in the 30 days after discontinuing 
investigational product, then investigators or other site personnel inform appropriate Sponsor 
representatives immediately, or no later than 24 hours of when he or she becomes aware of it. 


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The same timelines apply when outcome information is available. 
Paternal exposure 
Pregnancy of a subject’s partner is not considered to be an adverse event. However, any conception 
occurring from the date of dosing until 16 weeks after dosing should be reported to the trial Sponsor on 
a Pregnancy Report Form and followed up for its outcome. 
Guidelines for the EU 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 
 


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10.4.6 
POTENTIAL DRUG-DRUG INTERACTIONS 
Table 14: 
Examples of CYP3A and CYP2C9 Inhibitors/Inducers 
 
Moderate 
Strong 
CYP3A Inhibitor 
aprepitant, cimetidine, 
ciprofloxacin, clotrimazole, 
crizotinib, cyclosporine, 
dronedarone, erythromycin, 
fluconazole, fluvoxamine, imatinib, 
tofisopam, verapamil 
boceprevir, cobicistat, conivaptan, 
danoprevir and ritonavir, 
elvitegravir and ritonavir, 
grapefruit juice, indinavir and 
ritonavir, itraconazole, 
ketoconazole, lopinavir and 
ritonavir, paritaprevir and ritonavir 
and (ombitasvir and/or dasabuvir), 
posaconazole, ritonavir, saquinavir 
and ritonavir, telaprevir, tipranavir 
and ritonavir, troleandomycin, 
voriconazole 
CYP3A Inducer 
bosentan, efavirenz, etravirine, 
modafinil 
carbamazepine, enzalutamide, 
mitotane, phenytoin, rifampin, 
St. John’s wort 
CYP2C9 Inhibitor 
amiodarone, felbamate, 
fluconazole, miconazole, piperine 
- 
CYP2C9 Inducer 
aprepitant, carbamazepine, 
enzalutamide, rifampin, ritonavir 
- 
Note: The above lists are not exhaustive. See also: 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093
664.htm 
 


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10.4.7 
HY’S LAW DEFINITION 
(Excerpted/adapted from: https://www.fda.gov/media/116737/download)  
Hy’s Law is essentially a translation of Zimmerman’s observation that pure hepatocellular injury 
sufficient to cause hyperbilirubinemia is an ominous indicator of the potential for a drug to cause 
serious liver injury. Thus, a finding of ALT elevation, usually substantial, seen concurrently with bilirubin 
> 2×ULN, identifies a drug likely to cause severe drug-induced liver injury (DILI) (fatal or requiring 
transplant) at a rate roughly 1/10 the rate of Hy’s Law cases. It is critical to rule out other causes of 
injury (e.g., other drugs or viral hepatitis) and to rule out an obstructive basis for the elevated 
bilirubin, so that alkaline phosphatase (ALP) should not be substantially elevated. In all cases to date, 
the small number of Hy’s Law cases has arisen on a background of an increased incidence of more 
modest signs of hepatocellular injury (e.g., greater incidence of 3 × ULN elevations in AT than seen in a 
control group). 
Briefly, Hy’s Law cases have the following three components: 
1. The drug causes hepatocellular injury, generally shown by a higher incidence of 3-fold (3 ×) or greater 
elevations above the upper limit of normal (ULN) of ALT or AST than the (non-hepatotoxic) control 
drug or placebo 
2. Among trial subjects showing such aminotransferase (AT) elevations, often with ATs much greater 
than 3xULN, one or more also show elevation of serum total bilirubin (TBL) to > 2 × ULN, without initial 
findings of cholestasis (elevated serum ALP)  
3. No other reason can be found to explain the combination of increased AT and TBL, such as viral 
hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of causing the observed 
injury 
 
 


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10.5 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
9-APR-2018 
Added EUDRACT number, removed 
investigator prompt from title page. 
FDA approved protocol entered 
into Zeno Quality System. 
2.0 
12-JUL-2018 
Clarified, updated, streamlined language 
throughout the protocol to improve flow 
and readability 
Clarity and readability for the sites. 
3.0 
25-JUN-2019 
Update study design 
More efficient study design, 
optimizing dosing for efficacy and 
safety considerations, as well as 
implementing more stringent 
statistical futility criteria to 
minimize patients’ exposure. 
4.0 
14-FEB-2020 
Update study design 
Addition of a Phase 2 
Monotherapy part of the study and 
addition of a cohort with a lower 
dose of ZN-c5 in the Combination 
Phase 2 with palbociclib. 
5.0 
14-SEP-2020 
Update study design 
Addition of possibility to assess up 
to 3 dose levels in the 
Monotherapy Phase 2. 
6.0 
20-APR-2021 
Clarification Phase 2 assessments, food 
intake and abbreviated PK sampling 
Clarifications. 
In Phase 2, ZN-c5 can be taken 
with or without food. 
 
 
 


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11 REFERENCES 
1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA: Cancer J Clin 2010; 60: 277-300. 
2. EBCTCG. Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence 
and 15-year survival: an overview of the randomised trials. Lancet 2005; 365(9472):1687-1717. 
3. National Comprehensive Cancer Network. Guidelines for patients: Breast Cancer. 
http://www.nccn.com/cancer-guidelines.html 
4. Prowell TM, Davidson NE. What is the role of ovarian ablation in the management of primary 
and metastatic breast cancer today? The Oncologist. Breast Cancer. 2004; 9:507-517. 
5. Randomized Phase II Study OF Goserelin (G) Plus Fulvestrant (F) vs. G Plus Anastrozole (A) vs. G 
Alone for HR+, Tamoxifen Pretreated, Premenopausal Woman (ongoing). 
https://clinicaltrials.gov/ct2/show/NCT01266213 
6. Turner NC, Ro J, André F et al.  Palbociclib in Hormone-Receptor–Positive Advanced Breast 
Cancer. N Engl J Med 2015;373:209-19. 
 
 


P h as e 1/ 2  Z N -c 5 + P al b ocicli b i n E R + H E R 2- a d v a nc e d br e ast c a nc er  
Pr ot oc ol V ersi o n 6 . 0 
Pr ot oc ol Z N -c 5-0 0 1  
2 0 A pr  2 0 2 1  
C o nfi d e nti al  
8 8  
1 2  S P O N S O R SI G N A T U R E P A G E  
 
St u d y Titl e:  
A P h as e 1/ 2 O p e n L a b el, M ultic e nt er St u dy t o Ass ess t h e S af ety, 
T ol er a bility, P h ar m ac o ki n etics, a n d A nti -T u m or Activity of Z N -c 5 Al o n e a n d 
i n C o m bi n ati o n wit h P al b ocicli b i n S u bj ects wit h Estr o g e n-R ec e pt or 
P ositi v e, H u m a n E pi d er m al Gr o wt h F act or R ec e pt or -2 N e g ati v e A dv a nc e d 
Br e ast C a nc er  
St u d y N u m b er:  
Pr ot oc ol V ersi o n:  
Z N -c 5-0 0 1  
6 . 0 
Fi n al D at e:  
2 0 -A P R -2 0 2 1  
 
T his cli nic al st u dy pr ot oc ol w as s u bj ect t o critic al r e vi e w a n d h as b e e n a p pr ov e d by t h e s p o ns or.  
 
 
Si g n e d : 
 
 
D at e :  
 
 
 M D 
 Cli nic al D ev el o p m e nt 
Z e n o Al p h a, I nc.  
 
 
2 5 - A p r - 2 0 2 1  |  2 : 4 4  P M  P D T
P P D
P P D
P P D


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13 INVESTIGATOR SIGNATURE PAGE 
 
Study Title: 
A Phase 1/2 Open Label, Multicenter Study to Assess the Safety, 
Tolerability, Pharmacokinetics, and Anti-Tumor Activity of ZN-c5 Alone and 
in Combination with Palbociclib in Subjects with Estrogen-Receptor 
Positive, Human Epidermal Growth Factor Receptor-2 Negative Advanced 
Breast Cancer 
Study Number: 
Protocol Version 
ZN-c5-001 
6.0 
Final Date: 
20-APR-2021 
 
By signing this protocol, I confirm that I have read and agree to conduct the clinical trial as outlined in 
the protocol and in compliance with Good Clinical Practice, the Declaration of Helsinki as amended, and 
all other applicable regulatory requirements. Confidentiality of all information received or developed in 
connection with this protocol will be maintained by me, as well as all other personnel involved in the 
clinical trial who are employed by me. 
 
 
____________________________________ 
 
____________________________________ 
Print Name of Principal Investigator 
Signature of Principal Investigator 
 
 
____________________________________ 
Date 
 


Phase 1/2 ZN-c5 + Palbociclib in ER+ HER2- advanced breast cancer 
Protocol Version 6.0 
Protocol ZN-c5-001 
20 Apr 2021 
Confidential 
90 
14 REVISION HISTORY 
Summary of Changes from Previous Version: 
Section(s) 
Summary of Revisions Made 
Rationale 
Summary of Changes from Version 5.0 (14 Sep 2020) to Version 6.0 (20 Apr 2021) 
Statement of 
Compliance 
Clarification to include guidance for all countries 
Clarification 
1.3 Schedule of 
Activities 
 
The Cycle 1 Day 1, 2, 15, and 16 assessments are 
adapted/clarified for Phase 2: 
• 
No Days 2 and 16 assessments required 
• 
ECGs on Days 1 and 15 pre-dose and 2 hours 
post-dose 
• 
Vital signs on Days 1 and 15 pre-dose and 
2 hours post-dose 
• 
In the combination cohort, on days that 
palbociclib is to be dosed, it can be taken at 
the same time as the ZN-c5 dose 
Adaptation/clarification of 
assessments for Phase 2 
subjects 
4.3 Justification of 
dose 
6.1.2.1 Dosing and 
administration of 
ZN-c5  
As of the Phase 2 parts of the study, ZN-c5 can be taken 
with or without food 
Data from Study ZN-c5-006 
allow dosing regardless of 
food 
8.2.2.1 
Pharmacokinetic 
Samples 
Clarification that in the abbreviated sampling schedule, 
palbociclib will also be analyzed for subjects in the 
combination parts of the study 
Clarification 
Summary of Changes from Version 4.0 (14 Feb 2020) to Version 5.0 (14 Sep 2020) 
Global 
The document was edited for readability and 
consistency including but not limited to administrative 
changes, correction of typos and errors, and formatting. 
Administrative updates 
and clarifications 
Title page, header, 
Sponsor Signature 
Page, and Investigator 
Signature Page 
Amendment version and date updated 
Administrative 
1.3 Schedule of 
Activities 
8.2.2.5 Tumor Biopsy 
Tissue 
 
Clarifications of  
• 
Acceptance of procedures for Cycle 1 Day 1 
• 
When biopsies and PK sample need to be 
obtained in respect to dosing of ZN-c5 
• 
On study, serum or urine pregnancy tests are 
allowed 
Procedural clarifications 
1.1 Synopsis 
6.1.5 Combination 
Dose Escalation 
9.2.1 Monotherapy 
Dose Escalation and 
Increase the number of subjects in the combination 
dose escalation to approximately 40. 
The increase is including 
assessment of alternate 
dosing schedules, e.g., BID, 
and possible backfill 


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Protocol Version 6.0 
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Section(s) 
Summary of Revisions Made 
Rationale 
Combination Dose 
Escalation 
1.1 Synopsis 
5.1 Inclusion Criteria 
Clarification that for the Monotherapy Phase 2:  1 or 
2 prior lines of endocrine therapy for advanced or 
metastatic breast cancer are allowed 
Clarification 
1.1 Synopsis 
1.2 Schema 
6.1.7 Monotherapy 
Phase 2 
9.2.3 Monotherapy 
Phase 2 
Adapting the Monotherapy Phase 2 design so up to 
3 dose levels of ZN-c5 can be assessed. 
Gathering more data to 
declare the RP2D(s) of 
ZN-c5 as monotherapy 
with more precision 
2.2 Background 
6.5.3 Use of other 
inhibitors or inducers  
Update based on new preclinical data 
Update 
6.5.1 Prophylactic 
medications and 
therapy 
Clarification that for pre/perimenopausal women, 
a gonadotropin-releasing hormone agonist can be 
repeated on study as per the prescribing information of 
the product administered. 
Clarification 
8.2.1.6 Laboratory 
Assessments 
Clarification that the full lipid panel can be done 
regardless of fasting status 
Clarification 
10.4.5 Contraception 
and maternal/paternal 
exposure  
Removal of hormonal contraceptives from the list of 
protocol-specified contraceptive methods.  
Clarification on acceptable 
protocol-specified 
contraceptive methods. 
Hormone-based 
contraception is excluded 
because of the mechanism 
of action of ZN-c5 (SERD). 
Summary of Changes from Version 3.0 (25 Jun 2019) to Version 4.0 (14 Feb 2020) 
Global 
The document was edited for readability and 
consistency including but not limited to administrative 
changes, correction of typos and errors, and formatting. 
Administrative updates 
and clarifications 
Global 
Revised the description of study from a “dose 
escalation and expansion” study to “Phase 1/2” study 
Clarification 
Global 
References to “FDA/US” and “Europe” replaced by 
“Regulatory Authorities”, as appropriate, to reflect the 
expansion of the study to sites outside of the US and 
Europe. 
To reflect the expansion of 
study to other regions 
worldwide, which may be 
regulated by Health 
Authorities other than the 
FDA or European 
Medicines Agency. 
Title page, header, 
Sponsor Signature 
Page, and Investigator 
Signature Page 
Amendment version and date updated 
Administrative 


Phase 1/2 ZN-c5 + Palbociclib in ER+ HER2- advanced breast cancer 
Protocol Version 6.0 
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Section(s) 
Summary of Revisions Made 
Rationale 
Synopsis: 
• 
Description of the study design, study population, 
objectives, and endpoints were modified for the 
addition of the Monotherapy Phase 2 component 
to the study. 
• 
Revised the estimated numbers of total subjects 
and subjects participating in the Phase 2 
components of the study  
• 
Revised the dosing schedule and design description 
of the Phase 2 Combination component of the 
study 
• 
Updated the study duration from 36 to 48 months 
• 
Increased number of study sites from 30 to 60 
Addition of Monotherapy 
Phase 2 component (to 
estimate the CBR with 
certain confidence before 
proceeding with a larger 
confirmatory study) and 
addition of a cohort with a 
lower dose of ZN-c5 in the 
Combination Phase 2 
component (to assess in 
parallel both the 
combination RP2D and a 
lower dose of ZN-c5 in 
combination with 
palbociclib) 
Schema 
• 
Figure 1 revised to include the Monotherapy 
Phase 2 component  
• 
Figure 2 revised to reflect design changes to the 
Phase 2 Combination component  
Updates for the addition 
of the Phase 2 
Monotherapy component 
and the design changes for 
the Phase 2 Combination 
component 
Schedule of Activities 
• 
Sampling for ZN-c5 pharmacodynamic and 
exploratory biomarkers at the End-of-Treatment 
and Disease Follow-up visits were to be collected, 
as applicable, per the footnote (#13);  
• 
Tumor biopsy at End-of-Treatment and Disease 
Follow-up visits were to be collected, as applicable, 
per the footnote (#14); 
• 
At baseline, if opted in, a fresh tumor biopsy should 
be obtained (no archival material allowed); 
• 
Assessment of ESR1 mutation was changed to 
always be collected at C2D1 and Disease Follow-up, 
regardless of status at baseline per the footnote 
(#16); 
• 
Clarified that drug accountability would be 
assessed from the subject dosing diary (#6); 
• 
Clarified that pre-dosing assessments may be 
performed up to 2 days prior to the Cycle 1, Day 1; 
and for all subsequent visits, these assessments 
should be performed within 1 day of the planned 
visit; 
• 
Added text to footnotes clarifying which 
assessments would not be collected for 
Procedural clarifications 


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Protocol Version 6.0 
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Section(s) 
Summary of Revisions Made 
Rationale 
Monotherapy Phase 2, including non-fasting full 
lipid panel (#9). 
• 
Tumor biopsy: Clarified that subjects had the 
option to undergo a biopsy of a lesion at the time 
of disease progression. Also, if sufficient tumor 
material was available, it was clarified that part of 
the tumor biopsy at C2D1 was to be used for 
determination of ZN-c5 tissue concentration.  
Additionally, if a tumor biopsy was collected at 
C2D1 or beyond, a plasma PK sample was to be 
collected (#14). 
• 
Clarified the timing of the FES-PET scans (#19) 
Section 2.2 
• 
Changed all reference from KP-868 to ZN-c5 
• 
Added findings from nonclinical toxicology studies 
• 
Clarification of findings and interpretation of 
nonclinical toxicology studies. 
• Revisions to ensure 
consistent reference to 
the drug product 
• Safety updates based 
on completed 
nonclinical studies 
Section 2.3.1 
Added safety risks, including potential decrease in 
erythropoiesis/reticulocytes, sex organ effects, pruritus 
Safety updates based on 
completed nonclinical 
studies. 
Sections 2.3.2, 6.1.1.2 
Clarified that palbociclib has been approved by other 
Regulatory Authorities 
Clarification 
Section 3 
Added Objectives and Endpoints for Phase 2 
Monotherapy component 
Addition of the Phase 2 
Monotherapy Component 
Section 4.2 
Revised the design description from “Futility screening” 
to “Screening (estimation)” 
Revision of design 
description 
Section 5.1 
• 
Clarified which inclusion criteria are applicable to 
the Monotherapy Escalation and Monotherapy 
Phase 2 
• 
Added clarifications on counting prior lines of 
treatment  
• 
Modified the eligible hepatic function upper limit of 
normal for patients with liver metastases (#15) 
• Addition of Phase 2 
Monotherapy 
component 
• Clarification of prior 
treatments and 
eligibility 
Section 5.2 
• 
Changed restricted period of prior radiotherapy use 
from 28 days to 14 days (#1d) 
• 
Split Exclusion Criterion defining central nervous 
system metastases into two criteria with additional 
details for exclusion (#4 and #5)  
• 
Clarified that washout period for moderate or 
strong CYP3A or CYP2C9 inducers should be 14 
days or 5 half-lives, whichever is shorter, before 
first use of study drug (#15). 
Clarifications 


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Protocol Version 6.0 
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20 Apr 2021 
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Section(s) 
Summary of Revisions Made 
Rationale 
Section 5.4 
Clarified that subjects may be rescreened after 
discussion with the Sponsor. 
Procedural clarification 
Section 6.1.2.2 
Deleted “capsules” from palbociclib product 
description. 
Clarification 
Section 6.1.3 
Clarified that 85% of palbociclib doses was 18/21. 
Clarification 
Section 6.1.7 
Added new section with a description of the 
Monotherapy Phase 2 component  
Addition of Phase 2 
Monotherapy Component 
Section 6.1.8 
• 
Added description of dose selection and 
administration of ZN-c5 for the Combination 
Phase 2 component. 
• 
Added design details for the Combination Phase 2 
component of the study. 
• 
Clarified the number of subjects in each dose 
cohort and total sample size for the Combination 
Phase 2. 
• 
Clarified which subjects from the Combination 
Dose Escalation phase can be evaluated in which 
arm of the Combination Phase 2 component. 
Addition of the low ZN-c5 
dose to the Phase 2 in 
combination with 
palbociclib 
Section 6.2.1 
Clarified that study drug should be reconciled against 
the subject dosing diaries for accountability purposes 
Clarification  
Section 6.2.3 
Added that ZN-c5 capsules should also be protected 
from light during storage. 
Procedural clarification 
Section 6.5.2 
Clarified that washout period for moderate or strong 
CYP3A or CYP2C9 inducers should be 14 days or 5 half-
lives, whichever is shorter, before first use of study 
drug. 
Clarification 
Section 8.1.1 
Clarified that additional modalities of imaging tumors, 
beyond scans, would be acceptable. 
Procedural clarification 
Section 8.2.1.5 
Clarified that AE assessment should be performed after 
the last dose of study drug but prior to initiation of 
subsequent breast cancer therapy. 
Procedural clarification 
Section 8.2.1.6 
• 
Clarified that pre-dose sampling assessments 
should be drawn within 1 day of all visits 
subsequent to Cycle 1 Day 1. 
• 
Added clarification that non-fasting full lipid panel 
would not be assessed in the Monotherapy Phase 2 
component of the study in footnote d of Table 4. 
Procedural clarification 
Section 8.2.2.1 
• 
Added new table (Table 5) that provides a 
description and reference to the PK sampling 
schedule (full or abbreviated PK sampling schedule) 
for each study component. 
• 
Added new table (Table 7) that provides a 
description of the abbreviated PK sampling 
schedule. 
Adapted the PK schedule 
to full PK and an 
abbreviated PK schedule 
as appropriate and added 
clarifications 


