Clinical trial NCT03712930
Conditions: Metastatic Castration-Resistant Prostate Cancer (mCRPC) Homologous Recombination Deficiency (HRD)
Sponsor: BeiGene
Start date: 2019-02-05; Completion date: 2020-09-02
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is designed to evaluate the efficacy of pamiparib in participants with metastatic castration-resistant prostate cancer (mCRPC) positive for circulating tumor cells (CTC) with homologous recombination deficiency (CTC-HRD). All participants will receive pamiparib. The purpose of this study is to demonstrate that pamiparib will improve Objective Response Rate (ORR) and Prostate-Specific Antigen (PSA) response rate

Detailed description:
This is a global, Phase 2, open-label study of pamiparib in approximately 100 participants with metastatic castration-resistant prostate cancer (mCRPC) positive for circulating tumor cells (CTC) with homologous recombination deficiency (CTC-HRD). Participants in Cohort 1 will include 50 mCRPC participants with CTC-HRD-positive, measurable metastatic disease (soft tissue with/without bone lesions), and positive BRCA1/2 mutation or negative/unknown BRCA1/2 mutation. Cohort 2 will include 30 mCRPC CTC-HRD positive participants with bone metastasis only and positive or negative/unknown BRCA1/2. Cohort 3 and 4 will include 20 mCRPC CTC-HRD negative/unknown participants with BRCA1/2 positive mutations, metastatic disease (measurable soft tissue with/without bone), and bone only. Participants will undergo PSA level assessments approximately every 4 weeks as well as tumor assessments every 8 weeks for 24 weeks and the every 12 weeks, or as clinically indicated. Administration of pamiparib will continue until disease progression, unacceptable toxicity, death or another discontinuation criterion is met.

Arms: arm 1: Participants will receive pamiparib for a period up to 1 year
Interventions: intervention 1: Pamiparib
Intervention descriptions: intervention 1: 60 mg orally twice daily (BID)

Protocol documents:
Prot_000.pdf: 
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 CLINICAL STUDY PROTOCOL 
 
Protocol Title:  
A Phase 2, Open-Label, Single-Arm Study of Pamiparib (BGB-290) for 
the Treatment of Patients with Metastatic Castration-Resistant Prostate 
Cancer (mCRPC) with Homologous Recombination Deficiency (HRD) 
Protocol Identifier: 
Pamiparib (BGB-290-202) 
EudraCT Number: 
2018-002587-28 
Phase: 
2 
Protocol Version 0.0: 
27 July 2018 
Protocol Version 1.0: 
16 October 2018 
Sponsor: 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
2929 Campus Drive, Suite 300 
San Mateo, California 94403 
USA 
Sponsor Medical 
Monitor: 
 
 
 
 
Confidentiality Statement 
This document contains confidential information and is the proprietary property of BeiGene Ltd.  This 
document is for use by individuals and their designated representatives for their confidential review, 
consideration, and/or participation in investigational trial(s).  This document may not be copied or distributed 
for review by any unauthorized individuals without the prior written authorization of BeiGene Ltd.  Your 
acceptance of this document constitutes agreement that you will not disclose the information contained 
herein to others without the prior written authorization from BeiGene Ltd. 
 


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FINAL PROTOCOL APPROVAL SHEET 
A Phase 2, Open-Label, Single-Arm Study of Pamiparib (BGB-290) for the Treatment of Patients with 
Metastatic Castration-Resistant Prostate Cancer (mCRPC) with Homologous Recombination Deficiency 
(HRD) 
BeiGene Approval: 
 
______________________________________________ 
Sponsor Medical Monitor  
 
 ____________________________ 
Date 


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SYNOPSIS 
Name of 
Sponsor/Company: 
BeiGene, Ltd. 
Investigational 
Product: 
Pamiparib (BGB-290) capsule 
Title of Study: 
A Phase 2, Open-Label, Single-Arm Study of Pamiparib (BGB-290) for the 
Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer 
(mCRPC) with Homologous Recombination Deficiency (HRD) 
Protocol No: 
BGB-290-202 
Number of Patients: 
Approximately 100 patients 
Study Centers: 
Approximately 45 centers in Asia, Australia, Europe, and the United States 
Study Phase: 
2 
Treatment 
Duration: 
Patients will receive daily treatment during the study until occurrence of 
progressive disease (PD), unacceptable toxicity, death, withdrawal of 
consent, lost to follow-up, or study termination by sponsor. 
Study Objectives: 
Pamiparib, a potent and selective inhibitor of poly (ADP-ribose) polymerase (PARP)1 and PARP2, 
showed potent PARP-trapping activity and antiproliferative activity against several cell lines harboring 
BRCA gene mutations or other homologous recombination deficiencies (HRD). 
Primary Objective: 
 
To evaluate the efficacy of pamiparib in patients with metastatic castration-resistant prostate 
cancer (mCRPC) positive for circulating tumor cells (CTC) with homologous recombination 
deficiency (CTC-HRD-positive; per Epic Sciences assay), as per Prostate Cancer Clinical Trials 
Working Group [PCWG3] criteria 
Secondary Objectives: 
 
To further evaluate the efficacy of pamiparib in patients with CTC-HRD-positive mCRPC with 
measurable disease (Cohort 1 of Synopsis Table 1), as per PCWG3 criteria 
 
To further evaluate the efficacy of pamiparib in patients with CTC-HRD-positive mCRPC with 
or without measurable disease (Cohorts 1 and 2 of Synopsis Table 1, respectively), as per 
PCWG3 criteria 
 
To evaluate the safety and tolerability of pamiparib 
Exploratory Objectives: 


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 
 
 
 
Study Endpoints: 
Assessments are per the investigator except when indicated otherwise. Assessments will be conducted 
in accordance with Good Clinical Practice and all applicable regulatory requirements. 
Primary Endpoints: 
 
Objective response rate (ORR; defined as the proportion of patients with best objective response 
of complete response (CR) or partial response (PR) confirmed at a subsequent timepoint  4 
weeks later) by Independent Review Committee (IRC) for CTC-HRD-positive patients with 
measurable disease (Cohort 1 of Synopsis Table 1) 
 
Prostate-specific antigen (PSA) response rate (defined as the proportion of patients with PSA 
decline  50% from baseline [confirmed by a second PSA value  3 weeks later]) for 
CTC-HRD-positive patients with or without measurable disease (Cohorts 1 and 2 of Synopsis 
Table 1, respectively) 
Secondary Endpoints: 
Patients with CTC-HRD-Positive mCRPC with Measurable Disease (Cohort 1 of Synopsis 
Table 1) per PCWG3 Criteria 
 
Duration of response (DOR) by IRC 
 
ORR by investigator 
 
Time to objective response 
 
Clinical benefit rate (defined as the proportion of patients with a documented confirmed CR, 
PR, or stable disease) 
Patients with CTC-HRD-Positive mCRPC with or without Measurable Disease (Cohorts 1 and 2 
of Synopsis Table 1, respectively) per PCWG3 Criteria 
 
Time to PSA response 
 
Duration of PSA response 
 
Time to PSA progression (defined as the time from the date of the first dose of study drug to a 
 25% increase in PSA with an absolute increase of  2 ng/mL above the nadir [or above the 
baseline for patients with no PSA decline after 12 weeks], confirmed by a second value 
 3 weeks later) 
 
Time to symptomatic skeletal event (SSE; defined as time from the date of the first dose of 
study drug to the first symptomatic fracture, radiation or surgery to bone, or spinal cord 
compression) 
 
Radiographic progression-free survival (rPFS; defined as the time from the date of the first dose 
of study drug to radiographic disease progression by IRC or death due to any cause, whichever 


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occurs first) 
 
Overall survival (OS) 
All Patients (Cohorts 1, 2, 3, and 4 of Synopsis Table 1) 
 
Incidence, timing, and severity of treatment-emergent adverse events (TEAEs), graded 
according to National Cancer Institute-Common Terminology Criteria for Adverse Events 
(NCI-CTCAE) Version 4.03 or higher 
Exploratory Endpoints: 
 
 
 
 
 
Study Design: 
This is an open-label, single-arm, global Phase 2 study to evaluate the efficacy and safety of single-
agent poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitor pamiparib in biomarker positive 
mCRPC patients. Biomarker positivity is defined as CTC-HRD-positive and/or deleterious germline or 
somatic mutation in BRCA1 or BRCA2. 
To be eligible for the study, biomarker-positive patients must have progressed on or after at least 
one androgen receptor-targeted therapy for mCRPC (eg, enzalutamide, abiraterone acetate/prednisone, 
bicalutamide, flutamide, apalutamide, or nilutamide), received at least 1 taxane-based therapy for 
metastatic prostate cancer, and have PSA progression as per PCWG3 criteria at time of study entry. The 
primary endpoints are ORR by IRC for patients with measurable disease (n ≈ 50) and PSA response 
rate for patients with or without measurable disease (n ≈ 80) as per PCWG3 criteria. 
Cohort 1 will include 50 mCRPC patients with CTC-HRD-positive, measurable metastatic disease (soft 
tissue with/without bone lesions), and positive BRCA1/2 mutation or negative/unknown BRCA1/2 
mutation. Cohort 2 will include 30 mCRPC CTC-HRD positive patients with bone metastasis only and 
positive or negative/unknown BRCA1/2. Cohort 3 and 4 will include 20 mCRPC CTC-HRD 
negative/unknown patients with BRCA1/2 positive mutations, metastatic disease (measurable soft 
tissue with/without bone), and bone only (see Synopsis Table 1).  
After enrollment, patients will receive pamiparib 60 mg orally twice a day in cycles of 28 days. 
Safety assessments will occur on Day 1 of each cycle, on Day 15 of Cycles 1 and 2, and as needed. 
Dose modifications will be made if appropriate. Adverse events (AEs) will be followed and documented 
during the treatment phase and for approximately 30 days after the last dose of pamiparib or until 


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initiation of new anticancer therapy, whichever occurs first. AEs will be graded according to NCI-
CTCAE Version 4.03 or higher. A Safety Monitoring Committee will periodically review safety data. 
PK samples for pamiparib will be collected at various timepoints at all non-China centers and at centers 
with such capability in China. In addition, tumor tissue (if available) and blood samples will be obtained 
to explore biomarkers of pharmacodynamics, response, and resistance to pamiparib in mCRPC. 
Disease status will be assessed by the investigator using PCWG3 criteria. Patients will undergo tumor 
assessments every 8 weeks (± 7 days) for 24 weeks, then every 12 weeks (± 7 days), or as clinically 
indicated. PSA assessments will occur at screening, on Day 1, and then every 4 weeks (± 7 days), or as 
clinically indicated. 
Administration of pamiparib will continue until PD, unacceptable toxicity, death, or another 
discontinuation criterion is met. Once the treatment phase has been completed, an End-of-Treatment 
Visit should occur within 7 days of stopping pamiparib with subsequent phases of safety and long-term 
follow-up. 
Long-term follow-up will include tumor and PSA assessments every 12 weeks and 4 weeks (± 7 days), 
respectively, for those patients without PD, survival status, and initiation of new anticancer therapy. 
Long-term follow-up will continue until the patient dies or another criterion for discontinuation from 
study is met. 
Study Schema 
 
Abbreviations: CTC-HRD+, positive for circulating tumor cells with homologous recombination deficiency per Epic Sciences 
assay; mCRPC, metastatic castration-resistant prostate cancer; PARPi, PARP inhibitor; PCWG3, Prostate Cancer Clinical 
Trials Working Group 3; PD, progressive disease; PSA, prostate-specific antigen; RECIST, Response Evaluation Criteria in 
Solid Tumors. 
Notes: Key assessments during the treatment phase: tumor assessments every 8 weeks (± 7 days) for 24 weeks, then every 
12 weeks (± 7 days), or as clinically indicated; and patient-reported outcomes, PSA, adverse events, hematology, and chemistry 
every 4 weeks. Pamiparib is to be administered continuously. 


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Synopsis Table 1. Patient Cohorts 
 
Abbreviations: , biomarker status unknown; CTC-HRD-, negative for circulating tumor cells with homologous 
recombination deficiency per Epic Sciences assay; CTC-HRD+, positive for circulating tumor cells with homologous 
recombination deficiency per Epic Sciences assay. 
Summary of Eligibility Criteria: 
The population under study is men ( 18 years of age) with histologically or cytologically confirmed 
adenocarcinoma or poorly differentiated adenocarcinoma of the prostate without neuroendocrine 
differentiation with HRD deficiency by CTC-HRD assay and/or deleterious germline or somatic 
mutation in BRCA1 or BRCA2; mCRPC measurable disease as per Response Evaluation Criteria in 
Solid Tumors (RECIST) Version 1.1 and/or bone disease. Patients must have PSA progression with  3 
rising PSA levels with  1 week between determinations and a screening PSA  2 µg/L (2 ng/mL). 
Patients must be surgically or medically castrated with serum testosterone levels of  1.73 nmol/L (50 
ng/dL), must have received  1 prior androgen receptor-targeted therapy, and must have received 
1 taxane-based therapy. 
Test product, dose, 
and mode of 
administration: 
Pamiparib 60 mg orally twice a day 
Reference therapy, 
dose, and mode of 
administration: 
Not applicable 
Dose Modifications: 
Dosing of pamiparib can be withheld for up to 28 days consecutively. Dose reductions are allowed in 
20 mg per dose decrements. A maximum of 2 dose reductions is allowed before the patient must be 
permanently withdrawn from pamiparib. If drug is planned to be held  28 days, the medical monitor 
must be contacted before permanent patient discontinuation from pamiparib. 
Concomitant Therapy and Clinical Practice: 
All treatments and supportive care, including antiemetic therapy, hematopoietic growth factors, and/or 
red blood cell/platelet transfusions, that the investigator considers necessary for a patient’s welfare 
may be administered at the discretion of the investigator in keeping with the local standards of 
medical care.  
All concomitant medications, including all prescription and over-the-counter drugs, supplements, and 
intravenous medications and fluid supplementation, taken by or administered to the patient within 
28 days before Day 1 and 30 days after the last dose of pamiparib will be recorded. 
Patients are not allowed to receive other anticancer therapy, including chemotherapy, hormonal 
therapy, biologic therapy, radionuclide therapy, immunotherapy, investigational agent, Chinese 


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anticancer medicine, or herbal remedies  5 half-lives if the half-life is known,  14 days if not 
known, before Day 1 and during the study. In addition, patients are not allowed to receive 
radiotherapy ≤ 21 days (≤ 14 days, if a single fraction of radiotherapy) before Day 1 and during the 
study. Bisphosphonate and denosumab use is permitted if the patient had already been receiving it at a 
stable dose  28 days before Day 1. 
The primary metabolic pathway for pamiparib involves the cytochrome P450 (CYP)3A isoform. 
Administration of strong/moderate inhibitors of CYP3A or strong CYP3A inducers is not allowed. In 
addition, careful monitoring should be used when co-prescribing CYP2C9 substrates with a narrow 
therapeutic index, such as phenytoin and warfarin. 
Criteria for Evaluation: 
Efficacy: 
Following the screening tumor assessment, tumor assessments will occur at the schedule of every 
8 weeks (± 7 days) after Day 1 for 24 weeks, then every 12 weeks (± 7 days). Any measurable disease 
must be documented at screening and reassessed at each subsequent tumor evaluation. Response and 
DOR will be assessed by the investigator using PCWG3 criteria. The same imaging method(s) used at 
screening must be used throughout the study. A documented standard-of-care tumor assessment may be 
used as the screening assessment provided it meets protocol requirements.  
PSA levels will be collected and tested in a certified local laboratory during screening, on Day 1, and 
every 4 weeks (± 7 days), or as clinically indicated. In addition, at least, the 3 most recent PSA levels 
before Day 1 ( 1 week between determinations) must be provided to document PSA progression before 
study entry. Increases and decreases in PSA will be tracked to assess PSA responses as defined by the 
PCWG3 criteria. A PSA response or progression must be confirmed  3 weeks later. 
Patients who do not have objective disease progression at the time of pamiparib permanent 
discontinuation but meet other discontinuation criteria will continue to have tumor and PSA assessments 
per protocol. Survival status of patients will be monitored through all phases of the study. 
Safety: 
Safety will be monitored throughout the study. Safety assessments include AE monitoring and 
reporting, physical examinations, vital sign measurements, electrocardiograms, and clinical laboratory 
tests. 
Statistical Methods: 
Analysis Sets: 
 
Safety Analysis Set: includes all patients enrolled into the study who receive any dose of 
pamiparib. The Safety Analysis Set will be used for all safety analyses. 
 
Efficacy-Evaluable Analysis Set (ORR Assessment in Cohort 1 of Synopsis Table 1): includes 
all patients in the Safety Analysis Set who had measurable disease at baseline and at least 
1 postbaseline tumor assessment, unless they permanently discontinue pamiparib or the study 
early due to clinical progression or death before tumor assessment. The Efficacy-Evaluable 
Analysis Set is the primary analysis set for tumor response analysis. 
 
PSA-Evaluable Analysis Set (PSA Response Rate Assessment in Cohorts 1 and 2 of Synopsis 
Table 1): includes all patients in the Safety Analysis Set as per Inclusion Criterion 7 at baseline 
( 3 rising PSA levels with  1 week between determinations and screening PSA  2 µg/L) and 
who had at least 1 postbaseline PSA measurement, unless they permanently discontinue 
pamiparib or the study early due to clinical progression or death before completed PSA 


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assessment. 
 
PK Analysis Set: includes all patients who received pamiparib and for whom valid pamiparib 
PK parameters can be estimated. 
Efficacy Analyses: 
Primary Efficacy Endpoint Analysis: 
The primary endpoints of the study include ORR by IRC in CTC-HRD-positive patients with 
measurable disease and PSA response rate in CTC-HRD-positive patients with or without measurable 
disease per PCWG3 criteria. 
ORR is defined as the proportion of patients with best objective response of CR or PR confirmed at a 
subsequent timepoint  4 weeks later by IRC assessment. Patients without tumor assessment are 
considered non-responders.  
ORR is assumed as 35% for pamiparib and estimated as 15% for historical control in the study 
population. The null and alternative hypotheses are set as follows: 
 
H0 : ORR = 15% 
 
Ha : ORR > 15% 
PSA response rate is defined as the proportion of patients with PSA decline  50% from baseline 
(confirmed by a second PSA value  3 weeks later). 
PSA response rate is assumed as 50% for pamiparib and estimated as 30% for historical control in the 
study population. The null and alternative hypotheses are set as follows: 
 
H0 : ORR = 30% 
 
Ha : ORR > 30% 
Binomial exact tests will be performed for above hypotheses in the Efficacy-Evaluable Analysis Set. 
Two-sided binomial exact 95% confidence interval (CI) of response rate will be constructed to assess 
the precision of the estimates. 
To control the overall study type-I error rate, ORR and PSA response rate will be tested sequentially. If 
the ORR test shows significance at 1-sided 0.025 level, PSA response rate will be tested at a 1-sided 
0.025 significance level. 
The primary efficacy analyses will be conducted when mature response data have been observed, which 
will be determined by the sponsor. 
A sensitivity analysis of response rate will be conducted using the Safety Analysis Set. 
ORR and PSA response rate will be summarized in the specified subgroups: age group (< 65 versus 
 65), race, geographic region, Eastern Cooperative Oncology Group performance status, BRCA1/2-
mutant status, and number of prior lines of therapy. 
Secondary Efficacy Endpoint Analyses: 
DOR by IRC assessment, ORR by investigator, and time to objective response and clinical benefit rate 
as assessed by investigator will be evaluated in patients with CTC-HRD-positive mCRPC with 
measurable disease per PCWG3 criteria.  
Time to PSA response, duration of PSA response, time to PSA progression, time to SSE, rPFS by IRC, 
and OS will be evaluated in patients with CTC-HRD-positive mCRPC with or without measurable 
disease per PCWG3 criteria.  
DOR is defined as the time from the date of the earliest documented confirmed response of CR or PR 


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to radiographic disease progression by IRC or death due to any cause, whichever occurs first.  
Time to objective response is defined as the time from the date of the first dose of study drug to the first 
documented confirmed response of CR or PR.  
Clinical benefit rate is defined as the proportion of patients with a documented confirmed response of 
CR, PR, or stable disease.  
Time to PSA response is defined as the time from the date of the first dose of study drug to the first 
documented confirmed PSA response. 
Duration of PSA response is defined as the time from the date of the earliest documented confirmed 
PSA response to PSA progression or death due to any cause, whichever occurs first. 
Time to PSA progression is defined as the time from the date of the first dose of study drug to a  25% 
increase in PSA with an absolute increase of  2 µg/L above the nadir (or above the baseline for patients 
with no PSA decline after 12 weeks), confirmed by a second value  3 weeks later. 
Time to SSE is defined as the time from the date of the first dose of study drug to the first symptomatic 
fracture, radiation or surgery to bone, or spinal cord compression. 
rPFS is defined as the time from the date of the first dose of study drug to radiographic disease 
progression by IRC or death due to any cause, whichever occurs first. 
OS is defined as the time from the date of the first dose of study drug to death due to any cause. 
Time-to-event variables of DOR, duration of PSA response, time to PSA progression, time to SSE, 
rPFS, and OS will be estimated using the Kaplan-Meier method. Median of these time-to-event 
variables will be presented along with their 2-sided 95% CI using the Brookmeyer and Crowley method.  
Descriptive statistics will be provided for time to objective response and time to PSA response. Only 
responders will be included in analyses for DOR, duration of PSA response, time to response, and time 
to PSA response.  
The ORR as assessed by investigator and its exact 2-sided 95% CI will be reported. 
Pharmacokinetic Analyses: 
Pamiparib concentrations will be summarized by nominal time of collection. Descriptive statistics will 
include means, medians, ranges, and standard deviations, as appropriate.  
Population PK analysis may be carried out to include plasma concentrations from this study in an 
existing model. Additional PK parameters such as apparent clearance (CL/F) of the drug from plasma 
and area under the plasma concentration-time curve from 0 to 12 hours postdose (AUC0-12) may be 
derived from the population PK analysis if supported by data.  
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by data. The 
results of the population PK and exposure-response analyses may be reported separately from the 
clinical study report.  
Exploratory Efficacy Analyses: 
 


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. 
Safety Analysis: 
All TEAEs including, serious AEs, deaths,  Grade 3 TEAEs, pamiparib-related TEAEs, and TEAEs 
that led to pamiparib withholding or permanent discontinuation, will be summarized. Pamiparib 
exposure, vital sign measurements, electrocardiogram findings, and clinical laboratory results will also 
be summarized. 
Sample Size: 
This study is designed to provide adequate power for primary endpoints of ORR and PSA response rate. 
A sample size of approximately 100 patients is planned (at approximately 45 centers with a projected 
average enrollment of 2 to 3 patients per center). 
Assuming ORR of 35% for pamiparib in CTC-HRD-positive patients versus 15% for historical control 
in patients with measurable disease, the study power is 88% using a binomial exact test and 1-sided 
type-I error of 0.025 with n = 50. The binomial exact 95% CI of 35% ORR is 22.1% to 49.8% with a 
sample size of 50 patients. 
Assuming PSA response rate of 50% for pamiparib versus 30% for historical control in 
CTC-HRD-positive patients with or without measurable disease, a sample size of 80 patients in this 
population will provide 95% study power using a binomial exact test and 1-sided type-I error of 0.025. 
The binomial exact 95% CI of 50% response rate is 38.6% to 61.4% with n = 80.  
To explore the efficacy of pamiparib in patients with CTC-HRD-negative, but BRCA1/2-mutant 
mCRPC with or without measurable disease, approximately 20 patients will be enrolled in these cohorts. 
Interim Analysis: 
A non-binding interim futility analysis will be performed among the first 20 patients enrolled in Cohorts 
1 and 2 (Synopsis Table 1). If the confirmed PSA response rate is < 30% (< 6 responses), enrollment 
will be halted, and safety and efficacy data will be further evaluated before making the decision of 
stopping enrollment permanently. The decision to continue the enrollment may be made at any time the 
6 confirmed PSA responses in Cohorts 1 and 2 can be documented; enrollment of all 20 patients is not 
required before determining further patient accrual. 
 


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TABLE OF CONTENTS 
FINAL PROTOCOL APPROVAL SHEET ..........................................................................2 
SYNOPSIS ................................................................................................................................3 
TABLE OF CONTENTS ......................................................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................19 
1. 
INTRODUCTION......................................................................................................21 
1.1. 
Metastatic Castration-Resistant Prostate Cancer .............................................21 
1.2. 
Poly (ADP-ribose) Polymerase Inhibitors .......................................................21 
1.3. 
Biology of BRCA+ Prostate Cancers and PARP Inhibitors ............................22 
1.4. 
Circulating Tumor Cells as a Biomarker in Metastatic Castration-Resistant 
Prostate Cancer ................................................................................................23 
1.5. 
PARP Inhibitor Pamiparib ...............................................................................24 
1.5.1. 
Nonclinical Data for Pamiparib ........................................................24 
1.5.1.1. 
Nonclinical Safety Data ..................................................24 
1.5.1.2. 
Nonclinical Activity Data ...............................................25 
1.5.2. 
Clinical Data for Pamiparib ..............................................................27 
1.5.2.1. 
Pharmacokinetics Data for BGB-290-AU-002 ...............27 
1.5.2.2. 
Exploratory Biomarker Data ...........................................27 
1.5.2.3. 
Clinical Safety and Preliminary Efficacy for BGB-290-
AU-002 ...........................................................................28 
1.6. 
Rationale for Selection of Pamiparib Dose ......................................................29 
1.7. 
Study Rationale ................................................................................................29 
1.8. 
Risk-Benefit Assessment .................................................................................30 
1.9. 
Study Conduct ..................................................................................................30 
2. 
STUDY OBJECTIVES AND ENDPOINTS ............................................................31 
2.1. 
Study Objectives ..............................................................................................31 
2.1.1. 
Primary Objective .............................................................................31 
2.1.2. 
Secondary Objectives........................................................................31 
2.1.3. 
Exploratory Objectives .....................................................................31 
2.2. 
Study Endpoints ...............................................................................................31 
2.2.1. 
Primary Endpoints ............................................................................31 
2.2.2. 
Secondary Endpoints ........................................................................32 


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2.2.3. 
Exploratory Endpoints ......................................................................32 
3. 
STUDY DESIGN ........................................................................................................33 
3.1. 
Summary of Study Design ...............................................................................33 
3.2. 
Safety Monitoring Committee .........................................................................36 
3.3. 
Independent Review Committee ......................................................................36 
3.4. 
Duration of the Study .......................................................................................36 
4. 
STUDY POPULATION ............................................................................................36 
4.1. 
Inclusion Criteria .............................................................................................36 
4.2. 
Exclusion Criteria ............................................................................................38 
5. 
STUDY PHASES FROM SCREENING TO END OF STUDY ............................40 
5.1. 
Screening..........................................................................................................40 
5.2. 
Enrollment........................................................................................................40 
5.3. 
Treatment Phase ...............................................................................................40 
5.4. 
Unscheduled Visit ............................................................................................41 
5.5. 
Permanent Discontinuation of Pamiparib ........................................................41 
5.5.1. 
Reasons for Permanent Discontinuation of Pamiparib .....................41 
5.5.2. 
End-of-Treatment Visit .....................................................................41 
5.6. 
Follow-Up Phase ..............................................................................................42 
5.6.1. 
Safety Follow-up ...............................................................................42 
5.6.2. 
Long-term Follow-up ........................................................................42 
5.6.3. 
Lost to Follow-up ..............................................................................42 
5.6.4. 
Patient Discontinuation From Study (End of Study for an Individual 
Patient) ..............................................................................................42 
5.7. 
End of Study ....................................................................................................43 
6. 
STUDY TREATMENT .............................................................................................44 
6.1. 
Study Drug .......................................................................................................44 
6.1.1. 
Packaging and Labeling ....................................................................44 
6.1.2. 
Handling and Storage ........................................................................44 
6.1.3. 
Dosage and Administration...............................................................44 
6.1.4. 
Dose Hold and Modification .............................................................44 
6.1.5. 
Compliance and Accountability ........................................................49 
6.1.6. 
Disposal and Destruction ..................................................................49 


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6.2. 
Concomitant Medications and Nondrug Therapies .........................................50 
6.2.1. 
Permitted Medications and Supportive Care ....................................50 
6.2.2. 
Prohibited Medications .....................................................................50 
6.2.3. 
Medications to Be Used with Caution ..............................................50 
7. 
STUDY ASSESSMENTS ..........................................................................................51 
7.1. 
Study Flow and Visit Schedule ........................................................................51 
7.2. 
Patient Demographics and Other Baseline Characteristics ..............................51 
7.2.1. 
Demographics ...................................................................................51 
7.2.2. 
Medical History ................................................................................51 
7.2.3. 
Other Baseline Characteristics ..........................................................51 
7.3. 
Efficacy ............................................................................................................51 
7.3.1. 
Tumor Assessments ..........................................................................51 
7.3.1.1. 
Determination of Eligibility ............................................52 
7.3.1.2. 
Screening Tumor Assessment .........................................52 
7.3.1.3. 
On-Study Tumor Assessments ........................................53 
7.3.2. 
Prostate-Specific Antigen .................................................................53 
7.3.3. 
Survival Assessments........................................................................53 
7.3.4. 
Quality-of-Life Assessments ............................................................53 
7.4. 
Safety ...............................................................................................................53 
7.4.1. 
Adverse Events .................................................................................53 
7.4.2. 
Physical Examination, Vital Signs, ECOG Performance Status, 
Weight, and Height ...........................................................................54 
7.4.3. 
Electrocardiograms ...........................................................................54 
7.5. 
Safety Laboratory Assessments .......................................................................54 
7.5.1. 
Hematology .......................................................................................55 
7.5.2. 
Chemistry ..........................................................................................55 
7.5.3. 
Urinalysis ..........................................................................................55 
7.5.4. 
Hepatitis B and C Testing .................................................................55 
7.6. 
Circulating Tumor Cell Count .........................................................................55 
7.7. 
Pharmacokinetics .............................................................................................55 
7.8. 
Biomarkers .......................................................................................................55 
7.9. 
Appropriateness of Measurements ...................................................................56 