Phase 1/2 ZN-c5 + Palbociclib in ER+ HER2- advanced breast cancer 
Protocol Version 6.0 
Protocol ZN-c5-001 
20 Apr 2021 
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Section(s) 
Summary of Revisions Made 
Rationale 
• 
Clarified that an additional PK sample should be 
collected if an optional On-treatment tumor biopsy 
is performed regardless if tissue was obtained for 
ZN-c5 tissue concentration. 
Section 8.2.2.5 
• 
Added instruction that part of the C2D1 tumor biopsy 
is to be used for determination of ZN-c5 tissue 
concentration if sufficient tumor material is available; 
• 
At baseline, if opted in, a fresh tumor biopsy should 
be obtained (no archival material allowed). 
Procedural clarification 
Section 8.2.2.6 
• 
Added new section on collection of sample for ZN-c5 
tumor tissue concentration. 
• 
Clarified that a plasma PK sample should be collected 
if tumor tissue is collected for ZN-c5 concentrations. 
Procedural clarification 
Section 8.2.2.8 
Deleted specific timepoints for FES assessments and 
replaced with a reference to the Schedule of Assessments. 
Procedural clarification 
Sections 8.3.4, 8.3.5, 
8.3.6 
Re-arranged and clarified the process and timing of 
reporting AEs and SAEs in these sections. 
Procedural clarification 
Section 8.3.8 
Added instruction for reporting cases of overdose. 
Procedural clarification 
Section 8.4.3.3, Table 9 
Added instruction for dose adjustment instructions for 
Monotherapy Phase 2 component 
Procedural clarification 
Section 9.2.3 
Added description of the sample size estimates and design 
of the Monotherapy Phase 2 component of the study. 
Addition of Phase 2 
Monotherapy Component 
Section 9.2.4 
Revised and added additional information on the sample 
size estimate and design of the Combination Phase 2 
component of the study. 
Addition of the low ZN-c5 
dose to the Phase 2 in 
combination with 
palbociclib 
Section 9.4.2 
Added description of the analysis of endpoints in the 
Phase 2 Monotherapy component of the study. 
Addition of Phase 2 
Monotherapy Component 
Section 10.1.1.1 
Clarified that documentation of informed consent is 
required prior to study participation as opposed to 
“starting intervention/administering study intervention”. 
Procedural clarification 
Section 10.1.1.2 
Clarified that consent forms must be signed by the 
participants. 
Procedural clarification 
Section 10.1.6 
Clarified that safety oversight by Safety Review Committee 
would occur in the Phase 1 Monotherapy and Combination 
Dose Escalation phases. 
Clarification 
Section 10.4.1 
Replaced list of drugs known to predispose to Torsade de 
Pointes with an online guideline. 
To provide the most up-to-
date list and resource 
guidance for the 
Investigators 
 

SAP_001.pdf: 
Official Title: 
A PHASE 1/2 OPEN LABEL, MULTICENTER STUDY TO ASSESS 
THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND ANTI-
TUMOR ACTIVITY OF ZN-c5 ALONE AND IN COMBINATION 
WITH PALBOCICLIB IN SUBJECTS WITH ESTROGEN-RECEPTOR 
POSITIVE, HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR-
2 NEGATIVE ADVANCED BREAST CANCER 
NCT Number: 
NCT03560531 
Document Date: 
17-Feb-2023 
 


 
Statistical Analysis Plan 
Protocol No. ZN-c5-001 
Revision 00: 17Feb2023 
 
 
DOC.ST.101.04-01 Rev 00 
Page 1 of 47 
CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Trial Sponsor: 
Zeno Alpha, Inc. 
Protocol Number: 
ZN-c5-001 
IND Number: 
 
EUDRACT Number: 
2018-001364-27 
Investigational Drug: 
ZN-c5 
Indication: 
Advanced Breast Cancer 
 
Protocol Title: A Phase 1/2 open label, multicenter study to assess the safety, tolerability, 
pharmacokinetics, and anti-tumor activity of ZN-c5 alone and in combination with Palbociclib 
in subjects with estrogen-receptor positive, human epidermal growth factor receptor-2 negative 
advanced breast cancer 
 
Date of First Sign-off (Revision 00): 
17Feb2023 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0 : 1 7 Fe b 2 0 2 3  
 ( Pa ge 2  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 2  of 4 7  
C O N FI D E N TI A L  
 
S T A TI S TI C A L A N A L Y SI S P L A N SI G N -O F F ( R E VI SI O N 0 0) 
 
T his d oc u me nt was s u bject t o critical re vie w a n d h as bee n a p pr o ve d b y t he S p o ns or. Refer t o t he 
a ut h orize d electr o nic si g n at ure a n d d ate o n t he l ast p a ge.  
 
 
Si g ne d b y:  
 
E xec uti ve Direct or, Bi ost atistics & St atistic al P r o gr a m mi n g  
Ze n o Al p h a, I nc.  
  
  
 
P P D


 
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CHANGE LOG FOR CHANGES MADE AFTER THE INITIAL APPROVAL 
 
Revision 
Number 
Revision 
Date 
Section(s) Modified 
Brief Description of 
Revision(s) or Reason(s) for 
Revision 
Revision 00 
17Feb2023 
NA 
Original document creation 
 
 
 


 
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Protocol No. ZN-c5-001 
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TABLE OF CONTENTS 
 
1. 
INTRODUCTION .......................................................................................................................................... 10 
2. 
STUDY OBJECTIVES................................................................................................................................... 10 
2.1 
PRIMARY OBJECTIVES ............................................................................................................................... 10 
2.1.1 
Phase 1 ...................................................................................................................................... 10 
2.1.2 
Phase 2 ...................................................................................................................................... 10 
2.2 
SECONDARY OBJECTIVES .......................................................................................................................... 11 
2.2.1 
All Cohorts ............................................................................................................................... 11 
2.2.2 
Monotherapy Dose Escalation and Monotherapy Phase 2 ........................................................ 11 
2.2.3 
Combination Dose Escalation and Combination Phase 2 ......................................................... 11 
2.2.4 
Monotherapy Expansion Phase 1 .............................................................................................. 11 
2.2.5 
Monotherapy Dose Escalation and Monotherapy Expansion Phase 1 and Monotherapy Phase 2
 
11 
2.3 
TERTIARY/EXPLORATORY OBJECTIVES (ALL COHORTS) .......................................................................... 11 
3. 
STUDY DESIGN ............................................................................................................................................ 12 
3.1 
STUDY DESIGN .......................................................................................................................................... 12 
3.2 
RANDOMIZATION ...................................................................................................................................... 14 
3.3 
HYPOTHESIS TESTING ............................................................................................................................... 14 
3.4 
INTERIM ANALYSIS ................................................................................................................................... 14 
3.5 
SAMPLE SIZE ............................................................................................................................................. 15 
3.5.1 
Monotherapy Dose Escalation and Combination Dose Escalation ........................................... 15 
3.5.2 
Monotherapy Expansion ........................................................................................................... 15 
3.5.3 
Monotherapy Phase 2 ............................................................................................................... 16 
3.5.4 
Combination Phase 2 ................................................................................................................ 16 
3.6 
STUDY PROCEDURES ................................................................................................................................. 17 
3.7 
SCHEDULE OF ASSESSMENTS..................................................................................................................... 17 
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE ............................................................................. 23 
5. 
ANALYSIS POPULATIONS ........................................................................................................................ 23 
5.1 
FULL ANALYSIS SET (FAS) ....................................................................................................................... 23 
5.2 
TUMOR RESPONSE EVALUABLE SET ......................................................................................................... 23 
5.3 
SAFETY ANALYSIS SET ............................................................................................................................. 23 
5.4 
DLT-EVALUABLE ANALYSIS SET ............................................................................................................. 23 
5.5 
PHARMACODYNAMIC ANALYSIS SET ........................................................................................................ 23 
5.6 
PHARMACOKINETIC ANALYSIS SET ........................................................................................................... 24 
6. 
STATISTICAL METHODS .......................................................................................................................... 24 
6.1 
GENERAL DATA HANDLING RULES AND DEFINITIONS .............................................................................. 24 
6.2 
SUBJECT DISPOSITION ............................................................................................................................... 24 
6.3 
PROTOCOL DEVIATIONS ............................................................................................................................ 24 
6.4 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................................................................. 25 
6.5 
EFFICACY .................................................................................................................................................. 26 
6.5.1 
Study Day and Visit Window Definitions ................................................................................ 26 
6.5.2 
Tumor and Response Evaluations ............................................................................................. 26 
6.5.3 
Progression-Free Survival ........................................................................................................ 28 
6.5.4 
Duration of Response ............................................................................................................... 30 
6.5.5 
Overall Survival ........................................................................................................................ 31 


 
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6.5.6 
Pharmacokinetic Variables ....................................................................................................... 31 
6.5.7 
Pharmacodynamic/Biomarker Analysis.................................................................................... 32 
6.6 
SAFETY ..................................................................................................................................................... 32 
6.6.1 
Study Day and Visit Window Definitions ................................................................................ 32 
6.6.2 
Extent of Exposure to Study Medication .................................................................................. 32 
6.6.3 
Adverse Events ......................................................................................................................... 33 
6.6.4 
Laboratory Data ........................................................................................................................ 35 
6.6.5 
Vital Signs ................................................................................................................................ 37 
6.6.6 
Electrocardiogram (ECG) ......................................................................................................... 37 
6.6.7 
Physical Examination ............................................................................................................... 37 
6.6.8 
Pregnancy Test ......................................................................................................................... 37 
6.6.9 
Prior and Concomitant Medications/Procedures ....................................................................... 37 
6.6.10 
ECOG PS .................................................................................................................................. 38 
6.7 
PHARMACOKINETIC ANALYSIS .................................................................................................................. 38 
6.7.1 
General Considerations ............................................................................................................. 38 
6.7.2 
Plasma Concentrations .............................................................................................................. 39 
6.7.3 
Pharmacokinetic Endpoints ...................................................................................................... 39 
6.7.4 
Pharmacodynamic/Biomarker Analysis.................................................................................... 42 
7. 
ANALYSES PERFORMED BEFORE DATABASE CLOSURE .............................................................. 42 
8. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL ......................................................... 42 
9. 
STATISTICAL SOFTWARE ........................................................................................................................ 43 
10. 
REFERENCES ............................................................................................................................................... 43 
11. 
APPENDIX 1 NCI-CTCAE V4.03 TOXICITY GRADING ....................................................................... 44 
11.1 PANEL: CHEMISTRY .................................................................................................................................. 44 
11.2 PANEL: HEMATOLOGY .............................................................................................................................. 45 
11.3 PANEL: COAGULATION .............................................................................................................................. 46 
11.4 PANEL: LIPID PANEL ................................................................................................................................. 46 
12. 
APPENDIX 2 PROGRAMMING CODES FOR STATISTICAL ANALYSIS ......................................... 47 
 
 


 
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GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC0-12 
Area under the concentration-time curve from the time of dosing to the end of the 
dosing interval (12 h post-dose for BID dosing; ZN-c5 only) 
AUC0-24 
Area under the concentration-time curve from the time of dosing to the end of the 
dosing interval (24 h post-dose for QD dosing) 
AUClast 
Area under the plasma concentration-time curve from zero to the time of last 
quantifiable plasma concentration 
AUCtau 
Area under the concentration-time curve from the time of dosing to the end of the 
dosing interval (tau = 12 or 24 hours) 
β-hCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily 
BUN 
Blood urea nitrogen 
CBR 
Clinical benefit rate 
CI 
Confidence interval 
C0-12 
Concentration at the end of the dosing interval (BID dosing; ZN-c5 only) 
C0-24 
Concentration at the end of the dosing interval QD dosing only 
Cave 
Average steady-state plasma concentration 
CL/F 
Apparent total plasma clearance after a single dose oral administration 
CLss/F 
Apparent total plasma clearance after multiple dose oral administration 
Cmax 
Maximum observed plasma concentration after a single dose administration 
Cmax,ss 
Maximum observed plasma concentration after multiple dose administration 
CPK 
Creatine phosphokinase 
CR 
Complete response 


 
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GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Term 
CrCl 
Creatinine clearance 
Ctrough 
Concentration at the end of the dosing interval (tau = 12 or 24 hours) 
CV% 
Coefficient of variation 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ER 
Estrogen Receptor 
FAS 
Full analysis set 
FES 
18F-fluoroestradiol 
GGT 
Gamma-glutamyl-transferase 
HER2 
Human Epidermal Growth Factor Receptor-2 
ICH 
International Council for Harmonisation 
INR 
International normalized ratio 
z  (Lambda z) 
Terminal elimination phase rate constant 
LLN 
Lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
NA 
Not applicable 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
ORR 
Objective response rate 
OS 
Overall Survival 
PD 
Disease progression 
PET 
Positron emission tomography 


 
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GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Term 
PFS 
Progression-free survival 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PS 
Performance Status 
PT 
Prothrombin time 
QD 
Once daily 
QTcB 
QT interval adjusted using Bazett’s formula  
QTcF 
QT interval adjusted using Fridericia’s formula 
RAUC 
AUC accumulation ratio  
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SOC 
System Organ Class 
StD 
Standard deviation 
T1/2 
Apparent terminal elimination half life 
TEAE 
Treatment-emergent adverse events 
Tlast 
Time of last observed quantifiable concentration 
Tmax 
Time to maximum concentration after a single dose administration 
Tmax,ss 
Time of maximum observed plasma concentration after multiple dose 
administration 
ULN 
Upper limit of normal 
Vz/F 
Apparent volume of distribution after a single dose oral administration 
Vz,ss/F 
Apparent volume of distribution after multiple dose oral administration 


 
Statistical Analysis Plan 
Protocol No. ZN-c5-001 
Revision 00: 17Feb2023 
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DOC.ST.101.04-01 Rev 00 
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CONFIDENTIAL 
 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Term 
WBC 
White blood cell 
 
 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0 : 1 7 Fe b 2 0 2 3  
 ( Pa ge 1 0  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 1 0  of 4 7  
C O N FI D E N TI A L  
 
1.  I N T R O D U C TI O N  
T his Statistical A nal ysis Pla n ( S A P) o utli nes t he statistical met h o ds f or t he dis pla y, s u m mar y a n d a nal ysis 
of data c ollecte d wit hi n t he sc o pe of Z N -c 5 -0 0 1  Pr ot oc ol versi o n 6 . 0 date d 2 0 A pr 2 0 2 1 . As wit h a n y S A P , 
t he pr o p ose d met h o ds a n d a p pr oac hes t o t he data a nal ysis s h o ul d be dee me d as fle xi ble. T he a nal ysis of t he 
data s h o ul d all o w c ha n ges i n t he pla n t o t he e xte nt t hat de viati o ns fr o m t he ori gi nal pla n w o ul d pr o vi de a 
m ore rel ia ble a n d vali d a nal ysis of t he data. As s uc h, t he statistical a nal ysis t o a certai n de gree is iterati ve 
si nce m uc h of t he pla n ni n g is base d o n ass u m pti o ns t hat re q uire verificati o n. T he p ur p ose of t his pla n is t o 
pr o vi de ge neral g ui deli nes fr o m w hic h t he a nal ysis will pr ocee d. Ne vert heless, de viati o ns fr o m t hese 
g ui deli nes m ust be s u bsta ntiate d b y a s o u n d statistical rati o nale.  
T he S A P s h o ul d be rea d i n c o nj u ncti o n wit h t he st u d y p r ot oc ol a n d t he electr o nic c ase re p ort for ms 
(eC R F s). T his versi o n of t he S AP has bee n de vel o pe d usi n g t he fi nal versi o n of t he p r ot oc ol me nti o ne d 
a b o ve a n d t he Re visi o n 0 5  of t he a n n otate d eC R Fs date d 2 6 Se p 2 0 2 2 . 
T his is a P hase 1/ 2, o pe n -la bel, m ultice nter, d ose-escalati o n a n d e x pa nsi o n st u d y t o e val uate t he safet y,  
t olera bilit y, p har mac o ki netics , a n d a nti -t u m or acti vit y of Z N -c 5 al o ne a n d i n c o m bi nati o n wit h pal b ocicli b 
i n s u bjects wit h estr o ge n -rece pt or ( E R) p ositi ve, h u ma n e pi der mal gr o wt h fact or rece pt or-2 ( H E R 2) 
ne gati ve  a d va nce d breast ca ncer  ( See pr ot oc ol sectio ns 4 .1  t o 4 .4  f or details). 
2.  S T U D Y O B J E C TI V E S   
2. 1  Pri m ar y O bjecti ve s  
2. 1. 1  
P h ase 1   
•  
M o n ot hera p y D ose Escalati o n  
o  Deter mi ne a ma xi m u m t olerate d d ose ( M T D) or rec o m me n de d P hase 2 d ose ( R P 2 D) f or 
Z N -c 5 as a m o n ot hera p y  
•  
M o n ot hera p y E x pa nsi o n  
o  I n vesti gate t he safet y a n d t olera bilit y of Z N-c 5 as a m o n ot hera p y i n s u bjects wit h Estr o ge n 
Rece pt or ( E R) p ositi ve, H u ma n E pi der mal Gr o wt h Fact or Rece pt or -2 ( H E R 2) ne gati ve 
a d va nce d breast ca ncer  
•  
C o m bi nati o n D ose Escalati o n  
o  Deter mi ne a n M T D or R P 2 D f or Z N -c 5 w he n a d mi nistere d i n c o m bi nati o n wit h 
pal b ocicli b  
2. 1. 2  
P h ase 2   
•  
M o n ot hera p y P hase 2  
o  Deter mi ne preli mi nar y a nti -t u m or efficac y ( Cli nical Be nefit Rate [ C B R]) f or Z N-c 5 as a 
m o n ot hera p y  
•  
C o m bi nati o n P hase 2  


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0 : 1 7 Fe b 2 0 2 3  
 ( Pa ge 1 1  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 1 1  of 4 7  
C O N FI D E N TI A L  
 
o  Deter mi ne preli mi nar y a nti -t u mor efficac y ( C B R) f or Z N -c 5 w he n a d mi nistere d i n 
c o m bi nati o n wit h pal b ocicli b  
2. 2  Sec o n d ar y O bjecti ves   
2. 2. 1  
All C o h orts   
•  
Assess preli mi nar y efficac y of Z N -c 5 al o ne a n d i n c o m bi nati o n wit h pal b ocicli b b y O bj ecti ve 
Res p o nse Rate ( O R R), C B R, D urati o n of Res p o nse ( D O R), Pr o gressi o n -Free S ur vi val ( P F S) a n d 
O verall S ur vi val ( O S) usi n g Res p o nse E val uati o n Criteria i n S ol i d T u m ors ( R E CI S T v 1. 1) as 
assesse d b y i n vesti gat ors  
2. 2. 2  
M o n ot her a p y D ose Esc al ati o n a n d M o n ot her a p y P h ase 2   
•  
I n vesti gate t he safet y a n d t olera bilit y of Z N-c 5 as a m o n ot hera p y i n s u bj ects wit h E R p ositi ve, 
H E R 2 -ne gati ve a d va nce d  breast ca ncer  
2. 2. 3  
C o m bi n ati o n D ose Esc al ati o n a n d C o m bi n ati o n P h ase 2   
•  
I n vesti gate t he safet y a n d t olera bilit y of Z N-c 5 i n c o m bi nati o n wi t h pal b ocicli b i n s u bjects wit h E R 
p ositi ve, H E R 2 -ne gati ve a d va nce d breast ca ncer  
•  
C haracterize t he p har mac o ki netics ( P K ) of Z N -c 5 (a n d its p ote ntial meta b olites as a p plica ble) w he n 
gi ve n i n c o m bi nati o n wit h pal b ocicli b  
•  
C haracterize t he P K of pal b ocicli b w h e n gi ve n i n c o m bi nati o n wit h Z N -c 5  
2. 2. 4  
M o n ot her a p y E x p a nsi o n P h ase 1   
•  
I n vesti gate t he preli mi nar y a nti-t u m or efficac y ( C B R) f or Z N-c 5 as a m o n ot hera p y  
2. 2. 5  
M o n ot her a p y D ose Esc al ati o n a n d M o n ot her a p y E x p a nsi o n P h ase 1 a n d 
M o n ot her a p y P h ase 2   
•  
C haracterize t he P K of Z N -c 5 (a n d its p ote ntial meta b olites as a p plica ble) w he n gi ve n as oral 
m o n ot hera p y  
2. 3  Terti ar y/ E x pl o r at or y O bjecti ves  ( All C o h orts)  
•  
E val uate p har mac o d y na mic a n d pr o g n ostic bi o mar kers ass ociate d wit h disease pr o g n osis a n d/ or 
li keli h o o d of res p o nse t o Z N-c 5 
•  
Assess t he effect of Z N -c 5 o n t u m or’s a bilit y t o bi n d estra di ol as meas ure d b y u pta ke of 1 8F -
fl u or oestra di ol ( F E S) p ositr o n e missi o n t o m o gra p h y ( P E T) 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0 : 1 7 Fe b 2 0 2 3  
 ( Pa ge 1 2  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 1 2  of 4 7  
C O N FI D E N TI A L  
 
3.  S T U D Y D E SI G N   
3. 1  St u d y Desi g n   
T his is a P hase 1/ 2, o pe n -la bel, m ultice nter, d ose-escalati o n a n d e x pa nsi o n st u d y t o e val uate t he safet y, 
t olera bilit y, P K, a n d preli mi nar y efficac y of Z N-c 5 a d mi nistere d orall y  i n s u bjects wit h a d va nce d 
E R +/ H E R 2 -ne gati ve breast ca ncer, b ot h as m o n ot hera p y a n d i n c o m bi nati o n wit h pal b ocicli b (I B R A N C E® , 
Pfizer I nc.).  Refer  t o Fi g ure 1  a nd Fi g ure 2  f or a d diti o nal details. 
T his P hase 1/ 2 st u d y c o m prises t he f oll o wi n g parts:  
•  
M o n ot her a p y D ose Esc al ati o n : I n or der t o defi ne a n M T D  or t he R P 2 D ( defi ne d i n pr ot oc ol 
secti o n 6 .1 .3)  f or Z N-c 5 as  a si n gle a ge nt , the d ose escalati o n will f oll o w a sta n dar d 3 + 3 desi g n. At 
least 3 a n d u p t o 6 e val ua ble s u bjects will be e nr olle d f or eac h d ose c o h ort. Z N -c 5 will be 
a d mi nistere d orall y o nce dail y ( Q D) at se q ue ntiall y escalati n g d oses starti n g wit h 5 0 m g a n d 
p ote ntiall y u p t o 1 2 0 0 m g  (alter nati ve l y, t he t otal dail y d ose ma y be di vi de d b y 2 a n d a d mi nistere d 
e ver y t wel ve h o urs  [ BI D]) (pr ot oc ol s ecti o n 6 .1 . 2. 1), o n a 2 8 -da y c ycle (c o nti n u o us d osi n g) . D ose 
le vels a n d d osi n g fre q ue nc y ma y be a dj uste d d uri n g t he st u d y o n t he basis of e mer gi n g safet y a n d 
P K data. I nter me diate d ose le vels ma y be e val uate d. A d diti o nal s u bjects ca n be e nr olle d at a l o wer 
d ose le vel alrea d y dee me d well -t olerate d; t hese patie nts will be part of t he M o n ot hera p y E x pa nsi o n. 
•  
C o m bi n ati o n  D ose Esc al ati o n : D ose escalati o n i n c o m bi nati o n wit h pal b ocicli b will be i nitiate d at 
a Z N -c 5 d ose t hat is  dee m e d well -t olerate d i n t he M o n ot hera p y D ose Escalati o n a n d will pr ocee d 
wit h hi g her Z N -c 5 d oses, as t olerate d i n t he M o n ot hera p y D ose Escalati o n, b ase d o n sta n dar d r ules 
of 3 + 3 desi g n i n or der t o defi ne a n M T D/ R P 2 D f or Z N -c5  i n c o m bi nati o n wit h pal b ocicli b. D ose 
le vels a n d sc he d ule will f oll o w t he d ose le vels a n d sc he d ule per t he M o n ot hera p y D ose Escalati o n. 
T he d ose a n d sc he d ule of pal b ocicli b will be t he Re g ulat or y A ut h orit y’s a p pr o ve d d ose  a n d 
sc he d ule ( 1 2 5 m g oral l y [P O ] Q D × 2 1 da ys, f oll o we d b y 7 da ys off treat me nt) . A d diti o nal s u bjects 
ca n be e nr olle d at a l o wer d ose le vel alrea d y dee me d t olerate d ( bac kfill). At least 6 s u bjects will be 
treate d at t he M T D/ R P 2 D. T he s u bjects treate d i n t he C o m bi nati o n D ose Escalati o n ca n p ossi bl y 
c o u nt t o war ds t he f utilit y assess me nt sta ge accr ual ( C o m bi nati o n P hase 2). 
•  
M o n ot her a p y E x p a nsi o n : T o f urt her assess t he safet y , t olera bilit y, a n d preli mi nar y efficac y of 
Z N -c 5, t he d ose e x pa nsi o n wit h m o n ot hera p y will be i nitiate d at a d ose selecte d base d o n P K, 
safet y a n d a vaila ble bi o mar ker data fr o m t he M o n ot hera p y D ose Escalati o n. E x pa nsi o n at a s pecific 
d ose le vel will c o nti n ue u ntil a hi g her d ose has bee n dee me d well -t olerate d ( n o D L Ts i n 3 s u bjects 
or at m ost 1 D L T i n 6 s u bjects), at w hic h p oi nt e x pa nsi o n accr ual will s hift t o t he hi g her  d ose le vel.  
Efficac y i n t he M o n ot hera p y E x pa nsi o n will be deter mi ne d b y C B R. T he M o n ot hera p y E x pa nsi o n 
o verall will tar get bala nce d accr ual bet wee n t he 3 li nes of t hera p y ( 1 st, 2n d a n d 3 r d h or m o nal t hera p y 
li ne) acr oss all d ose le vels. 
•  
M o n ot her a p y P h ase 2 : T o esta blis h t he a p pr o priate d ose f or f urt her de vel o p me nt of Z N -c 5, 
a d diti o nal s u bjects will be e nr olle d t o f urt her assess t he safet y, t olera bilit y, a n d preli mi nar y efficac y 
of u p t o 3 d ose le vels of si n gle a ge nt Z N -c 5 ( w hic h ca n i ncl u de Q D or BI D d osi n g ). T he Z N-c 5 
d ose le vels will be selecte d base d o n a vaila ble safet y, P K, a nti -t u m or acti vit y a n d bi o mar ker data. 
T his M o n ot hera p y P hase  2 p orti o n will f oll o w a ra n d o mize d  (if 2 or m ore d oses), parallel c o h ort, 
n o n -c o m parati ve (esti mati o n) desi g n a n d u p t o 3 d ose le vels of Z N -c 5 will be assesse d.  
•  
C o m bi n ati o n P h ase 2 : F oll o wi n g t he deter mi nati o n of t he M T D/ R P 2 D f or Z N -c 5 i n c o m bi nati o n 
wit h pal b ocicli b, a d diti o nal s u bjects will be e nr olle d t o f urt her assess t he  safet y, t olera bilit y a n d 


 
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Protocol No. ZN-c5-001 
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preliminary efficacy of ZN-c5 in combination with palbociclib. ZN-c5 will be administered at the 
combination RP2D and potentially at a lower dose in combination with palbociclib. The lower 
ZN-c5 dose will be selected based on available safety, PK and biomarker data. Efficacy in the 
Combination Phase 2 portion will be determined by CBR. The Combination Phase 2 will target 
balanced accrual between the 2 lines of therapy (1st and 2nd hormonal therapy line) across dose 
levels.  The Combination Phase 2 portion will follow a randomized, parallel group, non-
comparative design, assuming the RP2D and the lower dose are investigated, or a single dose 
cohort, if only the RP2D is investigated. Each dose cohort will follow a Simon 2-stage design. 
Dose escalation will be determined by assessing DLTs during Cycle 1 (DLT assessment period). Single 
agent ZN-c5 and combination regimen dose escalation rules in Phase 1 are described in protocol sections 
6.1.3-6.1.5. 
Figure 1 ZN-c5-001 Phase 1 Monotherapy Dose Escalation, Expansion and Phase 2
  
 


 
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Figure 2 ZN-c5-001 Phase 1 Combination with Palbociclib Dose Escalation and Phase 2  
 
3.2 Randomization  
For Monotherapy Phase 2, up to 75 subjects will be enrolled per dose level using a randomized (if 2 or more 
doses), parallel cohort, non-comparative (estimation) design. 
The Combination Phase 2 portion will follow a randomized, parallel group, non-comparative design, 
assuming both the RP2D and the lower dose are investigated, or a single dose cohort, if only the RP2D is 
investigated. Approximately 56 subjects will be enrolled in each dose cohort. Each dose cohort will follow 
a Simon 2-stage design. 
3.3 Hypothesis Testing  
All statistical analyses will be descriptive in nature and no formal hypothesis testing will be performed. 
Phase 1 statistical methodology will be applied towards identification of the MTD and for Phase 2 towards 
estimation of anti-tumor activity. 
3.4 Interim Analysis  
Interim futility analyses will be conducted between stages during the Combination Phase 2. The guiding 
futility and promising criteria for the combination cohort are presented in Table 1. 
 
 
 
 
 


 
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Table 1 Sample Size Assumptions and Criteria for Simon’s Two-Stage Design  
 
CBR Assumptions 
2-Stage Sample Size 
Stage 1 Futility Criteria 
Poor 
Promising 
ZN-c5 
Combination 
 
 
1-sided 0.025 alpha level 
80% power 
 
+ Palbociclib 
50% 
70% 
51 evaluable subjects 
(approximately 56 total) 
≤ 10 of 19 (53%) 
3.5 Sample Size  
3.5.1 
Monotherapy Dose Escalation and Combination Dose Escalation  
The primary objective of this part of the study is to identify the MTD, if possible, or the RP2D of ZN-c5 as 
monotherapy and in combination with palbociclib, and to recommend dose(s) for evaluation in future 
clinical studies. Hence, the number of subjects in the cohorts has been based on the desire to obtain 
adequate tolerability, safety and PK and pharmacodynamics data while exposing as few subjects as possible 
to the investigational product and procedures. 
For the Monotherapy Dose Escalation phase of the study, cohorts of 3-6 evaluable subjects will be required. 
The total number of subjects will depend upon the number of dose escalations necessary, but it is estimated 
to be approximately 36 subjects. 
The Combination Dose Escalation with palbociclib will be initiated at a dose deemed well-tolerated in the 
Monotherapy Dose Escalation and proceed with higher ZN-c5 doses, as tolerated, based again on the 
standard rules of a 3+3 design (protocol section 6.1.4). The total number of subjects will depend upon the 
number of dose escalations necessary, but it is estimated to be approximately 40 subjects (including 
alternate dosing schedules, e.g., BID, and possible backfill). The subjects in the Combination Dose 
Escalation might also count towards the futility assessment stage accrual in the Combination Phase 2 
(protocol section 6.1.7, Combination Phase 2). 
3.5.2 
Monotherapy Expansion  
The Monotherapy Expansion will be initiated at a dose selected based on PK, safety and any available 
biomarker data from the ZN-c5 Monotherapy Dose Escalation at a specific dose level will continue until a 
higher dose has been deemed to be well-tolerated (no DLTs in 3 subjects or at most 1 DLT in 6 subjects in 
the Monotherapy Dose Escalation), at which point expansion accrual might shift to the higher dose level.  
The CBR as measured using RECIST v.1.1 will be assessed to provide preliminary anti-tumor activity 
evaluation in a subject population thought most likely to respond to ZN-c5. 
The Monotherapy Expansion overall will target balanced accrual between the 3 lines of therapy (1st, 2nd and 
3rd hormonal therapy line) across dose levels. The total cohort size necessary for futility has been estimated 
based on futility screening criteria targeting 10 evaluable subjects per line cohort at dose levels where any 
anti-tumor activity is demonstrated and providing an acceptable false negative risk of concluding that there 
is no activity if the true clinical benefit rate is at least 40%. 


 
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Subjects are evaluable for the CBR if they have at least 1 post baseline disease/tumor assessment (protocol 
section 9.3). CBR as measured using RECIST v.1.1 will be assessed to provide preliminary anti-tumor 
activity evaluation in a subject population thought most likely to respond to ZN-c5. Data from these cohorts 
will provide a preliminary assessment of anti-tumor activity based on CBR. 
The total number of subjects in all expansion cohorts will depend upon the number of dose escalations, but 
it is not estimated to exceed 45 subjects. 
3.5.3 
Monotherapy Phase 2  
Up to 3 dose levels with up to 75 subjects per dose level will be enrolled using a randomized (if 2 or more 
doses), parallel cohort, non-comparative (estimation) design. 
Efficacy in the Monotherapy Phase 2 will be assessed as in the Monotherapy Expansion and CBR outcomes 
in the Monotherapy Phase 2 will be combined with those from subjects in the Monotherapy Expansion arm 
who were treated with ZN-c5 as 2nd/3rd Line of treatment and dosed at the same ZN-c5 dose in the 
Monotherapy Expansion. The sample size is determined in order to estimate the CBR at each dose level 
with certain confidence before proceeding with a larger confirmatory study. Based on the targeted sample 
size, the precision for a 95% exact confidence interval around a hypothesized 40 – 50% CBR rate is ± 12% 
at each dose level studied. 
Historical estimates for the CBR rate specific to 2nd/3rd Line subjects (either post CDK4/6 inhibitor or not) 
are not readily available. The CBR range was estimated based on two studies, reporting a CBR rate for 
fulvestrant alone of 40% in 2nd Line or higher (PALOMA-3) and 56% CBR in 1st or 2nd Line (MONARCH-
2). The targeted precision will be adequately achieved within the specified range and it will increase further 
outside of the range, if the true CBR rate is further (higher or lower) from 50%. 
3.5.4 
Combination Phase 2  
The Combination Phase 2 portion follows a randomized, parallel group, non-comparative design, assuming 
both the RP2D and the lower dose are investigated, or a single dose cohort, if only the RP2D is 
investigated. Each dose cohort is independently powered (non-comparative) and follows a Simon 2-stage 
design. 
Approximately 56 subjects will be enrolled in each dose cohort. Subjects treated in the Combination Dose 
Escalation at lower doses can possibly also count towards the futility stage accrual, assuming the subjects 
are evaluable. The two dose cohorts evaluated in Phase 2 will not use the same subjects from lower dose 
cohorts in the Phase 1 Combination Dose Escalation phase; for example, ZN-c5 50 mg Combination Dose 
Escalation subjects may count for the 100 mg futility cohort in Phase 2, if that is selected as the lower dose 
cohort for the Phase 2 component but will not also count for the RP2D futility cohort, if a higher dose is 
selected as the RP2D. 
CBR as measured using RECIST v.1.1 will be assessed to provide preliminary anti-tumor activity 
evaluation in a subject population thought most likely to respond to ZN-c5. Subjects are evaluable for CBR 
if they have at least 1 post baseline disease/tumor assessment (protocol section 9.3). 
Sample size for each dose cohort is based on a Simon 2-stage design with 80% power at the 1-sided 2.5% 
alpha level to differentiate between 50% CBR (poor performance) and 70% CBR (promising performance). 
Fifty-one (51) evaluable subjects will be enrolled in two stages, with 19 subjects in Stage 1 and 32 subjects 
in Stage 2. The probability of early stopping is 68%. The Combination Phase 2 will target balanced accrual 
between the 2 lines of prior hormonal therapy (1st and 2nd hormonal therapy line) across dose levels. 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0 : 1 7 Fe b 2 0 2 3  
 ( Pa ge 1 7  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 1 7  of 4 7  
C O N FI D E N TI A L  
 
Sec o n d sta ge accr ual will be c o m plete d, ass u mi n g t hat Sta ge 1 f utilit y criteria are e xcee de d wit h at least 
1 1  s u bjects wit h C B R i n t he first 1 9 e val ua ble s u bjects, as o utli ne d i n Ta ble 1 . A n a p pr o xi mate 1 0 % l oss f or 
C B R e val ua bilit y has bee n ass u me d res ulti n g i n a sa m ple size of a p pr o xi matel y 5 6 s u bjects f or eac h c o h ort, 
res ulti n g i n a t otal sa m ple size of a p pr o xi matel y 1 1 2 s u bj ects f or t his trial sta ge. 
3. 6  St u d y P r oce d ures   
All  s u bj ects will be assesse d b y sc he d ule d cli nical, la b orat or y a n d ot her dia g n ostic assess me nts t hr o u g h o ut 
t he st u d y. All eff orts s h o ul d be ma de t o perf or m assess me nts as cl ose as p ossi ble t o t he sc he d ule d ti me  
p oi nts. Visit wi n d o ws are pr o vi de d bel o w i n  T a ble 2 . St u d y assess me nts are t o be perf or me d as f oll o ws: 
•  
Scree ni n g e val uati o ns are t o be perf or me d wit hi n 2 8  da ys pri or t o first st u d y dr u g d ose . 
•  
T he da y of first a d mi nistrati o n of st u d y dr u g will b e c o nsi dere d Da y 1 of st u d y.  
•  
C ycle 1 Da y 1, C ycle 1 Da y 2, C ycle 1 Da y 1 6 s h o ul d be c o n d ucte d o n t he da y of , t here is n o 
wi n d o w all o we d . C ycle 1 Da y 8 ma y be c o n d ucte d ± 1 da y , C ycle 1 Da y 1 5 ma y be c o n d ucte d ± 2  
da y s. 
•  
Da y 1 e val uati o ns f or C ycles  ≥ 2 ma y be c o n d ucte d  ± 4  da ys;  Da y 1 5 e val uati o ns f or C ycle  2 (o nl y 
f or s u bjects partici pati n g i n C o m bi nati o n T hera p y) ma y be c o n d ucte d  ±  2  da y s. I n t he C o m bi nati o n 
D ose Escalati o n a n d C o m bi nati o n P hase 2 wit h pal b ocicli b, t he wi n d o w f or t he Da y 1 visit f or 
s u bse q ue nt c ycles is o nl y + 4 da ys, si nce t here m ust al wa ys be at least a f ull 7 -da y off treat me nt 
rec o ver y peri o d f or pal b ocicli b bef ore starti n g t he ne xt 2 1-da y d osi n g c ycle . 
•  
T u m or assess me nts s h o ul d be perf or me d e ver y 8 wee ks ( ± 7 da ys) after C ycle 1  D ay 1 f or t he first 
2 4 wee ks. After 2 4 wee ks, sca ns ma y be perf or me d e ver y 1 2  wee ks ( 8 4  da ys)  ± 7  da ys, a n d at t he 
ti me of disc o nti n uati o n (if n ot perf or me d wit hi n t he last 4 wee ks  ± 7  da ys).  
•  
E n d of Treat me nt assess me nts s h o ul d be perf or me d wit hi n 7 da ys fr o m disc o nti n uati o n of st u d y 
dr u g.  
•  
Safet y f oll o w -u p assess me nts s h o ul d be perf or me d 3 0 da ys  ± 7  da ys after t he last a d mi nistrati o n of 
st u d y dr u g, a n d pri or t o t he start of ne w a ntica ncer treat me nt. 
•  
Disease assess me nt f oll o w -u p assess me nts s h o ul d be c o n d ucte d  e ver y 1 2  wee ks ( 8 4  da ys)  ± 7  da ys 
f or s u bjects wit h o ut disease pr o gressi o n ( P D ) at t he ti me of st u d y dr u g disc o nti n uati o n u ntil 
c o nfir mati o n of P D, i nitiati o n of t he first s u bse q ue nt a ntica ncer t hera p y, wit h dra wal of c o nse nt, 
deat h, l oss t o f oll o w -u p or u ntil t he st u d y is ter mi nate d , w hic he ver occ urs first. S ur vi val  f oll o w-u p 
s h o ul d be c o n d ucte d e ver y 1 2  wee ks ( 8 4  da ys)  ± 1 4  da ys  fr o m t he ti me disease pr o gressi o n is 
c o nfir me d or t he first s u bse q ue nt ne w breast ca ncer t hera p y is i nitiate d . 
3. 7  S c he d ule of Assess me nts   


 
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Table 2 Time and Events Schedule  
Study Phase 
Screening 
Cycle 1 
(28-day cycle) 
Cycles ≥ 2 
(28-day cycle) 
EOT 
30-day 
Safety 
Follow-up 
Disease 
Assessment 
Follow-up21 
(every 12 
weeks) 
Survival 
Follow-up22 
(every 12 
weeks) 
Cycle Day 
Day 
-28 
Day 
1 
Day 
2 
Day 
8 
Day 
15 
Day 
16 
Day 
1 
[Day 15* 
Cycle 2 
Combination only] 
 
 
 
 
Window (days) 
-28 to -1 
 
 
± 1 
± 2 
 
[± 423] 
[± 2] 
± 7 
± 7 
± 7 
± 14 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
Medication History1  
X 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination2 
X 
X 
 
X 
X 
 
X 
[X] 
X 
X 
 
 
ECOG Performance 
Status 
X 
X 
 
 
 
 
X 
[X] 
X 
X 
 
 
Vital Signs3 
X 
X 
 
X 
X 
 
X 
[X] 
X 
X 
 
 
Triplicate 12-lead 
ECG4 
X 
X 
[X] 
 
X 
[X] 
[X] 
 
X 
 
 
 
Adverse events/ 
Concomitant 
medications5 
[X] 
X 
[X] 
X 
X 
[X] 
X 
[X] 
X 
X 
 
 
Enrollment 
X 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X7 
X 
 
X 
X 
 
X 
[X] 
X 
X 
 
 
Chemistry 
X7 
X 
 
X 
X 
 
X 
[X] 
X 
X 
 
 
Coagulation8 
X7 
 
 
 
 
 
 
 
X 
 
 
 
Full Lipid Panel9 
 
[X] 
 
 
 
 
[X] 
 
 
 
 
 