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8. 
DATA HANDLING AND QUALITY ASSURANCE ............................................56 
8.1. 
Data Collection ................................................................................................56 
8.2. 
Data Management/Coding ...............................................................................57 
8.3. 
Quality Assurance ............................................................................................58 
9. 
SAFETY MONITORING AND REPORTING ......................................................58 
9.1. 
Adverse Events ................................................................................................58 
9.1.1. 
Definition and Reporting of an Adverse Event .................................58 
9.1.2. 
Assessment of Severity .....................................................................58 
9.1.3. 
Assessment of Causality ...................................................................59 
9.1.4. 
Follow-Up of Adverse Events ..........................................................60 
9.1.5. 
Laboratory Test Abnormalities .........................................................60 
9.2. 
Definition of a Serious Adverse Event ............................................................61 
9.3. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ................................................................................................62 
9.3.1. 
Adverse Event Reporting Period ......................................................62 
9.3.2. 
Eliciting Adverse Events...................................................................62 
9.4. 
Study-Specific Adverse Event and Serious Adverse Event Reporting 
Instructions .......................................................................................................62 
9.4.1. 
Disease Progression ..........................................................................62 
9.4.2. 
Death .................................................................................................62 
9.5. 
Prompt Reporting of Serious Adverse Events .................................................63 
9.5.1. 
Timeframes for Submitting Serious Adverse Events........................63 
9.5.2. 
Completion and Transmission of the Serious Adverse Event Report63 
9.5.3. 
Regulatory Reporting Requirements for Serious Adverse Events ....63 
9.6. 
Suspected Unexpected Serious Adverse Reactions and Expedited Reporting 64 
9.7. 
Pregnancy Reporting ........................................................................................64 
10. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN ....................64 
10.1. Analysis Sets ....................................................................................................64 
10.2. Efficacy Analyses ............................................................................................65 
10.2.1. Primary Efficacy Endpoint Analyses ................................................65 
10.2.2. Secondary Efficacy Endpoint Analyses ............................................66 
10.3. Pharmacokinetic Analyses ...............................................................................67 


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10.4. Exploratory Analyses .......................................................................................67 
10.5. Safety Analyses ................................................................................................67 
10.5.1. Extent of Exposure ............................................................................67 
10.5.2. Adverse Events .................................................................................68 
10.5.3. Laboratory Analyses .........................................................................68 
10.5.4. Physical Examinations ......................................................................68 
10.5.5. Vital Signs .........................................................................................68 
10.5.6. Electrocardiograms ...........................................................................68 
10.6. Sample Size Consideration ..............................................................................69 
10.7. Interim Analysis ...............................................................................................69 
11. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ...........69 
11.1. Regulatory Authority Approval .......................................................................69 
11.2. Investigator Responsibilities ............................................................................69 
11.2.1. Good Clinical Practice ......................................................................69 
11.2.2. Ethical Conduct of the Study and Ethics Approval ..........................70 
11.2.3. Informed Consent..............................................................................70 
11.2.4. Investigator Reporting Requirements ...............................................71 
11.2.5. Confidentiality ..................................................................................71 
11.2.6. Electronic Case Report Forms ..........................................................71 
11.2.7. Drug Accountability..........................................................................72 
11.2.8. Inspections ........................................................................................72 
11.2.9. Protocol Adherence ...........................................................................72 
11.3. Sponsor Responsibilities ..................................................................................72 
11.3.1. Protocol Modifications......................................................................72 
11.3.2. Use of Information and Publication ..................................................73 
11.4. Study and Study Center Closure ......................................................................73 
11.5. Records Retention and Study Files ..................................................................74 
11.5.1. Study Files and Retention of Records ...............................................74 
11.5.2. Provision of Study Results and Information to Investigators ...........75 
11.6. Information Disclosure and Inventions ............................................................75 
11.7. Joint Investigator/Sponsor Responsibilities .....................................................76 
11.7.1. Access to Information for Monitoring ..............................................76 


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11.7.2. Access to Information for Auditing or Inspections...........................76 
12. 
REFERENCES ...........................................................................................................78 
13. 
APPENDICES ............................................................................................................81 
APPENDIX 1. 
SCHEDULE OF ASSESSMENTS ................................................82 
APPENDIX 2. 
THE RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS (RECIST) GUIDELINES, VERSION 1.1 .............................................87 
APPENDIX 3. 
ECOG PERFORMANCE STATUS ..............................................96 
APPENDIX 4. 
CONTRACEPTION GUIDELINES AND DEFINITIONS OF 
“WOMEN OF CHILDBEARING POTENTIAL”, “NO CHILDBEARING 
POTENTIAL” 97 
APPENDIX 5. 
NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION ...................................................................................................99 
APPENDIX 6. 
PROHIBITED MEDICATIONS .................................................100 
APPENDIX 7. 
MEDICATIONS TO BE USED WITH CAUTION ..................101 
APPENDIX 8. 
EUROPEAN QUALITY OF LIFE 5-DIMENSIONS 5-LEVELS 
HEALTH QUESTIONNAIRE ...............................................................................102 
APPENDIX 9. 
BRIEF PAIN INVENTORY SHORT FORM ............................104 
APPENDIX 10. 
PROSTATE CANCER CLINICAL TRIALS WORKING 
GROUP 3 
106 
APPENDIX 11. 
CHRONIC KIDNEY DISEASE EPIDEMIOLOGY 
COLLABORATION (CKD-EPI) EQUATION ....................................................114 
APPENDIX 12. 
SIGNATURE OF INVESTIGATOR ..........................................115 
 
LIST OF TABLES 
Table 1: PARP Enzyme Inhibition and PARP Trapping Activity of PARP Inhibitors ........................ 25 
Table 2: Patient Cohorts ........................................................................................................................ 35 
Table 3: Dose Levels for Pamiparib ..................................................................................................... 45 
Table 4: Criteria for Modification of Pamiparib Dosing for Related Adverse Events ......................... 46 
Table 5: Timeframes and Documentation Methods for Reporting Serious Adverse Events to the 
Sponsor or Designee .......................................................................................................... 63 
 


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LIST OF FIGURES 
Figure 1: Correlation of PAR Inhibition in Peripheral Blood Mononuclear Cells with Pamiparib Dose
 ........................................................................................................................................... 28 
Figure 2: Study Schema ........................................................................................................................ 35 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
AML 
acute myeloid leukemia 
AUC 
area under the plasma concentration-time curve (drug exposure) 
AUC0-12 
area under the plasma concentration-time curve from 0 to 12 hours postdose 
BPI-SF 
Brief Pain Inventory Short Form 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Epidemiology Collaboration 
CR 
complete response 
CT 
computed tomography 
CTC 
circulating tumor cell 
CTC-HRD-negative 
or CTC-HRD- 
circulating tumor cells negative for homologous recombination deficiency per Epic 
Sciences assay 
CTC-HRD-positive 
or CTC-HRD+ 
circulating tumor cells positive for homologous recombination deficiency per Epic 
Sciences assay 
CYP 
cytochrome P450 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
End-of-Treatment (Visit) 
EQ-5D-5L 
European Quality of Life 5-Dimensions 5-Levels Health Questionnaire 
FDG 
fluorine-18 [F-18]fluorodeoxyglucose 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HRD 
homologous recombination deficiency 
IC50 
half-maximal inhibition concentration 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
mCRPC 
metastatic castration-resistant prostate cancer 
MDRD STUDY EQ 
Modification of Diet in Renal Disease study equation 
MDS 
myelodysplastic syndrome 
MRI 
magnetic resonance imaging 


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Abbreviation 
Definition 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NE 
not evaluable 
ORR 
objective response rate 
OS 
overall survival 
pamiparib 
BGB-290 
PAR 
poly (ADP-ribose) 
PARP 
poly (ADP-ribose) polymerase 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
progressive disease 
PET 
positron-emission tomography 
PK 
pharmacokinetic 
PR 
partial response 
PSA 
prostate-specific antigen 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
radiographic progression-free survival 
SAE 
serious adverse event 
SD 
stable disease 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US or USA 
United States or United States of America 


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1. 
INTRODUCTION 
1.1. 
Metastatic Castration-Resistant Prostate Cancer 
Prostate cancer is the second most common cancer in men worldwide, with an estimated 1.6 million 
cases and 366,000 deaths worldwide and the leading cause of cancer death in men in 29 countries 
(Global Burden of Disease Cancer Collaboration 2017). Rates of prostate cancer differ by over 25-fold 
in various countries around the world, with the highest incidence in Australia and western regions of 
the world such as the United States of America (USA) and Europe, and the lowest in Asian countries 
such as Japan, India, Hong Kong, and China (GLOBOCAN 2012; Crocetti 2015; SEER 2017; 
Gronberg 2003). Interpretation of these vast differences between regions may be accounted for by the 
increase in screening by prostate-specific antigen (PSA) and subsequently increased biopsies in 
Western countries compared with Asia. In the USA, prostate cancer is most commonly diagnosed in 
Black and non-Hispanic men who are 65 to 74 years of age, with a median diagnosis at 66 years age 
of and a median age of 80 years at death (SEER 2017).  
Patients who have evidence of progressive disease (PD) (eg, increase in serum PSA, new metastases, 
and/or progression of existing metastases) while being managed with androgen deprivation therapy 
are considered to have castration-resistant prostate cancer. 
For the past decade, the first-line treatment for metastatic castration-resistant prostate cancer 
(mCRPC) has been taxane-based treatments such as docetaxel and cabazitaxel in combination with 
prednisone. However, most patients develop resistance to these treatments and die within 2 to 3 years 
after initiation of treatment. Until recently, therapeutic options for docetaxel resistance were very 
limited in patients with mCRPC, but improvements in the understanding of castration-resistant 
prostate cancer biology led to the development of novel therapeutic agents that target the androgen 
receptor signaling pathway, such as abiraterone acetate and enzalutamide. Because men with mCRPC 
persistently maintain androgen receptor activity, despite castration levels of serum testosterone, novel 
androgen receptor-targeted agents can be effective for men with disease that is already resistant to 
androgen deprivation therapy. 
Several key Phase 3 randomized, controlled studies have revealed that these novel drugs significantly 
improved the survival of mCRPC patients in either pre- or post-chemotherapeutic settings. However, 
various androgen receptor-targeting drugs, including abiraterone acetate, enzalutamide, and orteronel 
(TAK-700), have shown inconsistent therapeutic effects on oncological outcomes in patients with 
mCRPC. Thus, no consensus has been reached regarding the agent that provides the best oncological 
outcomes (Kang et al 2017). 
1.2. 
Poly (ADP-ribose) Polymerase Inhibitors 
Poly (ADP-ribose) polymerase (PARP) proteins are involved in DNA replication, transcriptional 
regulation, and DNA damage repair. DNA-bound PARP1/2 catalyzes the synthesis of poly 
(ADP-ribose) (PAR) onto a range of DNA-associated proteins that mediate DNA repair. PARP1 also 
undergoes auto-PARylation, a molecular change that ultimately leads to its release from DNA. 
Inhibition of PARP converts common single-strand DNA breaks into double-strand breaks during 


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DNA replication. Small molecule inhibitors of PARP1/2 represent a class of anticancer agents that 
exert their cytotoxic effects by interfering with DNA repair mechanisms. Since the discovery of 
synthetic lethality of PARP inhibitors in BRCA-deficient cells and, more broadly, cells with 
homologous recombination deficiency (HRD), accumulation of unrepaired single-strand DNA breaks 
resulting from catalytic PARP inhibition has been considered central to the mechanism of action of 
PARP inhibitors. More recently, it has been demonstrated that PARP inhibitors also trap PARP1- and 
PARP2-DNA complexes at DNA damage sites and that PARP trapping can be more cytotoxic than 
unrepaired single-strand DNA breaks (Pommier et al 2016; O’Connor 2015; Lord and Ashworth 
2017). 
In the clinic, PARP inhibitors, including olaparib, rucaparib, niraparib, and talazoparib, have 
demonstrated sustained antitumor responses when used as a single agent in patients with BRCA1- or 
BRCA2-mutated tumors, while also achieving a favorable safety profile. Olaparib has been approved 
in the USA as a single agent for advanced ovarian cancer patients with a deleterious germline BRCA 
mutation; whereas, rucaparib has been approved for patients with a deleterious germline or somatic 
BRCA mutation (Lynparza [olaparib] prescribing information 2017; Rubraca [rucaparib] prescribing 
information 2018). Niraparib was approved by the US Food and Drug Administration in 2017 for the 
maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary 
peritoneal cancer who are in complete response (CR) or partial response (PR) to platinum-based 
chemotherapy (Zejula [niraparib] prescribing information 2017). 
1.3. 
Biology of BRCA+ Prostate Cancers and PARP Inhibitors 
Men with a BRCA2 mutation have a 5- to 9- fold increased risk of developing prostate cancer by 
age 65, perhaps translating to a risk of about 33% (Kote-Jarai et al 2011; Breast Cancer Linkage 
Consortium 1999). The risk of prostate cancer in men with a BRCA1 mutation is less clear, but also 
appears to be elevated by about 3.75-fold, translating to a risk of about 9% by age 65 (Leongamornlert 
et al 2012). In addition, men with metastatic prostate cancer and a BRCA2 mutation are known to 
have a poorer prognosis and overall survival (OS) compared with those without a BRCA2 mutation 
(Castro et al 2013). Furthermore, preliminary results have shown that these men may respond to 
treatment with a PARP inhibitor (Sandhu et al 2013a). 
Other DNA-repair gene mutations may also occur more frequently in men with aggressive prostate 
cancer, but there are no data on the activity of PARP inhibitors in patients with mutations in other 
DNA repair genes (Pritchard et al 2016). 
The PARP inhibitor olaparib was studied in 49 evaluable men with castration-resistant prostate cancer 
(Mateo et al 2015). In this Phase 2 study, all patients had received at least 2 prior regimens for 
castration-resistant disease and all had received prior docetaxel chemotherapy. All patients had tissue 
assessed for the presence of abnormalities in a predetermined panel of DNA-repair genes. 
Abnormalities were detected in 16 patients (33%), the most common of which were in BRCA2. 
The primary endpoint of the study was a composite response rate that included objective response 
(Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1) in those with assessable 
disease, a  50% decrease in serum PSA or a confirmed reduction in circulating tumor cells (CTCs) 


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from  5 cells per 7.5 mL of blood to < 5 cells per 7.5 mL. Among the men with a DNA repair gene 
abnormality, 14 (88%) had a response based upon these criteria. By contrast, only 1 of 33 (3%) 
without an identified DNA-repair gene abnormality responded. Radiographic progression-free 
survival (rPFS) was significantly longer in those with biomarker-positive disease compared with 
biomarker-negative disease (9.8 versus 2.7 months), as was OS (13.8 versus 7.5 months). 
In a Phase 2 study, 153 men with castration-resistant prostate cancer were randomly assigned to 
abiraterone plus prednisone or to abiraterone, prednisone, and veliparib (Hussain et al 2018). There 
were no significant differences in the PSA response rate with or without the addition of veliparib 
(72% versus 64%, respectively) or in progression-free survival (11 versus 10.1 months). A defect in 
a DNA repair gene was present in 20 of 75 evaluable patients (27%), and in these patients, the 
differences in the PSA response rates with or without the addition of veliparib (90% versus 56%, 
respectively) and measurable disease response rates (88% versus 38%) were statistically significant. 
In a Phase 2 study of men with mCRPC, 142 patients were randomly assigned to receive olaparib and 
abiraterone (n = 71) or placebo and abiraterone (n = 71). Median rPFS was 13.8 months (95% 
confidence interval [CI]: 10.8% to 20.4%) with olaparib and abiraterone and 8.2 months (95% CI: 
5.5% to 9.7%) with placebo and abiraterone (hazard ratio 0.65, 95% CI: 0.44% to 0.97%, p = 0.034) 
(Clarke et al 2018). 
Niraparib is a third PARP inhibitor. In a Phase 1 dose-escalation study, niraparib showed evidence of 
activity in prostate cancer patients with mutations in BRCA1 or BRCA2 (Sandhu et al 2013b). 
Currently a Phase 2 study with niraparib in mCRPC patients with DNA-repair anomalies is ongoing. 
1.4. 
Circulating Tumor Cells as a Biomarker in Metastatic Castration-Resistant 
Prostate Cancer 
Precision-based therapeutics targeting specific genomic alterations offer great promise for men with 
mCRPC. However, current approaches for genomic characterization are primarily tissue-based and 
are hindered by the low overall success rate (64%) for CT-guided bone biopsies in men with mCRPC 
for isolation of molecular material for sequencing as well as the high failure rate (58%) of sequencing 
bone-derived DNA (Holmes et al 2017; Cheng et al 2017). Efforts to utilize circulating tumor DNA 
for HRD determination in men with mCRPC, while having the potential to overcome the obstacles of 
obtaining bone-derived DNA for sequencing-based HRD determination, are hindered by limitations 
in detecting critical chromosomal rearrangements and copy-number variations (eg, BRCA deletions) 
(Hoppe et al 2018). Finally, DNA sequencing-based approaches for HRD determination using fixed 
gene panels, irrespective of sample analyte, are limited by the known biology of HRD and may not 
accurately predict clinical response in mCRPC (Hoppe et al 2018). As such, HRD determination 
using the phenotypic characterization of HRD+ CTCs may have significant clinical utility in the 
setting of mCRPC. 
A recent meta-analysis conducted across 5 randomized Phase 3 clinical studies suggests that CTC 
enumeration may be a robust predictor of OS in mCRPC (Heller et al 2018). Furthermore, CTC-based 
detection of the AR-V7 mRNA assay has been shown to be prognostic in men with mCRPC treated 
with first- and second-line abiraterone and enzalutamide (Antonarakis et al 2017). HRD status in 


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patients was assessed using a quantitative CTC biomarker assay that detects HRD+ CTCs in whole 
blood based on their phenotypic features. This assay, recently shown to predict response to veliparib 
in men with mCRPC (Dittamore et al 2018), utilizes an analytically validated microscopy-based CTC 
detection technology (Werner et al 2015; Scher et al 2017) for the identification of CTCs from whole 
blood, and subsequent computer vision/digital pathology based characterization of each identified 
CTC to asses HRD specific features.  
Historically, distinct patterns of genomic alterations have been used to identify HRD in tumors 
(Marquard et al 2015). CTCs positive for these genomic alterations have also been associated with 
HRD were previously shown (Feng et al 2016; Scher et al 2017) to have specific phenotypic features 
when measured by US Food and Drug Administration cleared digital pathology methods 
(Wilbur et al 1998; O’Leary et al 1998; Biscotti et al 2005). Applied here, the CTC-HRD-positive 
(circulating tumor cells positive for homologous recombination deficiency per Epic Sciences assay) 
classifier will be used to identify patients for PARP inhibition based on the prevalence of CTCs with 
these phenotypic features.  
1.5. 
PARP Inhibitor Pamiparib 
1.5.1. 
Nonclinical Data for Pamiparib 
Pamiparib is a potent and selective inhibitor of PARP1 and PARP2 that combines potent PARP-
trapping activity with significant brain penetrance. 
1.5.1.1. 
Nonclinical Safety Data 


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In summary, all available toxicologic studies and data are adequate to support clinical development 
of pamiparib for treatment of patients with advanced cancer. Please refer to the Pamiparib 
Investigator’s Brochure for additional information. 
1.5.1.2. 
Nonclinical Activity Data 
 


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Please refer to the Pamiparib Investigator’s Brochure for additional information. 


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1.5.2. 
Clinical Data for Pamiparib 
There are 5 ongoing studies with pamiparib with available preliminary data: ongoing monotherapy 
studies BGB-290-AU-002 and BGB-290-102; and combination therapy studies BGB-290-103 
(pamiparib in combination with temozolomide), BGB-290-104 (pamiparib in combination with 
radiation and/or temozolomide), and BGB-A317/BGB-290_Study_001 (pamiparib in combination 
with the anti-PD-1 antibody tislelizumab [also known as BGB-A317]). The study data from 
BGB-290-AU-002 are the most mature and interim results are summarized below. 
1.5.2.1. 
Pharmacokinetics Data for BGB-290-AU-002 
1.5.2.2. 
Exploratory Biomarker Data 


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1.5.2.3. 
Clinical Safety and Preliminary Efficacy for BGB-290-AU-002 
BGB-290-AU-002 is a Phase 1a/1b study to evaluate the safety, PK, food effect, and antitumor 
activity of pamiparib in patients with advanced solid tumors. The Phase 1A portion is a first-in-human 
study evaluating pamiparib to characterize the safety, the maximum tolerated dose, preliminary 
antitumor activity, and the PK of pamiparib given as a monotherapy in a 3+3 dose escalation scheme. 
In Phase 1a Part 1, pamiparib was administered in doses ranging from 2.5 to 120 mg orally twice a 
day. 
The study is being conducted in Australia. Preliminary data for 45 patients in the Phase 1a Part 1 
portion of the study are available (cutoff date of 01 December 2017) and are presented below unless 
noted otherwise.  
The preliminary safety data indicate that the most frequent nonhematologic adverse events (AEs) 
( 10% of patients) were nausea (64%, n = 29), vomiting (36%, n = 16), fatigue (33%, n = 15), 
diarrhea (29%, n = 13), abdominal pain (22%, n = 10), constipation, urinary tract infection (each 18%, 
n = 8), upper respiratory tract infection (16%, n = 7), ascites, pyrexia, headache, and decreased 
appetite (each 11%, n = 5). 
Hematologic AEs are of interest in this study. Anemia was most frequent (33%, n = 15), followed by 
neutropenia (11%, n = 5) and platelet count decreased (4%, n = 2). 
Twenty-seven (60%) patients experienced  Grade 3 AEs (regardless of relatedness). Ten (22%) 
patients experienced  Grade 3 AEs that were considered related to pamiparib by the investigator: 
anemia (13%, n = 6), neutropenia (7%, n = 3), nausea, fatigue, diarrhea, oral paresthesia, paresthesia, 
and hypophosphatemia (each 2%, n = 1).  
Serious AEs (SAEs) were reported in 25 (56%) patients, and for 3 (7%) patients they were considered 
related to pamiparib by the investigator: anemia (4%; n = 2) and nausea (2%; n = 1). Three (7%) 
patients discontinued study drug because of an AE: vomiting, paresthesia of the hands and mouth, 
and traumatic hematoma (due to a fall) (each n = 1). 


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Overall, 4 patients in the entire study experienced a fatal AE: 1 AE of pleural effusion in a breast 
cancer patient who died of PD complicated by respiratory failure; 1 AE of intestinal obstruction in an 
ovarian cancer patient; 1 AE of intestinal perforation in an ovarian cancer patient; and 1 AE of gastric 
obstruction in a fallopian tube cancer patient. All 4 fatal events were assessed by the investigator as 
not related to pamiparib. 
Four patients experienced AEs that were considered dose-limiting toxicities: Grade 2 nausea in 
2 patients; Grade 2 anorexia and Grade 2 nausea in 1 patient; and Grade 2 nausea, Grade 3 fatigue, 
and Grade 3 paresthesia in 1 patient. Based on the encountered dose-limiting toxicities and the overall 
safety profile of pamiparib, the maximum tolerated dose of pamiparib was determined to be 80 mg 
orally twice a day (160 mg/day). 
Myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) are recognized AEs in patients 
receiving PARP inhibitors (Ricks et al 2015). To date, no cases of MDS or AML have been observed 
in any study that includes pamiparib. 
In the Phase 1A portion of the study, 10 patients achieved either a CR (n = 3) or PR (n = 7); all 
responses were observed in patients with gynecologic cancers. 
1.6. 
Rationale for Selection of Pamiparib Dose 
Based upon the overall safety, efficacy, and PK profile of pamiparib, the dose of pamiparib 60 mg 
orally twice a day was selected using available clinical data from Study BGB-290-AU-002 
(Section 1.5.2.3). The study determined the maximum tolerated dose of pamiparib to be 80 mg orally 
twice a day (160 mg/day). The dose of 60 mg twice a day was selected for further evaluation based 
on the following findings (refer to the Pamiparib Investigator’s Brochure): 
 A linear PK profile observed up to 80 mg twice a day 
 Overlapping pamiparib exposure among patients treated with 40 mg, 60 mg, and 80 mg twice a 
day 
 Similar toxicity profiles at 60 mg and 80 mg twice a day with the following differences: 
o Fewer patients at 60 mg twice a day experienced treatment-related treatment-emergent 
adverse events (TEAEs) of anemia and neutropenia. 
o There was a slightly higher rate of dose interruptions at 80 mg versus 60 mg twice a day 
for anemia and nausea. 
 Responses were observed across the dose range evaluated 
1.7. 
Study Rationale 
For men with advanced prostate cancer, androgen deprivation therapy usually can provide disease 
control for a substantial period of time. However, most men eventually develop PD that is resistant to 
further hormonal treatment. A number of new therapies (including anti-androgen treatments) have 
been shown to prolong survival in this setting, but there remains a need for additional approaches that 
can control disease and prolong survival. 


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An increasing understanding of the biology of prostate cancer is leading to the development of new 
therapies that can target specific abnormalities in prostate cancer, such as HRD. As stated earlier, men 
with metastatic prostate cancer and a BRCA2 mutation are known to have a poorer prognosis and OS 
compared with those without a BRCA2 mutation. As discussed in Section 1.3, preliminary results 
have shown that these patients may respond to treatment with a PARP inhibitor as these specifically 
target cancers with HRD. However, remaining challenges are obtaining adequate tumor material for 
successful sequencing, in addition to identifying the correct patients whose tumors are bona fide HRD. 
The aim of this study is to assess the efficacy of pamiparib in mCRPC patients with disease 
progression as assessed by the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria 
and with homologous recombination deficiency (HRD-positive) by Epic Sciences assay; thus, 
establishing the association between CTC-HRD status and pamiparib activity. 
1.8. 
Risk-Benefit Assessment 
Pamiparib has been studied in nonclinical toxicity and Phase 1 clinical studies. Pamiparib toxicities 
are largely consistent with the safety profile shared by other PARP inhibitors. The safety profile and 
adverse drug reactions observed in patients treated with pamiparib monotherapy are summarized in 
Section 6, Summary of Data and Guidance for the Investigator of the Pamiparib Investigator’s 
Brochure. 
MDS and AML have been reported in a small number (< 1%) of patients treated with PARP inhibitors, 
especially in patients harboring a germline BRCA mutation (Ricks et al 2015). Typically, patients 
who develop MDS and AML while on therapy with a PARP inhibitor have a history of extensive 
previous chemotherapy and some have a history of previous cancer or bone marrow abnormalities. 
To date, there have been no reports of MDS or AML in patients treated with pamiparib and no fatal 
adverse drug reactions. Patients in this study will be monitored monthly for hematologic toxicities 
and events of MDS and AML will be reported as SAEs. 
Preliminary data from ongoing monotherapy studies show that pamiparib appears to be generally well 
tolerated in patients with advanced solid tumors. The safety profile for single-agent pamiparib is 
similar to those observed in other PARP inhibitors. Some antitumor activity has been observed across 
the dose ranges evaluated in patients. Therefore, the risk-benefit profile for pamiparib monotherapy 
is considered acceptable in a patient population with metastatic cancer. 
1.9. 
Study Conduct 
This study will be conducted in compliance with the protocol approved by the Institutional Review 
Board (IRB) or Independent Ethics Committee (IEC), and regulatory authorities, and in accordance 
with Good Clinical Practice standards. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective 
 To evaluate the efficacy of pamiparib in patients with metastatic castration-resistant prostate 
cancer (mCRPC) positive for circulating tumor cells with homologous recombination deficiency 
(CTC-HRD-positive; per Epic Sciences assay), as per Prostate Cancer Clinical Trials Working 
Group [PCWG3] criteria 
2.1.2. 
Secondary Objectives 
 To further evaluate the efficacy of pamiparib in patients with CTC-HRD-positive mCRPC with 
measurable disease (Cohort 1 of Table 2), as per PCWG3 criteria 
 To further evaluate the efficacy of pamiparib in patients with CTC-HRD-positive mCRPC with 
or without measurable disease (Cohorts 1 and 2 of Table 2, respectively), as per PCWG3 criteria 
 To evaluate the safety and tolerability of pamiparib 
2.1.3. 
Exploratory Objectives 





2.2. 
Study Endpoints 
Assessments are per the investigator except when indicated otherwise. Assessments will be conducted 
in accordance with Good Clinical Practice and all applicable regulatory requirements. 
2.2.1. 
Primary Endpoints 
 Objective response rate (ORR; defined as the proportion of patients with best objective response 
of CR or PR confirmed at a subsequent timepoint  4 weeks later) by Independent Review 
Committee (IRC) for CTC-HRD-positive patients with measurable disease (Cohort 1 of Table 2) 
 Prostate-specific antigen (PSA) response rate (defined as the proportion of patients with PSA 
decline  50% from baseline [confirmed by a second PSA value  3 weeks later]) for CTC-HRD-
positive patients with or without measurable disease (Cohorts 1 and 2 of Table 2, respectively) 


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2.2.2. 
Secondary Endpoints 
Patients with CTC-HRD-Positive mCRPC with Measurable Disease (Cohort 1 of Table 2) per 
PCWG3 Criteria 
 Duration of response (DOR) by IRC 
 ORR by investigator 
 Time to objective response 
 Clinical benefit rate (defined as the proportion of patients with a documented confirmed CR, PR, 
or stable disease) 
Patients with CTC-HRD-Positive mCRPC with or without Measurable Disease (Cohorts 1 
and 2 of Table 2, respectively) per PCWG3 Criteria 
 Time to PSA response 
 Duration of PSA response 
 Time to PSA progression (defined as the time from the date of the first dose of study drug to a 
 25% increase in PSA with an absolute increase of  2 ng/mL above the nadir [or above the 
baseline for patients with no PSA decline after 12 weeks], confirmed by a second value  3 weeks 
later) 
 Time to symptomatic skeletal event (SSE; defined as the time from the date of the first dose of 
study drug to the first symptomatic fracture, radiation or surgery to bone, or spinal cord 
compression) 
 Radiographic progression-free survival (rPFS; defined as the time from the date of the first dose 
of study drug to radiographic disease progression by IRC or death due to any cause, whichever 
occurs first) 
 Overall survival (OS) 
All Patients (Cohorts 1, 2, 3, and 4 of Table 2) 
 Incidence, timing, and severity of TEAEs, graded according to National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03 or higher 
2.2.3. 
Exploratory Endpoints 
 
 
 
 


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3. 
STUDY DESIGN 
3.1. 
Summary of Study Design 
This is an open-label, single-arm, global Phase 2 study to evaluate the efficacy and safety of single-
agent poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitor pamiparib in mCRPC patients with 
CTC-HRD-positive disease or who have a deleterious germline or somatic mutation in BRCA1 or 
BRCA2. 
To be eligible for the study, biomarker-positive patients must have progressed on or after at least 
one androgen 
receptor-targeted 
therapy 
for 
mCRPC 
(eg, 
enzalutamide, 
abiraterone 
acetate/prednisone, bicalutamide, flutamide, apalutamide, or nilutamide), received at least 1 taxane-
based therapy for metastatic prostate cancer, and have PSA progression as per PCWG3 criteria at time 
of study entry. The primary endpoints are ORR by IRC for patients with measurable disease (n ≈ 50) 
and PSA response rate for patients with or without measurable disease (n ≈ 80) as per PCWG3 
criteria. 
Cohort 1 will include 50 mCRPC patients with CTC-HRD-positive, measurable metastatic disease 
(soft tissue with/without bone lesions), and positive BRCA1/2 mutation or negative/unknown 
BRCA1/2 mutation. Cohort 2 will include 30 mCRPC CTC-HRD positive patients with bone 
metastasis only and positive or negative/unknown BRCA1/2. Cohort 3 and 4 will include 20 mCRPC 
CTC-HRD negative/unknown patients with BRCA1/2 positive mutations, metastatic disease 
(measurable soft tissue with/without bone), and bone only (see Table 2).  
After enrollment, patients will receive pamiparib 60 mg orally twice a day in cycles of 28 days. 
Safety assessments will occur on Day 1 of each cycle, on Day 15 of Cycles 1 and 2, and as needed. 
Dose modifications will be made if appropriate (Section 6.1.4). AEs will be followed and documented 
during the treatment phase and for approximately 30 days after the last dose of pamiparib or until 
initiation of new anticancer therapy, whichever occurs first (Section 9 and Appendix 1). AEs will be 
graded according to NCI-CTCAE Version 4.03 or higher. A Safety Monitoring Committee will 
periodically review safety data. 
PK samples for pamiparib will be collected at various timepoints at all non-China centers and at 
centers with such capability in China. In addition, tumor tissue (if available) and blood samples will 


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be obtained to explore biomarkers of pharmacodynamics, response, and resistance to pamiparib in 
mCRPC. 
Disease status will be assessed by the investigator using PCWG3 criteria (Appendix 10). Patients will 
undergo tumor assessments every 8 weeks (± 7 days) for 24 weeks, then every 12 weeks (± 7 days), 
or as clinically indicated. PSA assessments will occur at screening, on Day 1, and then every 4 weeks 
(± 7 days), or as clinically indicated. 
Administration of pamiparib will continue until PD, unacceptable toxicity, death, or another 
discontinuation criterion is met (Sections 5.5.1 and 5.6.4). Once the treatment phase has been 
completed, an End-of-Treatment (EOT) Visit should occur within 7 days of stopping pamiparib with 
subsequent phases of safety and long-term follow-up. 
Long-term follow-up will include tumor and PSA assessments every 12 weeks and 4 weeks 
(± 7 days), respectively, for those patients without PD, survival status, and initiation of new anticancer 
therapy. Long-term follow-up will continue until the patient dies or another criterion for 
discontinuation from study is met (Section 5.6.4). 
Study procedures and assessments are detailed in Section 7 and Appendix 1. The patient cohorts are 
presented in Table 2 and study schema is presented in Figure 2. 