 
Statistical Analysis Plan 
Protocol No. ZN-c5-001 
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Study Phase 
Screening 
Cycle 1 
(28-day cycle) 
Cycles ≥ 2 
(28-day cycle) 
EOT 
30-day 
Safety 
Follow-up 
Disease 
Assessment 
Follow-up21 
(every 12 
weeks) 
Survival 
Follow-up22 
(every 12 
weeks) 
Cycle Day 
Day 
-28 
Day 
1 
Day 
2 
Day 
8 
Day 
15 
Day 
16 
Day 
1 
[Day 15* 
Cycle 2 
Combination only] 
 
 
 
 
Window (days) 
-28 to -1 
 
 
± 1 
± 2 
 
[± 423] 
[± 2] 
± 7 
± 7 
± 7 
± 14 
Urinalysis10  
X7 
 
 
 
 
 
 
 
X 
 
 
 
Pregnancy Test11 
X 
X 
 
 
 
 
X 
 
X 
X 
 
 
PK12 
 
[X] 
[X] 
[X] 
[X] 
[X] 
[X] 
 
 
 
 
 
ZN-c5 pharmaco-
dynamic and 
exploratory 
biomarkers in blood13 
 
X 
 
 
 
 
X 
 
[X] 
 
[X] 
 
Tumor Biopsy14 
[X] 
 
 
 
 
 
[X] 
 
[X] 
 
[X] 
 
ESR1 Mutation15 
 
X 
 
 
 
 
X 
 
[X] 
 
[X] 
 
CT/MRI16 
X 
 
 
 
 
 
X 
 
X 
 
[X] 
 
4β-
hydroxycholesterol / 
cholesterol17 
 
X 
 
 
X 
 
X 
 
 
 
 
 
FES-PET18 
[X] 
 
 
 
 
 
[X] 
 
 
 
 
 
ZN-c5 oral dosing19 
 
X 
 
 
 
 
Palbociclib oral 
dosing (Combo 
only)20 
 
[X] 
 
 
 
 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 2 0  of 4 7 ) 
 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 2 0  of 4 7  
C O N FI D E N TI A L  
 
St u d y P h as e  
Scr e e ni n g  
C ycl e 1  
( 2 8-d a y c ycl e)  
C ycl es ≥ 2  
( 2 8-d a y c ycl e)  
E O T  
3 0 -d a y 
S af et y 
F oll o w -u p  
Dis e as e 
Ass ess m e nt 
F oll o w -u p 2 1 
( e v er y 1 2 
w e e ks)  
S ur vi v al 
F oll o w -u p 2 2 
( e v er y 1 2 
w e e ks)  
C ycl e D a y  
D a y  
-2 8  
D a y  
1  
D a y  
2  
D a y  
8  
D a y  
1 5  
D a y  
1 6  
D a y  
1  
[ D a y 1 5 * 
C ycl e 2 
C o m bi n ati o n o nl y]  
 
 
 
 
Wi n d o w ( d a ys)  
-2 8 t o -1  
 
 
± 1  
± 2  
 
[ ± 42 3] 
[ ± 2] 
± 7  
± 7  
± 7  
± 1 4  
S u bj ect D osi n g Di ar y 
Acc o u nt a bilit y a n d/ or 
Dis p e nsi n g 6 
 
X  
 
 
 
 
X  
 
X  
 
 
 
L T F U 2 2 
 
 
 
 
 
 
 
 
 
 
 
[ X] 
 
N otes: X = Re q uire d; [ X] = O nl y a p plica ble as per f o ot n ote as i n dicate d b y t he Assess me nt  
C ycle 1 Da y 1 safet y la b sa m ples, p h ysical e xa mi nati o n, E C O G stat us a n d pre g na nc y test ma y be assesse d u p t o 3 da ys pri or t o t he Da y 1 visit. O n 
s u bse q ue nt visits t hr o u g h o ut t he st u d y, t hese pr oce d ures/assess me nts are all o we d t o be perf or me d wit hi n 1 da y pri or t o t he pla n ne d visit.  
C ycle 1 Da ys 2 a n d 1 6 are o nl y re q uire d f or s u bj ects partici pati n g i n t he P hase 1 parts of t he pr ot oc ol.  
* C ycle 2 Da y 1 5 visit –  o nl y f or  s u bjects partici pati n g i n C o m bi nati o n T hera p y ( C o m bi nati o n D ose Escalati o n a n d P hase 2)  
Please refer t o Secti o n 8  f or details o n c ha n ges o n data c ollecti o n after t he s pecific c ut-off date.  
 
1.  Me dical hist or y i ncl u des si g nifica nt past me dical e ve nts (e. g., pri or h os pitalizati o ns or s ur geries), a re vie w of t he disease  u n der st u d y, 
pri or a nti -ca ncer t hera pies, a n d a n y c o nc urre nt me dical ill nesses.  
2.  Scree ni n g a n d E n d of Treat me nt P h ysical E xa mi nati o ns ( P E) will be a c o m plete P E. Be gi n ni n g at C 1 D 1, a m o difie d p h ysical e xa mi nati o n 
ma y be perf or me d. Wei g ht ( wit h o ut s h oes) s h o ul d be meas ure d at eac h P E. Hei g ht ( wit h o ut s h oes)  is meas ure d at Scree ni n g o nl y. 
3.  C 1 D 1 Vital Si g ns will be ta ke n wit hi n 1 5 mi n pre -Z N -c 5 d ose a n d 2 a n d 4 h o urs p ost -d ose ( P hase 1) or pre -d ose a n d 2 h o urs p ost -d ose 
( P hase 2); vital si g ns will be ta ke n pre-d ose o nl y at all s u bse q ue nt visits. O x y ge n sat urati o n will be teste d wit h a p ulse o xi meter.  
4.  Resti n g, se mi rec u m be nt tri plicate E C Gs will be c ollecte d at a n y ti me d uri n g Scree ni n g wi n d o w, Da y 1 of e ver y ot her c ycle (al ter nati n g 
c ycles) starti n g wit h C ycle 2 (at pre -d ose), a n d at E O T. I n P hase 1, tri plicate E C Gs will be c ollecte d o n C 1 D 1 a n d C 1 D 1 5 at pre -d ose, 8 
h o urs, a n d 2 4 h o urs p ost -d ose ( pre -d ose o n C 1 D 2 a n d C 1 D 1 6). I n P hase 2, tri plicate E C Gs will be c ollecte d o n C 1 D 1 a n d C 1 D 1 5 at pre -
d ose a n d 2 h o urs p ost -d ose. E C Gs s h o ul d prefera bl y be c ollecte d pri or  t o P K ( or a n y ot her bl o o d dra w) if t he y are t o be c ollecte d at t he 
sa me n o mi nal ti me p oi nt.  E C Gs s h o ul d be c ollecte d o ver a 5 mi n ute wi n d o w at eac h ti me p oi nt. 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 2 1  of 4 7 ) 
 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 2 1  of 4 7  
C O N FI D E N TI A L  
 
5.  A Es will be assesse d usi n g N CI C T C A E ( v 4. 0 3) criteria. S u bjects will als o ret ur n t o cli nic at  3 0 -da ys ( ± 7 da ys) p ost last I P d ose ( b ut 
pri or t o i nitiati o n of s u bse q ue nt breast ca ncer t hera p y) t o assess A Es a n d S A Es. At Scree ni n g, all me dicati o ns ta ke n u p t o 3 0  da ys pri or t o 
Scree ni n g will be d oc u me nte d i n t he e C R F.  
6.  S u bj ects will be gi ve n a S u bj ec t Diar y o n w hic h t he y will rec or d dates/ti mes of st u d y dr u g a d mi nistrati o n. C o m plia nce wit h st u d y dr u g(s) 
will be assesse d a n d re vie we d d uri n g visits.  
7.  Scree ni n g c he mistr y, he mat ol o g y, c oa g ulati o n, a n d uri nal ysis s h o ul d be c ollecte d wit hi n 7 da ys of C 1 D 1.  
8.  C oa g ulati o n assess me nt i ncl u des P T/I N R, a P T T.  
9.  A n o n -fasti n g f ull li pi d pa nel will be perf or me d o n C 1 D 1, C 3 D 1 (c oi nci di n g wit h t he first o n-st u d y t u m or assess me nt after 8 wee ks) a n d 
C 7 D 1 ( 6 m o nt hs i nt o t he st u d y). T his will n ot be c ollecte d i n t he M o n ot hera p y P hase 2.  
1 0.  Uri nal ysis assess me nt i ncl u des vis ual i ns pecti o n, micr osc o pic e xa mi nati o n, a n d di pstic k test f or p H, pr otei n, gl uc ose, W B C, b ilir u bi n, a n d 
bl o o d.  
1 1.  Ser u m pre g na nc y testi n g will be c o n d ucte d at Scree ni n g ( wit hi n ≤ 7 da ys of C 1 D 1). Ser u m or uri ne p re g na nc y tests t hereafter will be d o ne 
o n Da y 1 of e ver y c ycle f or all pre me n o pa usal a n d peri me n o pa usal fe male s u bj ects of c hil d beari n g p ote ntial, i ncl u di n g E O T a n d  t he 
Safet y F oll o w -u p Visit.  
1 2.  Plas ma sa m ples f or P K a nal ysis of Z N -c 5 ( ha vi n g bee n a d mi nister e d wit h o ut f o o d [at least 1 h o ur bef ore a n d 2 h o urs after a meal]) a n d of 
pal b ocicli b ( ha vi n g bee n a d mi nistere d wit h f o o d) will be c ollecte d relati ve t o i n gesti o n of eac h dr u g as per Pr ot oc ol T a ble 6 a n d Ta ble 7.  
Re gar di n g t he P K sa m pli n g f or Z N -c 5 if a d mi nistere d t wice dail y ( BI D), a sa m ple at 1 2 h o urs p ost m or ni n g d ose a n d i m me diatel y 
prece di n g t he sec o n d dail y d ose ma y als o be c ollecte d ( o pti o nal).  N ote:  If t he o pti o nal, O n -Treat me nt t u m or bi o ps y is perf or me d, a n 
a d diti o nal P K sa m ple s h o ul d be c ollect e d at t hat ti me.   
1 3.  W h ole bl o o d, ser u m a n d/ or plas ma will be c ollecte d f or e x pl orat or y bi o mar kers at C 1 D 1, C 2 D 1, a n d at ti me of disease pr o gressi o n.  
1 4.  T u m or bi o ps y:  At baseli ne, de n o v o bi o ps y of a n y a me na ble site of disease (at i n vesti gat or’s discreti o n). A d diti o nal t u m or bi o ps y at 
C 2 D 1 or a n y ti me be y o n d ma y als o be o btai ne d. T he o n -treat me nt bi o ps y s h o ul d be o btai ne d 2 –  4 h o urs after t he s u bj ect has ta ke n t he 
Z N -c 5 d ose t hat da y. S u bj ects will als o ha ve t he o pti o n t o u n der g o a bi o ps y of a lesi o n at t he ti me of disease pr o gressi o n. Sa m ples will be 
c ollecte d, la belle d, st ore d a n d s hi p pe d as detaile d i n t he la b orat or y ma n ual. A n y resi d ual t u m or re mai ni n g after a nal ysis ma y  be use d f or 
e x pl orat or y researc h i nt o fact ors t hat ma y i nfl ue nce de vel o p me nt of breast ca ncer a n d/ or res p o nse t o Z N -c 5. All t u m or bi o psies are 
o pti o nal f or all s u bjects partici pati n g d uri n g t he st u d y.  Bi o psies m ust n ot be ta ke n fr o m tar get lesi o ns use d t o assess a nti -t u m or efficac y, if 
p ossi ble. If s ufficie nt t u m or material is a vaila ble, pa rt of t he t u m or bi o ps y at C 2 D 1 will be use d f or deter mi nati o n of Z N-c 5 tiss ue 
c o nce ntrati o n.  If a bi o ps y is o btai ne d o n C 2 D 1 or be y o n d, a plas ma P K sa m ple s h o ul d als o be c ollecte d, as cl ose as p ossi ble,  wit hi n 2 
h o urs pri or t o t he bi o ps y.  
1 5.  A bl o o d sa m ple f or t he assess me nt of E S R 1 m utati o ns will be dra w n at C 1 D 1, C 2 D 1, a n d at ti me of pr o gressi o n.  
1 6.  T u m or e val uati o n b y C T/ M RI or a p plica ble sca n will be perf or me d d uri n g Scree ni n g ( wit hi n 2 8 da ys of C ycle 1 Da y 1) a n d e ver y 8 wee ks 
( ± 7 da ys) after C 1 D 1 f or t he first 2 4 wee ks. After 2 4 wee ks, sca ns ma y be perf or me d e ver y 1 2 wee ks ( ± 7 da ys). T he sa me ra di o gra p hic 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 2 2  of 4 7 ) 
 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 2 2  of 4 7  
C O N FI D E N TI A L  
 
pr oce d ure use d t o defi ne meas ura ble lesi o ns m ust be use d t hr o u g h o ut t he st u d y f or eac h s u bject. A p plica ble sca ns t o be d o ne a t E O T visit 
if n ot d o ne withi n t he pre vi o us 4 wee ks.  
1 7.  Plas ma sa m ples f or 4 β -h y dr o x yc h olester ol a n d c h olester ol will be c ollecte d pre -d ose o n C 1 D 1, C 1 D 1 5, a n d pre -d ose o n Da y 1 of C ycles 
2 -4 of t he M o n ot hera p y D ose Escalati o n a n d E x pa nsi o n.  
1 8.  A F E S -P E T sca n ( o pti o nal) s h o ul d be c o n d ucte d at Scree ni n g a n d at least after 1 m o nt h of treat me nt ( prefera bl y wit hi n t he first 2 m o nt hs, 
i n C ycle 2). 
1 9.  Be gi n ni n g o n C 1 D 1, s u bjects will ta ke Z N -c 5 o nce dail y (alter nati vel y, t his t otal dail y d ose ma y be di vi de d b y 2 a n d a d mi nistere d BI D 
[e ver y 1 2 h o urs]).  Z N-c 5 d osi n g a n d a d mi nistrati o n as per assi g ne d c o h ort (see Secti o n 6. 1. 2. 1).  
2 0.  I n P hase 1, be gi n ni n g o n C 1 D 1, s u bjects i n t he c o m bi nati o n treat me nt c o h orts will ta ke pal b ocicli b at t he la bel i n dicate d d ose of 1 2 5 m g 
orall y o nce dail y ( 2 h o urs after t he  Z N -c 5 d ose was ta ke n) f or 2 1 c o nsec uti ve da ys f oll o we d b y 7 da ys off treat me nt ( 1 c ycle of treat me nt 
= 2 8 da ys) (see Secti o n 6. 1. 2. 2). I n P hase 2, s u bjects i n t he c o m bi nati o n treat me nt c o h orts will ta ke pal b ocicli b at t he la be l i n dicate d d ose 
of 1 2 5 m g or all y o nce dail y (at t he sa me ti me t he Z N -c 5 d ose is ta ke n) f or 2 1 c o nsec uti ve da ys f oll o we d b y 7 da ys off treat me nt ( 1 c ycle 
of treat me nt = 2 8 da ys).  
2 1.  Disease Assess me nt F oll o w -u p Visit: S u bjects wit h o ut pr o gressi o n of disease ( P D) at t he ti me of st u d y dr u g  disc o nti n uati o n will c o nti n ue 
t o u n der g o disease e val uati o ns e ver y 1 2 wee ks ± 7 da ys u ntil c o nfir mati o n of P D, i nitiati o n of t he first s u bse q ue nt ca ncer t hera p y, 
wit h dra wal of c o nse nt, deat h, l oss t o f oll o w -u p, or u ntil t he st u d y is ter mi nate d.  O nce a s u bject has c o nfir mati o n of P D or has i nitiate d 
s u bse q ue nt ca ncer t hera p y, w hic he ver occ urs first, disease f oll o w-u p will disc o nti n ue.  
2 2.  L o n g -ter m F oll o w-u p ( L T F U) –  S u bjects will be c o ntacte d e ver y 3 m o nt hs ( p h o ne or me dical rec or ds) f or s ur vi val stat us a n d c ollecti o n of 
s u bse q ue nt breast ca ncer treat me nts. 
2 3.  I n t he C o m bi nati o n D ose Escalati o n a n d C o m bi nati o n P hase 2 wit h pal b ocicli b, t he wi n d o w f or t he Da y 1 visit f or s u bse q ue nt c ycles is 
o nl y + 4 da ys, si nce t here m ust al wa ys be at least a f ull 7 -da y off treat me nt rec o ver y peri o d f or pal b ocicli b bef ore starti n g t he ne xt 2 1 -d a y 
d osi n g c ycle.  
 


 
Statistical Analysis Plan 
Protocol No. ZN-c5-001 
Revision 00: 17Feb2023 
 (Page 23 of 47) 
 
DOC.ST.101.04-01 Rev 00 
Page 23 of 47 
CONFIDENTIAL 
 
4. DATA AND ANALYTICAL QUALITY ASSURANCE  
The overall quality assurance procedures for the study data, statistical programming and analyses are 
described in Everest’s Standard Operating Procedures. Detailed data management procedures are 
documented in the Data Management Plan, Data Validation Check Specifications, and Safety Data Review 
Plan. Detailed statistical and programming quality control and quality assurance procedures are documented 
in the Statistical Analysis and Programming QC/QA Plan. 
The study endpoints and analytic approaches are both prospectively defined and documented in the protocol 
and in this SAP. The SAP will be finalized prior to the database lock and data analysis. 
5. ANALYSIS POPULATIONS  
5.1 Full Analysis Set (FAS)  
The FAS includes all subjects who receive ≥ 1 dose of study drug. This analysis set will be used for subject 
characteristics and efficacy endpoints. 
5.2 Tumor Response Evaluable Set  
The Tumor Response Evaluable Set includes all subjects in the FAS with at least 1 evaluable post-baseline 
response assessment using RECIST 1.1. Subjects who develop PD, intolerable toxicity or death or who 
discontinue study treatment prior to the first post-baseline assessment will also be considered evaluable and 
will be classified as non-responders. This analysis set will be used for futility assessment in the Phase 2 
combination (if that part is executed) as well as a supportive population in the analysis of efficacy endpoints 
involving tumor response data.  Objective response rate will be assessed in the subset of subjects with 
measurable disease at baseline. 
5.3 Safety Analysis Set  
The Safety Analysis Set for this study will be the same as FAS. This analysis set will be used for safety 
endpoints, study treatment administration and post-study therapy. 
5.4 DLT-Evaluable Analysis Set  
The DLT-Evaluable Analysis Set includes all subjects in the Safety Analysis Set who take ≥ 24/28 (≥ 85%) 
scheduled Cycle 1 doses of ZN-c5 (or less, if for reasons due to DLTs) and/or the cumulative dose of 
palbociclib was ≥ 85% in Cycle 1 (or less, if for reasons due to DLTs) and underwent all treatment and 
safety procedures through Day 28 or experienced a DLT prior to Day 28. Determination of the MTD will be 
in the DLT-Evaluable Analysis Set. 
5.5 Pharmacodynamic Analysis Set  
The Pharmacodynamic Analysis Set consists of all subjects in the FAS who have the necessary baseline and 
on-study measurements to provide interpretable results for the pharmacodynamic parameters of interest. 