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Figure 2: Study Schema 
 
Abbreviations: CTC-HRD+, positive for circulating tumor cells with homologous recombination deficiency per Epic 
Sciences assay; mCRPC, metastatic castration-resistant prostate cancer; PARPi, PARP inhibitor; PCWG3, Prostate 
Cancer Clinical Trials Working Group 3; PD, progressive disease; PSA, prostate-specific antigen; RECIST, Response 
Evaluation Criteria in Solid Tumors. 
Notes: Key assessments during the treatment phase: tumor assessments every 8 weeks (± 7 days) for 24 weeks, then every 
12 weeks (± 7 days), or as clinically indicated; and patient-reported outcomes, PSA, adverse events, hematology, and 
chemistry every 4 weeks. Pamiparib is to be administered continuously. 
Table 2: Patient Cohorts 
 
Abbreviations: , biomarker status unknown; CTC-HRD-, negative for circulating tumor cells with homologous 
recombination deficiency per Epic Sciences assay; CTC-HRD+, positive for circulating tumor cells with homologous 
recombination deficiency per Epic Sciences assay. 


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3.2. 
Safety Monitoring Committee 
The Safety Monitoring Committee will be composed, at a minimum, of clinicians and a statistician. 
These members will have experience in the fields of oncology, clinical study conduct and monitoring, 
and biostatistics. 
The Safety Monitoring Committee will provide safety oversight for the study population and will 
advise the study team of the need for study modification or termination based on regular reviews of 
accumulating safety data. Regular safety monitoring will be performed by the Safety Monitoring 
Committee. Details of the membership, scope of data review, and meeting frequency will be provided 
in the Safety Monitoring Committee charter. 
Following Safety Monitoring Committee review and discussion, the sponsor will make final decisions 
regarding any change in the study conduct. Please see the details in the Safety Monitoring Committee 
charter. 
3.3. 
Independent Review Committee 
Tumor images will be collected and reviewed by the IRC for baseline tumor status during screening, 
on-study tumor monitoring, and adjudication of the selected efficacy endpoints. The protocol-specific 
review function and processes of the IRC will be described in the IRC charter. 
3.4. 
Duration of the Study 
The duration of the study from first enrolled patient to last patient is off study is estimated to be 
approximately 31 months. 
4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for the study: 
1. Sign informed consent form (ICF): must be able to provide written informed consent and can 
understand the nature, significance, and consequences of participating in the clinical study 
2. Agrees not to participate in another interventional study while on pamiparib 
3. If receiving bisphosphonate or other approved bone-targeting therapy, must have been on stable 
doses for at  28 days before start of pamiparib on Day 1 
4. Adult males  18 years of age at the time of informed consent and has signed informed consent 
before any study-related activities and according to local guidelines 
5. Histologically or cytologically confirmed adenocarcinoma or poorly differentiated 
adenocarcinoma of the prostate without neuroendocrine differentiation 
 Mixed histology is acceptable. 
 Pure small cell histology is excluded. 


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6. Metastatic castration-resistant prostate cancer (mCRPC) with 1 or 2 of the following: 
a) Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 (Appendix 2), involving viscera (lung, liver, adrenal glands, or other) 
and/or extrapelvic nodes (retroperitoneal, mediastinal, thoracic, or other)  
b) Bone disease 
7. Prostate cancer progression defined as follows: 
a) Prostate-specific antigen (PSA) progression with  3 rising PSA levels with  1 week 
between determinations 
b) Screening PSA  2 µg/L (2 ng/mL) 
8. Surgical or medical castration (bilateral orchiectomy or ongoing treatment with a 
gonadotropin-releasing hormone [GnRH] agonist or antagonist, respectively) 
9. Serum testosterone  1.73 nmol/L (or  50 ng/dL) at screening 
10.  1 androgen receptor-targeted therapy for mCRPC (eg, enzalutamide, abiraterone 
acetate/prednisone, bicalutamide, flutamide, apalutamide, or nilutamide) 
11.  1 taxane-based therapy for metastatic castration-resistant prostate cancer  
12. Prostate cancer with homologous recombination deficiency (HRD) as evidenced by 1 or 2 of 
the following: 
a) Positive for circulating tumor cells with homologous recombination deficiency per 
Epic Sciences assay (CTC-HRD-positive) 
b) Deleterious germline or somatic mutation in BRCA1 or BRCA2 
13. Agreement to provide tumor tissue, if available, and blood samples for molecular analysis 
 Note: If archival tumor tissue is not available, an optional fresh biopsy is highly 
recommended. 
14. Eastern Cooperative Oncology Group (ECOG) performance status  1 (Appendix 3) 
15. Ability to swallow whole capsules 
16. Ability to comply with study requirements and complete study questionnaires 
17. Adequate hematologic and end-organ function, as defined by the following laboratory results 
(obtained  14 days before Day 1): 
a) Absolute neutrophil count  1.5 x 109/L 
b) Platelet count  100 x 109/L 
c) Hemoglobin  9 g/dL ( 28 days after growth factor support or transfusion) 
d) Estimated glomerular filtration rate  30 mL/min/1.73 m2 by the Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation (Appendix 11) 
e) Total serum bilirubin  1.5 x upper limit of normal (ULN) 


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 
 4 x ULN, if Gilbert’s syndrome or if indirect bilirubin concentrations are 
suggestive of extrahepatic source of elevation 
f) Aspartate and alanine aminotransferase  3 x ULN 
 
≤ 5 x ULN for a patient with liver metastases 
18. Nonsterile males and female partners of nonsterile male study patients must agree to practice 
highly effective methods of birth control (Appendix 4) for the duration of the study and for at 
least 6 months after the last dose of pamiparib. Nonsterile males must avoid sperm donation 
for the duration of the study and for at least 6 months after the last dose of pamiparib. 
4.2. 
Exclusion Criteria 
Patients will be excluded from the study for any of the following reasons: 
1. Unresolved acute adverse effects of prior therapy of  Grade 2 
 Except for AEs not considered a likely safety risk by investigator judgement 
(eg, alopecia, neuropathy, and specific laboratory abnormalities) 
2. Chemotherapy, hormonal therapy, biologic therapy, radionuclide therapy, immunotherapy, 
investigational agent, Chinese anticancer medicine, or herbal remedies  5 half-lives if the 
half-life is known, ≤ 14 days if not known, before Day 1 
 Continued treatment with a bisphosphonate or denosumab is allowed, if administered 
at a stable dose  28 days before Day 1 
3. Radiotherapy ≤ 21 days (≤ 14 days, if a single fraction of radiotherapy) before Day 1 
4. Prior treatment for prostate cancer with any of the following: 
a) PARP inhibitor 
b) Platinum 
c) Cyclophosphamide 
d) Mitoxantrone 
 Prior treatment with sipuleucel-T or a checkpoint inhibitor (eg, nivolumab or 
pembrolizumab) is allowed. 
5. Major surgical procedure, open biopsy, or significant traumatic injury  14 days before Day 1, 
or anticipation of need for major surgical procedure during the course of the study  
 Placement of a vascular access device is not considered major surgery. 
6. Diagnosis of myelodysplastic syndrome (MDS) 
7. Other diagnosis of malignancy (including, but not limited to AML) 
 Except for surgically excised nonmelanoma skin cancer, adequately treated non-
invasive bladder cancer, or a malignancy diagnosed > 2 years ago with no current 
evidence of disease and no therapy  2 years before Day 1 
8. Leptomeningeal disease or uncontrolled, untreated brain metastases 


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 Patients with a history of treated and, at the time of screening, asymptomatic brain 
metastases are eligible, provided they meet all of the following: 
o Only supratentorial metastases 
o Brain imaging at screening without evidence of interim progression 
o No ongoing requirement for corticosteroids as therapy for brain metastases 
 Anticonvulsants at a stable dose allowed 
o No stereotactic radiation or whole-brain radiation ≤ 14 days before Day 1 
9. Active infection requiring systemic treatment, acute/viral hepatitis or active chronic hepatitis B 
or C infection, or active tuberculosis 
 Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers 
whose HBV DNA is > 500 IU/mL or patients with active hepatitis C should be 
excluded. Note: Inactive hepatitis B surface antigen carriers, treated and stable 
hepatitis B (HBV DNA < 500 IU/mL), and cured hepatitis C patients can be enrolled. 
10. Any of the following cardiovascular criteria: 
a) Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily 
living,  28 days before Day 1 
b) Symptomatic pulmonary embolism  28 days before Day 1 
c) Any history of acute myocardial infarction  6 months before Day 1 
d) Any history of heart failure meeting New York Heart Association Classification III or 
IV (Appendix 5)  6 months before Day 1 
e) Any event of ventricular arrhythmia  Grade 2 in severity  6 months before Day 1  
f) Any history of cerebral vascular accident  6 months before Day 1 
11. Previous complete gastric resection, chronic diarrhea, active inflammatory gastrointestinal 
disease, or any other disease-causing malabsorption syndrome 
 Gastroesophageal reflux disease under treatment with proton-pump inhibitors is 
allowed.  
12. Active bleeding disorder, including gastrointestinal bleeding, as evidenced by hematemesis, 
significant hemoptysis, or melena  6 months before Day 1 
13. Use  5 half-lives if the half-life is known, ≤ 14 days if not known, before Day 1 or anticipated 
need for food or drugs known to be strong or moderate cytochrome P450 (CYP) 3A inhibitors 
or strong CYP3A inducers (Appendix 6) 
14. Serum creatinine > 2.5 mg/dL at screening 
15. Significant intercurrent illness that may result in the patient’s death before death from prostate 
cancer 
16. Known history of intolerance to the excipients of the pamiparib capsule 


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5. 
STUDY PHASES FROM SCREENING TO END OF STUDY 
5.1. 
Screening 
As part of the Screening Visit, study center personnel will explain to the potential patient all aspects 
of the study, obtain signed informed consent, and document the informed consent process in the 
patient’s source documents before any study-specific procedures are conducted. The signed ICF 
initiates screening that must occur within 28 days before Day 1. 
Required screening assessments, some with shorter screening windows, are listed in Appendix 1. 
Assessments obtained within 7 days of Day 1 do not have to be repeated on Day 1. Patient treatment 
authorization may occur as late as Day 1 before the first dose of pamiparib. Results of standard of-
care tests or examinations performed before obtaining informed consent and within the screening 
windows may be used and do not have to be repeated as long as they meet protocol specifications. 
The investigator and study center radiologist will assess the potential patient for eligibility. Repeating 
screening assessments within the original screening window is allowed if the patient did not 
previously meet certain eligibility criteria. Tumor assessments should not be repeated. Screen failures 
and consent withdrawals will be documented in the patients’ source documents. 
5.2. 
Enrollment 
After consent has been obtained, each patient will be assigned a unique patient number that cannot be 
reassigned to any other patient. Patient numbers will be assigned in chronological order starting with 
the lowest number. After determination of eligibility, the investigator will complete the supporting 
documentation and provide them to the sponsor and/or designee for review and subsequent approval. 
No eligibility waivers will be granted. 
5.3. 
Treatment Phase 
The treatment phase is defined as the time elapsed between the first dose of pamiparib and the last 
dose of pamiparib administered. 
Day 1 of Cycle 1 is the first day of pamiparib administration (there is no Day 0 in this protocol). 
Patients must initiate study treatment within 4 days after authorization for treatment. 
Study procedures of each clinic visit are outlined in Appendix 1. 
Assessments should be obtained before pamiparib administration unless stated otherwise in 
Appendix 1 and should be performed in order of least invasive to most invasive assessment. All 
safety-related assessments must be reviewed and dose modifications, if necessary, be made by the 
investigator or subinvestigator before pamiparib administration. 
Patient-reported outcome questionnaires should be completed before any other study activities occur. 
Pamiparib dosing should be interrupted if at least 1 of the reasons listed in Section 5.5.1 is present, 
and the reason(s) for interruption should be recorded in the source document and in the corresponding 
electronic case report form (eCRF). 


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5.4. 
Unscheduled Visit 
Unscheduled visits may occur at any time as necessary as per investigator decision or patient’s request 
for reasons such as assessment or follow up of AEs. Study assessments of an unscheduled visit should 
be performed based on the reason for the unscheduled visit and are outlined in Appendix 1. If PD is 
suspected, imaging studies should be performed and blood for biomarkers should be obtained as 
appropriate. 
5.5. 
Permanent Discontinuation of Pamiparib 
5.5.1. 
Reasons for Permanent Discontinuation of Pamiparib 
Patients may permanently discontinue pamiparib for any of the following reasons: 
 PD 
 AEs 
o AEs that could lead to discontinuation of study drug are described in Table 4 within 
Section 6.1.4 
 Major protocol deviation  
 Patient withdrew consent for study treatment 
o Patients may voluntarily withdraw consent from study treatment at any time 
o Patients should be requested to participate in the follow-up phase, if patient withdraws 
consent from the treatment phase only 
 Investigator’s discretion 
 Initiation of new anticancer therapy 
The reason for permanent discontinuation of pamiparib will be recorded on the eCRF. Patients may 
discontinue pamiparib for other reasons but these will result in premature discontinuation from study 
(Section 5.6.4). 
5.5.2. 
End-of-Treatment Visit 
The EOT Visit should occur within 7 days after pamiparib has been permanently discontinued. 
Required assessments are listed in Appendix 1. A visit should be scheduled as soon as possible, but 
the EOT Visit may occur later after discussion with the medical monitor for specific circumstances, 
such as prolonged hospitalization. The visit at which tumor assessments showed PD may be used as 
the EOT Visit if all required assessments were performed. Tumor assessments do not have to be 
repeated if they were performed within 14 days of the EOT Visit or at a prior response evaluation that 
documented PD. An ECG does not have to be repeated if it was performed within 14 days of the EOT 
Visit. 


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5.6. 
Follow-Up Phase 
5.6.1. 
Safety Follow-up 
All patients who permanently discontinue pamiparib and have not initiated new anticancer therapy 
will be followed for AEs and SAEs as outlined in Section 9.3.1. Approximately 30 days after the last 
dose of pamiparib or before initiation of new anticancer therapy, whichever occurs first, the Safety 
Follow-up Visit will occur with the safety assessments outlined in Appendix 1. If new anticancer 
therapy is inadvertently initiated before the Safety Follow-up Visit (eg, without the knowledge of the 
study center team), a Safety Follow-up Visit should be scheduled as soon as possible. 
For patients who do not want to or cannot return to the clinic for the Safety Follow-up Visit, the 
patient should be contacted by telephone for a review of AEs. If these attempts of contact are 
unsuccessful, the additional attempts detailed in Section 5.6.3 should be made. 
5.6.2. 
Long-term Follow-up 
Patients will be followed for survival and initiation of new anticancer therapy via telephone contact 
or other means (eg, clinic visit) approximately every 12 weeks (Appendix 1). 
Patients who do not have objective disease progression at the time of pamiparib permanent 
discontinuation but meet other discontinuation criteria (eg, discontinued for AE and no new anticancer 
therapy) will continue to have tumor and PSA assessments every 12 weeks and 4 weeks (± 7 days), 
respectively, until PD or any other reason listed in Section 5.6.4, whichever occurs first. For efficacy 
assessments as per protocol, refer to Section 7.3 and Appendix 1. If the patient refuses to return for 
these PSA and tumor assessments or is unable to do so, every effort should be made to contact the 
patient by telephone to determine the patient’s disease status and survival. 
5.6.3. 
Lost to Follow-up 
If a patient is lost to follow-up, study center personnel must do their utmost to re-establish contact 
with the patient and determine the reason for withdrawal. All measures taken to follow up with the 
patient should be recorded. 
Should attempts to contact the patient by telephone be unsuccessful, the following additional attempts 
should be made to obtain protocol-required follow-up information. The patient should be contacted 
by mail in a manner that provides proof of receipt by the patient. If unsuccessful, other contacts should 
be explored, such as referring physicians or relatives. Attempts of contact should be documented in 
the patient’s source documents. If a patient cannot be contacted despite all attempts, the patient will 
be considered lost to follow-up, and death information should be obtained through a public record 
search if local agencies permit. 
5.6.4. 
Patient Discontinuation From Study (End of Study for an Individual Patient) 
Premature discontinuation from the study (without EOT and any follow-up visits) will occur under 
the following circumstances: 
 Patient withdrew consent for study participation 


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o Patients may voluntarily withdraw consent from the study at any time 
 Investigator’s discretion 
 Lost to follow-up 
o Lost to follow-up should be recorded as such in the eCRF 
o The investigator should show due diligence by documenting in the source documents steps 
taken to contact the patient (Section 5.6.3) 
 Death 
 Study termination by sponsor 
 Other, as per the discretion of the sponsor or health authority 
When a patient withdraws before the end of the study, the reason for withdrawal should be recorded 
in the source document and eCRF. Patients who withdraw from the study will not be replaced. 
5.7. 
End of Study 
The end of study is defined as the last patient last visit at the end of the long-term follow-up phase. 
This is the last timepoint for data collection. A patient is considered on study as long as the patient is 
still in long-term follow-up. 
The sponsor has the right to terminate this study at any time. Reasons for terminating the study early 
may include, but are not limited to, the following:  
 The incidence or severity of AEs in this or other studies indicates a potential health hazard to 
patients 
 Overall patient enrollment is unsatisfactory 
 Data recording is inaccurate or incomplete 
 Evidence of no clinical benefit 
The sponsor will notify each investigator if a decision is made to terminate the study. Should this be 
necessary, prematurely discontinued patients should be seen as soon as possible for an EOT Visit and 
Safety Follow-up Visit. 
The investigators may be informed of additional procedures to be followed to ensure that adequate 
consideration is given to the protection of the patient’s interests. The investigator will be responsible 
for informing IRBs/IECs of the early termination of the study. 
The sponsor has the right to close a study center at any time. The decision will be notified to the center 
in advance. Reasons for closing a center may include but are not limited to the following:  
 Excessively slow recruitment 
 Poor protocol adherence 
 Inaccurate or incomplete data recording 


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 Good Clinical Practice noncompliance 
 Study activity is completed (ie, all patients have completed and all obligations have been 
fulfilled)] 
6. 
STUDY TREATMENT 
6.1. 
Study Drug 
6.1.3. 
Dosage and Administration 
Pamiparib capsules will be administered orally twice a day, once in the morning and once in the 
evening. The time difference between 2 consecutive doses should be approximately 8 to 12 hours. 
Patients will be instructed to swallow the capsules whole, in rapid succession, with water. 
 
 
A dose of pamiparib should be skipped if it is not taken within 2 hours of the scheduled time. An extra 
dose of pamiparib should not be taken to make up for a missed dose. If vomiting occurs during the 
course of treatment, no re-dosing of the patient is allowed before the next scheduled dose. 
6.1.4. 
Dose Hold and Modification 
AEs should be assessed as best as possible regarding their relatedness to pamiparib. Patients should 
continue on study with follow-up as outlined in Sections 5.5 and 5.6. 


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Investigators should make every effort to maintain dose intensity in patients. Dosing of pamiparib can 
be withheld for up to 28 days consecutively. Dose reductions are allowed in 20 mg per dose 
decrements. If drug is held  28 days, the medical monitor must be contacted before permanent patient 
discontinuation from pamiparib. 
Criteria for treatment modifications and suggested guidelines for the management of some toxicities 
related to pamiparib are summarized below. These general guidelines may be modified at the 
discretion of the investigator based on discussions with the medical monitor and the best clinical 
judgment at that time; any decisions should be documented. Any toxicities related to pamiparib should 
be managed according to standard medical practice. 
A maximum of 2 dose reductions is allowed before the patient must be permanently withdrawn from 
pamiparib. Dose levels for pamiparib are summarized in Table 3. Pamiparib will be dose modified as 
outlined in Table 4. For prolonged hematologic toxicities, interrupt treatment and monitor blood 
counts weekly until recovery. If the levels have not recovered to NCI-CTCAE Grade 1 or less after 4 
weeks, further investigations should be considered, including bone marrow analysis and blood sample 
for cytogenetics. If MDS or AML is confirmed, discontinue pamiparib. 
Table 3: Dose Levels for Pamiparib 
Dose Level 
Pamiparib 
1 
60 mg orally twice a day 
-1 
40 mg orally twice a day 
-2 
20 mg orally twice a day 
Pamiparib may be dose-reduced for a maximum of 2 dose reductions. 
 


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Table 4: Criteria for Modification of Pamiparib Dosing for Related Adverse Events 
Toxicity 
Recommended Dose Modificationa 
Hematologic 
Anemia (hemoglobin) 
Hgb < 9.0 g/dL 
 First occurrence of Hgb < 9.0 g/dL:  
Hold pamiparib and treat as medically indicated to get Hgb to ≥ 9 g/dL, and 
then  pamiparib by 1 dose level to 40 mg BID 
Grade 2 (Hgb 
<10 - 8 g/dL)  
Hgb <10 - 9 g/dL 
Continue dosing at current dose level and treat with appropriate supportive care 
as medically indicated 
Hgb <9 - 8 g/dL 
 
Subsequent occurrence following dose reduction for anemia:  
o Continue pamiparib without interruption with appropriate supportive 
care based on clinical assessment OR 
o Hold pamiparib and treat as medically indicated to get Hgb to ≥ 9 g/dL, 
then restart at reduced dose level OR 
o Hold pamiparib and treat as medically indicated to get Hgb to ≥ 9 g/dL, 
then  pamiparib by 1 additional dose level to 20 mg BID 
Grade 3 (Hgb <8 g/dL) 
 
Subsequent occurrence following dose reduction for anemia:  
o Continue pamiparib without interruption with appropriate supportive 
care based on clinical assessment OR 
o Hold pamiparib and treat as medically indicated to get Hgb to ≥ 9 g/dL, 
then restart at reduced dose level OR 
o Hold pamiparib and treat as medically indicated to get Hgb to ≥ 9 g/dL, 
then  pamiparib by 1 additional dose level to 20 mg BID 
Grade 4 (life-threatening 
consequences; urgent intervention 
indicated) 
 
Second occurrence following dose reduction for anemia:  
o Hold pamiparib and treat as medically indicated to get Hgb to ≥ 9 g/dL, 
then  pamiparib by 1 additional dose level to 20 mg BID 
 
Third occurrence following 2 dose reductions for anemia:  
o Discontinue pamiparib if anemia is not caused by any other confounding 
event, eg GI hemorrhage. 
o Hold pamiparib and treat as medically indicated to get Hgb to ≥ 9 g/dL, 
then restart at reduced dose level. 
 Note: 
1) Weekly hematology test should be done for the first 3 cycles during the study. For all Grade 2 or higher 
anemia, hematology test should be done weekly thereafter until adequate recovery. 
2) For any patients showing Hgb dropping > 2 g/dL especially within a short time without alternative explanation 
such as gastrointestinal bleeding,  pamiparib by 1 dose level should be considered. 
3) Dose increase can be considered in certain cases, depending on approval from the medical monitor, provided 
Hgb has been maintained above 9 g/dL for at least 3 months 


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Toxicity 
Recommended Dose Modificationa 
Neutropenia (absolute neutrophil count) 
Grade 3 (absolute neutrophil count 
< 1.0 - 0.5 x 109/L) 
Hold pamiparib until resolved to ≤ Grade 2 or baseline 
 If resolved ≤ 7 days, then maintain dose levels 
 If resolved > 7 days, then  pamiparib by 1 dose level 
Grade 4 (absolute neutrophil count 
< 0.5 x 109/L) 
Hold pamiparib until resolved to ≤ Grade 1 or baseline and 
 pamiparib by 1 dose level 
Febrile neutropenia (absolute 
neutrophil count < 1.0 x 109/L with 
single temperature of > 38.3°C or 
sustained temperature of ≥ 38°C for 
> 1 hour) 
Hold pamiparib until resolved and 
 pamiparib by 1 dose level 
Thrombocytopenia (platelet count) 
Grade 3 (platelet count < 50 - 25 x 
109/L) 
Hold pamiparib until resolved to ≤ Grade 1 or baseline and 
 pamiparib by 1 dose level 
Grade 4 (platelet count < 25 x 109/L) 
Hold pamiparib until resolved to ≤ Grade 1 or baseline and 
 pamiparib by 1 dose level 
Renal 
Estimated glomerular filtration rate (CKD-EPI equation; Appendix 11) 
If ≥ 60 mL/min/1.73 m2 at baseline: 
< 30 to 15 mL/min/1.73 m2 
or 
If < 60 mL/min/1.73 m2 at baseline: 
≥ 50% reduction from baseline 
Hold pamiparib until resolved to ≥ 60 mL/min/1.73 m2  
 If resolved ≤ 7 days, then maintain dose levels 
 If resolved > 7 days, then  pamiparib by 1 dose level 
Regardless of baseline: 
< 15 mL/min/1.73 m2 
Permanently discontinue pamiparib 
Table 4: Criteria for Modification of Pamiparib Dosing for Related Adverse Events 
(Continued) 
Toxicity 
Recommended Dose Modificationa 
Hepatic 
Bilirubin 
 
Grade 2 (> 1.5 - 3.0 x ULN) 
Only applies to patients with 
normal bilirubin at baseline 
Hold pamiparib until resolved to ≤ Grade 1 or baseline  
 If resolved ≤ 7 days, then maintain dose levels 
 If resolved > 7 days, then  pamiparib by 1 dose level 
Grade 3 (> 3.0 - 10.0 x ULN) 
Hold pamiparib until resolved to ≤ Grade 1 or baseline  
 If resolved ≤ 7 days, then maintain dose levels 
 If resolved > 7 days, then  pamiparib by 1 dose level 


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Toxicity 
Recommended Dose Modificationa 
Grade 4 (> 10.0 x ULN) 
Permanently discontinue pamiparib 
Note: If Grade 3 or 4 hyperbilirubinemia is due to the indirect (unconjugated) 
component only, and hemolysis as the etiology has been ruled out as per 
institutional guidelines (eg, review of peripheral blood smear and haptoglobin 
determination), then  pamiparib by 1 dose level and continue treatment at the 
discretion of the investigator in discussion with the medical monitor 
Aspartate aminotransferase and/or alanine aminotransferase 
Grade 3 (> 5 and ≤ 20 x ULN) 
 
 
Hold pamiparib until aspartate aminotransferase and/or alanine aminotransferase 
resolved to ≤ 5 x ULN or baseline 
 If not resolved within 7 days to ≤5 x ULN*, then pamiparib should be 
decreased by 1 dose level  
 If second episode, permanently discontinue pamiparib 
*if other etiologies have been reasonably excluded and not solely based on 
abnormality/increase of AST/ALT laboratory results 
Grade 4 (> 20 x ULN) 
Permanently discontinue pamiparib 
Pancreatic 
Pancreatitis 
Grade 3 or 4 
Permanently discontinue pamiparib 
Cardiac 
Cardiac - Prolonged QTc interval 
QTcF > 500 msec  
or 
Change in QTc interval > 60 msec 
from the highest value at baseline 
or predose 
 Obtain triplicate electrocardiograms (2 to 3 minutes apart) ~1 hour after 
initial electrocardiogram 
 If mean QTcF > 500 ms or mean change in QTc interval > 60 msec, hold 
pamiparib until evaluation of electrocardiograms by cardiologist  
o Cardiology evaluation as soon as practical but within 7 days of initial 
abnormal electrocardiogram 
 If mean QTcF > 500 ms or mean change in QTc interval > 60 msec is 
confirmed by cardiologist, permanently discontinue pamiparib 


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Table 4: Criteria for Modification of Pamiparib Dosing for Related Adverse Events 
(Continued) 
Toxicity 
Recommended Dose Modificationa 
Cardiac - General 
Grade 3 
Hold pamiparib until resolved to ≤ Grade 1 or baseline and ↓ pamiparib by 1 
dose level 
In the event of acute coronary syndrome, congestive heart failure and 
myocardial infarction, treatment should be permanently discontinued 
Grade 4 
Permanently discontinue pamiparib 
Other adverse events 
Grade 3 
Hold pamiparib until resolved to ≤ Grade 1 or baseline and 
 pamiparib by 1 dose level 
No dose reduction required for asymptomatic laboratory abnormalities 
Grade 4 
Permanently discontinue pamiparib 
Abbreviations: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; QTcF, QT interval corrected for heart 
rate using Fridericia’s formula; ULN, upper limit of normal. 
a 
Dosing of pamiparib can be withheld for up to 28 days consecutively.  
 
6.1.5. 
Compliance and Accountability 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient. 
The investigator and/or study personnel will keep accurate records of the quantities of capsules 
dispensed and used by each patient. This information must be captured in the source document at the 
end of each cycle. The investigator is responsible for pamiparib accountability, reconciliation, and 
record maintenance. In accordance with all applicable regulatory requirements, the investigator or 
designated study center personnel must maintain pamiparib accountability records throughout the 
course of the study. This person will document the amount of pamiparib received from the sponsor, 
the amount supplied, and/or administered to and returned by patients, if applicable. 
6.1.6. 
Disposal and Destruction 
At times throughout the study, all unused pamiparib will be inventoried and packaged for return 
shipment by the hospital unit pharmacist or other designated study center personnel. The inventoried 
supplies can be destroyed on site or at the depot according to institutional policies, after receiving 
written sponsor approval. 


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6.2. 
Concomitant Medications and Nondrug Therapies 
6.2.1. 
Permitted Medications and Supportive Care 
All treatments and supportive care, including antiemetic therapy, hematopoietic growth factors, 
and/or red blood cell/platelet transfusions, that the investigator considers necessary for a patient’s 
welfare may be administered at the discretion of the investigator in keeping with the local standards 
of medical care. 
All concomitant medications, including all prescription and over-the-counter drugs, supplements, and 
intravenous medications and fluid supplementation, taken by or administered to the patient within 28 
days before Day 1 and 30 days after the last dose of pamiparib will be recorded. 
6.2.2. 
Prohibited Medications 
Patients are not allowed to receive other anticancer therapy, including chemotherapy, hormonal 
therapy, biologic therapy, radionuclide therapy, immunotherapy, investigational agent, Chinese 
anticancer medicine, or herbal remedies ≤ 5 half-lives if the half-life is known, ≤ 14 days if not known, 
before Day 1 and during the study. In addition, patients are not allowed to receive radiotherapy ≤ 21 
days (≤ 14 days, if a single fraction of radiotherapy) before Day 1 and during the study. 
Bisphosphonate and denosumab use is permitted if the patient had already been receiving it at a stable 
dose  28 days before Day 1. 
The primary metabolic pathway for pamiparib involves the CYP3A isoform. Administration of 
strong/moderate inhibitors of CYP3A or strong CYP3A inducers is not allowed. Please refer to the 
drugs/substances listed in Appendix 6. Consumption of grapefruit and Seville oranges or their juices 
are not allowed throughout the study. No other dietary restrictions will apply. 
6.2.3. 
Medications to Be Used with Caution 
Based on preliminary in vitro screening assays, pamiparib is not a strong inhibitor of other human 
CYP isoenzymes tested. It is a moderate inhibitor of CYP2C9 (IC50 = 6.48 M). Investigators need 
to be aware that pamiparib has the potential to interfere with the appropriate metabolism of 
medications that rely on CYP2C9 and follow the prescribing information recommendations for use 
with CYP2C9 inhibitors. Therefore, careful monitoring should be used when co-prescribing CYP2C9 
substrates with a narrow therapeutic index, such as phenytoin and warfarin. 
Examples of these medications are listed in Appendix 7 and these should be used cautiously with drug 
concentration monitoring where appropriate. 
In addition to CYP3A, pamiparib can also be metabolized by CYP2C8 in human liver microsomes, 
but to a lesser extent. See Appendix 7 for medications that should be used with caution for that reason. 


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7. 
STUDY ASSESSMENTS 
7.1. 
Study Flow and Visit Schedule 
The study-specific assessments and procedures with allowed time windows are outlined in Appendix 
1. Assessments of efficacy will occur as outlined in Section 7.3. Assessments of safety will be based 
on AE monitoring and reporting (including attribution of AEs and SAEs), physical examinations, vital 
signs, ECGs, and clinical laboratory tests as outlined in Section 7.4. 
7.2. 
Patient Demographics and Other Baseline Characteristics 
7.2.1. 
Demographics 
Demographic data will include gender, year of birth (or age), and race/ethnicity. 
7.2.2. 
Medical History 
Clinically significant medical history findings (eg, previous diagnoses, diseases, or surgeries) that 
were present before signing the ICF and considered relevant for the patient’s study eligibility will be 
collected and captured. Clinically significant is defined as any events, diagnoses, or laboratory values 
that require treatment or follow-up, or the presence of signs or symptoms that require medical 
intervention. Concurrent medical signs and symptoms must be documented to establish baseline 
severities. 
For cancer history, the date of initial diagnosis and current disease status, staging, sites of disease, 
smoking history, prior anticancer therapies and dates administered, responses, and DOR to these 
treatments will also be recorded. 
7.2.3. 
Other Baseline Characteristics 
Information will also be collected regarding smoking history, prior medications/significant nondrug 
therapies, childbearing potential (Appendix 4), and any other assessments that are performed for the 
purpose of eligibility for inclusion in the study (Section 5), such as physical examination, vital signs, 
hematology, chemistry, and ECG. 
7.3. 
Efficacy 
7.3.1. 
Tumor Assessments 
Following the screening tumor assessment, tumor assessments will occur at the schedule of every 
8 weeks (±7 days) after Day 1 for 24 weeks, then every 12 weeks (± 7 days). Any measurable disease 
must be documented at screening and reassessed at each subsequent tumor evaluation. Response and 
DOR will be assessed by the investigator using PCWG3 criteria (Appendix 10). 
The same imaging method(s) used at screening must be used throughout the study. Computed 
tomography (CT) scan with intravenous contrast and magnetic resonance imaging (MRI) are the 
preferred imaging methods. A documented standard-of-care tumor assessment may be used as the 
screening assessment provided it meets the requirements (Section 7.3.1.2). 


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All screening and on-study radiographs will be collected centrally so that review of the radiographs 
by an IRC may be performed. Instructions for submission of the radiographs will be provided in the 
study manual. 
7.3.1.1. 
Determination of Eligibility 
The investigator and study center radiologist will review tumor assessments to determine whether the 
patient has progression of soft tissue disease by modified RECIST Version 1.1 or PCWG3 criteria. 
7.3.1.2. 
Screening Tumor Assessment 
The baseline tumor assessment should include the following: 
 Diagnostic-quality, contrast-enhanced CT scans of chest, abdomen, and pelvis 
o To be suitable for RECIST Version 1.1 assessments, CT scans should have a maximum 
thickness of 5 mm and no gaps. 
o CT is the preferred imaging method for tumor assessments of chest, abdomen, and pelvis. 
o If a positron-emission tomography/CT scan is performed, the CT portion should meet the CT 
scan requirements described above. 
o In patients for whom the preferred CT scans are contraindicated because of, for example, a 
CT intravenous contrast allergy, a CT of the chest without contrast and MRI of the abdomen 
and pelvis with contrast are recommended. 
o MRI scans may be performed in lieu of CT scans. At screening, tumor assessments should 
include a diagnostic quality, contrast-enhanced MRI scan of chest, abdomen, and pelvis. To 
be suitable for RECIST Version 1.1 assessments, MRI scans should ideally have a maximum 
thickness of 5 mm and minimal gaps. 
 Whole-body radionuclide bone scan to evaluate for bone metastases 
 CT scan of the neck, if clinically indicated 
o Only to be performed at screening if the patient has known or suspected metastases in this 
area 
o MRI scan of the neck may be substituted for CT scan of the neck. 
 MRI scan of the brain, if clinically indicated 
o Only to be performed at screening if the patient has symptoms that could be due to brain 
metastases 
o MRI is the preferred imaging method for tumor assessments of the brain. 
o In patients for whom MRI of the brain is not available or who are claustrophobic, a CT scan 
of the brain with intravenous contrast may be performed. 


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If brain metastases are present at baseline, the patient is eligible for this study if criteria listed under 
Exclusion Criterion 8 (Section 4.2) are met. 
7.3.1.3. 
On-Study Tumor Assessments 
All target and nontarget lesions must be assessed with the same imaging method used at baseline.  
 Diagnostic-quality, contrast-enhanced CT scans of chest, abdomen, and pelvis (every 8 weeks 
± 7 days for 24 weeks, then every 12 weeks ± 7 days) 
o CT scan with intravenous contrast is preferred, but the imaging method used at screening 
determines the imaging method of subsequent tumor assessments and must be used. 
 Imaging of all other known sites of disease (every 8 weeks ± 7 days for 24 weeks, then every 
12 weeks ± 7 days) 
In addition to the protocol-specified tumor assessments, CT scans or other imaging studies may be 
performed at the investigator’s discretion at any time as clinically indicated. 
7.3.2. 
Prostate-Specific Antigen 
PSA levels will be collected at timepoints specified in Appendix 1 and tested in a certified local 
laboratory. In addition, at least, the 3 most recent PSA levels before Day 1 ( 1 week between 
determinations) must be provided to document PSA progression before study entry. 
Increases and decreases in PSA will be tracked to assess PSA responses as defined by the PCWG3 
criteria described in Appendix 10. A PSA response or progression must be confirmed  3 weeks later. 
7.3.3. 
Survival Assessments 
Survival status of patients will be monitored through all phases of the study as outlined in Section 5 
and Appendix 1. The date and cause of death will be recorded. 
7.3.4. 
Quality-of-Life Assessments 
Patients will complete all questionnaires in the clinic before any other study activities occur at 
timepoints specified in Appendix 1. Patients should be given sufficient instruction, space, time, and 
privacy for completion of the questionnaires. A study center team member should check for 
completeness of answers and encourage the patient to complete any missing answers. The 
questionnaires are validated instruments to measure the health status of patients (EQ-5D-5L; 
Appendix 8) and the quality of life of cancer patients (BPI-SF [Appendix 9]). 
7.4. 
Safety 
7.4.1. 
Adverse Events 
Safety assessments should be performed at the study center visits indicated in Appendix 1. 


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All AEs and SAEs, regardless of their relationship to pamiparib, will be collected in the fashion and 
for the time periods outlined in Section 9. The regulatory definition of AEs and requirements for SAE 
reporting are outlined in Section 9. 
7.4.2. 
Physical Examination, Vital Signs, ECOG Performance Status, Weight, and Height 
A complete or limited physical examination, vital signs (systolic and diastolic blood pressure; pulse 
rate; and oral, temporal, tympanic, or armpit temperature), weight, height, and ECOG performance 
status will be performed at timepoints specified in Appendix 1. 
A complete physical examination should include an evaluation of head, eyes, ears, nose and throat, 
neck, heart, chest (including lungs), abdomen, extremities, skin, lymph nodes, cardiovascular status, 
and neurologic status. A limited physical examination should be directed at the evaluation of 
symptoms or specific safety issues. Changes from baseline abnormalities should be recorded at each 
subsequent physical examination. New or worsened abnormalities should be recorded as AEs if 
appropriate. 
ECOG performance status will be graded as outlined in Appendix 3. 
7.4.3. 
Electrocardiograms 
Single 12-lead ECGs with assessment of PR interval, QRS duration, and QT interval corrected for 
heart rate using Fridericia’s formula will be obtained at timepoints specified in Appendix 1. 
Additional ECGs will be performed if clinically indicated. To minimize postural variability, it is 
important that patients are resting and in a semirecumbent or supine position for  5 minutes before 
each ECG collection. Blood draws and other procedures should be avoided during the period 
immediately before ECG measurement, and activity should be controlled as much as possible to 
minimize variability because of the effects of physiologic stress. Screening ECG must be performed 
within 14 days before Day 1. For the scheduled ECG assessment at the EOT Visit, ECG does not have 
to be repeated if it was performed within 14 days of the EOT Visit. 
7.5. 
Safety Laboratory Assessments 
On-study clinical laboratory evaluations starting from screening shall be performed by a central 
laboratory, as regionally available. An investigator may obtain safety laboratory results from their 
local laboratory as clinically indicated (eg, on the day of a patient’s visit before results are available 
from the central laboratory for dose modifications or AE/SAE monitoring). Results from the central 
laboratory will serve as the official study laboratory result, where available. If required by local 
regulations, clinical laboratory evaluations performed by a local, instead of a central, laboratory are 
acceptable. 
A detailed description of the procedures for sample collection, handling, storage, and shipment of the 
laboratory samples and all material such as test tubes and labels is provided in the study manual. 
Laboratory assessments will be performed at the timepoints specified in Appendix 1 and may also be 
performed as clinically indicated. Laboratory assessments should be performed before pamiparib 


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administration. Screening blood tests must be performed within 14 days of Day 1. If tests were 
performed within 7 days of Day 1, they do not need to be repeated on Day 1. 
7.5.1. 
Hematology 
Hematology includes hemoglobin, platelet count, white blood cell count, neutrophil count, and 
lymphocyte count. 
7.5.2. 
Chemistry 
Chemistry 
includes 
albumin, 
alkaline 
phosphatase, 
alanine 
aminotransferase, 
aspartate 
aminotransferase, blood urea nitrogen, chloride, creatinine, glucose, lactate dehydrogenase, 
phosphate, potassium, sodium, total bilirubin, and total protein.  
7.5.3. 
Urinalysis 
Urinalysis includes blood, glucose, ketones, protein, red blood cells, and white blood cells. 
7.5.4. 
Hepatitis B and C Testing 
Testing will be performed by a central laboratory and/or the local laboratory at screening and as 
clinically indicated and will include HBV/hepatitis C virus (HCV) serology (hepatitis B surface 
antigen, hepatitis B surface antibody, hepatitis B core antibody, and HCV antibody) and viral load 
assessment (HBV DNA and HCV RNA). 
7.6. 
Circulating Tumor Cell Count 
Blood samples for CTC enumeration will be collected from patients at the timepoints specified in 
Appendix 1. 
7.7. 
Pharmacokinetics 
PK samples for pamiparib will be collected at all non-China centers and at centers with such capability 
in China. PK samples will be collected from patients at the following timepoints (Appendix 1): 
predose (within 30 minutes before dose) and 2 hours (± 30 minutes) postdose on Cycle 1 Day 1 and 
Cycle 1 Day 15. The time of pamiparib administration on the day before Day 15 (Cycle 1 Day 14) 
must be recorded on the eCRF. Details concerning collection, handling, and processing of the PK 
plasma samples will be provided in the laboratory manual.  
7.8. 
Biomarkers 
Blood samples for biomarker testing will be collected from patients at the timepoints specified in 
Appendix 1. A blood sample must be collected for prospective testing of CTC-HRD status during 
pre-screening or screening. Pre-screening for prospective testing of CTC-HRD status (blood sample) 
can be completed before the study eligibility screening. A separate pre-screening informed consent 
must be obtained. 


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An archived, formalin-fixed, paraffin-embedded tumor sample will be collected from patients, if 
available, for retrospective analysis of HRD mutational status. Archival tumor tissue shall be sent to 
the central laboratory for biomarker testing (either a formalin-fixed, paraffin-embedded block with 
tumor tissue [preferred] or approximately 10 unstained slides). The most recent tumor block is 
preferred. 
In the absence of archival tumor tissues, a fresh baseline biopsy of a tumor lesion is highly 
recommended. Written patient consent is required for fresh tumor biopsies. Optional biopsy will also 
be taken, if agreeable, at the EOT Visit for patients who have confirmed PD during the study from 
accessible tumor sites to obtain samples to explore resistance mechanisms. If feasible, any follow-up 
biopsy should, ideally, be taken from the same tumor lesion as the baseline biopsy. 
Patients will also provide blood samples to be processed into plasma and cell fractions for the analysis 
of genetic defects associated with prostate cancer including but not limited to HRD signatures, DNA 
repair deficiency, and confirmation of BRCA1/2 mutational status. 
Instructions for the processing, storage, and shipping of samples will be provided in the study manual. 
7.9. 
Appropriateness of Measurements 
All efficacy and safety assessments used in this study are standard and generally recognized as 
reliable, accurate, and relevant. 
8. 
DATA HANDLING AND QUALITY ASSURANCE 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. Study 
center audits may be made periodically by the sponsor’s or the contract research organization’s 
qualified compliance auditing team, which is an independent function from the study team responsible 
for conduct of the study. 
8.1. 
Data Collection 
Data will be entered into the eCRFs in an electronic data capture (EDC) system. 
Data collection on the eCRF must follow the instructions described in the eCRF completion 
guidelines. The investigator has ultimate responsibility for the collection and reporting of all clinical 
data entered on the eCRF. The investigator or designee must sign the completed casebooks to attest 
to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of BeiGene, Ltd. (hereafter referred to as BeiGene) 
and should not be made available in any form to third parties without written permission from 
BeiGene, except for authorized representatives of BeiGene or appropriate regulatory authorities. 


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8.2. 
Data Management/Coding 
All final patient data, both eCRF and external data (eg, laboratory data), collected according to the 
protocol, will be stored at BeiGene at the end of the study.  
Standard procedures (including following data review guidelines, computerized validation to 
produce queries, and maintenance of an audit file, which includes all database modifications) will 
be followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
An electronic data capture (EDC) system will be used for this study, meaning that all eCRF data 
will be entered in electronic forms at the study center. Data collection will be completed by 
authorized study center personnel designated by the investigator. Appropriate training and security 
measures will be completed with the investigator and all authorized study center personnel prior to 
the study being initiated and any data being entered into the system for any subjects. 
During the course of the study, a study monitor will make study center visits to review protocol 
compliance, compare eCRFs against individual patient’s medical records, and ensure that the study 
is being conducted according to pertinent regulatory requirements. 
The eCRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents used by 
the investigator or hospital that relate to the subject’s medical history, that verify the existence of 
the subject, the inclusion and exclusion criteria and all records covering the subject’s participation 
in the study. They include laboratory notes, ECG results, memoranda, pharmacy dispensing records, 
subject files, etc. 
eCRF entries will be verified with source documentation. The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. Checking the eCRFs for 
completeness, clarity, and cross checking with source documents is required to monitor the progress 
of the study. Direct access to source data is also required for inspections and audits, and will be 
carried out giving due consideration to data protection and medical confidentiality. 
The investigator is responsible for maintaining source documents. These will be made available for 
inspection by the study monitor at each monitoring visit. The investigator must submit a completed 
eCRF for each subject who receives the study drug, regardless of the duration. All supportive 
documentation submitted with the eCRF, such as laboratory or hospital records, should be clearly 
identified with the study and subject number. Any personal information, including subject name, 
should be removed or rendered illegible to preserve individual confidentiality. 
AEs will be coded using the Medical Dictionary for Regulatory Activities Version 20.0 or higher. 
Concomitant medications will be coded using the World Health Organization Drug Dictionary. 
Concomitant diseases/medical history will be coded using the Medical Dictionary for Regulatory 
Activities Version 20.0 or higher. 


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8.3. 
Quality Assurance 
To ensure compliance with Good Clinical Practice and all applicable regulatory requirements, the 
sponsor may conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory 
inspection of this study. Such audits/inspections can occur at any time during or after completion of 
the study. If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to the facilities used for this trial and all relevant documents and to 
allocate his/her time and the time of his/her personnel to the auditor/inspector to discuss findings and 
any relevant issues. 
9. 
SAFETY MONITORING AND REPORTING 
The investigator is responsible for the monitoring and documentation of events that meet the criteria 
and definition of an AE or SAE as provided in this protocol. 
9.1. 
Adverse Events 
9.1.1. 
Definition and Reporting of an Adverse Event 
An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease (new or exacerbated) temporally associated with the use of a pamiparib, whether 
considered related to pamiparib or not.  
Examples of an AE include:  
 Worsening of a chronic or intermittent preexisting condition including an increase in severity, 
frequency, duration, and/or has an association with a significantly worse outcome 
 New conditions detected or diagnosed after pamiparib administration even though the condition 
might have been present before the start of the study 
 Signs, symptoms, or the clinical sequelae of a suspected interaction 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either pamiparib or a 
concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory results, and diagnostics reports) relative to the AE or SAE. 
The investigator will then record all relevant information regarding an AE or SAE in the eCRF. 
However, there may be instances when copies of medical records for certain cases are requested by 
the sponsor. In this instance, all patient identifiers will be blinded on the copies of the medical records 
before submission to the sponsor.  
9.1.2. 
Assessment of Severity 
The investigator will assess the severity of each AE and SAE reported during the study. AEs and 
SAEs should be assessed and graded based upon the NCI-CTCAE Version 4.03 or higher. 


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Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
 Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living  
 Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living  
 Grade 4: Life-threatening consequences; urgent intervention indicated  
 Grade 5: Death related to an AE  
Note: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(eg, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or life-threatening 
[Grade 4]); whereas, seriousness is classified by the criteria based on the regulatory definitions. 
Seriousness serves as the guide for defining regulatory reporting obligations from the sponsor to 
applicable regulatory authorities as described in Section 9.5. 
9.1.3. 
Assessment of Causality 
The investigator is obligated to assess the relationship between pamiparib and the occurrence of 
each AE or SAE using best clinical judgment. Alternative causes, such as natural history of the 
underlying diseases, concomitant therapy, and other risk factors, and the temporal relationship of 
the AE or SAE to pamiparib will be considered and investigated. The investigator should consult 
the Pamiparib Investigator’s Brochure in the determination of his/her assessment. There may be 
situations when an SAE has occurred and the investigator has minimal information to include in the 
initial report to the sponsor. However, it is very important that the investigator always provides an 
assessment of causality for every SAE before transmission of the SAE report/eCRF to the sponsor 
because the causality assessment is one of the criteria used when determining regulatory reporting 
requirements. The investigator may change his/her opinion of causality based on follow-up 
information, amending the SAE report/eCRF accordingly.  
The causality of each AE should be assessed and classified by the investigator as “related” or “not 
related.” An AE is considered related if there is at least “a reasonable possibility” that the AE may 
have been caused by pamiparib (ie, there are facts, evidence, or arguments to suggest possible 
causation, or a causal relationship between the AE and the drug cannot be ruled out). A number of 
factors should be considered in making this assessment, including: 
 Temporal relationship of the AE to the administration of pamiparib/study procedure 
 Whether an alternative etiology has been identified 
 Mechanism of action of pamiparib 
 Biologic plausibility 


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An AE should be considered “related” to pamiparib if any of the following are met, otherwise the 
event should be assessed as “not related”: 
 There is clear evidence to suggest a causal relationship, and other possible contributing factors 
can be ruled out 
 There is evidence to suggest a causal relationship, and the influence of other factors is unlikely 
 There is some evidence to suggest a causal relationship (eg, the AE occurred within a reasonable 
time after administration of pamiparib). However, the influence of other factors may have 
contributed to the AE (eg, the patient’s clinical condition or other concomitant AEs). 
 A causal relationship between the AE and the study drug cannot be ruled out 
9.1.4. 
Follow-Up of Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each patient and 
provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be reviewed 
at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered chronic, 
the AE or SAE is otherwise explained, the patient is lost to follow-up, or the patient withdraws 
consent. Once resolved, the appropriate AE or SAE eCRF page(s) will be updated. The investigator 
will ensure that follow-up includes any supplemental investigations as may be indicated to elucidate 
the nature and/or causality of the AE or SAE. This may include additional laboratory tests or 
investigations, histopathologic examinations, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of the 
AE or SAE. The investigator is obligated to assist. If a patient dies during participation in the study 
or during a recognized follow-up period, the sponsor will be provided with a copy of any postmortem 
findings, including histopathology if conducted. 
New or updated information will be recorded on the originally completed SAE report/eCRF, with all 
changes signed and dated by the investigator. The updated SAE follow-up report/eCRF should be 
resent to the sponsor within the timeframes outlined in Section 9.5.1. 
9.1.5. 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, chemistry, hematology, or coagulation) or other abnormal 
assessments (eg, ECGs, x-rays, or vital signs) that are judged by the investigator as clinically 
significant will be recorded as AEs or SAEs. This includes clinically significant abnormal laboratory 
findings or other abnormal assessments that are present at baseline and significantly worsen during 
the study. The definition of clinically significant is entrusted to the judgment of the investigator. In 
general, these are the abnormalities that: 
 Are associated with clinical signs or symptoms, or 


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 Require active medical intervention, or 
 Lead to dose interruption or discontinuation, or  
 Require close observation, more frequent follow-up assessments, or 
 Further diagnostic investigation 
9.2. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose:  
 Results in death 
 Is life-threatening 
Note: The term “life-threatening” in the definition of “serious” refers to an AE in which the patient 
was at risk of death at the time of the AE. It does not refer to an AE that hypothetically might have 
caused death if it was more severe.  
 Requires hospitalization or prolongation of existing hospitalization 
Note: In general, hospitalization signifies that the patient was admitted (usually involving at least an 
overnight stay) to the hospital or emergency ward for observation and/or treatment that would not 
have been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the AE is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.  
 Results in disability/incapacity 
Note: The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental 
trauma (eg, sprained ankle), which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption.  
 Is a congenital anomaly/birth defect 
 Is considered a significant medical AE by the investigator based on medical judgment (eg, may 
jeopardize the patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
The following are NOT considered SAEs: 
 Hospitalization for elective treatment of a preexisting condition that did not worsen from baseline 
 Hospitalization for social/convenience considerations 
 Scheduled therapy for the target disease of the study, including admissions for transfusion support 
or convenience 


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9.3. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious Adverse 
Events 
9.3.1. 
Adverse Event Reporting Period 
After the ICF has been signed, but before initiation of pamiparib, only SAEs should be reported to 
the sponsor. 
After initiation of treatment, all AEs and SAEs, regardless of relationship to treatment, will be 
reported until 30 days after the last dose of pamiparib or initiation of new anticancer therapy, 
whichever occurs first. After this period, the investigator should report any SAEs that are believed to 
be related to prior study drug treatment. 
After a patient is discontinued from the study, investigators are not obligated to actively seek AEs or 
SAEs from the former patients. However, if the investigator learns of any SAE, including a death, at 
any time, and considers the SAE related to pamiparib, the investigator will notify the sponsor.  
9.3.2. 
Eliciting Adverse Events 
The investigator or designee will ask patients about AEs by asking the following standard questions: 
 How are you feeling? 
 Have you had any medical problems since your last visit? 
 Have you taken any new medicines since your last visit? 
9.4. 
Study-Specific Adverse Event and Serious Adverse Event Reporting Instructions 
9.4.1. 
Disease Progression 
“Disease progression” (including fatal disease progression), which is expected in this study 
population and measured as an efficacy endpoint, should not be reported as an event term. Instead, 
the symptoms, signs, or clinical sequelae that result from disease progression should be reported as 
the event terms. 
For example, a patient presents with pleural effusion resulting from disease progression of metastasis 
to lungs. The event term should be reported as “pleural effusion” instead of disease progression. If a 
patient experienced a fatal multiorgan failure due to disease progression, the term “multiorgan failure” 
should be reported as the SAE with death as outcome instead of reporting “fatal disease progression” 
or “death due to disease progression”. 
9.4.2. 
Death 
Death is an outcome and not usually considered an event. If the only information available is death 
and the cause of death is unknown, then the death is reported as an event, eg, “death”, “death of 
unknown cause”, or “death unexplained”. 