 
Statistical Analysis Plan 
Protocol No. ZN-c5-001 
Revision 00: 17Feb2023 
 (Page 24 of 47) 
 
DOC.ST.101.04-01 Rev 00 
Page 24 of 47 
CONFIDENTIAL 
 
5.6 Pharmacokinetic Analysis Set  
The Pharmacokinetic Analysis Set consists of all subjects in the FAS who have on-study measurements to 
provide interpretable results for the pharmacokinetic parameters of interest and who do not violate the 
protocol (i.e., not considered an important protocol deviation) in a way that may invalidate or bias the 
results. 
6. STATISTICAL METHODS  
6.1 General Data Handling Rules and Definitions  
All data collected on case report forms will be provided in listings, except data collected only for 
confirmation of study entry criteria and for study administrative purposes. If any enrolled subject is found 
not having valid documented informed consent, that subject’s data will be excluded from the report, except 
as necessary to document the error. 
All analyses will be conducted using SAS version 9.4 or later. 
Summary tables for continuous variables will include the following statistics: n (sample size), mean, 
standard deviation, 95% CIs on the mean (where applicable), median, minimum and maximum. Summary 
tables for categorical variables will include: n, proportion and 95% CIs on the proportion (where 
applicable). Unless otherwise indicated, 95% CIs for binary variables will be calculated using the binomial 
distribution (exact method) and will be 2-sided. 
Endpoints will be summarized by relevant study part (escalation, expansion, Phase 2), actual dose level 
received (on the first day of treatment), therapy (mono or combination), analysis set and time point. As 
appropriate, changes from Baseline to each subsequent timepoint will be described and summarized. 
Similarly, as appropriate, the best/worst change from Baseline during the study will also be described and 
summarized. 
The Baseline value will be the last (most recent) pre-treatment value. If there is a significant degree of non-
normality, analyses may be performed on log-transformed data or nonparametric tests may be applied, as 
appropriate. 
Missing data will be maintained as missing unless specified otherwise. For variables where missing data is 
imputed, the analysis dataset will contain one variable with the imputed value and the original variable with 
missing maintained as missing. 
6.2 Subject Disposition  
The number of subjects in each analysis set and the reasons for exclusion will be summarized for all 
subjects. In addition, the number of subjects who discontinued study treatment and study will also be 
summarized, along with the reasons for treatment and study discontinuation. Subject eligibility and 
enrollment details (study phase, cohort, reason subject was not enrolled, assigned dose/frequency) will be 
listed. 
6.3 
Protocol Deviations  
Important protocol deviations will be summarized by category for all subjects. 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 2 5  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 2 5  of 4 7  
C O N FI D E N TI A L  
 
6. 4  De m o gr a p hic s a n d B aseli ne C h ar acteristics  
De m o gra p hic a n d Baseli ne c haracteristics will be s u m marize d a n d liste d i n b y -s u bj ect listi n gs i n t he F A S 
( b y d ose le vel i n M o n ot hera p y D ose Escalati o n, b y d ose c o hort i n M o n ot hera p y  D ose E x pa nsi o n , 
C o m bi nati o n D ose Escalati o n , a n d P hase 2).  
T he f oll o wi n g de m o gra p hics, baseli ne c haracteristics, me dical hist or y a n d pri or ca ncer treat me nts will be 
s u m marize d: 
•  
De m o gra p hics varia bles i ncl u de a ge at c o nse nt, se x at birt h, c hil d beari n g p ote ntial (f or fe males) , 
race a n d et h nicit y. A ge gr o u p ( 1 8 -6 4, 6 5 -7 4, 7 5 -8 4, ≥ 8 5) will be deri ve d base d o n a ge.  
•  
Baseli ne c haracteristics i ncl u de E C O G P S, hei g ht a n d wei g ht , meas ura ble disease ( Yes/ N o, defi ne d 
as ha vi n g a n y tar get lesi o n i de ntifie d  at baseli ne), E S R1  stat us at baseli ne ( Wil d T y pe , M uta nt , N ot 
Assesse d ) a n d s u bcate g ories ( S N V, C N V, I nserti o n/ Deleti o n) as well as Pri or C D K 4/ 6 i n hi bit or f or 
a d va nce d/ metastatic disease ( a be macicli b, pal b ocicli b, or ri b ocicli b , Yes/ N o).  
•  
Me dical hist or y i ncl u des dia g n oses or s y m pt o ms e ntere d o n t he Me dical Hist or y f or m. Ver b ati m 
descri pti o ns of dia g n oses or s y m pt o ms will be c o de d usi n g t he Me dical Dicti o nar y f or Re g ulat or y 
Acti vities ( Me d D R A versi o n 2 5. 0  or later) . 
•  
Ca ncer hist or y i ncl u des  sta ge at i nitial dia g n osis, met h o d of dia g n osis, estr o ge n rece pt or stat us a n d 
res ult ( %) at dia g n osis, pr o gester o ne rece pt or stat us at dia g n osis, H E R 2 stat us at dia g n osis, H E R 2 
e val uati o n met h o d at dia g n osis , hist ol o g y,  a n d t he m ost rece nt t u m or sta ge, estr o ge n rece pt or stat us 
a n d res ult  ( %), pr o gester o ne rece pt or stat us, H E R 2 stat us a n d H E R 2 e val uati o n met h o d a n d sites of 
metastatic disease . 
•  
Ti me si nce i nitial dia g n osis i n m o nt hs will be deri ve d, defi ne d as: ( date of first treat me nt –  date of 
i nitial dia g n osis + 1) / 3 0. 4 3 7 5. F or t he p ur p oses of calc ulati o n, missi n g da y of dia g n osis will be 
i m p ute d as 1; missi n g m o nt h of dia g n osis will be i m p ute d as J a n uar y; n o i m p utati o n will be ma de 
f or missi n g year. 
•  
Pri or ca ncer treat me nts i ncl u de ra di ot hera pies e ntere d o n t he pri or ca ncer t hera pies  f or m, pri or 
ca ncer s ur geries e ntere d o n t he s ur gical hist or y  f or m a n d pri or s yste mic ca ncer treat me nts (i nte nt, 
re gi me n, start a n d e n d dates, best res p o nse, reas o n f or disc o nti n uati o n, date of rela pse/ pr o gressi o n 
o n re gi me n ) e ntere d o n t he pri or ca ncer  t hera pies f o r m. 
Pri or ca ncer treat me nts will be s u m marize d as f oll o ws:  
•  
Pri or ra di ot hera p y, occ urre nce ( Yes/ N o)  will be s u m marize d cate g oricall y f or eac h  i nte nt (a dj u va nt, 
a d va nce d/ metastatic, ne oa dj u va nt, ot her) . 
•  
Pri or s yste mic t hera p y occ urre nce ( Yes/ N o) wi ll be s u m marize d cate g oricall y f or eac h i nte nt 
(a dj u va nt, a d va nce d/ metastatic disease, ne oa dj u va nt, ot her), a n d n u m ber of pri or s yste mic re gi me ns 
( 0, 1, 2, ≥ 3), n u m ber of pri or s yste mic re gi me ns f or a d va nce d/ metastatic disease ( 0, 1, 2, ≥ 3) 
i ncl u di n g t he t y pes of t hera p y:  pri or e n d ocri ne t hera p y, pri or f ul vestra nt, pri or c he m ot hera p y, pri or 
C D K 4/ 6i, a n d pri or PI 3 Ki . 
•  
N u m ber of pri or s yste mic re gi me ns f or a d va nce d/ metastatic disease will be prese nte d or di nall y.  
•  
Pri or s ur gical pr oce d ure occ urre nce ( Yes/ N o) w ill be s u m marize d cate g oricall y. 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 2 6  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 2 6  of 4 7  
C O N FI D E N TI A L  
 
6. 5  Effic ac y   
6. 5. 1  
St u d y D a y a n d Visit  Wi n d o w Defi niti o ns   
St u d y da y is defi ne d as t he date of assess me nt –  first date of treat me nt e x p os ure + 1 f or assess me nts t hat 
occ ur o n or after t he first date of treat me nt e x p os ure; st u d y da y is defi ne d as t he date of assess me nt –  first 
date of treat me nt e x p os ure  f or assess me nts t hat occ ur pri or t o t he first date of treat me nt e x p os ure. 
T u m or e val uati o ns pri or t o first d ose are assi g ne d as baseli ne.  P ost d osi n g e val uati o ns /res p o nses d uri n g t he 
treat me nt peri o d will se q ue ntiall y assi g ne d base d o n c hr o n ol o g y as T u m or Assess me nt 1, T u m or 
Assess me nt 2, etc.  i ncl u di n g a n y e n d of treat me nt assess me nts.  Assess me nts c ollecte d d uri n g f oll o w -u p 
will be si milarl y assi g ne d base d o n c hr o n ol o g y as F oll o w -U p Assess me nt 1, F oll o w -U p Assess me nt 2, etc.  
6. 5. 2  
T u m or a n d Res p o nse E v al u ati o ns   
T u m or a n d res p o nse e val uati o ns, P F S a n d D O R a nal yses will be base d o n t he F A S a n d re peate d o n t he 
T u m or Res p o nse E val ua ble Set.  
T u m or a n d res p o nse e val uati o ns, P F S  a n d d urati o n of res p o n se a nal yses will be base d o n t he F A S a n d 
T u m or Res p o nse E val ua ble S u bj ects p o p ulati o n. Data will be s u m marize d b y d ose le vel i n D ose Escalati o n 
a n d b y c o h ort i n D ose E x pa nsi o n, a n d liste d i n b y -su bject listi n gs i n t he T u m or Res p o nse E val ua ble 
S u bj ects p o p u lati o n.  
Cli nic al Be nefit R ate ( C B R)  is t he pri mar y e n d p oi nt f or t he M o n ot hera p y P hase 2 a n d C o m bi nati o n P hase 
2  a n d a sec o n dar y e n d p oi nt f or t he M o n ot hera p y Escalati o n P hase 1, M o n ot hera p y E x pa nsi o n  P hase 1 , a n d 
C o m bi nati o n Escalati o n P hase 1 . It is defi ne d as t he pr o p orti o n of s u bjects w h o ha ve at least o ne c o nfir me d 
res p o nse of C R or P R ( o nl y if s u bject has meas ura ble disease), or S D ≥ 2 4 wee ks  ( or n o n-C R/ n o n -P D ≥ 2 4 
wee ks f or s u bjects wit h n o n-meas ura ble disease)  pri or t o a n y e vide nce of pr o gres si o n. S u bjects w h o 
de vel o p P D, i nt olera ble t o xicit y or deat h  or w h o disc o nti n ue st u d y treat me nt  pri or t o t he first p ost -Baseli ne 
assess me nt will be classifie d as n o n -res p o n ders. 
A c o nfir me d res p o nse of C R/ P R mea ns t hat a res p o nse of C R/ P R is rec or de d at o n e visit a n d c o nfir me d b y 
re peat i ma gi n g at least 4 wee ks later wit h n o e vi de nce of pr o gressi o n bet wee n c o nfir mati o n visits.  
I n case of S D, meas ure me nts s h o ul d ha ve met t he S D criteria f or a mi ni m u m i nter val of 8  wee ks ( 8 wee ks 
mi n us t he 7 -da y visit wi n d o w ) f oll o wi n g t he start of treat me nt. Si milarl y, f or n o n -meas ura ble disease, n o n -
C R/ n o n -P D s h o ul d be mai ntai ne d f or a mi ni m u m i nter val of 8  wee ks ( 8 wee ks mi n us t he 7-da y visit 
wi n d o w) f oll o wi n g t he start of treat me nt.  
Best o ver all res p o nse  ( B O R) will be deri ve d f or eac h s u bj ect, base d o n e val uati o n of res p o nse at eac h 
t u m or assess me nt visit per i n vesti gat or assess me nt usi n g Res p o nse E val uati o n Criteria i n S oli d T u m ors 
(R E CI S T ) v ersi o n 1. 1  a n d re p orte d i n t he f oll o wi n g cate g ories:  
•  
C o m plete Res p o nse ( C R ) 
•  
Partial Res p o nse ( P R ) 
•  
Sta ble Disease ( S D ) 
o  S D  ≥ 2 4 wee ks i n d urati o n  
o  8 wee ks < S D  < 2 4 wee ks i n d urati o n  
•  
N o n -C R/ n o n -P D  
•  
Pr o gressi ve Disease ( P D ) 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 2 7  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 2 7  of 4 7  
C O N FI D E N TI A L  
 
•  
N o n -Res p o n ders ( N R)  
•  
N ot E val ua ble ( N E ) 
C o nfir mati o n of P R a n d C R res p o nses will f oll o w t he c o nfir mati o n pr ocess  c o ntai ne d i n t he f oll o wi n g ta ble 
w here t he best t w o c o nsec uti ve ti me p oi nts are c o nsi dere d.  
 E arlier B est Res p o nse  
( n ot yet c o nfir me d) 
L ater Best Res p o nse  
(c o nfir m ati o n) 
Best O ver all Res p o nse  
C R  
C R  
C R  
C R  
N o C R or missi n g  
S D  
P R  
C R or P R  
P R  
P R  
S D or P D  or missi n g  
S D  
S D  
N A  –  n o c o nfir mati o n nee de d  
S D  
P D  
N A  
P D  
 
Res p o nses rec or de d after i nitiati o n of a nti -t u m or t hera p y are n ot use d ( n ot e val ua ble) n or are P D res p o nses 
after a misse d visit [ > 1 2 6 da ys  has ela pse d si nce t he last i ma ge -base d res p o nse assess me nt ( or first d ose 
date if n o pri or res p o nse) ] u p t o 2 4 wee ks after C 1 D 1 . If t he pre vi o us e val ua ble i ma ge-base d res p o nse 
assess me nt is m ore t ha n 2 4 wee ks after C 1 D 1, a  P D res p o nse  is c o nsi dere d t o be " misse d” if m ore t ha n 2 6 
wee ks ( 1 8 2 da ys) has ela pse d .  I n t he case of sta ble disease, meas ure me nts s h o ul d ha ve met t he sta ble 
disease criteria f or a mi ni m u m i nter val of 8 wee ks ( 8 wee ks mi n us t he 7 -da y visit wi n d o w  = 4 9 da ys ) 
f oll o wi n g t he start of treat me nt. 
D urati o n of S D  f or s u bj ects wit h best o verall res p o nse = S D is defi ne d a s t he ti me fr o m t he da y of first 
st u d y treat me nt t o t he start of ra di ol o gic disease pr o gressi o n or deat h. If t he s u bject d oes n ot ha ve a 
ra di ol o gical disease pr o gressi o n or deat h, t he d urati o n of S D is defi ne d as t he ti me fr o m t he da y of first 
st u d y treat me nt t o t he date of t he last S D assess me nt . T a ki n g sc he d uli n g of i ma gi n g i nt o acc o u nt, a 1 wee k 
wi n d o w will be utilize d s uc h t hat t he t hres h ol d f or 2 4 wee ks wi ll be 2 3 * 7 = 1 6 1 [res p o nse date –  first d ose 
date + 1 ≥ 1 6 1].  
W he n t he i n vesti gat or is i n d o u bt as t o w het her pr o gressi o n of disease has occ urre d a n d t heref ore reassesses 
t he s u bject at a later date, t he date of t he i nitial sca n s h o ul d be declare d as t he date of pr o gressi o n if t he 
re peat sca ns c o nfir m pr o gressi o n. 
O bjecti ve Res p o nse R ate ( O R R)  is a sec o n dar y e n d p oi nt f or all c o h orts. It is defi ne d as t he perce nta ge of 
s u bj ects wit h meas ura ble disease w h o ha ve at least o ne c o nfir me d res p o nse of C R or P R pri or t o a n y 
e vi de nce of pr o gressi o n (as defi ne d b y R E CI S T  v 1. 1).  S u bj ects w h o de vel o p P D, i nt olera ble t o xicit y or 
deat h or w h o disc o nti n ue st u d y treat me nt pri or t o t he first p ost -Baseli ne assess me nt will be classifie d as 
n o n -res p o n ders. 
Data o btai ne d u p u ntil  pr o gressi o n, or last e val ua ble assess me nt i n t he a bse nce of pr o gressi o n, will be 
i ncl u de d i n t he assess me nt of O R R. H o we ver, a n y c o m plete res p o nse or partial res p o nse w hic h occ urre d 
after a f urt her a ntica ncer t hera p y was recei ve d will n ot be i ncl u de d i n n u merat or of t he O R R calc ulati o n.  
T he c ha n ge fr o m Baseli ne a n d perce nt c ha n ge fr o m B aseli ne will be calc ulate d f or eac h res p o nse 
assess me nt f or t he s u m of tar get lesi o n meas ure me nts. T he best ( mi ni m u m) perce nt c ha n ge fr o m Baseli ne 
will be i de ntifie d f or eac h s u bj ect. 
F or f urt her details re gar di n g res p o nse criteria, refer t o pr ot oc ol  A p pe n di x 2 –  T u m or Res p o nse Criteria.  


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 2 8  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 2 8  of 4 7  
C O N FI D E N TI A L  
 
Best o verall res p o nse will be s u m marize d cate g oricall y base d o n t he f o ur R E CI S T cate g ories: c o m plete 
res p o nse ( C R), partial res p o nse ( P R), sta ble disease ( S D) a n d pr o gressi ve disease ( P D). T he s u m mar y will 
als o i ncl u de a cate g or y f or u ne val ua ble  ( N E) s u bjects if a p plica ble a n d o ne f or n o n -res p o n ders ( N R). P R 
a n d C R m ust be c o nfir me d b y re peat i ma gi n g at least 4 wee ks later wit h n o e vi de nce of pr o gressi o n 
bet wee n c o nfir mati o n visits . 
T he  cli nical be nefit rate ( C B R)  a n d o bjecti ve res p o nse rate ( O R R) esti mates will be prese nte d al o n g wit h 
t he ass ociate d Cl o p per-Pears o n 9 5 % CIs.  
6. 5. 2. 1  S u b gr o u p A n al yses   
S u b gr o u p a nal ysis o n C B R, O R R a n d B O R will be perf or me d  o n F A S as well as T u m or Res p o nse 
E val ua ble Set. T he f oll o wi n g are, b ut n ot li mite d t o, p ote ntial s u b gr o u ps f or a nal ysis:  
•  
Pr i or C D K 4/ 6 i n hi bit or f or a d va nce d/ metastatic disease (a be macicli b , pal b ocic li b, or ri b ocicli b; 
Yes, N o)  
•  
Baseli ne E S R 1 s tat us ( W T, Muta nt)   
It s h o ul d be n ote d t hat s u b gr o u p a nal yses lea d t o re d uce d, ofte n se verel y re d uce d, sa m ple sizes i n t he 
gr o u ps e val ua te d. T his i ncreases t he ris k f or c ha nce fi n di n gs a n d i nter pretati o n of a n y res ults ste m mi n g 
fr o m s u b gr o u p a nal yses s h o ul d be i nter prete d wit h great ca uti o n. O nl y s u b gr o u ps wit h a de q uate cell sizes 
(i.e. n = 5) will be prese nte d i n t he s u m maries. 
6. 5. 3  
Pr o g ressi o n -Free S ur vi v al   
Pr o gressi o n -free s ur vi val (P F S ) is a sec o n dar y e n d p oi nt f or all c o h orts. It  is defi ne d as t he ti me (i n m o nt hs) 
fr o m t he date of first d osi n g  u ntil  t he date of o bjecti ve  P D (as defi ne d b y R E CI S T versi o n 1. 1 ) or deat h  ( b y 
a n y ca use i n t he a bse nce of pr o gressi o n) , w hic he ver occ urs earlier: ( date of first ra di ol o gic P D or deat h  –  
date of first treat me nt +  1)  / 3 0. 4 3 7 5.  
S u bj ects  w h o ha ve n ot pr o gresse d or die d  at t he ti me of a nal ysis will be ce ns ore d at t he ti me of t he latest 
date of assess me nt fr o m t heir last e val ua ble R E CI S T assess me nt pri or t o recei vi n g a n ot her a ntica ncer 
t hera p y. If t he s u bject has n o e val ua ble visits or d oes n ot ha ve Baseli ne  data, t he y will be c e ns ore d at Da y 1  
u nless sit uati o n 3 , as descri be d i n Ta ble 3 , is e nc o u ntere d. 
T he distri b uti o n of P F S will be descri be d i n ta b ular f or mat  usi n g Ka pla n -Meier met h o d ol o g y 2, re p orti n g 
esti mate d me dia n (i n m o nt hs) wit h 9 5 % CI, 2 5 t h a n d 7 5 t h perce ntiles ( Br o o k me yer a n d Cr o wle y 1 9 8 2, Klei n 
a n d M oesc h ber ger 1 9 9 7) a n d K M esti mate d pr o ba bilities wit h c orres p o n di n g 9 5 % CI is ( Kal bfleisc h a n d 
Pre ntice 2 0 0 2) at se veral ti me p oi nts (i ncl u di n g 2, 4, 6, 8, 1 0 a n d 1 2 m o nt hs ). 
Refer t o  Ta ble 3  f or ce ns ori n g r ules f or P F S . 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 2 9  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 2 9  of 4 7  
C O N FI D E N TI A L  
 
T a ble 3  Ce ns ori n g R ules f or P r o gressi o n -F ree S ur vi v al   
Sit u ati o n  
E n d D ate  
Ce ns ore d  
1.  D oc u me nte d 
ra di ol o gical P D bef ore 
i nitiati o n of n o n-st u d y 
a nti -ca ncer treat me nt 
(f or s u bjects wit h 
misse d t u m or 
assess me nt, c hec k # 3)  
Date of t he first t u m or assess me nt t hat deter mi ne d 
P D  
N o  
1a *.  Cli nical P D  bef ore 
i nitiati o n of n o n-st u d y 
a nti -ca ncer treat me nt 
(f or s u bjects wit h 
misse d t u m or 
assess me nt, c hec k # 3)  
Date of Cli nical Pr o gressi o n  
N o  
2.  Deat h d uri n g t he st u d y 
wit h n o pri or P D a n d n o 
pri or i nitiati o n of n o n -
st u d y a nti-ca ncer 
treat me nt (f or s u bjects 
wit h misse d t u m or 
assess me nt, c hec k # 3)  
Date of deat h  
N o  
3.  Ra di ol o gic P D  or Deat h  
after m ore t ha n o ne  
misse d t u m or 
assess me nt 
Date of last a de q uate t u m or assess me nt pri or t o 
misse d  t u m or assess me nt 
M ore t ha n o ne  res p o nse assess me nt is c o nsi dere d t o 
be  “ misse d” if m ore t ha n 1 8  wee ks ( 1 2 6  da ys) has 
ela pse d si nce t he last e val ua ble i ma ge-base d 
res p o nse assess me nt ( or first d ose date if n o pri or 
res p o nse) u p t o 2 4 wee ks after C 1 D 1 . If t he last 
e val ua ble i ma ge -base d res p o nse assess me nt is m ore 
t ha n 2 4 wee ks after C 1 D 1, m ore t ha n o ne res p o nse 
assess me nt is c o nsi dere d t o be " misse d” if m ore 
t ha n 2 6 wee ks ( 1 8 2 da ys) has ela pse d.  If a s u bject 
de vel o ps pr o gressi ve disease or dies after t his 
i nter val, t he t u m or res p o nse assess me nt will be 
e xcl u de d fr o m t he a nal ysis a n d ce ns ore d at t he last 
e val ua ble assess me nt.  
Yes  
4.  N o n -st u d y a nti-ca ncer 
treat me nt i nitiate d 
bef ore ra di ol o gic P D 
Date of last a de q uate t u m or assess me nt pri or t o 
i nitiati o n of n o n-st u d y a nti-ca ncer treat me nt  
Yes  


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 3 0  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 3 0  of 4 7  
C O N FI D E N TI A L  
 
Sit u ati o n  
E n d D ate  
Ce ns ore d  
5.  S u bj ect s still f oll o we d 
wit h o ut  ra di ol o gic P D 
or deat h  as of c ut off 
date  
Date of last a de q uate t u m or assess me nt ( or date of 
first treat me nt if n o a de q uate p ost -Baseli ne  t u m or 
assess me nts)  
Yes  
6.  S u bj ect s wit h o ut 
a de q uate Baseli ne  t u m or 
assess me nt 
Date of  first treat me nt 
Yes  
Ge neral C o nsi derati o ns:  
Ra di ol o gic P D f or R E CI S T v 1. 1 is defi ne d as o verall res p o nse of ‘P D ’. 
* As a se nsiti vit y a nal ysis, P F S will als o be defi ne d usi n g Cli nical pr o gressi o n  as e q ui vale nt t o 
ra di ol o gical pr o gressi o n. Please refer t o sit uati o n 1a. T he date of cli nical pr o gressi o n is defi ne d as t he 
earliest date of a n y treat me nt disc o nti n uati o n f or d isease pr o gressi o n, i n t he a bse nce of ra di ol o gic P D. 
T u m or res p o nse assess me nt dates will be assi g ne d base d o n t he date t he i ma ge was perf or me d, n ot t he 
date t he i ma ge was assesse d.  
A n a de q uate/e val ua ble t u m or assess me nt is o ne wit h a n o verall res p o nse of C R, P R, S D or P D wit h o ut 
pri or ce ns ori n g e ve nts (a nti -t u m or t hera p y, misse d visit). 
6. 5. 3. 1  S u b gr o u p A n al ysis   
S u b gr o u p a nal ysis o n P F S will be perf or me d o n F A S as well as T u m or Res p o nse  E val ua ble Set  usi n g t he 
s u b gr o u ps defi ne d f or t he C B R s u b gr o u p a nal ysis. 
6. 5. 4  
D ur ati o n of Res p o nse   
D urati o n of Res p o nse ( D O R) is a sec o n dar y e n d p oi nt f or all c o h orts. It is defi ne d a s t he ti me (i n m o nt hs) 
fr o m t he date of first  d oc u me nte d res p o nse (t hat is s u bse q ue ntl y c o nfir me d per R E CI S T versi o n 1. 1) u ntil 
date of d oc u me nte d pr o gressi o n or deat h i n t h e a bse nce of P D: ( date of first ra di ol o gic P D or deat h  –  date 
of first res p o nse +  1 ) / 3 0. 4 3 7 5.  T he e n d of res p o nse s h o ul d c oi nci de wit h t he date of pr o gressi o n or deat h 
fr o m a n y ca use. T he ti me of i nitial res p o nse will be defi ne d as t he latest of t he dates c o ntri b uti n g t o t he first 
visit res p o nse of P R or C R.  
S u bj ects w h o ha ve n ot pr o gr esse d f oll o wi n g a res p o nse at t he ti me of a nal ysis will be ce ns ore d at t he date 
of last e val ua ble t u m or assess me nt. S u bjects w h o recei ve ot her a ntica ncer t hera p y pri or t o d oc u me nte d P D 
will be ce ns ore d t he da y t his s u bse q ue nt t hera p y starte d.  
D O R  will be s u m marize d usi n g Ka pla n-Meier met h o d ol o g y
2 i n a ta b ular f or mat. 
T he pr o p orti o n of s u bjects wit h a D O R of 6 m o nt hs or m ore will be s u m marize d.  
Ce ns ori n g r ules use d f or D O R are t he sa me as t he o nes f or P F S ( Ta ble 3 ).  
If t here are a s ufficie nt n u m ber of res p o nses ( n = 1 0), D O R will be a nal yze d usi n g t he sa me met h o d ol o g y as 
P F S . 


 
Statistical Analysis Plan 
Protocol No. ZN-c5-001 
Revision 00: 17Feb2023 
 (Page 31 of 47) 
 
DOC.ST.101.04-01 Rev 00 
Page 31 of 47 
CONFIDENTIAL 
 
6.5.5 
Overall Survival  
Overall Survival (OS) is a secondary endpoint for all cohorts. It is defined as the time from date of first 
dosing until the date of death. Subjects alive at the time of analysis will be censored at the time of the latest 
date of survival status assessment. 
6.5.6 
Pharmacokinetic Variables  
Plasma samples for ZN-c5 and its potential metabolites as applicable, and palbociclib (and metabolite) were 
collected as below. In case the dosing schedule was changed to BID dosing, an additional PK time point at 
12 hours post ZN-c5 dosing was drawn (optional). 
Day on Study 
Time 
(hr) 
Monotherapy 
Combination Therapy 
ZN-c5 
ZN-c5 
Palbociclib 
Cycle 1  
Day 1 and 15 
T=0 
PK (pre-dose, within 0.5 hrs) 
PK (pre-dose, within 0.5 hrs) 
NA 
Dose 
(fasted) 
Dose 
(fasted) 
NA 
0.5 
PK 
PK 
NA 
1  
PK 
PK 
NA 
2  
PK 
PK 
(prior to Palbociclib dosing) 
PK  
(pre-dose, within 
0.5 hrs) 
Dose 
(with food) 
2.5  
NA 
NA 
PK (0.5-hr) 
3  
NA 
NA 
PK    (1-hr) 
4  
PK 
PK 
PK    (2-hr) 
6  
PK 
PK 
PK    (4-hr) 
8  
PK 
PK 
PK    (6-hr) 
10  
NA 
NA 
PK    (8-hr) 
Cycle 1  
Day 2 and 16 
24  
PK 
PK 
NA 
26  
NA 
NA 
PK (24-hr) 
Cycle 1 Day 8 
 
PK (pre-dose, within 0.5 hrs) 
PK (pre-dose, within 0.5 hrs) 
PK 
Cycle 2 Day 1 
 
PK (pre-dose, within 0.5 hrs) 
PK (pre-dose, within 0.5 hrs) 
NA 
Cycle 3 Day 1 
 
PK (pre-dose, within 0.5 hrs) 
PK (pre-dose, within 0.5 hrs) 
NA 
Cycle 4 Day 1 
 
PK (pre-dose, within 0.5 hrs) 
PK (pre-dose, within 0.5 hrs) 
NA 
 NA= not applicable 
 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 3 2  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 3 2  of 4 7  
C O N FI D E N TI A L  
 
6. 5. 7  
P h ar m a c o d y n a mi c/ Bi o m a r ker A n al ysis   
E x pl orat or y a nal yses ma y b e perf or me d t o e val uate t he ass ociati o n of eac h bi o mar ker or c o m bi nati o n of 
bi o mar kers wit h cli nical o utc o mes, a n d t he m o d ulati o n of bi o mar kers relate d t o mec ha nis m of acti o n a n d 
P D.  
E x pl orat or y bi o mar kers a nal yses t hat ma y e n ha nce t he u n dersta n di n g of t he bi ol o gical eff ects, t he 
mec ha nis m of acti o n, or safet y, ma y be perf or me d. Bi o mar ker o bjecti ves ma y be f urt her descri be d a n d 
u p date d base d o n e v ol vi n g scie ntif ic k n o wle d ge of Z N-c 5 acti vit y.  
If a n e x pl orat or y bi o mar ker a nal ysis is t o be perf or me d, t his  S A P will be u p date d wit h details o n o bj ecti ves 
a n d a nal ysis met h o ds, pri or t o t he act ual data a nal ysis.  
6. 6  S afet y   
All safet y a nal yses will be base d o n t he Safet y A nal ysis Set, e xce pt f o r e val uati o n of D L Ts, w hic h will be 
base d o n t he D L T -E val ua ble A nal ysis Set.  
S afet y para meters t hat will be meas ure d i n t he st u d y are : 
•  
A d verse e ve nts  
•  
D ose -li miti n g t o xicities ( D L Ts; M o n ot hera p y a n d C o m bi nati o n T hera p y D ose Escalati o n s o nl y ) 
•  
La b orat or y meas ure me nts  ( he mat ol o g y, c oa g ulati o n, ser u m c he mistr y, uri nal ysis) 
•  
Vital si g ns  
•  
E C G  
•  
P h ysical e xa mi nati o n  
•  
E C O G P S  
 
Safet y data will be prese nte d descri pti vel y; n o f or mal statistical a nal yses will be perf or me d.  
6. 6. 1  
St u d y D a y a n d Visit Wi n d o w Defi niti o ns   
N o mi nal visit assi g n me nt as c ollecte d o n t he C R F  will be use d t o a nal yze safet y para meters prese nte d b y 
visit.  A n y u nsc he d ule d assess me nts  will n ot be i ncl u de d i n b y -visit s u m maries b ut are eli gi ble i n “ w orst 
case” a nal yses. E C G data c ollecte d i n tri plicate will be a vera ge d a n d ha n dle d as a si n gle c ollecti o n f or visit 
assi g n me nt.  
St u d y da y is defi ne d as t he date of assess me nt –  first date of e x p os ure + 1 f or assess me nts t hat occ ur o n or 
after t he first date of e x p os ure; st u d y da y is defi ne d as t he date of assess me nt –  fist date of e x p os ure  f or 
assess me nts t hat occ ur pri or t o t he first date of e x p os ure. T he sa me met h o d ol o g y will be use d t o defi ne 
relati ve c ycle da y, w here da y 1 of a gi ve n c ycle is defi ne d base d o n t he visit date re p orte d o n t he Date of 
Visit e C R F.  
6. 6. 2  
E xte nt of E x p os ure t o St u d y  Me dic ati o n   
T he f oll o wi n g e x p os ure para meters will be calc ulate d se paratel y f or eac h st u d y dr u g ( Z N -c 5, a n d 
pal b ocicli b, as a p plica ble), wit h dates of e x p os ure bei n g defi ne d as d ates w here a n y st u d y dr u g is ta ke n.  
T he tre at me nt d ur ati o n will be calc ulate d as last date of e x p os ure –  first date of e x p os ure + 1 f or Z N-c 5, 
a n d last date of e x p os ure –  first date of e x p os ure + 8 f or pal b ocicli b . 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 3 3  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 3 3  of 4 7  
C O N FI D E N TI A L  
 
T he n u m ber of d oses prescri be d  will be calc ulate d base d o n t he treat me nt d urati o n of st u d y dr u g . F or Z N-
c 5, t his will be t he n u m ber of da ys of st u d y dr u g f or s u bj ects assi g ne d t o Q D d osi n g sc he d ule a n d will be 
t he n u m ber of da ys of st u d y dr u g * 2 f or s u bj ects assi g ne d t o BI D d osi n g sc he d ule. F or pal b ocicli b , t his will 
be t he ceili n g (treat me nt d urati o n of st u d y dr u g  / 2 8) * 2 1. 
T he n u m ber of d oses t a ke n/ a d mi nistere d  will be calc ulate d as (treat me nt d urati o n of st u d y dr u g * 
pla n ne d n u m ber of d oses per da y) –  n u m ber of misse d d ose s. 
T he perce nt of e x pecte d d oses t a ke n/ a d mi nistere d  will be calc ulate d as [( n u m ber of d oses 
ta ke n/a d mi nistere d) / ( n u m ber of d oses prescri be d)] * 1 0 0 %. 
T he t ot al e x p os ure will be calc ulate d (i n m g) f or eac h st u d y dr u g  as t he s u m of d oses ta ke n/a d mi nistere d i n 
m g . 
T he act u al d ail y d ose  f or Z N-c 5 a n d pal b ocicl i b will be calc ulate d as t he t otal e x p os ure / n u m ber of da ys 
of st u d y dr u g.  
T he rel ati ve d ose i nte nsit y ( R DI)  f or Z N-c 5 a n d pal b ocicl i b will be calc ulate d as (act ual dail y d ose / 
pla n ne d dail y d ose) * 1 0 0 %.   
T h e occ urre nce of d ose m o dific ati o ns  ( Yes, N o) will be deri ve d b y s u bject a n d reas o n ( A E, ot her) f or 
eac h t y pe of m o dificati o n ( dr u g i nterr u pti o n , d ose re d uce d, d ose escalate d, dr u g disc o nti n ue d ).  
T he n u m ber of d ose m o dific ati o ns  will be deri ve d b y s u bject f or eac h t y pe of m o dificati o n. 
6. 6. 3  
A d verse E ve nts   
T he i nci de nce a n d se verit y of a d verse e ve nts is a pri mar y e n d p oi nt i n M o n ot hera p y E x pa nsi o n , al o n g wit h 
t he i nci de nce a n d se verit y of D L Ts d uri n g C ycle 1  f or M o n ot hera p y D ose Escalati o n a n d C o m bi nati o n 
D ose Escalati o n . T he i nci de nce a n d se verit y of a d verse e ve nts is als o a sec o n dar y e n d p oi nt f or all c o h orts.  
A d verse e ve nts will be c ollecte d a n d c o de d usi n g versi o n  2 5. 0  or later  of t he  Me dical Dicti o nar y f or  
Re g ulat or y Acti vities ( Me d D R A ) wit h descri pti o ns b y S yste m Or ga n Class ( S O C), Hi g h Le vel Gr o u p 
T er m, Hi g h -Le vel T er m, Preferre d T er m, a n d L o wer -L e vel Ter m . A nal ysis of a d verse e ve nts will be 
carrie d o ut o n t he Safet y A nal ysis Set . 
A ll A Es will be liste d. T he f oc us of A E s u m mar y will be o n treat me nt-e mer ge nt A Es ( T E A E). A T E A E is 
defi ne d as a n A E t hat occ urs or w orse ns i n t he peri o d fr o m t he first d ose of st u d y dr u g t o 3 0 da ys after t he 
last d ose of st u d y dr u g. 
T he se verit y of A Es wil l be gra de d b y t he I n vesti gat or acc or di n g t o t he N CI C T C A E, versi o n 4. 0 3 . T he 
relati o ns hi p of t he A E t o a n y st u d y dr u g will be cate g orize d as relate d or u nrelate d. 
A s u bj ect w h o re p orts m ulti ple T E A Es wit hi n t he sa me Preferre d Ter m ( or S O C) is c o u nte d o nl y  o nce f or 
t hat Preferre d T er m ( or S O C) usi n g t he w orst se verit y gra de.  
T he T E A Es will be s u m marize d b y st u d y part a n d d ose le vel.  S u m mar y ta bles will be prese nte d t o s h o w t he 
n u m ber of s u bjects re p orti n g T E A Es b y se verit y gra de a n d c orres p o n di n g perce nta ges. A E descri pti o ns will 
be prese nte d b y decreasi n g fre q ue nc y f or a gi ve n S O C a n d Preferre d T er m. Se parate listi n gs a n d s u m maries 
will be pre pare d f or t he f oll o wi n g t y pes of T E A Es:  
•  
All T E A Es  
•  
D L Ts ( M o n ot hera p y D ose Escalati o n a n d C o m bi nati o n D ose Escalati o n ) (listi n g o nl y) 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 3 4  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 3 4  of 4 7  
C O N FI D E N TI A L  
 
•  
T E A Es b y Gra de/ Se verit y  
•  
St u d y -dr u g -relate d T E A Es  –  f or t he P hase 1  C o m bi nati o n, t hese T E A Es will be s u m marize d base d 
o n relati o ns hi p t o a n y st u d y dr u g, as well se paratel y f or Z N -c 5 a n d Pal b ocicli b  
•  
T E A Es t hat are Gra de ≥ 3 i n se verit y  
•  
T E A Es lea di n g t o st u d y dr u g i nterr u pti o n a n d/ or d ose m o dificati o n  –  f or t he P hase 1  C o m bi nati o n, 
t hese T E A Es will be s u m marize d base d  o n i nterr u pti o n a n d/ or d ose m o dificati o n f or a n y st u d y 
dr u g, as well se paratel y f or Z N -c 5 a n d Pal b ocicli b 
•  
T E A Es l ea di n g t o st u d y dr u g disc o nti n uati o n  –  f or t he P hase 1  C o m bi nati o n, t hese T E A Es will be 
s u m marize d base d o n disc o nti n uati o n of a n y st u d y dr u g, as well se paratel y f or Z N -c 5 a n d 
Pal b ocicli b  
•  
T E A Es wit h o utc o me of deat h  (fatal T E A Es)  
•  
S eri o us T E A Es  
 
Missi n g Gr a de:  
Missi n g gra des will n ot be i m p ute d.  A Es wit h missi n g gra de will be re p orte d as ‘ N o Gra de’.  A Es wit h 
missi n g gra de will be c o u nte d i n “ All Gra des”, b ut will n ot be c o u nte d i n “ Gra de 3 or hi g her” c ol u m ns.  
Missi n g Rel ati o ns hi p t o St u d y Dr u g  
A n A E wit h a missi n g relati o ns hi p t o st u d y dr u g will be cate g orize d as ‘ N ot deter mi ne d’ a n d will be 
i ncl u de d i n s u m maries of relate d A Es . I m p ute d val ues will n ot be liste d i n data listi n gs. 
A d verse E ve nts wit h I nc o m plete D ates  
I m p utati o n of dates f or a d verse e ve nts wit h i nc o m plete dates will be perf or me d o nl y f or deter mi nati o n of 
treat me nt e mer ge nce. I m p ute d dates will n ot be prese nte d i n data listi n gs. T he f oll o wi n g al g orit h m will  be 
use d t o esti mate a d verse e ve nt start dates f or w hic h o nl y partial i nf or mati o n is k n o w n:  
•  
Missi n g da y a n d m o nt h  
o  If t he year is sa me as t he year of first da y o n dr u g, t he n t he da y a n d m o nt h of t he start date 
of dr u g will be assi g ne d t o t he missi n g fiel ds.  
o  If t he year is pri or t o t he year of first da y o n dr u g, t he n Dece m ber 3 1 will be assi gne d t o t he 
missi n g fiel ds.  
o  If t he year is after t he year of first da y o n dr u g, t he n J a n uar y 1 will be assi g ne d t o t he 
missi n g fiel ds.  
•  
Missi n g m o nt h o nl y  
o  Treat da y as missi n g a n d re place b ot h m o nt h a n d da y ac c or di n g t o t he a b o ve pr oce d ure.  
•  
Missi n g da y o nl y  
o  If t he m o nt h a n d year are same as t he year a n d m o nt h of first da y o n dr u g, t he n t he start 
date of dr u g will be assi g ne d t o t he missi n g da y.  


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 3 5  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 3 5  of 4 7  
C O N FI D E N TI A L  
 
o  If t he m o nt h a n d year are bef ore t he year a n d m o nt h of first da y o n dr u g, t he n t he last da y 
of t he m o nt h will b e assi g ne d t o t he missi n g da y.  
o  If t he m o nt h a n d year are after t he year a n d m o nt h of first da y o n dr u g, t he n t he first da y of 
t he m o nt h will be assi g ne d t o t he missi n g da y.  
If t he A E st o p date is c o m plete a n d t he i m p ute d start date as a b o ve is after t he st o p date, t he start date will 
be  i m p ute d usi n g t he st o p date. 
A d verse e ve nts wit h partiall y missi n g st o p dates will be i m p ute d a st o p date as f oll o ws: 
•  
Year  is missi n g –  date left missi n g.  
•  
M o nt h  is missi n g: 
o  If year = year of data e xtract, i m p ute as m o nt h of data e xtract; 
o  Else,  i m p ute ‘Dec e m ber ’. 
•  
Da y  is missi n g: 
o  If year a n d m o nt h = year a n d m o nt h of data e xtract, i m p ute as da y of data e xtract; 
o  Else i m p ute ‘last da y of t hat m o nt h’. 
6. 6. 3. 1  De at hs   
S u m maries of deat hs  wit hi n 3 0 da ys of  last d ose of st u d y me dicati o n (i ncl u di n g ca use of deat h) as well as a 
c o u nt of t h ose occ urri n g m ore t ha n 3 0 da ys after last d ose will be pr o vi de d. All deat hs re p orte d will als o be 
prese nte d i n a listi n g.  
6. 6. 4  
L a b or at or y D at a   
La b orat or y assess me nts i ncl u de:  
T a ble 4  L a b or at or y Tests   
C ate g or y  
P ar a meters  
He mat ol o g y  
H e m o gl o bi n, he mat ocrit, platelet c o u nt, W B C c o u nt wit h differe ntial ( ne utr o p hils, 
e osi n o p hils, bas o p hils, l y m p h oc ytes, m o n oc ytes)  
C oa g ulati o n  
P T /I N R, a P T T 
Ser u m 
C he mistr y  
T otal pr otei n, al b u mi n, B U N, creati ni ne,  calc ulate d Cr Cl,  t otal bilir u bi n wit h direct 
bilir u bi n as a p plica ble, A S T ( S G O T), A L T ( S G P T), al kali ne p h os p hatase, G G T, gl uc ose , 
s o di u m, p otassi u m, c hl ori de, calci u m, ma g nesi u m, p h os p hate, f ull li pi d pa nel 
Uri nal ysis  
vis ual i ns pecti o n, micr osc o pic e xa mi nati o n, a n d di ps tic k test f or p H, pr otei n, gl uc ose, 
W B C, bilir u bi n, a n d bl o o d  
Pre g na nc y 
T est  
β -h C G (f or w o me n of c hil d beari n g p ote ntial)  
D uri n g Scree ni n g, a ser u m pre g na nc y test m ust be perf or me d. D uri n g t he st u d y, uri ne or 
ser u m pre g na nc y tests ca n be perf or me d. 