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9.5. 
Prompt Reporting of Serious Adverse Events 
9.5.1. 
Timeframes for Submitting Serious Adverse Events 
SAEs will be reported promptly (within 24 hours) to the sponsor or designee as described in Table 5 
once the investigator determines that the AE meets the protocol definition of an SAE. 
Table 5: Timeframes and Documentation Methods for Reporting Serious Adverse Events to 
the Sponsor or Designee 
Type of SAE 
Initial SAE 
Report 
Document 
Follow-up SAE 
and AE of Special 
Interest Report 
Reporting 
Method 
All SAEs 
Within 24 hours of 
first knowledge of 
the SAE 
SAE report 
As expeditiously as 
possible 
Email or fax SAE 
form or Pregnancy 
form 
Abbreviations: AE, adverse event; SAE, serious adverse event. 
 
9.5.2. 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she will report the 
information to the sponsor within 24 hours as outlined in Section 9.5.1. The SAE Report will always 
be completed as thoroughly as possible with all available details of the event and forwarded to the 
sponsor or designee within the designated timeframes.  
If the investigator does not have all information regarding an SAE, he/she is not to wait to receive 
additional information before notifying the sponsor or designee of the SAE and completing the form. 
The form will be updated when additional information is received. 
The investigator will always provide an assessment of causality at the time of the initial report as 
described in Section 9.1.3. 
The sponsor will provide contact information for SAE receipt. 
9.5.3. 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 9.5.2. The sponsor has a legal responsibility to notify, as appropriate, both the local 
regulatory authority and other regulatory agencies about the safety of a product under clinical 
investigation.  
The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities and 
the IRB/IEC.  
All suspected unexpected serious adverse reactions (as defined in Section 9.6) will be submitted to 
all applicable regulatory authorities and investigators for pamiparib studies. 


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When a study center receives an initial or follow-up safety report or other safety information 
(eg, revised Investigator’s Brochure) from the sponsor, the investigator or designated responsible 
person is required to promptly notify his/her IRB or IEC. The investigator should place copies of 
Safety Reports from the sponsor in the Investigator Site File. 
9.6. 
Suspected Unexpected Serious Adverse Reactions and Expedited Reporting 
A suspected unexpected serious adverse reaction is a serious adverse reaction that is both unexpected 
(ie, not present in the product’s Reference Safety Information in the Investigator’s Brochure) and 
assessed as related to pamiparib either by the investigator or the sponsor. The sponsor will promptly 
assess the expectedness for all SAEs against the list of expected serious adverse reactions in the 
Reference Safety Information and expeditiously submit suspected unexpected serious adverse 
reactions to regulatory authorities, investigators, IRBs, and IECs based on applicable legislation. 
9.7. 
Pregnancy Reporting 
If the partner of a patient becomes pregnant while receiving pamiparib or within 6 months after 
completion of the last dose of pamiparib, a pregnancy report form is required to be completed and 
expeditiously submitted to the sponsor to facilitate outcome follow-up. Information on the status of 
the mother and child will be forwarded to the sponsor. Generally, follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will 
be reported. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective 
termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous, should be always reported as an SAE. 
Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to pamiparib should 
be recorded and reported as an SAE.  
10. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
Details of the statistical analyses will be included in the Statistical Analysis Plan. 
10.1. 
Analysis Sets 
 Safety Analysis Set: includes all patients enrolled into the study who receive any dose of 
pamiparib. The Safety Analysis Set will be used for all safety analyses. 
 Efficacy-Evaluable Analysis Set (ORR Assessment in Cohort 1 of Table 2): includes all patients 
in the Safety Analysis Set who had measurable disease at baseline and at least 1 postbaseline 
tumor assessment, unless they permanently discontinue pamiparib or the study early due to 
clinical progression or death before tumor assessment.  The Efficacy-Evaluable Analysis Set is 
the primary analysis set for tumor response analysis. 
 PSA-Evaluable Analysis Set (PSA Response Rate Assessment in Cohorts 1 and 2 of Table 2): 
includes all patients in the Safety Analysis Set as per Inclusion Criterion 7 at baseline ( 3 rising 


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PSA levels with  1 week between determinations and screening PSA  2 µg/L) and who had at 
least 1 postbaseline PSA measurement, unless they permanently discontinue pamiparib or the 
study early due to clinical progression or death before completed PSA assessment. 
 PK Analysis Set: includes all patients who received pamiparib and for whom valid pamiparib PK 
parameters can be estimated. 
10.2. 
Efficacy Analyses 
10.2.1. 
Primary Efficacy Endpoint Analyses 
The primary endpoints of the study include ORR by IRC assessment in CTC-HRD-positive patients 
with measurable disease and PSA response rate in CTC-HRD-positive patients with or without 
measurable disease per PCWG3 criteria. 
ORR is defined as the proportion of patients with best objective response of CR or PR confirmed at a 
subsequent timepoint  4 weeks later by IRC assessment. Patients without tumor assessment are 
considered non-responders.  
ORR is assumed as 35% for pamiparib and estimated as 15% for historical control in the study 
population. The null and alternative hypotheses are set as follows: 
 
H0: ORR = 15% 
 
Ha: ORR > 15% 
PSA response rate is defined as the proportion of patients with PSA decline  50% from baseline 
(confirmed by a second PSA value  3 weeks later). 
PSA response rate is assumed as 50% for pamiparib and estimated as 30% for historical control in the 
study population. The null and alternative hypotheses are set as follows: 
 
H0 : ORR = 30% 
 
Ha : ORR > 30% 
Binomial exact tests will be performed for above hypotheses in the Efficacy-Evaluable Analysis Set. 
Two-sided binomial exact 95% CI of response rate will be constructed to assess the prevision of the 
estimates. 
To control the overall study type-I error rate, ORR and PSA response rate will be tested sequentially. 
If the ORR test shows significance at 1-sided 0.025 significance level, PSA response rate will be 
tested at a 1-sided 0.025 significance level.  
The primary efficacy analyses will be conducted when mature response data have been observed, 
which will be determined by the sponsor. 
A sensitivity analysis of response rate will be conducted using the Safety Analysis Set. 


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ORR and PSA response rate will be summarized in the specified subgroups: age group (< 65 versus 
 65), race, geographic region, ECOG performance status, BRCA1/2-mutant status, and number of 
prior lines of therapy. 
10.2.2. 
Secondary Efficacy Endpoint Analyses 
DOR by IRC assessment, ORR by investigator, and time to objective response and clinical benefit 
rate as assessed by investigator will be evaluated in patients with CTC-HRD-positive mCRPC with 
measurable disease per PCWG3 criteria.  
Time to PSA response, duration of PSA response, time to PSA progression, time to SSE, rPFS by 
IRC, and OS will be evaluated in patients with CTC-HRD-positive mCRPC with or without 
measurable disease per PCWG3 criteria.  
DOR is defined as the time from the date of the earliest documented confirmed response of CR or PR 
to radiographic disease progression by IRC or death due to any cause, whichever occurs first. 
Time to objective response is defined as the time from the date of the first dose of study drug to the 
first documented confirmed response of CR or PR.  
Clinical benefit rate is defined as the proportion of patients with a documented confirmed response of 
CR, PR, or stable disease.  
Time to PSA response is defined as the time from the date of the first dose of study drug to the first 
documented confirmed PSA response. 
Duration of PSA response is defined as the time from the date of the earliest documented confirmed 
PSA response to PSA progression or death due to any cause, whichever occurs first.  
Time to PSA progression is defined as the time from the date of the first dose of study drug to a  25% 
increase in PSA with an absolute increase of  2 µg/L above the nadir (or above the baseline for 
patients with no PSA decline after 12 weeks), confirmed by a second value  3 weeks later. 
Time to SSE is defined as the time from the date of the first dose of study drug to the first symptomatic 
fracture, radiation or surgery to bone, or spinal cord compression. 
rPFS is defined as the time from the date of the first dose of study drug to radiographic disease 
progression by IRC or death due to any cause, whichever occurs first. 
rPFS censoring rule will follow US Food and Drug Administration Guidance for Industry, Clinical 
Trial Endpoints for Approval of Cancer Drugs and Biologics (FDA 2007). Data for patients without 
PD or death at the time of analysis will be censored at the date of the last tumor assessment. Data for 
patients who initiated new anticancer therapy will be censored at the last tumor assessment date before 
the introduction of new anticancer therapy. Data for patients who had 2 or more consecutive missed 
scheduled tumor assessments immediately before PD will be censored at the last tumor assessment 
date before the 2 missed tumor assessments. Further details will be described in the Statistical 
Analysis Plan. 
OS is defined as the time from the date of the first dose of study drug to death due to any cause. 


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Time-to-event variables of DOR, duration of PSA response, time to PSA progression, time to SSE, 
rPFS, and OS will be estimated using the Kaplan-Meier method. The median of these time-to-event 
variables will be presented along with their 2-sided 95% CI using the Brookmeyer and Crowley 
method (Brookmeyer and Crowley 1982).  
Descriptive statistics will be provided for time to objective response and time to PSA response. Only 
responders will be included in analyses for DOR, duration of PSA response, time to response, and 
time to PSA response.  
The ORR as assessed by investigator and its exact 2-sided 95% CI will be reported. 
10.3. 
Pharmacokinetic Analyses 
Pamiparib concentrations will be summarized by nominal time of collection. Descriptive statistics 
will include means, medians, ranges, and standard deviations, as appropriate.  
Population PK analysis may be carried out to include plasma concentrations from this study in an 
existing model. Additional PK parameters such as apparent clearance (CL/F) of the drug from plasma 
and area under the plasma concentration-time curve from 0 to 12 hours postdose (AUC0-12) may be 
derived from the population PK analysis if supported by data.  
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by data. 
The results of the population PK and exposure-response analyses may be reported separately from the 
clinical study report. 
10.4. 
Exploratory Analyses 
10.5. 
Safety Analyses 
Safety will be assessed by monitoring and recording of all AEs. Laboratory values, vital signs, 
physical examinations, and ECG findings will also be used in determining the safety of the study 
treatment. 
10.5.1. 
Extent of Exposure 
Extent of exposure to pamiparib will be summarized descriptively as the duration of exposure (days), 
cumulative total dose received per patient (mg), dose intensity (mg/day), and relative dose intensity. 


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The number (percentage) of patients requiring dose reductions, pamiparib holds, and permanent 
pamiparib discontinuation due to AEs will be summarized. Frequency of dose reductions and 
pamiparib withholding will be summarized by categories. 
10.5.2. 
Adverse Events 
The AE will be coded using Medical Dictionary for Regulatory Activities Version 20.0 or higher and 
graded using NCI-CTCAE Version 4.03 or higher. 
A TEAE is defined as an AE that had an onset date on or after first dose of pamiparib or was worsening 
in severity from baseline (pretreatment) up to 30 days following permanent discontinuation of 
pamiparib or initiation of new anticancer therapy, whichever occurs first. All TEAEs will be included 
in summary tables and in-patient data listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
system organ class and preferred term. A patient will be counted only once by the highest grade 
according to NCI-CTCAE Version 4.03 or higher within a system organ class and preferred term, 
even if the patient experienced more than one TEAE within a specific system organ class and 
preferred term. The number (percentage) of patients with TEAEs will also be summarized by 
relationship to the study treatment. Treatment-related AEs include those events considered by the 
investigator to be related to study treatment or with missing assessment of the causal relationship. 
SAEs, deaths, TEAEs  Grade 3, pamiparib-related TEAEs, and TEAEs that led to pamiparib 
withholding or permanent discontinuation will also be summarized. 
10.5.3. 
Laboratory Analyses 
Clinical laboratory (eg, hematology and chemistry) values to be evaluated will be specified in the 
Statistical Analysis Plan and collected in the EDC system. Collected values may be a subset of all the 
values obtained in the requested sampling, eg, a complete blood count with differential may be 
requested for the evaluation of neutrophils only. Analyzed laboratory values that are abnormal will 
be flagged and identified as outside (above or below) the normal range. 
Laboratory parameters that are graded in NCI-CTCAE Version 4.03 or higher will be summarized by 
NCI-CTCAE grade. Shift tables will be provided as appropriate. 
10.5.4. 
Physical Examinations 
Physical examination results collected in association with an AE will be listed and summarized. 
10.5.5. 
Vital Signs 
Specific vital signs (eg, blood pressure and temperature) will be summarized and listed. The change 
from baseline will also be presented. 
10.5.6. 
Electrocardiograms 
The percentage of patients with abnormal and clinically significant ECG findings will be presented. 


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10.6. 
Sample Size Consideration 
This study is designed to provide adequate power for primary endpoints of ORR and PSA response 
rate. A sample size of approximately 100 patients is planned (at approximately 45 centers with a 
projected average enrollment of 2 to 3 patients per center). 
Assuming ORR of 35% for pamiparib in CTC-HRD-positive patients versus 15% for historical 
control in patients with measurable disease, the study power is 88% using a binomial exact test and 
1-sided type-I error of 0.025 with n = 50. The binomial exact 95% CI of 35% ORR is 22.1% to 49.8% 
with a sample size of 50 patients. 
Assuming PSA response rate of 50% for pamiparib versus 30% for historical control in CTC-HRD-
positive patients with or without measurable disease, a sample size of 80 patients in this population 
will provide 95% study power using a binomial exact test and 1-sided type-I error of 0.025. The 
binomial exact 95% CI of 50% response rate is 38.6% to 61.4% with n = 80.  
To explore the efficacy of pamiparib in patients with CTC-HRD-negative, but BRCA1/2-mutant 
mCRPC with or without measurable disease, approximately 20 patients will be enrolled in these 
cohorts. 
10.7. 
Interim Analysis 
A non-binding interim futility analysis will be performed among the first 20 patients enrolled in 
Cohorts 1 and 2 (Table 2). If the confirmed PSA response rate is < 30% (< 6 responses), enrollment 
will be halted and safety and efficacy data will be further evaluated before making the decision of 
stopping enrollment permanently. The decision to continue the enrollment may be made at any time 
the 6 confirmed PSA responses in Cohorts 1 and 2 can be documented; enrollment of all 20 patients 
is not required before determining further patient accrual. 
11. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
11.1. 
Regulatory Authority Approval 
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements or file the protocol to 
appropriate regulatory agency before the study is initiated at a study center in that country. 
11.2. 
Investigator Responsibilities 
11.2.1. 
Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” International Council for Harmonisation guidelines, and that the basic 
principles of “Good Clinical Practice,” as outlined in 21 Code of Federal Regulations 312, Subpart 
D, “Responsibilities of Sponsors and Investigators,” 21 Code of Federal Regulations, Part 50, and 21 
Code of Federal Regulations, Part 56, are adhered to. In addition, this clinical study will be conducted 


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in the European Union according to Directive 2001/20/EC, until the application of Regulation EU No 
536/2014, which will then be followed. 
Investigators and all subinvestigators must provide documentation of their financial interest or 
arrangements with BeiGene or proprietary interests in the drug being studied. This documentation 
must be provided before the participation of the investigator and any subinvestigator. The investigator 
and subinvestigator agree to notify BeiGene or its authorized representative of any change in 
reportable interests during the study and for 1 year following completion of the study.  
11.2.2. 
Ethical Conduct of the Study and Ethics Approval 
This study will be conducted by the principal investigator and the study center in accordance with 
Good Clinical Practice and all applicable regulatory requirements, including, where applicable, the 
current version of the Declaration of Helsinki. 
The investigator (or sponsor, where applicable) is responsible for ensuring that this protocol, the study 
center’s ICF, and any other information that will be presented to potential patients (eg, advertisements 
or information that supports or supplements the ICF) are reviewed and approved by the appropriate 
IEC/IRB. 
The IEC/IRB must be constituted in accordance with all applicable regulatory requirements. The 
sponsor will provide the investigator with relevant document(s)/data that are needed for IEC/IRB 
review and approval of the study. 
Before pamiparib can be shipped to the study center, the sponsor or its authorized representative must 
receive copies of the IEC/IRB approval, the approved ICF, and any other information that the 
IEC/IRB has approved for presentation to potential patients. 
If the protocol, the ICF, or any other information that the IEC/IRB has approved for presentation to 
potential patients is amended during the study, the investigator is responsible for ensuring the 
IEC/IRB reviews and approves, where applicable, these amended documents. The investigator must 
follow all applicable regulatory requirements pertaining to the use of an amended ICF including 
obtaining IEC/IRB approval of the amended form before new patient consent to take part in the study 
using this version of the form. Copies of the IEC/IRB approval of the amended ICF/other information, 
the approved amended ICF/other information and all related correspondence must be forwarded to 
the sponsor promptly. 
11.2.3. 
Informed Consent 
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 
utilize an IRB/IEC-approved ICF for documenting written informed consent. Each ICF will be 
appropriately signed and dated by the patient or the patient’s legally authorized representative and the 
person obtaining consent. 


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Informed consent will be obtained before the patient can participate in the study. The contents and 
process of obtaining informed consent will be in accordance with all applicable regulatory 
requirements. 
11.2.4. 
Investigator Reporting Requirements 
As indicated in Section 9.5, the investigator (or sponsor, where applicable) is responsible for reporting 
SAEs to the IEC/IRB in accordance with all applicable regulations. Furthermore, the investigator may 
be required to provide periodic safety updates on the conduct of the study at his/her study center and 
notification of study closure to the IEC/IRB. Such periodic safety updates and notifications are the 
responsibility of the investigator and not of the sponsor. 
11.2.5. 
Confidentiality 
Information on maintaining patient confidentiality in accordance with individual local and national 
patient privacy regulations must be provided to each patient as part of the informed consent process, 
either as part of the ICF or as a separate signed document (for example, in the USA, a study center-
specific HIPAA consent may be used). The investigator must ensure that patients’ anonymity will be 
strictly maintained and that their identities are protected from unauthorized parties. Only patient 
initials, year of birth, and an identification code (ie, not names) should be recorded on any form or 
biologic sample submitted to the sponsor, IRB, or laboratory. The investigator must keep a screening 
log showing codes, names, and addresses for all patients screened and for all patients enrolled in the 
study. 
The investigator agrees that all information received from BeiGene, including but not limited to the 
Investigator’s Brochure, this protocol, eCRFs, the Investigational New Drug application, and any 
other study information, remain the sole and exclusive property of BeiGene 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 BeiGene. The investigator further agrees to take all reasonable precautions to prevent 
the disclosure by any employee or agent of the study center to any third party or otherwise into the 
public domain. 
11.2.6. 
Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed and signed by the principal investigator or 
subinvestigator within a reasonable time period after data collection. This also applies to records for 
those patients who discontinue the study early. If a patient withdraws from the study, the reason must 
be noted on the eCRF. If a patient is withdrawn from the study because of a treatment-limiting AE, 
thorough efforts should be made to clearly document the outcome. 
The eCRFs exist within an EDC system with controlled access managed by BeiGene or its authorized 
representative for this study. Study staff will be appropriately trained in the use of eCRFs and 
applications of electronic signatures before the study start and before being given access to the EDC 
system. Original data and any changes of data will be recorded using the EDC system, with all changes 


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tracked by the system and recorded in an electronic audit trail. The investigator attests that the 
information contained in the eCRFs is true by providing an electronic signature within the EDC 
system. After final database lock, the investigator will receive a copy of the patient data on CD-ROMs 
for archiving the data at the study center.  
11.2.7. 
Drug Accountability 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability of 
all used and unused pamiparib. This includes acknowledgment of receipt of each shipment of 
pamiparib (quantity and condition), patient dispensing records, and returned or destroyed pamiparib. 
Dispensing records will document quantities received from BeiGene and quantities dispensed to 
patients, including lot number, date dispensed, patient identifier number, patient initials, and the 
initials of the person dispensing the medication. 
At study initiation, the monitor will evaluate the study center’s standard operating procedure for 
pamiparib disposal/destruction to ensure that it complies with BeiGene requirements specified in the 
Pharmacy Manual. At appropriate times during the conduct of the study or at the end of the study, 
following final drug inventory reconciliation by the monitor, the study center will dispose of and/or 
destroy all unused pamiparib supplies, including empty containers, according to these procedures. If 
the study center cannot meet BeiGene’s requirements specified in the Pharmacy Manual for disposal, 
arrangements will be made between the study center and BeiGene or its representative for destruction 
or return of unused pamiparib supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
11.2.8. 
Inspections 
The investigator should understand that source documents for this study should be made available to 
appropriately qualified personnel from BeiGene or its representatives, to IRBs/IECs, or to regulatory 
authority or health authority inspectors. 
11.2.9. 
Protocol Adherence 
The investigator is responsible for ensuring that the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators assert that they will apply due 
diligence to avoid protocol deviations. 
11.3. 
Sponsor Responsibilities 
11.3.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
initiated only by BeiGene. All protocol modifications must be submitted to regulatory authorities and 
the IRB/IEC together with, if applicable, a revised model ICF in accordance with local requirements. 
As applicable by local requirements, written documentation of regulatory authorities, IRB/IEC, and 
required study center approval must be obtained by the sponsor before changes can be implemented. 


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Information on any change in risk and/or change in scope must be provided to patients already actively 
participating in the study, and they must read, understand, and sign each revised ICF confirming 
his/her willingness to remain in the study. 
11.3.2. 
Use of Information and Publication 
A clinical study report will be prepared and provided to the regulatory agency(ies) of participating 
countries. The sponsor will ensure that the report meets the standards set out in the International 
Council for Harmonisation Guideline for Structure and Content of Clinical Study Reports (ICH E3). 
Note that an abbreviated report may be prepared in certain cases. 
The sponsor recognizes the importance of communicating medical study data, and therefore, 
encourages their publication in reputable scientific journals and at seminars or conferences. The 
details of the processes of producing and reviewing reports, manuscripts, and presentations based on 
the data from this study will be described in the clinical study agreement. 
If a written contract for the conduct of the study, which includes publication provisions inconsistent 
with this statement, is executed, that contract’s publication provisions shall apply rather than this 
statement. 
11.4. 
Study and Study Center Closure 
Upon completion of the study, the monitor will conduct the following activities in conjunction with 
the investigator or study center personnel, as appropriate: 
 Return of all study data to the sponsor 
 Data queries 
 Accountability, reconciliation, and arrangements for unused pamiparib 
 Review of study records for completeness 
 Return of treatment codes to the sponsor 
 Shipment of PK samples to assay laboratories 
In addition, the sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study either at a single study center or at all study centers at any time for reasons including but not 
limited to safety or ethical issues or severe noncompliance with this protocol, GCP, the clinical study 
agreement, or applicable laws and regulations. If the sponsor determines such action is needed, the 
sponsor will discuss this with the investigator (including the reasons for taking such action) at that 
time. When feasible, the sponsor will provide advance notification to the investigator of the 
impending action before it takes effect. 
The sponsor will promptly inform all other investigators and/or institutions conducting the study if 
the study is suspended or terminated for safety reasons and will also inform the regulatory authorities 
of the suspension or termination of the study and the reason(s) for the action. If required by applicable 


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regulations, the investigator must inform the IEC/IRB promptly and provide the reason for the 
suspension or termination. 
If the study is prematurely discontinued, all study data must still be provided to the sponsor. In 
addition, arrangements will be made for all unused pamiparib in accordance with the applicable 
sponsor procedures for the study. 
Financial compensation to investigators and/or institutions will be in accordance with the agreement 
established between the investigator and the sponsor. 
11.5. 
Records Retention and Study Files 
11.5.1. 
Study Files and Retention of Records 
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 into at least the following 2 categories: (1) investigator’s study file and (2) patient clinical 
source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, IRB/IEC, 
and governmental approval with correspondence, ICF, drug records, staff curriculum vitae and 
authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include (although not be limited to) the 
following: patient hospital/clinic records, physician’s and nurse’s notes, appointment book, original 
laboratory reports, ECG, electroencephalogram, x-ray, pathology and special assessment reports, 
consultant letters, screening and enrollment log, etc. 
Following closure of the study, the investigator must maintain all study records in a safe and secure 
location. The records must be maintained to allow easy and timely retrieval when needed (eg, audit 
or inspection) and, whenever feasible, to allow any subsequent review of data in conjunction with 
assessment of the facility, supporting systems, and personnel. Where permitted by local 
laws/regulations or institutional policy, some or all of these records can be maintained in a format 
other than hard copy (eg, microfiche, scanned, or electronic); however, caution needs to be exercised 
before such action is taken. The investigator must ensure that all reproductions are legible, are a true 
and accurate copy of the original, and meet accessibility and retrieval standards, including 
regenerating a hard copy, if required. Furthermore, the investigator must ensure that there is an 
acceptable backup of these reproductions and that an acceptable quality control process exists for 
making these reproductions. 
The sponsor will inform the investigator of the timeperiod for retaining these records to comply with 
all applicable regulatory requirements. The minimum retention time will meet the strictest standard 
applicable to that study center for the study, as dictated by any institutional requirements or local laws 
or regulations, or the sponsor’s standards/procedures; otherwise, the retention period will default to 
15 years. 


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The investigator must notify the sponsor of any changes in the archival arrangements, including but 
not limited to the following: archiving at an off-site facility and transfer of ownership of or 
responsibility for the records in the event that the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study center for any or all of the 
documents, special arrangements must be made between the investigator and BeiGene to store these 
in sealed containers outside of the study center so that they can be returned sealed to the investigator 
in case of a regulatory audit. When source documents are required for the continued care of the patient, 
appropriate copies should be made for storage outside of the study center. 
Biologic samples at the conclusion of this study may be retained in storage by the sponsor as outlined 
in the study manual. 
11.5.2. 
Provision of Study Results and Information to Investigators 
When the clinical study report is completed, the sponsor will provide the major findings of the study 
to the investigator. 
In addition, details of the pamiparib assignment will be provided to the investigator to enable him/her 
to review the data to determine the outcome of the study for his/her patient(s). 
The sponsor will not routinely inform the investigator or patient of the test results because the 
information generated from this study will be preliminary in nature and the significance and scientific 
validity of the results will be undetermined at such an early stage of research. 
11.6. 
Information Disclosure and Inventions 
All information provided by the sponsor and all data and information generated by the study center 
as part of the study (other than a patient’s medical records) are the sole property of the sponsor. 
All rights, title, and interests in any inventions, know-how, or other intellectual or industrial property 
rights that are conceived or reduced to practice by the study center personnel during the course of or 
as a result of the study are the sole property of the sponsor and are hereby assigned to the sponsor. 
If a written contract for the conduct of the study that includes ownership provisions inconsistent with 
this statement is executed between the sponsor and the study center, that contract’s ownership 
provisions shall apply rather than this statement. 
All information provided by the sponsor and all data and information generated by the study center 
as part of the study (other than a patient’s medical records) will be kept confidential by the investigator 
and other study center personnel. This information and data will not be used by the investigator or 
other study center personnel for any purpose other than conducting the study without the prior written 
consent of the sponsor. 
These restrictions do not apply to: 
 Information that becomes publicly available through no fault of the investigator or study center 
personnel 


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 Information that is necessary to disclose in confidence to an IEC/IRB solely for the evaluation of 
the study 
 Information that is necessary to disclose to provide appropriate medical care to a patient 
 Study results that may be published as described in Section 11.3.2. 
If a written contract for the conduct of the study that includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 
11.7. 
Joint Investigator/Sponsor Responsibilities 
11.7.1. 
Access to Information for Monitoring 
In accordance with International Council for Harmonisation Good Clinical Practice guidelines, the 
study monitor must have direct access to the investigator’s source documentation to verify the data 
recorded in the eCRFs for consistency. 
The monitor is responsible for routine review of the eCRFs 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 patient records needed to verify the entries 
on the eCRFs. The investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved. 
11.7.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits any time 
during or after completion of this clinical study. If the investigator is notified of an inspection by a 
regulatory authority the investigator agrees to notify the sponsor or its designee immediately. The 
investigator agrees to provide to representatives of a regulatory agency or BeiGene access to 
records, facilities, and personnel for the effective conduct of any inspection or audit. 
 
11.7.3 Publication Policy 
 
The results of this study will be published or presented at scientific meetings in a timely, objective, 
and clinically meaningful manner that is consistent with good science, industry and regulatory 
guidance, and the need to protect the intellectual property of BeiGene (sponsor), regardless of the 
outcome of the study.  The data generated in this clinical study are the exclusive property of the 
sponsor and are confidential.  For multicenter studies, the first publication or disclosure of study 
results shall be a complete, joint multicenter publication or disclosure coordinated by the sponsor.  
Thereafter, any secondary publications will reference the original publication(s).  Authorship will be 
determined by mutual agreement and all authors must meet the criteria for authorship established by 
the International Committee of Medical Journal Editors Uniform Requirements for Manuscripts or 
stricter local criteria (International Committee of Medical Journal Editors 2016). 
 
After conclusion of the study and without prior written approval from BeiGene, investigators in this 


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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 
BeiGene in an abstract, manuscript, or presentation form; or 
 The study has been completed at all study sites for the earlier of: at least 2 years or the period 
indicated in the clinical study agreement. 
 No such communication, presentation, or publication will include BeiGene’s confidential 
information. 
 Each investigator agrees to submit all manuscripts or congress abstracts and 
posters/presentations to the sponsor prior to submission in accordance with the clinical study 
agreement.  This allows the sponsors to protect proprietary information, provide comments 
based on information from other studies that may not yet be available to the investigator, and 
ensure scientific and clinical accuracy.  The details of the processes of producing and reviewing 
reports, manuscripts, and presentations based on the data from this trial will be presented in the 
investigator’s clinical study agreement. Each investigator agrees that, in accordance with the 
terms of clinical study agreement, a further delay of the publication/presentation may be 
requested by the sponsor to allow for patent filings and/or protection in advance of the 
publication/presentation. 
 
 
 


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13. 
APPENDICES 
 
 


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APPENDIX 1. 
SCHEDULE OF ASSESSMENTS 
Study Phase 
Pre-
screeninga 
Screeninga 
Treatmentb 
Un- 
scheduled 
Visitc 
End-of-
Treatmen
t 
(EOT) 
Visitd 
Safety 
Follow-
upe 
Long-term 
Follow-upf 
Day of Phase 
≤ 28 
-28 to -1 
Cycle 1 
Cycle 2 
Cycle ≥3 
Day 1 Day 15 Day 1 Day 15 
Day 1 
Allowed time window 
 
 
 
± 2 
± 3 
± 3 
± 5 
Study Day 
≤ 28 
-28 to -1 
1 
15 
29 
43 
57, 85, etc. 
Varies 
Varies 
Varies 
Varies 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
 
X 
 
 
 
 
 
 
 
 
 
Demographics, medical history, 
smoking history 
 
X 
 
 
 
 
 
 
 
 
 
Complete physical examination 
 
X 
 
 
 
 
 
 
X 
 
 
Limited physical examination 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Vital signs and weightg 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
ECOG performance status 
 
X 
X 
 
X 
 
X 
X 
X 
 
 
12-lead ECGh 
 
X (-14 to -1) 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematologyi 
 
X (-14 to -1) 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistryi 
 
X (-14 to -1) 
X 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysisi 
 
X (-14 to -1) 
X 
 
 
 
 
X 
X 
 
 
HBV/HCV testsj 
 
X 
As clinically indicated 
 
BPI-SF and EQ-5D-5L 
questionnaires 
 
 
X 
 
X 
 
X 
 
X 
 
 
PSA levelsk 
 
X 
X 
 
X 
 
X (q4w ± 7d) 
X 
X 
 
X 
(q4w ± 7d) 
Testosteronew 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 


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APPENDIX 1. 
SCHEDULE OF ASSESSMENTS 
Study Phase 
Pre-
screeninga 
Screeninga 
Treatmentb 
Un- 
scheduled 
Visitc 
End-of-
Treatmen
t 
(EOT) 
Visitd 
Safety 
Follow-
upe 
Long-term 
Follow-upf 
Day of Phase 
≤ 28 
-28 to -1 
Cycle 1 
Cycle 2 
Cycle ≥3 
Day 1 Day 15 Day 1 Day 15 
Day 1 
Allowed time window 
 
 
 
± 2 
± 3 
± 3 
± 5 
Study Day 
≤ 28 
-28 to -1 
1 
15 
29 
43 
57, 85, etc. 
Varies 
Varies 
Varies 
Varies 
CT with intravenous contrast of 
chest, abdomen and pelvisl 
 
X 
 
 
 
 
X (q8w ± 7d  
for 24 weeks, 
then q12w 
± 7d) 
X 
X 
 
X (~q12w) 
Bone scanm 
 
X 
 
 
 
 
X (q8w ± 7d 
for 24 weeks, 
then q12w 
± 7d) 
X 
X 
 
X (~q12w) 
MRI scan of brain, if clinically 
indicatedn 
 
X 
 
 
 
 
 
X 
 
 
 
Patient treatment authorization 
 
Xa 
 
 
 
 
 
Pamiparib 
 
 
Twice a day dosing continuously 
 
 
 
 
Pamiparib 
dispensing/accountability 
 
 
X 
 
X 
 
X 
X 
X 
 
 
Adverse eventso 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication(s)p 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X (~q12w) 
Pharmacokineticsq 
 
 
X 
X 
 
 
 
 
 
 
 
Blood sample for CTCsr 
X 
X 
X 
 
 
 
X (q8w ± 7d 
for 24 weeks, 
then q12w 
± 7d) 
 
X 
 
 
 


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APPENDIX 1. 
SCHEDULE OF ASSESSMENTS 
Study Phase 
Pre-
screeninga 
Screeninga 
Treatmentb 
Un- 
scheduled 
Visitc 
End-of-
Treatmen
t 
(EOT) 
Visitd 
Safety 
Follow-
upe 
Long-term 
Follow-upf 
Day of Phase 
≤ 28 
-28 to -1 
Cycle 1 
Cycle 2 
Cycle ≥3 
Day 1 Day 15 Day 1 Day 15 
Day 1 
Allowed time window 
 
 
 
± 2 
± 3 
± 3 
± 5 
Study Day 
≤ 28 
-28 to -1 
1 
15 
29 
43 
57, 85, etc. 
Varies 
Varies 
Varies 
Varies 
Blood sample for biomarkerss 
 
 
X 
 
 
 
X (q8w ± 7d 
for 24 weeks, 
then q12w 
± 7d) 
 
X 
 
 
Archival tumor tissuet 
 
X 
 
 
 
 
 
 
 
 
 
Fresh tumor tissue (additional 
consent required)u 
 
X 
 
 
 
 
 
 
X 
 
 
Survival follow-upv 
 
 
 
 
 
 
 
 
 
 
X (~q12w) 
Abbreviations: -7/-14/-28 to -1, Day -7/-14/-28 to Day -1 of screening; AE, adverse event; BPI-SF, Brief Pain Inventory Short Form; CT, computed tomography; 
CTC, circulating tumor cell; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, End-of-Treatment; EQ-5D-5L, European Quality of 
Life 5-Dimensions 5-Levels Health Questionnaire; HBV, hepatitis B virus; HCV, hepatitis C virus; HRD, homologous recombination deficiency; MRI, magnetic 
resonance imaging; PARP, poly (ADP-ribose) polymerase; PCWG3, Prostate Cancer Clinical Trials Working Group 3; PD, progressive disease; 
PK, pharmacokinetic; PSA, prostate-specific antigen; q4w ± 7d, every 4 weeks ±7 days; q8w ± 7d, every 8 weeks ±7 days; ~q12w, approximately every 
12 weeks; SAE, serious adverse event. 
a. 
Pre-screening for prospective testing of CTC-HRD status (blood sample) can be completed before the study eligibility screening. A separate pre-screening 
informed consent must be obtained. Screening must occur within 28 days before Day 1. Some assessments have a narrower screening window as shown in 
the table. Assessments obtained within 7 days of Day 1 do not have to be repeated on Day 1. Patient treatment authorization may occur as late as Day 1 
before the first dose of pamiparib. 
b. Patients must initiate study treatment within 4 days after authorization for treatment. Administration of pamiparib will continue until PD, as assessed by 
investigator per PCWG3 criteria, unacceptable toxicity, death, or another discontinuation criterion is met (Sections 5.5.1 and 5.6.4. A cycle is 28 days. 
Assessments shown for Cycle 3 apply to all subsequent cycles, unless noted otherwise. 
c. 
Unscheduled visits may occur at any time as necessary as per investigator decision or patient’s request for reasons such as assessment or follow-up of AEs. 
Study assessments of an unscheduled visit, as indicated by ‘X,’ should be performed based on the reason for the unscheduled visit. If PD is suspected, 
imaging studies should be performed and blood for biomarkers should be obtained as appropriate. 


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d. The EOT Visit should occur within 7 days after pamiparib has been permanently discontinued. A visit should be scheduled as soon as possible, but the EOT 
Visit may occur later after discussion with the medical monitor for specific circumstances, such as prolonged hospitalization. The visit at which tumor 
assessments showed PD may be used as the EOT Visit if all required assessments were performed. Tumor assessments do not have to be repeated if they 
were performed within 14 days of the EOT Visit or at a prior response evaluation that documented PD. An ECG does not have to be repeated if it was 
performed within 14 days of the EOT Visit. 
e. 
Approximately 30 days after the last dose of pamiparib or before initiation of new anticancer therapy, whichever occurs first, the Safety Follow-up Visit will 
occur with the outlined safety assessments. If new anticancer therapy is inadvertently initiated before the Safety Follow-up Visit, (eg, without the knowledge 
of the study center team), a Safety Follow-up Visit should be scheduled as soon as possible. For patients who do not want to or cannot return to the clinic for 
the Safety Follow-up Visit, the patient should be contacted by telephone for a review of AEs. If these attempts of contact are unsuccessful, the additional 
attempts detailed in Section 5.6.3 should be made. 
f. 
Patients will be followed for survival and initiation of new anticancer therapy via telephone contact or other means (eg, clinic visit) approximately every 
12 weeks. 
Patients who were permanently discontinued from pamiparib for reasons other than PD and meet criteria otherwise (eg, discontinued for AE and no new 
anticancer therapy) will be followed with tumor and PSA assessments every 12 weeks and 4 weeks (±7 days), respectively, until PD or any other reason 
listed in Section 5.6.4, whichever occurs first. For efficacy assessments as per protocol, refer to Section 7.3. If the patient refuses to return for these PSA and 
tumor assessments or is unable to do so, every effort should be made to contact the patient by telephone to determine the patient’s disease status and 
survival. 
Should attempts of telephone contact be unsuccessful, the additional attempts detailed in Section 5.6.3 should be made. If a patient cannot be contacted 
despite all attempts, the patient will be considered lost to follow-up. 
g. Vital signs (systolic and diastolic blood pressure; pulse rate; and oral, temporal, tympanic, or armpit temperature) will be measured before pamiparib 
administration and approximately 15 minutes before each collection of PK blood samples, if applicable, during the treatment phase. 
h. ECGs will be obtained approximately every 28 days and at each subsequent visit including EOT. Additional ECGs will be performed, if clinically indicated.  
i. 
Hematology includes hemoglobin, platelet count, white blood cell count, neutrophil count, and lymphocyte count. 
Chemistry includes albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, chloride, creatinine, glucose, 
lactate dehydrogenase, phosphate, potassium, sodium, total bilirubin, and total protein. 
Urinalysis includes blood, glucose, ketones, protein, red blood cells, and white blood cells. 
j. 
Testing will be performed by a central laboratory and/or the local laboratory at screening and as clinically indicated and will include HBV/HCV serology 
(hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, and HCV antibody) and viral load assessment (HBV DNA and HCV 
RNA). 
k. PSA levels will be assessed during screening, on Day 1, and every 4 weeks (± 7 days), or as clinically indicated. Responses by PCWG3 criteria must be 
confirmed  3 weeks later. Patients without PD at the EOT Visit should be followed with PSA assessments every 4 weeks (± 7 days) during the long-term 
follow-up phase. 
l. 
Following the screening tumor assessment, tumor assessments will occur at the schedule of every 8 weeks (±7 days) after Day 1 for the first 24 weeks, then 
at the schedule of every 12 weeks (± 7 days). Any measurable disease must be documented at screening and reassessed at each subsequent tumor evaluation. 
The same imaging method(s) used at screening must be used throughout the study. A documented standard-of-care tumor assessment may be used as the 
screening assessment provided it meets protocol requirements (Section 7.3.1.2). CT scan with intravenous contrast is the preferred imaging method for 
assessment of chest, abdomen, and pelvis. Other imaging methods are allowed as outlined in Section 7.3.1.2. Imaging of other areas of disease should be 
performed every 8 weeks ± 7 days for 24 weeks, then every 12 weeks ± 7 days. Patients without PD at the EOT Visit should be followed with tumor 


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assessments every 12 weeks (± 7 days) during the long-term follow-up phase.  
m. Whole-body radionuclide bone scan must be performed at screening and will then occur at the schedule of every 8 weeks (± 7 days) after Day 1 for the first 
24 weeks, then at the schedule of every 12 weeks (± 7 days). Patients without PD at the EOT Visit should be followed with bone scans every 12 weeks 
(± 7 days) during the long-term follow-up phase. 
n. MRI scan of the brain to assess for brain metastases must be performed at screening if the patient has symptoms that could be due to brain metastases. CT 
scan with intravenous contrast is acceptable if MRI is not available or the patient is claustrophobic. If brain metastases are present at baseline, the patient is 
eligible for this study if criteria listed under Exclusion Criterion 8 are met. 
o. AEs and laboratory safety measurements will be recorded at each study visit, graded per National Cancer Institute-Common Terminology Criteria for 
Adverse Events Version 4.03 or higher, and assessed as outlined in Section 9. After the informed consent form has been signed, but before initiation of 
pamiparib, only SAEs should be reported. After initiation of pamiparib, all AEs and SAEs, regardless of relationship to pamiparib, will be reported until 
30 days after last dose of pamiparib or initiation of new anticancer therapy, whichever occurs first. After this period, the investigator should report any SAEs 
that are believed to be related to pamiparib. 
p. All concomitant medications taken by or administered to the patient within 28 days before Day 1 and 30 days after the last dose of pamiparib will be 
recorded. Concomitant medications include new anticancer therapy information acquired during the long-term follow-up phase. 
q. PK samples for pamiparib will be collected at various timepoints at all non-China centers and at centers with such capability in China. PK samples will be 
collected from patients at the following timepoints: predose (within 30 minutes before dose) and 2 hours (± 30 minutes) postdose on Cycle 1 Day 1 and 
Cycle 1 Day 15. The time of pamiparib administration on the day before Day 15 must be recorded on the electronic case report form. Details concerning 
collection, handling, and processing of the PK plasma samples will be provided in the laboratory manual. 
r. 
One blood sample (10 mL) must be collected for prospective testing of CTC-HRD status and CTC enumeration during pre-screening or screening. Blood 
samples (10 mL each) will then be collected every 8 weeks (± 7 days) after Day 1 for the first 24 weeks, then at the schedule of every 12 weeks (± 7 days), 
as well as at the EOT Visit (unless they had been collected within 14 days). Instructions for the processing, storage, and shipping of samples will be provided 
in the study manual. 
s. 
One blood sample (8 mL) must be collected before initiation of pamiparib on Day 1 of Cycle 1 for the assessment of BRCA1/2 germline mutations. Two 
blood samples (10 mL each) will be collected for the assessment of plasma biomarkers of PARP inhibitor response/resistance before pamiparib 
administration every 8 weeks (± 7 days) after Day 1 for the first 24 weeks, then at the schedule of every 12 weeks (± 7 days), as well as at the EOT Visit 
(unless they had been collected within 14 days). Instructions for the processing, storage, and shipping of samples will be provided in the study manual. 
t. 
Archival tumor tissue, if available, shall be sent to the central laboratory testing for retrospective analysis of HRD mutational status.  
u. In the absence of archival tumor tissues, a fresh baseline biopsy of a tumor lesion is highly recommended. Written patient consent is required for fresh tumor 
biopsies. Optional biopsy will also be taken, if agreeable, at the EOT Visit for patients who have confirmed PD during the study from accessible tumor sites 
to obtain samples to explore resistance mechanism. If feasible, any follow-up biopsy should, ideally, be taken from the same tumor lesion as the baseline 
biopsy. 
v. Patients will be followed for survival via telephone contact approximately every 12 weeks or as further detailed in Sections 5.6.2 and 5.6.3. 
w. Testosterone must be collected either at Pre-screening or at screening. 
 
 


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APPENDIX 2. 
THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES, VERSION 1.1 
The text below was obtained from the following reference: Eisenhauer EA, Therasse P, Bogaerts J, 
et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45:228-247 (Eisenhauer et al 2009). 
DEFINITIONS 
Response and progression will be evaluated in this study using the international criteria proposed by 
the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (Version 1.1). Changes in 
only the largest diameter (unidimensional measurement) of the tumor lesions are used in the RECIST 
criteria. Note: Lesions are either measurable or nonmeasurable using the criteria provided below. The 
term “evaluable” in reference to measurability will not be used because it does not provide additional 
meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice thickness 
and a minimum of 10 mm). 
 10 mm caliper measurement by clinical examination (when superficial). 
 20 mm by chest x-ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be  15 mm in short axis when assessed by computed tomography (CT) scan (CT scan slice 
thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
Nonmeasurable Disease 
All other lesions (or sites of disease), including small lesions (longest diameter  10 to < 15 mm with 
conventional techniques or < 10 mm using spiral CT scan), are considered nonmeasurable disease. 
Leptomeningeal disease, ascites, pleural, or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by 
physical examination that is not measurable by reproducible imaging techniques are all 
nonmeasurable. 
Bone lesions: 
 Bone scan, positron-emission tomography (PET) scan, or plain films are not considered adequate 
imaging techniques to measure bone lesions. However, these techniques can be used to confirm 
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 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can 
be evaluated by cross sectional imaging techniques such as CT or magnetic resonance imaging 
(MRI) can be considered as measurable lesions if the soft tissue component meets the definition 
of measurability described above. 
 Blastic bone lesions are nonmeasurable. 
Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor nonmeasurable) since they are, by definition, simple 
cysts. 
 Cystic lesions thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if noncystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other locoregional 
therapy, are usually not considered measurable unless there has been demonstrated progression in 
the lesion. Trial protocols should detail the conditions under which such lesions would be 
considered measurable. 
Target Lesions 
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total should be 
identified as target lesions and recorded and measured at baseline. Target lesions should be selected 
on the basis of their size (lesions with the longest diameter), be representative of all involved organ, 
but in addition should be those that lend themselves to reproducible repeated measurements. 
Lymph nodes merit special mention since they are normal anatomical structures that may be visible 
by imaging even if not involved by tumor. Pathological nodes that are defined as measurable and may 
be identified as target lesions must meet the criterion of a short axis of  15 mm by CT scan. Only the 
short axis of these nodes will contribute to the baseline sum. The short axis of the node is the diameter 
normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is normally 
reported as 2 dimensions in the plane in which the image is obtained (for CT scan this is almost always 
the axial plane; for MRI the plane of acquisition may be axial, sagittal, or coronal). The smaller of 
these measures is the short axis. For example, an abdominal node which is reported as being 20 mm 
x 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In this example, 
20 mm should be recorded as the node measurement. All other pathological nodes (those with short 
axis  10 mm but < 15 mm) should be considered nontarget lesions. Nodes that have a short axis < 10 
mm are considered nonpathological and should not be recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline sum 


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diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
Nontarget Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
nontarget lesions and should also be recorded at baseline. Measurements are not required and these 
lesions should be followed as “present”, “absent”, or in rare cases “unequivocal progression” (more 
details to follow). In addition, it is possible to record multiple nontarget lesions involving the same 
organ as a single item on the electronic case report form (eCRF) (eg, “multiple enlarged pelvic lymph 
node” or “multiple liver metastases”). 
GUIDELINES FOR EVALUATION OF MEASURABLE DISEASE 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging based evaluation should always be done 
rather than clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical examination. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and 
 10 mm in diameter as assessed using calipers (eg, skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is suggested. 
As noted above, when lesions can be evaluated by both clinical examination and imaging, imaging 
evaluation should be undertaken since it is more objective and may also be reviewed at the end of the 
trial. 
Chest x-ray: Chest CT is preferred over chest x-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than x-ray, particularly in identifying new lesions. However, 
lesions on chest x-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (eg, for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next. If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is 
concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. 


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Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response (CR) or 
surgical resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If markers 
are initially above the upper normal limit, they must normalize for a patient to be considered in CR. 
Because tumor markers are disease specific, instructions for their measurement should be 
incorporated into protocols on a disease specific basis. Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and prostate-specific antigen response (in recurrent prostate cancer), 
have been published. In addition, the Gynecologic Cancer Intergroup has developed CA-125 
progression criteria that are to be integrated with objective tumor assessment for use in first-line trials 
in ovarian cancer. 
Cytology, histology: These techniques can be used to differentiate between partial response (PR) and 
CR in rare cases if required by protocol (for example, residual lesions in tumor types such as germ 
cell tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (eg, with certain taxane compounds or angiogenesis inhibitors), 
the cytological confirmation of the neoplastic origin of any effusion that appears or worsens during 
treatment can be considered if the measurable tumor has met criteria for response or stable disease 
(SD) to differentiate between response (or SD) and progressive disease (PD). 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
CR: Disappearance of all target lesions. Any pathological lymph nodes (whether target or nontarget) 
must have reduction in short axis to < 10 mm. 
PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline 
sum diameters. 
PD: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest 
sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. 
SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as 
reference the smallest sum diameters while on study. 
Lymph nodes: Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline examination), even if 
the nodes regress to below 10 mm on study. This means that when lymph nodes are included as target 
lesions, the “sum” of lesions may not be zero even if CR criteria are met, since a normal lymph node 
is defined as having a short axis of < 10 mm. Case report recorded in a separate section where, to 
qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD, and PD, the actual short 
axis measurement of the nodes is to be included in the sum of target lesions. 


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Target lesions that become “too small to measure”: While on study, all lesions (nodal and non-nodal) 
recorded at baseline should have their actual measurements recorded at each subsequent evaluation, 
even when very small (eg, 2 mm). However, sometimes lesions or lymph nodes which are recorded 
as target lesions at baseline become so faint on CT scan that the radiologist may not feel comfortable 
assigning an exact measure and may report them as being “too small to measure”. When this occurs 
it is important that a value be recorded on the eCRF. If it is the opinion of the radiologist that the 
lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed 
to be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
(Note: It is less likely that this rule will be used for lymph nodes since they usually have a definable 
size when normal and are frequently surrounded by fat such as in the retroperitoneum; however, if a 
lymph node is believed to be present and is faintly seen but too small to measure, a default value of 5 
mm should be assigned in this circumstance as well). This default value is derived from the 5 mm CT 
slice thickness (but should not be changed with varying CT slice thickness). The measurement of 
these lesions is potentially nonreproducible; therefore, providing this default value will prevent false 
responses or progressions based upon measurement error. To reiterate, however, if the radiologist is 
able to provide an actual measure, that should be recorded, even if it is below 5 mm. 
Lesions that split or coalesce on treatment: When non-nodal lesions “fragment”, the longest diameters 
of the fragmented portions should be added together to calculate the target lesion sum. Similarly, as 
lesions coalesce, a plane between them may be maintained that would aid in obtaining maximal 
diameter measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the vector of the longest diameter in this instance should be the maximal 
longest diameter for the “coalesced lesion”. 
Evaluation of Nontarget Lesions 
While some nontarget lesions may actually be measurable, they need not be measured and instead 
should be assessed only qualitatively at the timepoints specified in the protocol. 
CR: Disappearance of all nontarget lesions and normalization of tumor marker level. All lymph nodes 
must be nonpathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more nontarget lesion(s) and/or maintenance of tumor marker 
level above the normal limits. 
PD: Unequivocal progression (see comments below) of existing nontarget lesions. 
When the patient also has measurable disease: In this setting, to achieve “unequivocal progression” 
on the basis of the nontarget disease, there must be an overall level of substantial worsening in 
nontarget disease such that, even in presence of SD or PR in target disease, the overall tumor burden 
has increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size of one 
or more nontarget lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in nontarget disease in the face of SD 
or PR of target disease will therefore be extremely rare. 


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When the patient has only nonmeasurable disease: This circumstance arises in some Phase 3 trials 
when it is not a criterion of trial entry to have measurable disease. The same general concept apply 
here as noted above, however, in this instance there is no measurable disease assessment to factor into 
the interpretation of an increase in nonmeasurable disease burden. Because worsening in nontarget 
disease cannot be easily quantified (by definition: if all lesions are truly nonmeasurable) a useful test 
that can be applied when assessing patients for unequivocal progression is to consider if the increase 
in overall disease burden based on the change in nonmeasurable disease is comparable in magnitude 
to the increase that would be required to declare PD for measurable disease: ie, an increase in tumor 
burden representing an additional 73% increase in “volume” (which is equivalent to a 20% increase 
diameter in a measurable lesion). Examples include an increase in a pleural effusion from “trace” to 
“large”, an increase in lymphangitic disease from localized to widespread, or may be described in 
protocols as “sufficient to require a change in therapy”. If “unequivocal progression” is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to nonmeasurable disease, the very nature of that disease makes it 
impossible to do so; therefore, the increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments on 
detection of new lesions are important. There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not attributable 
to differences in scanning technique, change in imaging modality or findings thought to represent 
something other than tumor (for example, some “new” bone lesions may be simply healing or flare 
of preexisting lesions). This is particularly important when the patient’s baseline lesions show PR or 
CR. For example, necrosis of a liver lesion may be reported on a CT scan report as a “new” cystic 
lesion, which it is not. 
A lesion identified on a follow-up trial in an anatomical location that was not scanned at baseline is 
considered a new lesion and will indicate disease progression. An example of this is the patient who 
has visceral disease at baseline and while on trial has a CT or MRI brain ordered which reveals 
metastases. The patient’s brain metastases are considered to be evidence of PD even if he/she did not 
have brain imaging at baseline. 
If a new lesion is equivocal, for example because of its small size, continued therapy and follow-up 
evaluation will clarify if it represents truly new disease. If repeat scans confirm there is definitely a 
new lesion, then progression should be declared using the date of the initial scan. 
While fluorine-18 [F-18]fluorodeoxyglucose (FDG)-PET (PET scanning with the tracer FDG) 
response assessments need additional study, it is sometimes reasonable to incorporate the use of FDG-
PET scanning to complement CT scanning in assessment of progression (particularly possible “new” 
disease). New lesions on the basis of FDG-PET imaging can be identified according to the following 
algorithm: 
 Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-


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PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up CT 
scans are needed to determine if there is truly progression occurring at that site (if so, the date of 
PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET at follow-
up corresponds to a preexisting site of disease on CT that is not progressing on the basis of the 
anatomic images, this is not PD. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study drug treatment until 
the end of treatment taking into account any requirement for confirmation. On occasion a response 
may not be documented until after the end of therapy so protocols should be clear if post-treatment 
assessments are to be considered in determination of best overall response. Protocols must specify 
how any new therapy introduced before progression will affect best response designation. The 
patient’s best overall response assignment will depend on the findings of both target and nontarget 
disease and will also take into consideration the appearance of new lesions. Furthermore, depending 
on the nature of the trial and the protocol requirements, it may also require confirmatory measurement. 
Specifically, in nonrandomized trials where response is the primary endpoint, confirmation of PR or 
CR is needed to deem either one the “best overall response”. 
The best overall response is determined once all the data for the patient is known. Best response 
determination in trials where confirmation of CR or PR IS NOT required: Best response in these trials 
is defined as the best response across all timepoints (for example, a patient who has SD at first 
assessment, PR at second assessment, and PD on last assessment has a best overall response of PR). 
When SD is believed to be best response, it must also meet the protocol specified minimum time from 
baseline. If the minimum time is not met when SD is otherwise the best timepoint response, the 
patient’s best response depends on the subsequent assessments. For example, a patient who has SD at 
first assessment, PD at second and does not meet minimum duration for SD, will have a best response 
of PD. The same patient lost to follow-up after the first SD assessment would be considered 
unevaluable. 
Target Lesions 
Nontarget 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 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial 
response; SD, stable disease. 


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Note: When nodal disease is included in the sum of target lesions and the nodes decrease to “normal” 
size (< 10 mm), they may still have a measurement reported on scans. This measurement should be 
recorded even though the nodes are normal in order not to overstate progression should it be based on 
increase in size of the nodes. As noted earlier, this means that patients with CR may not have a total 
sum of “zero” on the eCRF. 
In trials where confirmation of response is required, repeated ‘not evaluable (NE)’ timepoint 
assessments may complicate best response determination. The analysis plan for the trial must address 
how missing data/assessments will be addressed in determination of response and progression. For 
example, in most trials it is reasonable to consider a patient with timepoint responses of PR-NE-PR 
as a confirmed response. 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration”. Every effort should be made to document objective progression even after 
discontinuation of treatment. Symptomatic deterioration is not a descriptor of an objective response: 
it is a reason for stopping trial therapy. 
Conditions that define “early progression, early death, and inevaluability” are trial specific and should 
be clearly described in each protocol (depending on treatment duration, treatment periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When 
the evaluation of CR depends upon this determination, it is recommended that the residual lesion be 
investigated (fine needle aspirate/biopsy) before assigning a status of CR. FDG-PET may be used to 
upgrade a response to a CR in a manner similar to a biopsy in cases where a residual radiographic 
abnormality is thought to represent fibrosis or scarring. The use of FDG-PET in this circumstance 
should be prospectively described in the protocol and supported by disease specific medical literature 
for the indication. However, it must be acknowledged that both approaches may lead to false positive 
CR due to limitations of FDG-PET and biopsy resolution/ sensitivity. 
For equivocal findings of progression (eg, very small and uncertain new lesions, cystic changes, or 
necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at the 
next scheduled assessment, progression is confirmed, the date of progression should be the earlier 
date when progression was suspected. 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
Confirmation 
In nonrandomized trials where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also permit 
appropriate interpretation of results in the context of historical data where response has traditionally 
required confirmation in such trials. However, in all other circumstances, ie, in randomized trials 
(Phase 2 or 3) or trials where SD or PD are the primary endpoints, confirmation of response is not 
required since it will not add value to the interpretation of trial results. However, elimination of the 


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requirement for response confirmation may increase the importance of central review to protect 
against bias, in particular in trials which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after trial entry at a 
minimum interval (in general not less than 6 weeks). 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively documented 
(taking as reference for PD the smallest measurements recorded on study). 
The duration of overall CR is measured from the time measurement criteria are first met for CR until 
the first date that recurrent disease is objectively documented. 
Duration of Stable Disease 
SD is measured from the start of the treatment (in randomized trials, from date of randomization) until 
the criteria for progression are met, taking as reference the smallest sum on study (if the baseline sum 
is the smallest, this is the reference for calculation of PD). 
The clinical relevance of the duration of SD varies in different studies and diseases. If the proportion 
of patients achieving SD for a minimum period of time is an endpoint of importance in a particular 
trial, the protocol should specify the minimal time interval required between 2 measurements for 
determination of SD. 
Note: The duration of response and SD as well as the progression-free survival are influenced by the 
frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to define a 
standard follow-up frequency. The frequency should take into account many parameters including 
disease types and stages, treatment periodicity, and standard practice. However, these limitations of 
the precision of the measured endpoint should be taken into account if comparisons between trials are 
to be made. 
 
 
 


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APPENDIX 3. 
ECOG PERFORMANCE STATUS 
Grade 
Description 
0 
Fully active, able to carry on all pre-diseases performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature (eg, 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 
As published by (Oken et al 1982). Eastern Cooperative Oncology Group, Robert Comis MD, Group Chair. 