 
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ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; β-hCG = beta-human chorionic gonadotropin; BUN = blood urea nitrogen; CPK = 
creatine phosphokinase; CrCl = creatinine clearance; GGT = gamma-glutamyl-transferase; PT/INR = 
Prothrombin Time – International Normalized Ratio; SGOT = serum glutamic-oxaloacetic transaminase; 
SGPT = serum glutamic pyruvic transaminase; WBC = white blood cell 
A full lipid panel, regardless of fasting status, will be performed on C1D1, C3D1 (coinciding with the 
first on-study tumor assessment after 8 weeks) and C7D1 (6 months into the study).  This will not be 
assessed in the Monotherapy Phase 2 part of the study. 
 
In addition:  Plasma 4β-hydroxycholesterol and cholesterol will be analyzed (from the same blood draw as 
for PK) at the following time points of the Monotherapy Dose Escalation and Expansion cohorts: 
[Cycle 1 Day 1] pre-dose (0 hr) 
[Cycle 1 Day 15] pre-dose (0 hr) 
[Cycles 2, 3 and 4 Day 1] pre-dose (0 hour) 
All laboratory data will be stored in the database with the units in which they are originally reported. 
Laboratory data in summary tables and subject data listings will be presented in the International System of 
Units (SI units; Système International d’Unités). 
Hematology, serum chemistry and coagulation tests will be programmatically graded according to NCI-
CTCAE v4.03 toxicity grading as detailed in Appendix 1 NCI-CTCAE V4.03 Toxicity Grading when 
applicable. For parameters for which a CTCAE scale does not exist, reference ranges from the local 
laboratory will be used to determine programmatically if a laboratory parameter is below, within or above 
the normal range for the subject’s age, sex, etc. 
Treatment-emergent laboratory abnormalities will be identified and will be the focus of laboratory data 
summarization. A treatment-emergent laboratory abnormality is defined as an abnormality that, compared 
to baseline, worsens by ≥ 1 grade in the period from the first dose of study drug to 30 days after the last 
dose of study drug. If baseline data are missing, then any graded abnormality (i.e., an abnormality that is 
Grade ≥ 1 in severity) will be considered treatment-emergent. 
For laboratory results entered with inequality symbols (<, ≤, >, ≥), numeric values will be imputed by 
ignoring the inequality symbol(s) (e.g. “<1.71” will be imputed as 1.71 for numeric analyses). Imputed 
values will not be listed in data listings. 
For each laboratory test, Baseline and worst (maximum) CTCAE grade post-Baseline will be identified for 
each subject. For parameters for which a CTCAE scale does not exist, the Baseline and worst post-Baseline 
value will be identified as being below, within or above the normal range as detailed above. Change from 
Baseline will be calculated for all post-Baseline results. 
Subjects will be characterized only once for a given assay, based on the worst severity grade observed 
during a period of interest (e.g., during the study or from Baseline to a particular visit). 
Hematology, coagulation and serum chemistry data, and changes from Baseline will be summarized by 
dose level, by visit for visits from Baseline to C2D1 as well as EOT. Urinalysis and pregnancy test results 
will be listed only. Plasma 4β-hydroxycholesterol and cholesterol will be listed only. 


 
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Protocol No. ZN-c5-001 
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Shift tables for hematology, coagulation and serum chemistry will also be presented by showing change in 
CTCAE severity grade from Baseline to worst grade post-Baseline. A shift table for hematology showing 
change in CTCAE severity grade from Baseline to worst Cycle 1 value will also be presented. 
For parameters for which a CTCAE scale does not exist, shift tables will be presented showing change in 
results from Baseline to worst post-Baseline category (below, within, or above normal range).  
Separate listings and summaries may be prepared for laboratory abnormalities that are Grade ≥ 3 in 
severity. 
6.6.5 
Vital Signs  
Vital signs include height (Baseline only), weight, temperature, pulse rate, respiration rate, systolic blood 
pressure and diastolic blood pressure, and oxygen saturation. Vital signs and their changes from Baseline 
will be summarized by visit for visits from Baseline to C2D1 as well as EOT. 
6.6.6 
Electrocardiogram (ECG)  
The electrocardiogram assessment includes PR interval (msec), RR interval (msec), QRS interval (msec), 
QT interval (msec), QTcB interval (msec), and QTcF interval (msec). Change from Baseline will be 
calculated for all post-Baseline results. For ECG parameters measured in triplicates, the average of 
available measures will be computed for each timepoint. 
If QTcB is missing and QT and either QTcB or RR is not missing, QTcB will be derived using one of the 
following formulas: 
QTcB=QT/(QT/QTcF)3/2 
QTcB=QT/RR1/2 
The maximum post-Baseline QTcB value will be determined for each subject and categorized (≤ 450, > 450 
and ≤ 480, > 480 and ≤ 500, > 500). 
The maximum increase from Baseline in QTcB value will be determined for each subject and categorized 
(≤ 30, > 30 and ≤ 60, > 60). 
6.6.7 
Physical Examination  
The physical examination results will be listed. Clinically relevant abnormalities will be summarized 
separately as medical history and/or adverse events. 
6.6.8 
Pregnancy Test  
The pregnancy test results will be listed. 
6.6.9 
Prior and Concomitant Medications/Procedures  
Verbatim descriptions of prior and concomitant medications and therapies will be mapped to the World 
Health Organization Drug Global version Q1 2022 or later. 
Verbatim descriptions of concomitant procedures will be coded using version 25.0 or later of the Medical 
Dictionary for Regulatory Activities (MedDRA) with descriptions by System Organ Class (SOC), High 
Level Group Term, High-Level Term, Preferred Term, and Lower-Level Term. 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 3 8  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 3 8  of 4 7  
C O N FI D E N TI A L  
 
A s u bj ect w h o re p orts m ulti ple me dicati o ns/ pr oce d ure s wit hi n t he sa me Preferre d T er m ( or S O C or A T C  
c o de ) is c o u nte d o nl y o nce f or t hat Preferre d T er m ( or S O C or A T C c o de ) usi n g t he first occ urre nce 
c hr o n ol o gicall y.  
Partial me dicati o n / pr oce d ure dates will be i m p ute d t he sa me wa y as a d verse e ve nts dates  f or t he p ur p ose of 
disti n g uis hi n g pri or a n d  c o nc o mi ta nt me dicati o ns/pr oce d ures . Pri or me dicati o ns/ pr oce d ures are defi ne d as 
me dicati o ns/ pr oce d ures wit h start date pri or t o t he first d ose of st u d y me dicati o n. C o nc o mita nt 
me dicati o ns/ pr oce d ures are defi ne d as me dicati o ns /pr oce d ures wit h start date or e n d dat e after t he first d ose 
of st u d y me dicati o n  or are o n g oi n g. Me dicati o ns t hat start pri or t o first d ose a n d c o nti n ue p ost first d ose are 
c o nsi dere d b ot h pri or a n d c o nc o mita nt . 
Pri or a n d c o nc o mita nt me dicati o ns will be s u m marize d se paratel y b y A nat o mical -T her a pe utic -C he mical 
classificati o n ( A T C) class (le vel 1) a n d preferre d dr u g na me.   
C o nc o mita nt pr oce d ures will be liste d . Base d o n s p o ns or re vie w, c o nc o mita nt a nti -ca ncer s ur geries a n d 
ra di ot hera p y will be fla g ge d i n t he listi n g. 
6. 6. 1 0  
 E C O G P S    
 E C O G perf or ma nce stat us  s hifts fr o m Baseli ne t o w orst p ost baseli ne sc ore will be s u m marize d.  
6. 7  P h ar m a c o ki netic A n al ysis   
6. 7. 1  
Ge ner al C o nsi der ati o ns   
T he P K A nal ysis Set will be use d f or P K a nal ysis.  A n y pr ot oc ol de viati o ns  (c o nsi dere d i m p orta nt pr ot oc ol 
de viati o ns)  t hat c o ul d i m pact P K para meter esti mates will be disc usse d wit h t he S p o ns or t o deter mi ne 
w het her a n y data or s u bject -le vel e xcl usi o ns are necessar y. All data t hat are e xcl u de d will be liste d a n d t he 
reas o n f or e xcl usi o n clearl y n ote d. 
If a q ua ntifia ble  pre -d ose c o nce ntrati o n of Z N -c 5 or pal b ocicli b  or meta b olites  is detecte d a n d it re prese nts 
n o m ore t ha n 5 % of t he C ma x  val ue f oll o wi n g t he first d ose of t his st u d y, t he s u bject’s data will be i ncl u de d 
i n t he n o nc o m part me ntal  a nal ysis  ( N C A), wit h o ut a dj ust me nts. If t he o bser ve d pre-d ose val ue is greater 
t ha n 5 % of t he Cma x  val ue f oll o wi n g t he first d ose of t his st u d y, t he s u bject’s data will be e xcl u de d fr o m 
N C A . 
Act ual sa m pli n g ti me p oi nts relati ve t o d osi n g of eac h res pecti ve dr u g  will be use d f or  N C A , e xce pt f or t he 
pre -d ose ti me p oi nts at Da y 1 a n d Da y 1 5, w here t he pre -d ose ti me p oi nt will be set t o 0 . If t he act ual 
c ollecti o n ti me is u n k n o w n , t he n o mi nal c ollecti o n ti me will  be use d f or  t he p ur p oses of P K para meter 
esti mati o n.  
C o nce ntrati o n val ues t hat are bel o w t he l o wer li mit of q ua ntificati o n ( B Q L) will be i m p ute d as f oll o ws f or 
N C A:  
•  
B Q L val ues at ti me  p oi nts pri or t o a n y meas ura ble c o nce ntrati o n s f or t he first d ose or at ti me p oi nts 
i m me diatel y pri or t o d osi n g f or m ulti ple d ose will be  i m p ute d as 0. 
•  
A n y ot her B Q L val ues will be  set t o missi n g. 
T he a b o ve r ules s h o ul d be a p plie d se paratel y f or  C ycle 1  Da y 1 a n d Da y 1 5  P K para meter esti mati o n s. 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 3 9  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 3 9  of 4 7  
C O N FI D E N TI A L  
 
If t here is i ns ufficie nt a m o u nt of sa m ple f or t he la b orat or y t o re p ort a c o nce ntrati o n, t he n it will be treate d 
as missi n g. 
All  P K c o nce ntrati o n pr ofiles will be s u m marize d o ver ti me  b y  visit,  c o h ort , d osi n g re gi me n,  a n d a nal yte  i n 
ta b ular a n d gra p hical f or mats a n d p har mac o ki netic data will be pre se nte d i n listi n gs. 
All c o nce ntrati o n -ti me data a n d s u m mar y statistics  will be re p orte d t o t he sa me n u m ber of si g nifica nt 
fi g ures as dis pla ye d i n t he bi oa nal ytical data, e xce pt f or perce nta ges, w hic h will be re p orte d t o o ne deci mal 
place . 
All P K para meter esti mates a n d s u m mar y statistics  will be re p orte d t o 3 si g nifica nt fi g ures, wit h t he 
e xce pti o n of acc u m ulati o n rati os ( R A U C), meta b olic rati os ( M R) , w hic h will be re p orte d t o 3 deci mal 
places , ti me-relate d para meters (i ncl u di n g Tlast, Tma x , a n d T1/ 2, w hic h will be re p orte d t o t w o deci mal place s, 
a n d A U C e xtr a n d C V % w hic h will be re p orte d t o 1 deci mal place . 
6. 7. 2  
Pl as m a C o nc e ntr ati o n s  
T he plas ma  c o nce ntrati o ns of Z N -c 5, pal b ocicl i b, a n d/ or meta b olite s will be s u m marize d usi n g  n o mi nal 
sa m pli n g ti me b y visit, c o h ort , d osi n g  re gi me n (i.e. Q D or BI D), a n d a nal yte usi n g descri pti ve statistics. A 
listi n g b y s u bject of plas ma c o nce ntrati o ns a n d/ or t u m or c o nce ntrati o ns of Z N -c 5 (if a vaila ble) , sa m ple 
c ollecti o n ti mes, a n d deri ve d sa m pli n g ti me de viati o ns will be pr o vi de d.  
N o mi nal sa m pli n g ti me p oi nts relati ve t o d osi n g will be use d f or mea n pl ots of c o nce ntrati o n -ti me data. 
Act ual sa m pli n g ti mes will be use d f or i n di vi d ual c o nce ntrati o n -ti me pl ots, i ncl u di n g all rec or de d 
c o nce ntrati o ns re gar dless of ti mi n g. B Q L c o nce ntrati o n val ues will be set t o 0  f or pre d ose of Da y 1, a n d set 
t o a val ue e q ual t o t he L L O Q  f or all ot her ti me p oi nts f or calc ula ti o n of s u m mar y statistics a n d dis pla y. 
S u m mar y statistics f or c o nce ntrati o n -ti me data will  i ncl u de n , m ea n, S D, arit h metic coefficie nt of v ariati o n 
( %), m i ni m u m, m e dia n, m a xi m u m, g e o metric m ea n, a n d g e o metric coefficie nt of v ariati o n ( %). 
T he arit h metic a n d ge o metric mea ns of plas ma c o nce ntrati o ns of Z N -c 5, pal b ocicli b, a n d meta b olites,  will 
be prese nte d gra p hicall y o n b ot h li near a n d se mi -l o garit h mic scales b y visit,  c o h ort , d osi n g re gi me n, a n d 
a nal yte . F or i n di vi d ual pr ofiles, fi g ures wil l be prese nte d f or eac h s u bj ect wit h c o nce ntrati o n-ti me pr ofiles 
o n b ot h li near a n d se mi -l o garit h mic scales. C o nce ntrati o n val ues of 0 will n ot be pl otte d i n t he se mi-
l o garit h mic pl ots. T he f oll o wi n g fi g ures will be pr o d uce d:  
•  
I n di vi d ual c o nce ntrati o n vers us act ual ti me –  li near scale ( o verlai d f or eac h c o h ort) 
•  
I n di vi d ual c o nce ntrati o n vers us act ual ti me –  se mi-l o g scale ( o verlai d f or eac h c o h ort) 
•  
Arit h metic Mea n c o nce ntrati o n vers us n o mi nal ti me –  li near scale ( o verlai d f or all c o h orts) 
•  
Arit h metic Mea n c o nc e ntrati o n vers us n o mi nal ti me –  se mi-l o g scale ( o verlai d f or all c o h orts) 
•  
Ge o metric Mea n c o nce ntrati o n vers us n o mi nal ti me –  li near scale ( o verlai d f or all c o h orts) 
•  
Ge o metric Mea n c o nce ntrati o n vers us n o mi nal ti me –  se mi-l o g scale ( o verlai d f or all c o h orts) 
6. 7. 3  P h ar m a c o ki netic E n d p oi nts   
T he f oll o wi n g P K para meters f or Z N -c 5, pal b ocicli b , a n d meta b olites will be esti mate d b y N C A usi n g t he 
s oft ware P h oe ni x ®  Wi n N o nli n
®  Versi o n 8. 3 ( Certara, U S A).  
 


 
Statistical Analysis Plan 
Protocol No. ZN-c5-001 
Revision 00: 17Feb2023 
 (Page 40 of 47) 
 
DOC.ST.101.04-01 Rev 00 
Page 40 of 47 
CONFIDENTIAL 
 
Table 5 Pharmacokinetic Parameters  
PK Parameter 
Definition 
Cycle 1 Day 1 
 
Adjusted R2 
Adjusted coefficient of determination 
AUC0-8 
Area under the plasma concentration time curve from 0 to 8 hours post-dose 
AUC0-12 
Area under the concentration-time curve from the time of dosing to the end of the 
dosing interval (12 h post-dose for BID dosing; ZN-c5 only) 
AUC0-24  
Area under the concentration-time curve from the time of dosing to the end of the 
dosing interval (24 h post-dose for QD dosing) 
AUClast 
Area under the plasma concentration-time curve from time 0 to time of last 
quantifiable plasma concentration 
AUCinf 
Area under the plasma concentration-time curve from time 0 extrapolated to infinity 
AUCextr 
The proportion of AUC0-∞ due to extrapolation from time Tlast to infinity, expressed 
as a % 
Cmax 
Maximum observed plasma concentration after a single dose administration 
C0-12 
Concentration at the end of the dosing interval (BID dosing; ZN-c5 only) 
C0-24 
Concentration at the end of the dosing interval QD dosing only) 
Tmax 
Time of maximum observed plasma concentration after a single dose administration 
z 
Terminal elimination phase rate constant 
T1/2 
Apparent terminal elimination half life 
Tlast 
Time of last observed quantifiable concentration 
CL/Fa 
Apparent total plasma clearance after a single dose administration 
Vz/Fa 
Apparent volume of distribution after a single dose oral administration 
MRb 
Metabolic ratio of the conversion of a parent drug to its metabolite using AUC0-12 or 
AUC0-24 as MR = AUC (metabolite)/AUC (parent), for BID dosing or QD dosing, as 
appropriate. 
Cycle 1 Day 15 
 
Adjusted R2 
Adjusted coefficient of determination 
AUC0-8 
Area under the plasma concentration time curve from 0 to 8 hours post-dose 
AUCtau 
Area under the concentration-time curve from the time of dosing to the end of the 
dosing interval (tau = 12 or 24 hours) 
AUC0-24 
Area under the concentration-time curve calculated as 2 × AUC0-12 for the BID dose 
only. 
Cmax,ss 
Maximum observed plasma concentration after multiple dose administration 
Tmax,ss 
Time of maximum observed plasma concentration after multiple dose administration 
z (Lambda z) 
Terminal elimination phase rate constant 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 4 1  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 4 1  of 4 7  
C O N FI D E N TI A L  
 