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APPENDIX 4. 
CONTRACEPTION GUIDELINES AND DEFINITIONS OF “WOMEN 
OF CHILDBEARING POTENTIAL”, “NO CHILDBEARING 
POTENTIAL” 
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and pregnancy 
testing in clinical trials include the use of highly effective forms of birth control. These methods 
include the following: 
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with the 
inhibition of ovulation (oral, intravaginal, or transdermal) 
 Progestogen-only hormonal contraception associated with the inhibition of ovulation (oral, 
injectable, or implantable) 
 Intrauterine device 
 Intrauterine hormone-releasing system 
 Bilateral tubal occlusion 
 Vasectomized male partner, provided that the vasectomized partner is the sole sexual partner of 
the woman of childbearing potential study participant and that the vasectomized partner has 
received medical assessment of surgical success 
 Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of 
exposure associated with the study treatment) 
NOTE: Total sexual abstinence should only be used as a contraceptive method if it is in line 
with the patient’s usual and preferred lifestyle.  
Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods), 
declaration of abstinence for the duration of exposure to study drug, and withdrawal are not 
acceptable methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) is 
not considered a highly effective method of contraception and if used, this method must be combined 
with another acceptable method listed above. 
Definitions of “Women of Childbearing Potential”, “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are females who are physiologically 
capable of becoming pregnant. 
Conversely, “women of no childbearing potential” are defined as females meeting any of the 
following criteria: 
 Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or hysterectomy) 


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 Postmenopausal, defined as: 
o ≥ 55 years of age with no spontaneous menses for ≥ 12 months OR 
o < 55 years of age with no spontaneous menses for ≥ 12 months AND with a 
postmenopausal follicle-stimulating hormone concentration > 30 IU/mL and all 
alternative medical causes for the lack of spontaneous menses for ≥ 12 months have been 
ruled out, such as polycystic ovarian syndrome, hyperprolactinemia, etc. 
If an FSH measurement is required to confirm postmenopausal state, concomitant use of hormonal 
contraception or hormonal replacement therapy should be excluded. 
 
Adapted from Clinical Trials Facilitation Group (CTFG). Recommendations related to contraception and pregnancy 
testing in clinical trials. September 15, 2014. http://www hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf 


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APPENDIX 5. 
NEW YORK HEART ASSOCIATION FUNCTIONAL 
CLASSIFICATION 
 
Class 
Symptoms 
I 
No limitation of physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea (shortness of breath). 
II 
Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity 
results in fatigue, palpitation, dyspnea (shortness of breath). 
III 
Marked limitation of physical activity. Comfortable at rest, but less than ordinary 
activity causes fatigue, palpitation, or dyspnea. 
IV 
Unable to carry on any physical activity without discomfort. Symptoms of heart failure 
at rest. If any physical activity is undertaken, discomfort increases. 
Adapted from Dolgin M, Association NYH, Fox AC, Gorlin R, Levin RI, New York Heart Association. Criteria 
Committee. Nomenclature and criteria for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, MA: 
Lippincott Williams and Wilkins; March 1, 1994. 
Original source: Criteria Committee, New York Heart Association, Inc. Diseases of the Heart and Blood 
Vessels. Nomenclature and Criteria for diagnosis, 6th edition Boston, Little, Brown and Co. 1964, p 114. 
 
 


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APPENDIX 6. 
PROHIBITED MEDICATIONS 
 
Strong and Moderate CYP3A Inhibitors and Strong CYP3A Inducers 
Strong CYP3A Inhibitors 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals: boceprevir, telaprevir 
Other: cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone 
Protease inhibitors: indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir 
 
Strong CYP3A Inducers 
Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. John’s 
wort (Hypericum perforatum) 
 
Moderate CYP3A Inhibitors 
Antibiotics: ciprofloxacin, erythromycin 
Antifungals: fluconazole 
Protease inhibitors: amprenavir, atazanavir, darunavir, fosamprenavir 
Calcium channel blockers: diltiazem, verapamil 
Tyrosine kinase inhibitors (anticancer): imatinib 
Food products: grapefruit and juice (Citrus paradisi), Seville orange and juice (Citrus aurantium) 
Herbal medications: Schisandra sphenanthera 
Others: aprepitant, casopitant, cimetidine, cyclosporine, dronedarone, tofisopam 
Data compiled from the United States Food and Drug Administration “Guidance for Industry, Drug Interaction 
Studies;” 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.ht
m from the Indiana University School of Medicine’s “Clinically Relevant” Table 
http://medicine.iupui.edu/flockhart/table.htm; from the University of Washington’s Drug Interaction Database 
www.druginteractioninfo.org 


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APPENDIX 7. 
MEDICATIONS TO BE USED WITH CAUTION 
 
Sensitive CYP2C9 Substrates or CYP2C9 Substrates with Narrow Therapeutic Index 
 Celecoxiba 
 Phenytoinb 
 Warfarinb 
 
a  
Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when 
coadministered with a known potent inhibitor, where AUCi is the AUC of the substrate when 
coadministered with a known potent inhibitor and AUC is the AUC of substrate alone. 
b  
Substrates with narrow therapeutic index: Drugs whose exposure-response indicates that increases in 
their exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns 
(eg, Torsade de Pointes). 
 
 
Strong CYP2C8 Inhibitors 
 Gemfibrozil 
 
 
 
 
 


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APPENDIX 10. 
PROSTATE CANCER CLINICAL TRIALS WORKING GROUP 3 
The information below was obtained from the following reference: Scher HI, Morris MJ, 
Stadler WM. Prostate Cancer Clinical Trials Working Group 3. Trial design and objectives for 
castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical 
Trials Working Group 3. J Clin Oncol. 2016 Apr 20;34(12):1402-18 (Scher et al 2016). 
Standard Baseline Disease Assessments Recommended by PCWG3 
Assessment 
PCWG3 
Histology 
Adenocarcinoma 
Adenocarcinoma with small-cell or neuroendocrine features 
Small-cell carcinoma 
Report Gleason sum for primary 
Consider rebiopsy of metastatic disease 
Clinical 
Age, pain, analgesic consumption, performance status, 
comorbidity assessment, history, and physical examination; 
prior local therapy; TNM stage at diagnosis; and PSA 
Prior systemic treatment 
Record each line of systemic therapy (single agent or 
combination) in order of administration, including start and 
stop dates, dose(s), and schedule(s), the disease state in which 
it was administered, and response (resistant versus sensitive) 
on the basis of PSA if appropriate 
Record type of progression on prior therapy (PSA, 
radiographic [bone, nodal, visceral], clinical [eg, pain 
escalation]) 
Prior radiation therapy 
Site, administered dose per fraction, and treatment duration 
Blood-based biomarkers 
Host: CBC with differential, ALP, kidney/liver function, 
albumin, LDH, testosteronea 
Tumor: PSA and cPSA kinetics 
Optional: CEA, chromogranin A, neuron-specific enolase, 
CTC enumeration 
Imaging 
   Prostate/ prostate bed 
Retained, cross-sectional imaging of prostate region if 
applicable 
   Nodal 
CT or MRI: 
Nodes  1.5 cm in the short axis are considered measurable; 
nodes  1.0 and less than 1.5 cm in the short axis are 
considered pathologic according to clinical discretion, and 
nontarget; nodes less than 1.0 cm in the short axis are 
nonpathologic 
Record pelvic and extrapelvic (retroperitoneal, mediastinal, 
thoracic, other) nodal disease separately; up to 5 nodes in 
total 


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Assessment 
PCWG3 
Record new lesions versus growth of pre-existing lesions, and 
sites of new lesions 
   Visceral 
CT or MRI: 
Record individual sites of spread (lung, liver, adrenal, CNS) 
separately; up to five lesions per site 
Lesions  1.0 cm in the longest dimension are considered 
measurable 
Record new lesions versus growth of pre-existing lesions, and 
sites of new lesions 
   Bone 
Record new lesions and sites of new lesions 
Tumor profiling for determinants of 
prognostic, predictive, and resistance 
biomarkers 
Consider rebiopsy of metastatic or locally recurrent lesion(s) 
for biologic characterization 
Patient-reported outcomes 
Pain assessment, opiate analgesia consumption, physical 
functioning (functional status), health-related quality of life; 
consider fatigue and PRO-CTCAE. Validated PRO 
instruments strongly recommended 
Abbreviations: ALP, alkaline phosphatase; CBC, complete blood count; CEA, carcinoembryonic antigen; 
CNS, central nervous system; cPSA, complexed prostate-specific antigen; CT, computed tomography; 
CTC, circulating tumor cell; LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PCWG3, Prostate 
Cancer Clinical Trials Working Group 3; PRO, patient-reported outcome; PRO-CTCAE, Patient-Reported 
Outcomes version of the Common Terminology Criteria for Adverse Events; PSA, prostate-specific antigen. 
a. Ultrasensitive testosterone measures may be indicated where appropriate on the basis of drug under study and 
context. 
 
Criteria for Progression at Trial Entry by Disease Manifestation 
Variable 
PCWG3 
Blood-based 
   PSA 
 
Obtain sequence of rising values at a minimum of 1-week 
intervals 
1.0 ng/mL is the minimal starting value if confirmed rise is 
only indication of progression unless pure small-cell 
carcinoma 
Estimate pretherapy PSADT if at least 3 values available 
 4 weeks apart 
Imaging  
   Nodes 
 
Nodal progression sufficient for trial entry independent of 
PSA 
Measurable lesions not required for entry 
Modified RECIST 1.1 criteria, separate pelvic and 
extrapelvic disease, up to 5 nodal lesions total recorded 


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Variable 
PCWG3 
Previously normal (< 1.0 cm) lymph nodes must have grown 
by ≥ 5 mm in the short axis from baseline or nadir and be 
≥ 1.0 cm in the short axis to be considered to have progressed 
If the node progresses to ≥ 1.5 cm in the short axis, it is 
measurable; nodes that have progressed to 1.0 to less than 
1.5 cm are pathologic, subject to clinical discretion, and 
nonmeasurable 
For existing pathologic adenopathy, progression is defined 
per RECIST 1.1 
Record presence of nodal and/or visceral disease separately 
Nodal sites: 
Locoregional: pelvic only 
Extrapelvic: retroperitoneal, mediastinal, thoracic, or other 
   Viscera 
Visceral progression sufficient for trial entry independent of 
PSA, record separately by site of spread (lung, liver, adrenal, 
CNS); up to 5 lesions per site of spread 
Measurable lesions not required for entry 
Use RECIST to record visceral lesions as target or nontarget 
Record presence of nodal and/or visceral disease separately, 
Visceral sites: lung, liver, adrenal, CNS 
   Prostate/prostate bed (primary site) 
Record prior treatment of primary tumor 
Perform directed pelvic imaging (CT, MRI, PET/CT, 
endorectal MRI, transrectal ultrasound) to document presence 
or absence of disease 
   Bone 
Two new lesions 
Confirm ambiguous results by other imaging modalities 
(eg, CT or MRI), but only positivity on the bone scan defines 
metastatic disease to bone 
Other sites of disease 
Patients with treated epidural lesions and no other epidural 
progression are eligible 
Type of progression at trial entry 
Report separately: 
PSA only 
Bone only ± nodal disease 
Nodal disease only (no bone disease present) 
Visceral (lung, liver, adrenal, CNS) disease (± other sites) 
Record new lesions and site of new lesions versus growth of 
preexisting lesions, or both 


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Variable 
PCWG3 
Other markers 
   Patient-reported outcomes 
For pain palliation analyses, presence of clinically 
meaningful pain at baseline (eg, ≥ 4 on a 10-point pain 
intensity scale) is a prerequisite; for pain progression 
analyses, patients may have any level of pain at baseline, 
including no pain 
Abbreviations: CNS, central nervous system; CT, computed tomography; MRI, magnetic resonance imaging; 
PCWG3, Prostate Cancer Clinical Trials Working Group 3; PET, positron emission tomography; PSA, prostate-
specific antigen; PSADT, PSA doubling time; RECIST, Response Evaluation Criteria in Solid Tumors. 
 
Suggested Frequency of Assessment for Commonly Used Measures in Metastatic Prostate 
Cancer Clinical Trials 
Assessmenta 
PCWG3 
Clinical 
   Symptoms/ performance status 
 
Every cycle 
Blood-based markers 
   PSA 
   ALP, LDH 
   Serum chemistry, CBC 
   Circulating tumor cells 
 
By cycle (every 3 or 4 weeks) 
By cycle (every 3 or 4 weeks) 
By cycle (every 3 or 4 weeks) 
By cycle (every 3 to 4 weeks) if available 
Imaging  
   Bone scans 
 
   CT/MRI 
 
 
Every 8 to 9 weeks for first 24 weeks, then every 
12 weeksb 
Every 8 to 9 weeks for first 24 weeks, then every 
12 weeksb 
Patient-reported outcomes 
   Analgesic consumption (opioids/no opioids) 
By cycle (every 3 to 4 weeks) 
By cycle (every 3 to 4 weeks) 
Abbreviations: ALP, alkaline phosphatase; CT, computed tomography; LDH, lactate dehydrogenase; 
MRI, magnetic resonance imaging; PCWG3, Prostate Cancer Clinical Trials Working Group 3; PSA, prostate-
specific antigen. 
a. 
All measures should be assessed at baseline to determine changes over time. 
b. There may be exceptions to these suggestions: in nonmetastatic castration-resistant prostate cancer trials, for 
example, imaging assessment intervals of 16 weeks are advised. Likewise, in long-term responders  
(> 2 to 3 years of clinical benefit and no signs of clinical or biomarker progression), reduced frequency of 
imaging is reasonable, such as every 16 to 24 weeks (4 to 6 months). 
 


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Suggested Outcome Measures for Clinical Trials in Metastatic Prostate Cancer: Report by 
Disease Manifestation 
Assessment 
PCWG3 
Histology 
Encourage rebiopsy of metastatic sites or local recurrence at 
progression to evaluate for histologic (ie, neuroendocrine/ small 
cell) transformation; in the context of clinical trials, encourage 
rebiopsy for biomarker assessment 
Blood-based biomarkers 
   PSA 
 
 
Recognize that a favorable effect on PSA may be delayed for 
 12 weeks, even for a cytotoxic drug 
Monitor PSA by cycle but plan to continue through early rises 
for a minimum of 12 weeks unless other evidence of 
progression 
Ignore early rises (before 12 weeks) in determining PSA 
response 
For control/relieve/eliminate endpoints: 
Record the percent change from baseline (rise or fall) at 
12 weeks, and separately, the maximal change (rise or fall) at 
any time using a waterfall plot, except with timing (8-9 or 
12 weeks) depending on trial design 
Separately report the proportion of patients who have 
undergone radical prostatectomy and achieved a nadir less than 
0.2 ng/mL versus primary radiation therapy-treated patients 
who achieved a nadir less than 0.5 ng/mL 
Describe absolute changes in PSA over time from baseline to 
best response 
For delay/prevent endpoints (progression): 
After decline from baseline: record time from start of therapy to 
first PSA increase that is  25% and  2 ng/mL above the nadir, 
and which is confirmed by a second value  3 weeks later (ie, a 
confirmed rising trend); the requirement for an increase of 
5 ng/mL was decreased to 2 ng/mL, and the requirement for a 
50% increase was reduced to 25% (standards for reporting PSA 
progression date may not indicate a need to stop treatment). 
Recording the duration of PSA decline of little value. 
Relate to mechanism of drug and anticipated timing of potential 
favorable/unfavorable effects on PSA, if present 
   CTC 
Enumerate at the start of treatment: Record as favorable (4 or 
fewer cells per 7.5 mL of blood) or unfavorable (5 or more cells 
per 7.5 mL) 
If unfavorable, monitor for changes after treatment 
For control/relieve/eliminate endpoints: 
Report as change from unfavorable (5 or more cells per 7.5 mL 
of blood) to favorable (4 or fewer cells per 7.5 mL) and 


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Assessment 
PCWG3 
separately, the percent change from baseline using a waterfall 
plot 
For delay/prevent endpoints: no validated definition exists 
(however, rising CTC counts are associated with a poor 
prognosis) 
   LDH, total alkaline phosphatase, 
bone-specific alkaline phosphatase, 
urine N-telopeptide, hemoglobin, 
NLR 
Descriptively report changes over time, may include the 
proportion showing normalization of a given biomarker and/or 
waterfall plots of percent change from baseline in a given 
biomarker 
Report institutional normal ranges to determine normalization 
of a given biomarker 
Imaging biomarkers: nodal and 
visceral 
   For control/relieve/eliminate 
endpoints 
      General 
 
 
 
 
Record changes in lymph nodes, lung, liver, adrenal, and CNS 
sites separately 
Record up to 5 lesions per site of disease 
Use RECIST 1.1 with caveats: 
Record changes in size using waterfall plot 
Confirm favorable change with second scan 
Record complete elimination of disease at any site separately 
      Nodes 
Only report changes in lymph nodes that were  1.5 cm in the 
short axis 
Record changes in pelvic (regional) nodes versus extrapelvic 
(distant/metastatic) nodes separately 
      Visceral 
 
Use RECIST 1.1 with caveats: 
Record changes in liver, lung, adrenal, and CNS separately 
Only report changes in lesions  1.0 cm in the longest 
dimension 
   For delay/prevent endpoints 
      Nodal and visceral 
General: 
Record changes in nodal and visceral (lung, liver, adrenal, and 
CNS) disease separately 
Use RECIST 1.1 but clearly record type of progression (growth 
of existing lesions versus development of new lesions) 
separately by site 
The recommendations apply to both nmCRPC and mCRPC 
Record up to 5 lesions per site of spread 
Report the proportion who have not progressed at fixed 
timepoints (6 or 12 months) 
Note that for some treatments, a lesion may increase in size 
before it decreases 


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Assessment 
PCWG3 
      Nodal 
Previously normal (< 1.0 cm) lymph nodes must have grown by 
 5 mm in the short axis from baseline or nadir and be  1.0 cm 
in the short axis to be considered to have progressed 
Nodes that have progressed to 1.0 to less than 1.5 cm are 
pathologic, subject to clinical discretion, and nonmeasurable 
For existing pathologic adenopathy ( 1.5 cm), progression is 
defined per RECIST 1.1 
Imaging biomarkers: bone 
   Metastatic 
For control/relieve/eliminate endpoints: 
Record changes as improved or stable (no new lesions) or 
worse (new lesions), with of resolved bone lesion 
Changes in intensity of uptake alone do not constitute 
progression or regression 
No new lesions: continue therapy in absence of other signs of 
progression 
New lesions (See Progression below)  
For delay/prevent endpoints (progression): 
Progression: 
Exclude pseudoprogression in the absence of symptoms or 
other signs of progression 
At least 2 new lesions on first post-treatment scan, with at least 
2 additional lesions on the next scan (2 + 2 rule) 
If at least 2 additional new lesions are seen on the next 
(confirmatory) scan, the date of progression is the date of the 
first post-treatment scan, when the first 2 new lesions were 
documented 
For scans after the first post-treatment scan, at least 2 new 
lesions relative to the first post-treatment scan confirmed on a 
subsequent scan 
Date of progression is the date of the scan that first documents 
the second lesion 
Changes in intensity of uptake alone do not constitute either 
progression or regression 
Report the proportion of patients who have not progressed at 
fixed time intervals (6 and 12 months) 
   nmCRPC 
Nonmetastatic to metastatic progression: 
Any new unequivocal bone lesion, except if that lesion appears 
in the first post-treatment scan; in that case, document the 
event, continue treatment until 2 additional new lesions appear, 
and record both events 
Patient-reported outcomes 
Pain palliation assessment requires a patient population with 
clinically meaningful pain at baseline (eg,  4 on a 10-point 
pain intensity scale) and response defined as a clinically 
meaningful score improvement at a subsequent timepoint (eg, a 


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Assessment 
PCWG3 
30% relative or 2-point absolute improvement from baseline at 
12 weeks, confirmed at least 2 weeks later, without an overall 
increase in opiate use) 
For control/relieve/eliminate endpoints: 
Serial (eg, daily x 7 days) assessments at each timepoint can 
improve the stability of values 
Principles may be extended for any PRO for which a clinically 
meaningful baseline PRO score has been determined together 
with a responder definition that is based on a sustained 
clinically meaningful score improvement 
For delay/prevent endpoints: 
Patients with any level of baseline pain, including no pain, are 
eligible to be evaluated for prevent/delay endpoints; those 
without pain are followed for development of pain, whereas 
those with baseline pain are followed for progression (eg, a 
2-point increase without an overall decrease in opiate use) 
Pain assessment should be administered at treatment 
discontinuation and once again if feasible (eg, 2 to 4 weeks 
later) 
Time to deterioration of physical function and/or HRQoL 
scores should also be included, with a priori thresholds defining 
clinically meaningful deterioration score changes that are based 
on prior published data for the selected questionnaire 
Abbreviations: CNS, central nervous system; CTC, circulating tumor cell; HRQoL, health-related quality of life; 
LDH, lactate dehydrogenase; mCRPC, metastatic castration-resistant prostate cancer; 
NLR, neutrophil/lymphocyte ratio; nmCRPC, nonmetastatic castration-resistant prostate cancer; 
PCWG3, Prostate Cancer Clinical Trials Working Group 3; PRO, patient-reported outcome; PSA, prostate-
specific antigen; RECIST, Response Evaluation Criteria in Solid Tumors. 
 
 
 


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APPENDIX 11. 
CHRONIC KIDNEY DISEASE EPIDEMIOLOGY COLLABORATION 
(CKD-EPI) EQUATION 
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation1 
and the Modification of Diet in Renal Disease (MDRD) Study equation. The National Kidney 
Disease Education Program (NKDEP) calculators rely on creatinine determinations which are 
isotope dilution mass spectrometry (IDMS) traceable. All laboratories should be using creatinine 
methods calibrated to be IDMS traceable. Read more about creatinine standardization. 
This CKD-EPI equation calculator should be used when Scr reported in mg/dL. This equation is 
recommended when eGFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 body 
surface area, which is an accepted average adult surface area. 
The online calculator for CKD-EPI can be found here: https://www.niddk.nih.gov/health-
information/health-communication-programs/nkdep/lab-evaluation/gfr-calculators/Pages/gfr-
calculators.aspx 
1. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 
2009;150(9):604-12. 


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APPENDIX 12. 
SIGNATURE OF INVESTIGATOR 
 
Protocol Title: 
A Phase 2, Open-Label, Single-Arm Study of Pamiparib (BGB-290) for 
the Treatment of Patients with Metastatic Castration-Resistant Prostate 
Cancer (mCRPC) with Homologous Recombination Deficiency (HRD) 
 
Protocol Identifier:  
BGB-290-202 
 
This protocol is a confidential communication of BeiGene, Ltd., and its subsidiaries. I confirm that I 
have read this protocol, I understand it, and I will work according to this protocol and the terms of 
the clinical study agreement governing the study. I will also work consistently with the ethical 
principles that have their origin in the Declaration of Helsinki and that are consistent with good 
clinical practices and the applicable laws and regulations. Acceptance of this document constitutes 
my agreement that no unpublished information contained herein will be published or disclosed 
without prior written approval from BeiGene, Ltd., or one of its subsidiaries. 
 
Instructions for Investigator: Please SIGN and DATE this signature page. PRINT your 
name, title, and the name of the center in which the study will be conducted. Return the 
signed copy to BeiGene, Ltd. or its designee. 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator:  
 
_______________________________   Date:  _____________ 
Printed Name:  
 
 
 
 
_______________________________ 
Investigator Title:  
 
 
 
_______________________________ 
Name/Address of Center:  
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 
 
 
 
 
 
 
 
_______________________________ 
 
 

SAP_001.pdf: 
 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-290-202 
Study Protocol 
Title: 
A Phase 2, Open-Label, Single-Arm Study of Pamiparib (BGB-290) for 
the Treatment of Patients with Metastatic Castration-Resistant Prostate 
Cancer (mCRPC) with Homologous Recombination Deficiency (HRD) 
 
Date: 
Nov 2, 2020 
Version: 
1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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TABLE OF CONTENTS 
1 
INTRODUCTION 
6 
2 
STUDY OVERVIEW 
6 
3 
STUDY OBJECTIVES 
7 
3.1 
Primary Objective 
7 
3.2 
Secondary Objectives 
7 
3.3 
Exploratory Objectives 
8 
4 
STUDY ENDPOINTS 
8 
4.1 
Primary Endpoints 
8 
4.2 
Secondary Endpoints 
8 
4.3 
Exploratory Endpoints 
9 
5 
SAMPLE SIZE CONSIDERATIONS 
9 
6 
STATISTICAL METHODS 
10 
6.1 
Analysis Populations 
10 
6.2 
Data Analysis General Considerations 
10 
6.2.1 
Definitions and Computations 
10 
6.2.2 
Conventions 
11 
6.2.3 
Handling of Missing Data 
11 
6.2.4 
Multiplicity Adjustment 
12 
6.3 
Patient Characteristics 
12 
6.3.1 
Patient Disposition 
12 
6.3.2 
Protocol Deviations 
13 
6.3.3 
Demographics and Other Baseline Characteristics 
13 
6.3.4 
Prior Anti-Cancer Systemic Therapies 
13 
6.3.5 
Prior and Concomitant Medications 
13 
6.3.6 
Medical History 
14 
6.4 
Efficacy Analysis 
14 
6.4.1 
Primary Efficacy Endpoints 
15 
6.4.2 
Secondary Efficacy Endpoints 
16 
6.4.3 
Subgroup Analyses 
19 
6.4.4 
Exploratory Efficacy Endpoints 
19 
6.5 
Safety Analyses 
21 
6.5.1 
Extent of Exposure 
21 
6.5.2 
Adverse Events 
21 
6.5.3 
Laboratory Values 
22 
6.5.4 
ECOG Performance Status 
23 
6.6 
Pharmacokinetic Analysis 
23 
6.7 
Biomarker Analysis 
23 
7 
INTERIM ANALYSIS 
23 
8 
CHANGES IN THE PLANNED ANALYSIS 
23 


 
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9 
REFERENCES 
24 
10 
APPENDICES 
25 
10.1 
Handling Missing Date Information 
25 
10.2 
Censoring Rules 
28 
10.3 
PROs:  Instruments and Scoring Methods 
29 
 
List of Tables 
Table 1 Patient Cohorts 
6 
Table 2  Primary and Secondary Efficacy Endpoint Analysis Populations 
14 
Table 3  Exploratory Efficacy Endpoint Analysis Populations 
19 
Table 4  Serum Chemistry and Hematology Laboratory Tests 
22 
Table 5  Censoring Rules for Analysis of rPFS 
28 
 
 
 
 
 
 
 
 


 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AML 
acute myeloid leukemia 
AUC 
area under the plasma concentration-time curve (drug exposure) 
AUC0-12 
area under the plasma concentration-time curve from 0 to 12 hours postdose 
BPI-SF 
Brief Pain Inventory Short Form 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Epidemiology Collaboration 
CR 
complete response 
CT 
computed tomography 
CTC 
circulating tumor cell 
CTC-HRD-negative 
or CTC-HRD- 
circulating tumor cells negative for homologous recombination deficiency per Epic 
Sciences assay 
CTC-HRD-positive 
or CTC-HRD+ 
circulating tumor cells positive for homologous recombination deficiency per Epic 
Sciences assay 
CYP 
cytochrome P450 
DOR 
duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
End-of-Treatment (Visit) 
EQ-5D-5L 
European Quality of Life 5-Dimensions 5-Levels Health Questionnaire 
FDG 
fluorine-18 [F-18]fluorodeoxyglucose 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HRD 
homologous recombination deficiency 
HRQoL 
Health-related quality of life 
IC50 
half-maximal inhibition concentration 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 


 
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Abbreviation 
Definition 
LDH 
Lactate dehydrogenase 
mCRPC 
metastatic castration-resistant prostate cancer 
MDRD STUDY EQ 
Modification of Diet in Renal Disease study equation 
MDS 
myelodysplastic syndrome 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NE 
not evaluable 
ORR 
objective response rate 
OS 
overall survival 
pamiparib 
BGB-290 
PAR 
poly (ADP-ribose) 
PARP 
poly (ADP-ribose) polymerase 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
progressive disease 
PET 
positron-emission tomography 
PK 
pharmacokinetic 
PR 
partial response 
PRO 
patient-reported outcome 
PSA 
prostate-specific antigen 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
radiographic progression-free survival 
SAE 
serious adverse event 
SD 
stable disease 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US or USA 
United States or United States of America 
VAS 
visual analog scale 


 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for protocol: A Phase 2, Open-Label, 
Single-Arm Study of Pamiparib (BGB-290) for the Treatment of Patients with Metastatic 
Castration-Resistant Prostate Cancer (mCRPC) with Homologous Recombination Deficiency 
(HRD). The focus of this SAP is for the planned analyses specified in the study protocol Version 
1.0.  
2 
STUDY OVERVIEW 
This is an open-label, single-arm, global Phase 2 study to evaluate the efficacy and safety of 
single-agent poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitor pamiparib in biomarker 
positive mCRPC patients. Biomarker positivity is defined as circulating tumor cells positive for 
homologous recombination deficiency per Epic Sciences assay (CTC-HRD-positive) (Cohorts 1 
and 2) or deleterious germline or somatic mutation in BRCA1 or BRCA2 (Cohorts 3 and 4). 
To be eligible for the study, biomarker-positive patients must have progressed on or after at least 
one androgen receptor-targeted therapy for mCRPC (eg, enzalutamide, abiraterone 
acetate/prednisone, bicalutamide, flutamide, apalutamide, or nilutamide), received at least 1 
taxane-based therapy for metastatic prostate cancer and have prostate-specific antigen (PSA) 
progression as per Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria at time of 
study entry. The primary endpoints are objective response rate (ORR) by Independent Review 
Committee (IRC) for patients with measurable disease (Cohort 1, n ≈ 50) and PSA response rate 
for patients with or without measurable disease (Cohorts 1 and 2, n ≈ 80) as per PCWG3 criteria. 
Cohort 1 will include 50 mCRPC patients with CTC-HRD-positive, measurable metastatic 
disease (soft tissue with/without bone lesions), and positive BRCA1/2 mutation (Cohort 1A) or 
negative/unknown BRCA1/2 mutation (Cohort 1B). Cohort 2 will include 30 mCRPC CTC-
HRD positive patients with bone metastasis only and positive (Cohort 2A) or negative/unknown 
BRCA1/2 (Cohort 2B). Cohort 3 and 4 will include 20 mCRPC CTC-HRD negative/unknown 
patients with BRCA1/2 positive mutations, metastatic disease (measurable soft tissue 
with/without bone), and bone disease only, respectively (see Table 1).  
Table 1 Patient Cohorts 
 