P K P ar a meter  
Defi niti o n  
T 1/ 2 
A p pare nt ter mi nal eli mi nati o n half life  
T last 
Ti me of last o bser va ble q ua ntifia ble c o nce ntrati o n  
C tr o u g h 
C o nce ntrati o n at t he e n d of t he d osi n g  i nter val (ta u = 1 2 or 2 4 h o urs) 
C a ve 
A vera ge stea d y -state plas ma c o nce ntrati o n 
C L ss/ Fa 
A p pare nt t otal plas ma cleara nce after  m ulti ple d ose  oral a d mi nistrati o n  
V z,ss/ Fa 
A p pare nt v ol u me of distri b uti o n after m ulti ple d ose oral a d mi nistrati o n  
M R
b 
Meta b olic rati o of t he c o n versi o n of a pare nt dr u g t o its meta b olite usi n g A U C ta u as 
M R = A U C ( meta b olite )/ A U C (pare nt ), ta u = 1 2 or 2 4 h o urs f or BI D d osi n g or Q D 
d osi n g , res pecti vel y. 
R A U C  
A U C acc u m ulati o n rati o defi ne d as A U C  Da y 1 5/ A U C  Da y 1  ( w here Da y 1 A U C 0 -1 2 or 
A U C 0 -8 [ BI D d osi n g] or A U C0 -2 4 [ Q D D osi n g] a n d Da y 1 5 A U C0 -8 ( BI D d osi n g o nl y) 
or A U C ta u; ta u = 1 2 ( BI D d osi n g) or 2 4 h o urs) 
a Deter mi n e d f or pare nt dr u g o nl y  
b Deter mi n e d f or pal b ocicli b a n d its meta b olite  
C ma x , Cma x ss , C 0 -1 2, C0 -2 4, C tr o u g h, T ma x , a n d T ma x, ss  will be o btai ne d directl y fr o m e x peri me ntal o bser vati o ns. If 
m ulti ple ma xi ma occ ur at e q ual c o nce ntrati o ns, t he first te m p oral val ue will be ta ke n as t he C
ma x / Cma x ss  a n d 
T ma x / Tma x, ss . 
T 1/ 2, w here deter mi na ble, will be calc ulate d as t he nat ural l o garit h m of  2 di vi de d b y t he ter mi nal p hase rate 
c o nsta nt, la m b da z (λ z). T he n u m ber of data p oi nts i ncl u de d i n t he re gressi o n will be deter mi ne d b y vis ual 
i ns pecti o n, b ut a mi ni m u m of 3 data p oi nts i n t he ter mi nal p hase, e xcl u di n g Cma x / Cma x,ss , is re q uire d t o 
esti mate λ z. I n a d diti o n, T1/ 2 s h o ul d be deter mi ne d wit h a s pa n ≥ 2 wit h s pa n defi ne d as t he ti me i nter val 
use d t o deter mi ne la m b da _z (i.e., u p per la m b da _z mi n us l o wer la m b da _z) di vi de d b y t he T 1/ 2. If t his criteria 
is n ot met, t he T 1/ 2  data will be e xcl u de d fr o m s u m mar y statistics b ut will liste d a n d fla g ge d.  
I n or der f or λz-deri ve d para meters ( λ z, V z/ F, Vss/ F, a n d T 1/ 2) t o be liste d a n d s u m marize d, t he a dj uste d r 2 
val ue re p orte d i n P h oe ni x ® Wi n N o nli n
® m ust be ≥ 0. 8 . I n a d diti o n, A U Ce xtr m ust be < 2 0 % f or C ycle 1 Da y 1 
P K para meters o nl y ( A U C i nf). All P K para meters t hat d o n ot meet t hese criteria will be liste d. 
Re gressi o n para meters f or esti mati o n of  λ z, i ncl u di n g t he n u m ber of ti me p oi nts use d, ti me  p oi nt ra n ge, r -
s q uare d, a dj uste d r-s q uare d, a n d s pa n will be liste d. 
F or t he p ur p ose of calc ulati n g A U C, all missi n g val ues will be treate d as missi n g i n t he P K a nal ysis a n d 
e xcl u de d fr o m a nal ysis e xce pt w he n t he y occ ur at pre -d ose ( of Da y 1), w here t he y will be set t o 0 . Missi n g 
pre -d ose val u es f or all ot her da ys will be ha n dle d o n a case -b y -case basis a n d ma y be i m p ute d usi n g t he 
C tr o u g h val ue f or t hat c orres p o n di n g d osi n g i nter val. If C tr o u g h val ue is missi n g, t he missi n g pre -d ose will be 
i m p ute d usi n g t he l o west c o nce ntrati o n val ue o bser ve d f or t hat c orres p o n di n g d osi n g i nter val, if warra nte d. 
All A U Cs  i ncl u di n g partial A U Cs (A U C 0 -8, A U C 0 -1 2, A U C0 -2 4, a n d A U Cta u) will be calc ulate d usi n g t he 
li near tra pez oi dal met h o d a n d act ual ela pse d ti me val ues.  A U C 0 -2 4 f or t he BI D d osi n g will be deter mi ne d b y 
esti mati n g 2  ×  A U C 0 -1 2 f or C ycle 1 Da y 1 5. If n o P K sa m ple was c ollecte d at t he 1 2 or 2 4 h o ur p ost d ose 
f or eit her t he BI D or Q D d osi n g re gi me n, o ne of t w o a p pr oac hes will be ta ke n t o all o w f or t he 
deter mi nati o n of  A U C 0 -8, A U C 0 -1 2, A U C0 -2 4 , or A U C ta u: 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 4 2  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 4 2  of 4 7  
C O N FI D E N TI A L  
 
•  F or C ycle 1 Da y 1, t he 1 2 or 2 4 h o ur p ost -d ose sa m ple will be calc ulate d via a n e xtra p olati o n met h o d  
usi n g P h oe ni x ®  Wi n N o nli n
®  sta n dar d calc ulati o ns. If n o la m b da z is esti mate d, A U C 0 -8, A U C 0 -1 2 or 
A U C 0 -2 4 will n ot be esti mate d. M ore o ver, t he a dj uste d r 2 val ue m ust be ≥ 0. 8  a n d A U C e xtr m ust be < 2 0 % 
f or A U C 0 -8, A U C 0 -1 2,  a n d A U C 0 -2 4 t o be esti mate d b y e xtra p olati o n.  
•  F or C ycle 1 Da y 1 5, t he 1 2 or 2 4 h o ur p ost -d ose sa m ple will be i m p ute d usi n g t he pre -d ose 
c o nce ntrati o n or t he mi ni m u m o bser ve d c o nce ntrati o n wit hi n t hat BI D or Q D d osi n g i nter val (if t he pre -
d ose c o nce ntrati o n is missi n g) t o o btai n t he A U C ta u. 
C L/ F o n Da y 1 will be calc ulate d as D ose ( D)/ A U C 0 -1 2 or A U C 0 -2 4 a n d C L ss/ F o n Da y 1 5 will be calc ulate d 
as D ose ( D)/ A U Cta u ( w here ta u = 1 2 or 2 4 h o urs). 
V/ F o n Da y 1  will be calc ulate d as D/( λ * A U C 0 -1 2 or A U C 0 -2 4) a n d V z,ss/ F o n Da y 1 5 will be calc ulate d as 
D/( λ * A U C ta u) ( w here ta u = 1 2 or 2 4 h o urs). 
C a ve will be calc ulate d as A U C ta u/ 1 2 or A U C ta u/ 2 4 ( w here ta u = 1 2 or 2 4 h o urs) . 
Plas ma P K para meters (see  T a ble 5 ) will be liste d a n d s u m marize d b y c o h ort , a nal yte, a n d visit  ( C ycle 1 
Da y 1 or C ycle 1 Da y 1 5) usi n g descri pti ve statistics  f or t he Safet y A nal ysis Set a n d P K A nal ysis Set. 
S u m mar y statistics  f or all ot her P K para meters i ncl u de n , m ea n, S D, arit h metic coefficie nt of v ariati o n ( %), 
m e dia n, m i ni m u m, m a xi m u m, g e o metric m ea n, a n d g e o metric coefficie nt of v ariati o n ( %).  S u m mar y 
statistics f or t he P K para meters T ma x , T1/ 2, a n d Tlast will i ncl u de n , m ea n, S D, m e dia n, m i ni m u m, a n d 
m a xi m u m.  
6. 7. 4  
P h ar m a c o d y n a mi c/ Bi o m a r ker A n al ysis   
All p har mac o d y na mic/ bi o mar ker  data will be prese nte d i n listi n gs.  
Descri pti ve statistics of Baseli ne a n d c ha n ge i n bi o mar kers will be pr o vi de d at eac h sa m pli n g ti me f or all 
s u bj ects, a n d b y d ose/c o h ort (as a p plica ble). 
L o n git u di nal pl ots will be prese nte d f or selecte d p har mac o d y na mic/ bi o mar ker para meters.  
7.  A N A L Y S E S P E R F O R M E D B E F O R E D A T A B A S E C L O S U R E   
I nteri m f utilit y a nal yses will be c o n d ucte d i n bet wee n sta ges d uri n g t he P hase 2  C o m bi nati o n , if a p plica ble. 
T he g ui di n g f utilit y a n d pr o misi n g criteria f or eac h c o h ort are prese nte d i n T a ble 1  a n d  t he pri mar y a nal ysis 
is detaile d i n Secti o n 6. 5. 2 . 
8.  C H A N G E S F R O M M E T H O D S  P L A N N E D I N T H E P R O T O C O L   
I n re gar d t o t he M o n ot hera p y P hase 2 Efficac y, secti o n 6. 1. 7 of t he  pr ot oc ol state t hat e fficac y i n t he 
M o n ot hera p y P hase 2 will be deter mi ne d b y C B R a n d res ults will be c o m bi ne d wit h t h ose fr o m s u bjects 
wit h si milar treat me nt c haracteristics ( 2 n d/ 3r d Li ne t hera p y) a n d treate d at t he sa me d ose le vel of Z N -c 5 i n 
t he M o n ot hera p y E x pa nsi o n ar m. T he a nal ysis will si m pl y be d o ne b y p hase. 
A n a d diti o nal p o p ulati o n n ot defi ne d i n t he pr ot oc ol, t he T u m or Res p o nse E val ua ble Set  has bee n defi ne d 
f or use i n efficac y a nal yses. 
I n a Pr ot oc ol Clarificati o n Letter ( 1 5 J u ne 2 0 2 2), it was a n n o u nce d t hat st u d y has reac he d t he ti me p oi nt 
w here a data c ut -off of 1 8 Ma y 2 0 2 2 has bee n esta blis he d after t he pri mar y o bj ecti ves of t he st u d y ha ve 


 
St atistic al A n al ysis Pl a n  
Pr ot oc ol N o. Z N -c 5 -0 0 1  
Re visi o n 0 0: 1 7 Fe b 2 0 2 3  
 ( Pa ge 4 3  of 4 7 ) 
 
D O C. S T. 1 0 1. 0 4 -0 1 Re v 0 0  
Pa ge 4 3  of 4 7  
C O N FI D E N TI A L  
 
bee n met . Be y o n d t his c ut-off, o nl y li mite d i nf or mati o n i ncl u di n g st u d y dr u g a d mi nistrati o n, st u d y dr u g 
acc o u nta bilit y, a n d n o n -seri o us a n d seri o us a d verse e ve nts were  c ollecte d i n a d diti o n t o a n y cases of 
pre g na nc y, o ver d ose, or me dicati o n err or. E n d of treat me nt i nf or mati o n (reas o n f or disc o nti n uati o n f or m 
o nl y [ E O T], n ot t he f ull visit) a n d Safet y F oll o w -u p i nf or mati o n ( Date of Visit [ D O V] f or m o nl y, n ot t he 
f ull visit) were  als o c ollecte d . 
Beca use t his c ut-off was a d o pte d b y t he sites at differe nt dates , s u bjects w h o were o n g oi n g ma y ha ve data 
re p orte d be y o n d t his c ut-off  date . 
9.  S T A TI S TI C A L S O F T W A R E   
S A S Versi o n 9. 4 or later will be use d f or all statistical a nal yses.  
T he P K para meters will be esti mate d b y n o nc o m part me ntal a nal ysis ( N C A ) usi n g t he s oft ware P h oe ni x ®  
Wi n N o nli n
®  versi o n 8. 1 ( Certara, U S A). 
1 0.  R E F E R E N C E S   
1.  Br o o k me yer a n d Cr o wle y, A C o nfi de nce I nter val f or t he Me dia n S ur vi val Ti me, Bi o metrics 3 8, 2 9 -4 1, 
Marc h 1 9 8 2.  
2.  Ka pla n, E. L. Meier, P. ( 1 9 5 8). N o n para metric esti mati o n fr o m i nc o m plete o bser vati o ns . J. A mer. 
Statist. Ass n . 5 3  ( 2 8 2): 4 5 7– 4 8 1.  J S T O R 2 2 8 1 8 6 8 . 
3.  Klei n, J. P. a n d M oesc h ber ger, M. L. ( 1 9 9 7), S ur vi val A nal ysis: T ec h ni q ues f or Ce ns ore d a n d Tr u ncate d 
Da ta, Ne w Y or k: S pri n ger-Verla g.  
4.  Kal bfleisc h J D, Pre ntice R L. ( 2 0 0 2) T he Statistical A nal ysis of Fail ure Ti me Data. Wile y Series i n 
Pr o ba bilit y a n d Statistics.  
5.  Cli nical Trial E n d p oi nts f or t he A p pr o val of Ca ncer Dr u gs a n d Bi ol o gics, F D A g ui da nce, Ma y 2 0 0 7.  
6.  K ratz, A, Le wa n dr o ws ki, K. B. ( 1 9 9 8). N or mal Refere nce La b orat or y Val ues. T he Ne w E n gla n d J o ur nal 
of Me dici ne , 3 3 9, 1 0 6 3-1 0 7 2.  
7.  Kratz, A., Ferrar o, M., Sl uss, P. M., Le wa n dr o ws ki, K. B. ( 2 0 0 4). N or mal Refere nce La b orat or y Val ues. 
T he Ne w E n gla n d J o ur nal of Me di ci ne, 3 5 1, 1 5 4 8 -1 5 6 3.  
8.  P h U S E C S S De vel o p me nt of Sta n dar d Scri pts f or A nal ysis a n d Pr o gra m mi n g W or ki n g Gr o u p. ( 2 0 1 4). 
A nal yses a n d Dis pla ys Ass ociate d t o N o n -C o m part me ntal P har mac o ki netics –  Wit h a F oc us o n Cli nical 
Trials [ W hite pa per].  Retrie ve d A pril  9 , 2 0 1 9  fr om : htt ps:// w w w. p h use.e u/ d oc u me nts/ w or ki n g -
gr o u ps/ deli vera bles/a nal yses -dis pla ys -ass ociate d -t o-n o n -c o m part me ntal -p har mac o ki netics -versi o n -1 0 -
2 5 -mar -1 4 -p df -1 1 8 0 3. p df  
9.  G ui deli ne, I C H Har m o nise d Tri partite. T he Cli nical E val uati o n of Q T/ Q T c I nter val Pr ol o n gati o n a n d 
Pr oarr h yt h mic P ote ntial f or N o n -A ntiarr h yt h mic Dr u gs E 1 4. 2 0 0 5.  


 
Statistical Analysis Plan 
Protocol No. ZN-c5-001 
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11. APPENDIX 1 NCI-CTCAE V4.03 TOXICITY GRADING  
11.1 Panel: Chemistry  
Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Albumin, serum- low 
(hypoalbuminemia)  
g/L 
[30, LLN) 
[20, 30) 
<20 
life-threatening 
consequences; 
urgent 
intervention 
indicated 
Alkaline phosphatase 
(ALK) increased 
U/L 
(ULN, 
2.5*ULN] 
(2.5*ULN, 
5*ULN] 
(5*ULN, 
20*ULN] 
>20*ULN 
Alanine aminotransferase 
(ALT) increased 
U/L 
(ULN, 
3.0*ULN] 
(3.0*ULN, 
5.0*ULN] 
(5*ULN, 
20*ULN]; 
>20*ULN 
Aspartate 
aminotransferase (AST) 
increased 
U/L 
(ULN, 
3.0*ULN] 
(3.0*ULN, 
5.0*ULN] 
(5*ULN, 
20*ULN]; 
>20*ULN 
Bilirubin increased 
μmol/L 
(ULN, 
1.5*ULN] 
(1.5*ULN, 
3*ULN] 
(3*ULN, 
10*ULN] 
>10*ULN 
Calcium high 
(hypercalcemia)  
mmol/L 
(ULN, 2.9] 
(2.9, 3.1] 
(3.1, 3.4]; 
hospitalization 
indicated 
>3.4; life-
threatening 
consequences 
Calcium low 
(hypocalcemia)  
mmol/L 
[2.0, LLN) 
[1.75, 2.0) 
[1.5, 1.75); 
hospitalization 
indicated 
[0, 1.5); life 
threatening 
consequences 
Creatine phosphokinase 
(CPK) increased 
U/L 
(ULN, 
2.5*ULN] 
(2.5*ULN, 
5*ULN] 
(5*ULN, 
10*ULN] 
>10*ULN 
Creatinine increased 
μmol/L 
 (1 – 
1.5*baseline]; 
(ULN, 
1.5*ULN] 
(1.5 – 3.0* 
baseline]; 
(1.5*ULN, 
3*ULN] 
>3.0*baseline; 
(3*ULN, 
6*ULN] 
>6*ULN 
Gamma-glutamyl-
transferase 
U/L 
 (ULN, 
2.5*ULN] 
 (2.5*ULN, 
5*ULN] 
(5*ULN, 
20*ULN] 
>20*ULN 
Glucose high 
(hyperglycemia) 
mmol/L 
(ULN, 8.9] 
(8.9, 13.9] 
(13.9, 27.8]; 
hospitalization 
indicated 
>27.8; life 
threatening 
consequences 
Glucose low 
(hypoglycemia) 
mmol/L 
[3.0, LLN) 
[2.2, 3.0) 
[1.7, 2.2) 
[0, 1.7); life 
threatening 
consequences; 
seizures 


 
Statistical Analysis Plan 
Protocol No. ZN-c5-001 
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Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Magnesium low 
(hypomagnesemia) 
mmol/L 
[0.5, LLN) 
[0.4, 0.5) 
[0.3, 0.4) 
<0.3; life-
threatening 
consequences 
Magnesium high 
(hypermagnesemia) 
mmol/L 
(ULN, 1.23] 
undefined 
(1.23, 3.3] 
>3.3; life-
threatening 
consequences 
Phosphates 
(hypophosphatemia) 
mmol/L 
[0.8, LLN) 
[0.6, 0.8) 
[0.3, 0.6) 
[0, 0.3); life 
threatening 
consequences; 
seizures 
Potassium high 
(hyperkalemia)  
mmol/L 
(ULN, 5.5] 
(5.5, 6] 
(6, 7]; 
hospitalization 
indicated 
>7; life-
threatening 
consequences 
Potassium low 
(hypokalemia)  
mmol/L 
[3, LLN) 
[3, LLN); 
symptomatic; 
intervention 
indicated 
[2.5, 3); 
hospitalization 
indicated 
[0, 2.5); life-
threatening 
consequences 
Sodium high 
(hypernatremia) 
mmol/L 
(ULN, 150] 
(150, 155] 
(155, 160]; 
hospitalization 
indicated 
>160; life-
threatening 
consequences 
Sodium low 
(hyponatremia) 
mmol/L 
[130, LLN) 
undefined 
[120, 130) 
[0, 120); life-
threatening 
consequences 
11.2 Panel: Hematology  
Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hemoglobin increased 
g/dL 
 
Increase in >0 -
2 gm/dL above 
ULN or above 
baseline if 
baseline is 
above ULN 
Increase in >2 -
4 gm/dL above 
ULN or above 
baseline if 
baseline is 
above ULN 
Increase in >4 
gm/dL above 
ULN or above 
baseline if 
baseline is 
above ULN 
undefined 
Hemoglobin decreased 
g/L 
[100, LLN) 
[80, 100) 
[0, 80); 
transfusion 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Platelet count decreased 
10^9/L 
[75, LLN) 
[50, 75) 
[25, 50) 
[0, 25) 
WBC increased 
10^9/L 
undefined 
undefined 
>100 
undefined 
WBC decreased 
10^9/L 
[3, LLN) 
[2, 3) 
[1, 2) 
[0, 1) 
Lymphocytes increased 
10^9/L 
undefined 
(4, 20] 
>20 
undefined 
Lymphocytes decreased 
10^9/L 
[0.8, LLN)  
[0.5, 0.8) 
[0.2, 0.5) 
[0, 0.2) 


 
Statistical Analysis Plan 
Protocol No. ZN-c5-001 
Revision 00: 17Feb2023 
 (Page 46 of 47) 
 
DOC.ST.101.04-01 Rev 00 
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CONFIDENTIAL 
 
Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neutrophil count 
decreased 
10^9/L 
[1.5, LLN) 
[1, 1.5) 
[0.5, 1) 
[0, 0.5) 
11.3 Panel: Coagulation  
Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
International normalized 
ratio of prothrombin time 
(INR) increased 
NA 
(ULN, 
1.5xULN] 
(1.5xULN, 
2xULN] 
>2xULN 
- 
Activated partial 
thromboplastin time 
prolonged 
Seconds 
(ULN, 
1.5xULN] 
(1.5xULN, 
2.5xULN] 
>2.5 x ULN 
- 
11.4 Panel: Lipid Panel  
Lab Test 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Cholesterol high 
mmol/L 
(ULN, 7.75] 
(7.75, 10.34] 
(10.34, 12.92] 
>12.92 
Triglycerides high 
(hypertriglyceridemia) 
mmol/L 
(1.71, 3.42] 
(3.42, 5.7] 
(5.7, 11.4] 
>11.4 
* Conditions will not be checked programmatically. 
Reference: https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06 14_QuickReference_5x7.pdf 


 
Statistical Analysis Plan 
Protocol No. ZN-c5-001 
Revision 00: 17Feb2023 
 (Page 47 of 47) 
 
DOC.ST.101.04-01 Rev 00 
Page 47 of 47 
CONFIDENTIAL 
 
12. APPENDIX 2 PROGRAMMING CODES FOR STATISTICAL ANALYSIS  
Programming of the tables, listings and figures will be performed using SAS Version 9.4 or later, running 
under UNIX environment. The following table presents the SAS codes for the analyses of response 
endpoints. 
Endpoint 
Test 
SAS Code  
ORR, CBR 
Clopper-Pearson (exact) 95% 
confidence interval  
ods listing close; 
proc freq data = indata; 
 
ods output BinomialCLs=CI BinomialProp=prop; 
 
table objresp / binomial(level = 1 exact) out=freq1 
(keep=objresp count); 
run; 
ods listing; 
PFS, DOR, OS 
Kaplan-Meier: median, 95% 
CI, 25th-75th percentile 
ods listing close; 
ods output Quartiles=Quartile; 
proc lifetest data=indata; 
 
time timevar*censvar(1); 
run; 
ods output close; 
ods listing; 
 


PPD