Abbreviations: , biomarker status unknown; CTC-HRD-, negative for circulating tumor cells with homologous recombination 


 
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deficiency per Epic Sciences assay; CTC-HRD+, positive for circulating tumor cells with homologous recombination deficiency 
per Epic Sciences assay. 
After enrollment, patients will receive pamiparib 60 mg orally twice a day in cycles of 28 days. 
Safety assessments will occur on Day 1 and Day 15 of Cycles 1 and 2, on Day 1 of every cycle 
thereafter and as clinically indicated. Dose modifications will be made if appropriate. Adverse 
events (AEs) will be followed and documented during the treatment phase and for approximately 
30 days after the last dose of pamiparib or until initiation of new anticancer therapy, whichever 
occurs first. AEs will be graded according to National Cancer Institute-Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) Version 4.03 or higher. A Safety Monitoring 
Committee will periodically review safety data.   
Pharmacokinetic (PK) samples for pamiparib will be collected at various timepoints at all non-
China centers and at centers with such capability in China. In addition, tumor tissue (if available) 
and blood samples will be obtained to explore biomarkers of pharmacodynamics, response, and 
resistance to pamiparib in mCRPC.   
Disease status will be assessed by the investigator using PCWG3 criteria. Patients will undergo 
tumor assessments every 8 weeks (± 7 days) for 24 weeks, then every 12 weeks (± 7 days), or as 
clinically indicated. PSA assessments will occur at screening, on Day 1, and then every 4 weeks 
(± 7 days), or as clinically indicated.   
Administration of pamiparib will continue until progressive disease (PD), unacceptable toxicity, 
death, or another discontinuation criterion is met. Once the treatment phase has been completed, 
an End-of-Treatment (EOT) Visit should occur within 7 days of stopping pamiparib with 
subsequent phases of safety and long-term follow-up.   
Long-term follow-up will include tumor and PSA assessments every 12 weeks and 4 weeks 
(± 7 days), respectively, for those patients without PD, survival status, and initiation of new 
anticancer therapy. Long-term follow-up will continue until the patient dies or another criterion 
for discontinuation from study is met.   
3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVE  
• To evaluate the efficacy of pamiparib in patients with positive mCRPC for circulating 
tumor cells with homologous recombination deficiency (CTC-HRD-positive; per Epic 
Sciences assay), as per PCWG3 criteria   
3.2 
SECONDARY OBJECTIVES  
• To further evaluate the efficacy of pamiparib in patients with CTC-HRD-positive 
mCRPC with measurable disease (Cohort 1 of Table 1), as per PCWG3 criteria 
• To further evaluate the efficacy of pamiparib in patients with CTC-HRD-positive 
mCRPC with or without measurable disease (Cohorts 1 and 2 of Table 1, respectively), as 


 
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per PCWG3 criteria 
• To evaluate the safety and tolerability of pamiparib   
3.3 
EXPLORATORY OBJECTIVES 
• 
• 
• 
• 
4 
STUDY ENDPOINTS 
4.1 
PRIMARY ENDPOINTS 
• Objective response rate (ORR; defined as the proportion of patients with best objective 
response of complete response (CR) or partial response (PR) confirmed at a subsequent 
timepoint  4 weeks later) by Independent Review Committee (IRC) for CTC-HRD-
positive patients with measurable disease (Cohort 1 of Table 1) 
• PSA response rate (defined as the proportion of patients with PSA decline  50% from 
baseline [confirmed by a second PSA value  3 weeks later]) for CTC-HRD-positive 
patients with or without measurable disease (Cohorts 1 and 2 of Table 1, respectively) 
4.2 
SECONDARY ENDPOINTS 
For Patients with CTC-HRD-Positive mCRPC with Measurable Disease (Cohort 1 of Table 1) 
per PCWG3 Criteria: 
• Duration of response (DOR) by IRC 
• ORR by investigator 
• Time to objective response 
• Clinical benefit rate (defined as the proportion of patients with a documented confirmed 
CR, PR, or stable disease) 
For Patients with CTC-HRD-Positive mCRPC with or without Measurable Disease (Cohorts 1 
and 2 of Table 1, respectively) per PCWG3 Criteria: 
• Time to PSA response 


 
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• Duration of PSA response 
• Time to PSA progression (defined as the time from the date of the first dose of study drug 
to a  25% increase in PSA with an absolute increase of  2 ng/mL above the nadir [or 
above the baseline for patients with no PSA decline] after 12 weeks, confirmed by a 
second value  3 weeks later) 
• Time to symptomatic skeletal event (SSE; defined as time from the date of the first dose 
of study drug to the first symptomatic fracture, radiation or surgery to bone, or spinal 
cord compression) 
• Radiographic progression-free survival (rPFS; defined as the time from the date of the 
first dose of study drug to radiographic disease progression by IRC or death due to any 
cause, whichever occurs first) 
• Overall survival (OS) 
For All Patients (Cohorts 1, 2, 3, and 4 of Table 1): 
• Incidence, timing, and severity of treatment-emergent adverse events (TEAEs), graded 
according to NCI-CTCAE Version 4.03 or higher   
4.3 
EXPLORATORY ENDPOINTS 
• 
• 
• 
• 
• 
5 
SAMPLE SIZE CONSIDERATIONS 
This study is designed to provide adequate power for primary endpoints of ORR and PSA 
response rate. A sample size of approximately 100 patients is planned (at approximately 45 
centers with a projected average enrollment of 2 to 3 patients per center). 


 
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Assuming ORR of 35% for pamiparib in CTC-HRD-positive patients versus 15% for historical 
control in patients with measurable disease, the study power is 88% using a binominal exact test 
and 1-sided type-I error of 0.025 with n = 50. The binominal exact 95% CI of 35% ORR is 
22.1% to 49.8% with a sample size of 50 patients. 
Assuming PSA response rate of 50% for pamiparib versus 30% for historical control in 
CTC-HRD-positive patients with or without measurable disease, a sample size of 80 patients in 
this population will provide 95% study power using a binominal exact test and 1-sided type-I 
error of 0.025. The binominal exact 95% CI of 50% response rate is 38.6% to 61.4% with n = 80.  
To explore the efficacy of pamiparib in patients with CTC-HRD-negative, but BRCA1/2-mutant 
mCRPC with or without measurable disease, approximately 20 patients will be enrolled in these 
cohorts.   
6 
STATISTICAL METHODS 
6.1 
ANALYSIS POPULATIONS 
• Safety Analysis Set (SAF): includes all patients enrolled in the study who receive any 
dose of pamiparib. The Safety Analysis Set will be used for all safety analyses. 
• Efficacy-Evaluable Analysis Set (ORR Assessment in Cohort 1 of Table 1): includes all 
patients in the Safety Analysis Set who had measurable disease at baseline and at least 
1 postbaseline tumor assessment, unless they permanently discontinue pamiparib or the 
study early due to clinical progression or death prior to tumor assessment. A similar 
analysis population will exist for exploratory analyses of Cohort 3.  
• Efficacy-Evaluable Analysis Set (PSA Response Rate Assessment in Cohorts 1 and 2 of 
Table 1): includes all patients in the Safety Analysis Set as per Inclusion Criterion 7 at 
baseline ( 3 rising PSA levels with  1 week between determinations and screening PSA 
 2 µg/L) and who had at least 1 postbaseline PSA measurement, unless they 
permanently discontinue pamiparib or the study early due to clinical progression or death 
before completed PSA assessment. A similar analysis population will exist for 
exploratory analyses of Cohorts 3 and 4.  
• PK Analysis Set: includes all patients who received pamiparib and contributed at least 
one plasma concentration.   
6.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
6.2.1 Definitions and Computations 
Study day: Study day will be calculated in reference to the date of the first dose of study 
treatment.  For assessments conducted on or after the date of the first dose of study treatment, 
study day will be calculated as (assessment date – date of first dose of study treatment + 1).  For 
assessments conducted before the date of the first dose of study treatment, study day is calculated 
as (assessment date – date of first dose of study treatment). There is no study day 0.  


 
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In the situation where the event date is partial or missing, the date will appear partial or missing 
in the listings. Study day and any corresponding durations will be presented based on the 
imputations specified in Appendix Error! Reference source not found..   
Treatment duration: The treatment duration will be calculated as (date of last dose of study 
treatment – date of first dose of study treatment + 1). 
Baseline: Unless otherwise specified, a baseline value is defined as the last non-missing value 
collected on or before the first dose date.  
All calculations and analyses will be conducted using SAS version 9.2 or higher. 
6.2.2 Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses:   
 
• 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
decimal place.   
• 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded up 
to 1 decimal place.   
• P-values will be rounded to 4 decimal places.  P-values that round to 0.0000 will be 
presented as ‘< 0.0001’ and p-values that round to 1.000 will be presented as ‘> 0.9999’.   
• Duration of imaging-based event endpoints (such as PFS) will be based on the actual date 
the radiograph was obtained rather than the associated visit date.   
• Missing efficacy or safety data will not be imputed unless otherwise specified.   
• For laboratory results collected as < or >, a numeric value, 0.0000000001 will be 
subtracted or added, respectively, to the value.   
• For by-visit observed data analyses, percentages will be calculated based on the number 
of patients with nonmissing data as the denominator, unless otherwise specified.   
• For continuous endpoints, summary statistics will include n, mean, standard deviation, 
median, Q1, Q3 and range (minimum and maximum).   
• For discrete endpoints, summary statistics will include frequencies and percentages. 
6.2.3 Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in the SAP. Missing dates 
or partially missing dates will be imputed conservatively for adverse events and 
prior/concomitant medications/procedures.  Specific rules for handling of missing or partially 
missing dates for adverse events and prior/concomitant medications/procedures are provided in 
Appendix 10.1. 


 
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By-visit endpoints will be analyzed using observed data, unless otherwise specified. For 
observed data analyses, missing data will not be imputed and only the observed records will be 
included.  
When summarizing categorical variables, patients with missing data are included in the 
denominator to calculate percentages unless otherwise specified. When needed, the category of 
“Missing” is created and the number of patients with missing data is presented. 
When summarizing continuous variables, patients with missing data are not included in 
calculations. No imputations are made. 
For the Health-related quality of life (HRQoL) questionnaires, the missing data will be handled 
in accordance with the scoring manual of each patient-reported outcome (PRO) questionnaire 
(Cleeland, 2009). 
6.2.4 Multiplicity Adjustment 
To control the overall study type I error rate, the primary efficacy endpoint analyses for ORR 
and PSA response rate will be tested sequentially.   
If the hypothesis test for ORR is statistically significant at a one-sided 0.025 level (ie, one-sided 
p-value < 0.025), then the PSA response rate will be tested at a one-sided 0.025 significance 
level.  If the primary endpoint of ORR is not statistically significant, the primary endpoint of 
PSA response rate will not be tested for statistical significance.   
6.3 
PATIENT CHARACTERISTICS 
6.3.1 Patient Disposition 
The following patient disposition information will be summarized: 
• Number of patients treated 
• Number (%) of treated patients who discontinued from treatment  
• Reason(s) for treatment discontinuation 
• Number (%) of treated patients who remain on treatment 
• Number (%) of treated patients who discontinued from study 
• Reason(s) for study discontinuation 
• Number (%) of treated patients who remain in study 
• Treatment follow-up time: defined as the time from the first dose date to the end of 
treatment date for patients discontinued from the treatment, or the database cutoff date for 
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• Study follow-up time: defined as the time from the first dose date to death date or end of 
study date (whichever occurred first) for patients who discontinued study or the data 
cutoff date for ongoing patients. 
6.3.2 Protocol Deviations 
Major protocol deviation criteria will be established and patients with major protocol deviations 
will be identified and documented before the database lock. Major protocol deviations will be 
presented for the Safety Analysis Set in a listing.  
6.3.3 Demographics and Other Baseline Characteristics 
Demographics and baseline characteristics including following variables will be summarized using 
descriptive statistics:  
• Race 
• Age (years) and age group (years) as < 65, ≥ 65  
• Ethnicity 
• Eastern Cooperative Oncology Group (ECOG) performance status at screening 
• Time form initial diagnosis to study entry (Year) 
• Metastases (Liver or lung) 
• Baseline PSA  
• Baseline hemoglobin 
• Baseline LDH 
• Baseline ALP 
6.3.4 Prior Anti-Cancer Systemic Therapies  
The number of prior line of anti-cancer therapies and number of prior regimens will be 
summarized by cohort and overall for the Safety Analysis Set. The therapies with the same 
sequence/regimen number are counted as one prior therapy.   
6.3.5 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the version of World Health Organization 
Drug Dictionary (WHO DD) drug codes and will be further classified to the appropriate 
Anatomical Therapeutic Chemical (ATC) code.  
The number and percentage of patients reporting prior and concomitant medications will be 
summarized by ATC medication class and WHO DD preferred term for the Safety Analysis Set 
by cohort and overall. Prior medications are defined as medications that started and ended before 
the first dose date. Concomitant medications are defined as medications that (1) started before 
the first dose of study treatment and were continuing at the time of the first dose of study 
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the patient’s last dose or initiation of a new anti-cancer therapy. A listing of prior and 
concomitant medications will be provided.   
6.3.6 Medical History 
Medical History will be coded using MedDRA (version 20.0 or higher). The number and 
percentage of patients reporting a history of any medical condition, as recorded on the electronic 
case report form (eCRF), will be summarized by system organ class (SOC) and preferred term 
(PT) for the Safety Analysis Set by cohort and overall. A listing of medical history will be 
provided.   
6.4 
EFFICACY ANALYSIS 
Table 2 summarizes the primary and secondary efficacy endpoints and corresponding analysis 
populations.  If applicable, the specific cohort(s) or evaluable population being analyzed for each 
efficacy analysis will be specified.   
Table 2  Primary and Secondary Efficacy Endpoint Analysis Populations 
 
Efficacy Endpoint 
Analysis Population 
Primary 
ORR by IRC 
Efficacy-Evaluable Analysis Set (ORR Assessment in Cohort 1) 
PSA Response 
Efficacy-Evaluable Analysis Set (PSA Response Rate 
Assessment in Cohorts 1 and 2) 
Secondary 
DOR by IRC 
Efficacy-Evaluable Analysis Set (ORR Assessment in Cohort 1), 
those w/objective response per IRC 
ORR by INV 
Efficacy-Evaluable Analysis Set (ORR Assessment in Cohort 1) 
Time to Objective Response 
by INV 
Efficacy-Evaluable Analysis Set (ORR Assessment in Cohort 1), 
those w/confirmed objective response per INV 
Clinical Benefit Rate by INV Efficacy-Evaluable Analysis Set (ORR Assessment in Cohort 1) 
Time to PSA Response 
Efficacy-Evaluable Analysis Set (PSA Response Rate 
Assessment in Cohorts 1 and 2), those w/confirmed PSA 
response 
Duration of PSA Response 
Efficacy-Evaluable Analysis Set (PSA Response Rate 
Assessment in Cohorts 1 and 2), those w/confirmed PSA 
response 
Time to PSA Progression 
Safety Analysis Set (Cohorts 1 and 2) 
Time to SSE 
Safety Analysis Set (Cohorts 1 and 2) 
rPFS by IRC 
Safety Analysis Set (Cohorts 1 and 2) 
OS 
Safety Analysis Set (Cohorts 1 and 2) 
Abbreviations: DOR = duration of response; INV = investigator; IRC = independent review committee; ORR = 
objective response rate; OS = overall survival; PSA = prostate-specific antigen; rPFS = radiographic progression-free 
survival; SSE = symptomatic skeletal event.  
 


 
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6.4.1 Primary Efficacy Endpoints 
Objective Response Rate (ORR) by IRC 
ORR is defined as the proportion of patients with a best objective response of CR or PR 
confirmed at a subsequent timepoint ≥ 4 weeks later.  For this primary efficacy endpoint, the 
tumor assessments will be performed by the IRC and will be summarized for the 
Efficacy-Evaluable Analysis Set (ORR Assessment in Cohort 1).   
ORR (number and proportion of patients) will be presented along with its Clopper-Pearson 
2-sided 95% confidence interval.  The number and proportion of patients who achieve an 
unconfirmed best objective response of CR or PR will also be summarized.   
ORR will be tested against a historical control ORR, and the null and alternative hypotheses are 
as follows: 
 
H0: ORR = 15% 
 
Ha: ORR > 15% 
A binomial exact test will be performed for the above hypotheses at a one-sided 0.025 
significance level.  If the result for ORR is statistically significant, ie, one-sided p-value < 0.025, 
then the primary efficacy endpoint of PSA response rate will be tested for statistical significance.   
If the Efficacy-Evaluable Analysis Set (ORR Assessment in Cohort 1) is not equivalent to the 
Safety Analysis Set for Cohort 1, a sensitivity analysis of ORR will be conducted on the Safety 
Analysis Set for Cohort 1. The sensitivity analysis will be carried out in the Safety Analysis Set. 
Patients without postbaseline tumor assessment will be considered as non-responders in the 
Safety Analysis Set and will be classified as “not assessed.” 
Waterfall plots will be provided for the maximum tumor shrinkage from baseline based on the 
sum of diameters of all target lesions.   
Subgroup analyses for ORR will be performed as described in Section 6.4.3.  
PSA Response Rate 
PSA response rate is defined as the proportion of patients with a PSA decline ≥ 50% from 
baseline confirmed by a second PSA value ≥ 3 weeks later. For this primary efficacy endpoint, 
the PSA assessments will be summarized for the Efficacy-Evaluable Analysis Set (PSA 
Response Rate Assessment in Cohorts 1 and 2).   
PSA response rate (number and proportion of patients) will be presented along with its Clopper-
Pearson 2-sided 95% confidence interval.  The number and proportion of patients who achieve 
an unconfirmed PSA decline ≥ 50% from baseline will also be summarized.   


 
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If the primary efficacy endpoint of ORR is statistically significant, PSA response rate will be 
tested against a historical control PSA response rate, and the null and alternative hypotheses are 
as follows: 
 
H0: PSA response rate = 30% 
 
Ha: PSA response rate > 30% 
A binomial exact test will be performed for the above hypotheses at a one-sided 0.025 
significance level.  If the result for PSA response rate is statistically significant, ie, one-sided p-
value < 0.025, then PSA response rate will be considered statistically significant.  Note that if the 
primary efficacy endpoint of ORR is not statistically significant, then no claims of statistical 
significance can be made for the primary efficacy endpoint of PSA response rate.   
If the Efficacy-Evaluable Analysis Set (PSA Response Rate Assessment in Cohorts 1 and 2) is 
not equivalent to the Safety Analysis Set for Cohorts 1 and 2, a sensitivity analysis of PSA 
response rate will be conducted on the Safety Analysis Set for Cohorts 1 and 2.  The sensitivity 
analysis will be carried out in the Safety Analysis Set. Patients without postbaseline tumor 
assessment will be considered as non-responders in the Safety Analysis Set and will be classified 
as “not assessed.” 
Subgroup analyses for PSA response rate will be performed as described in Section 6.4.3.   
6.4.2 Secondary Efficacy Endpoints 
Duration of Response (DOR) by IRC 
DOR is defined as the time from the date of the earliest documented CR or PR (that is 
subsequently confirmed) to radiographic disease progression or death due to any cause, 
whichever occurs first.  The censoring rules for DOR will be similar to those for rPFS described 
in Appendix 10.2 except that the situation of “No baseline tumor assessments” will not apply to 
DOR.  For this secondary efficacy endpoint, the tumor assessments will be performed by the IRC 
and will be summarized for patients in the Efficacy-Evaluable Analysis Set (ORR Assessment in 
Cohort 1) who have achieved a confirmed objective response.   
DOR will be estimated using the Kaplan-Meier method, and the median DOR will be presented 
along with its 2-sided 95% confidence interval using the Brookmeyer and Crowley method 
(Brookmeyer and Crowley 1982).  The event-free rate at select timepoints will be calculated 
along with 2-sided 95% confidence intervals using Greenwood’s formula.  
ORR by Investigator (INV) 
ORR is defined as for the primary efficacy endpoint.  For this secondary efficacy endpoint, the 
tumor assessments will be performed by the investigator and will be summarized for the 
Efficacy-Evaluable Analysis Set (ORR Assessment in Cohort 1).   


 
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ORR (number and proportion of patients) will be presented along with its Clopper-Pearson 2-
sided 95% confidence interval.  The number and proportion of patients who achieve an 
unconfirmed best objective response of CR or PR will also be summarized.   
Time to Objective Response by INV 
Time to objective response is defined as the time from the date of the first dose of study drug to 
the first documented confirmed response of CR or PR.  For this secondary efficacy endpoint, the 
tumor assessments will be performed by the investigator and will be summarized for patients in 
the Efficacy-Evaluable Analysis Set (ORR Assessment in Cohort 1) who have achieved a 
confirmed objective response.   
Time to objective response will be presented using descriptive statistics (e.g., n, mean, standard 
deviation, median, Q1, Q3, minimum, maximum).   
Clinical Benefit Rate by INV 
Clinical benefit rate is defined as the proportion of patients with a documented confirmed CR, 
PR or SD.  For this secondary efficacy endpoint, the tumor assessments will be performed by the 
investigator and will be summarized for the Efficacy-Evaluable Analysis Set (ORR Assessment 
in Cohort 1).   
The clinical benefit rate (number and proportion of patients) will be presented along with its 
Clopper-Pearson 2-sided 95% confidence interval.   
Time to PSA Response 
Time to PSA response is defined as the time from the date of the first dose of study drug to the 
first PSA decline ≥ 50% that is subsequently confirmed.  For this secondary efficacy endpoint, 
the PSA assessments will be summarized for patients in the Efficacy-Evaluable Analysis Set 
(PSA Response Rate Assessment in Cohorts 1 and 2) who have achieved a confirmed PSA 
response.   
Time to PSA response will be presented using descriptive statistics (e.g., n, mean, standard 
deviation, median, Q1, Q3, minimum, maximum).   
Duration of PSA Response 
Duration of PSA response is defined as the time from the date of the earliest documented PSA 
response (that is subsequently confirmed) to PSA progression or death due to any cause, 
whichever occurs first.  PSA progression is defined as a ≥ 25% increase in PSA with an absolute 
increase of ≥ 2 µg/L above the nadir (or above the baseline for patients with no PSA decline after 
12 weeks), confirmed by a second value ≥ 3 weeks later. The nadir is defined as the lowest value 
at or after baseline. For patients who have not died or had a PSA progression event as of the data 
cutoff date, duration of PSA response will be censored at the date of the last PSA assessment.  
The PSA assessments will be summarized for patients in the Efficacy-Evaluable Analysis Set 


 
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(PSA Response Rate Assessment in Cohorts 1 and 2) who have achieved a confirmed PSA 
response.   
Duration of PSA response will be estimated using the Kaplan-Meier method, and the median 
duration of PSA response will be presented along with its 2-sided 95% confidence interval using 
the Brookmeyer and Crowley method.  The event-free rate at select timepoints will be calculated 
along with 2-sided 95% confidence intervals using Greenwood’s formula.   
Time to PSA Progression 
Time to PSA progression is defined as the time from the date of the first dose of study drug to 
the date of a ≥ 25% increase in PSA with an absolute increase of ≥ 2 µg/L above the nadir (or 
above the baseline for patients with no PSA decline after 12 weeks), confirmed by a second 
value ≥ 3 weeks later.  For patients who have not had a PSA progression event as of the data 
cutoff date, time to PSA progression will be censored at the date of the last PSA assessment.  For 
this secondary efficacy endpoint, the PSA assessments will be summarized for the Safety 
Analysis Set (Cohorts 1 and 2).   
Time to PSA progression will be estimated using the Kaplan-Meier method, and the median time 
to PSA progression will be presented along with its 2-sided 95% confidence interval using the 
Brookmeyer and Crowley method.  The event-free rate at select timepoints will be calculated 
along with 2-sided 95% confidence intervals using Greenwood’s formula.   
Time to Symptomatic Skeletal Event (SSE) 
Time to SSE is defined as the time from the date of the first dose of study drug to the date of the 
first symptomatic fracture, radiation or surgery to bone or spinal cord compression.  For patients 
who have not had an SSE as of the data cutoff date, time to SSE will be censored at the date of 
the last visit. This secondary efficacy endpoint will be summarized for the Safety Analysis Set 
(Cohorts 1 and 2).   
Time to SSE will be estimated using the Kaplan-Meier method, and the median time to SSE will 
be presented along with its 2-sided 95% confidence interval using the Brookmeyer and Crowley 
method.  The event-free rate at select timepoints will be calculated along with 2-sided 95% 
confidence intervals using Greenwood’s formula.   
Radiographic Progression-Free Survival (rPFS) by IRC 
rPFS is defined as the time from the date of the first dose of study drug to radiographic disease 
progression or death due to any cause, whichever occurs first.  Censoring rules for rPFS will be 
described in Appendix 10.2.  For this secondary efficacy endpoint, the tumor assessments will be 
performed by the IRC and will be summarized for the Safety Analysis Set (Cohorts 1 and 2).   
rPFS will be estimated using the Kaplan-Meier method, and the median rPFS will be presented 
along with its 2-sided 95% confidence interval using the Brookmeyer and Crowley method.  The 
event-free rate at select timepoints will be calculated along with 2-sided 95% confidence 


 
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intervals using Greenwood’s formula.  The median follow-up will be estimated using the reverse 
Kaplan-Meier.   
Overall Survival (OS) 
OS is defined as the time from the date of the first dose of study drug to death due to any cause.  
Patients who remained alive before data cutoff or discontinuation of the study (discontinued 
study due to reasons other than “Death”) will be censored at the time of data cutoff or the last 
date the patient was known to be alive.  This secondary efficacy endpoint will be summarized for 
the Safety Analysis Set (Cohorts 1 and 2).   
OS will be estimated using the Kaplan-Meier method, and the median OS will be presented 
along with its 2-sided 95% confidence interval using the Brookmeyer and Crowley method.  The 
event-free rate at select timepoints will be calculated along with 2-sided 95% confidence 
intervals using Greenwood’s formula.  The median follow-up will be estimated using the reverse 
Kaplan-Meier.   
6.4.3 Subgroup Analyses 
The primary efficacy endpoints of ORR and PSA response rate will be summarized within their 
respective analysis populations for the following subgroups: 
• Age group (< 65 years vs ≥ 65 years) 
• Race (White vs other) 
• Geographic Region (North America vs rest of world) 
• ECOG performance status (0 vs 1) 
• BRCA 1/2-mutant status (mutated vs unmutated) 
• Number of prior lines of therapy (0-2 vs 3+) 
6.4.4 Exploratory Efficacy Endpoints 
Table 3  Exploratory Efficacy Endpoint Analysis Populations 


 
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6.5 
SAFETY ANALYSES 
All safety analyses will be performed by cohort and overall for the Safety Analysis Set. The 
incidence of treatment-emergent adverse events (TEAEs) will be summarized. Laboratory test 
results and vital signs will be provided in listings.   
6.5.1 Extent of Exposure 
The number (and percentage) of patients requiring dose reductions, dose missed and dose on hold will 
be summarized. One cycle is defined as 28 days of treatment. The duration of treatment (days) will be 
summarized with descriptive statistics. 
Actual dose intensity per patient (in mg/day) and relative dose intensity (total dose received / total dose 
planned) per patient will be summarized. Actual dose intensity is calculated as the total dose (mg) 
taken by a patient divided by overall duration of exposure (= Date of last non-zero dose – Date of first 
dose + 1) for individual patient. Relative dose intensity is calculated as the total dose (mg) taken by a 
patient divided by the total dose planned for the patient by study design.  
Patient data listings will be provided for all dosing records, including dose reduction, dose missed 
and treatment discontinuation.  
6.5.2 Adverse Events  
AEs will be graded by the investigators using CTCAE v4.03. The AE verbatim descriptions 
(investigator terms from the CRF) will be classified into standardized medical terminology using 
the Medical Dictionary for Regulatory Activities (MedDRA) Version 20.0 or higher.   
A treatment emergent adverse event (TEAE) is defined as an AE that had an onset (including 
worsening from pretreatment) date on or after the first dose of study treatment through 30 days 
after the last dose of study treatment or initiation of new anti-cancer therapy, whichever occurs 
first.  Only TEAEs will be included in summary tables.  All AEs, treatment emergent or 
otherwise, will be presented in patient data listings.   
An overview table, including the number and percentage of patients with TEAEs, serious 
TEAEs, grade 3 or higher TEAEs, treatment-related TEAEs, TEAEs that led to death, and 
TEAEs that led to treatment discontinuation, dose reduction or dose interruption will be 
provided. Treatment-related TEAEs include those events considered by the investigator to be 
related to study treatment or with missing assessment of the causal relationship.   
The incidence of TEAEs will be reported as the number and percentage of patients with TEAEs 
by SOC and PT.  A patient will be counted only once by the highest severity grade within an 
SOC and PT, even if the patient experienced more than 1 TEAE within a specific SOC and PT.  
The number and percentage of patients will be summarized by SOC and/or PT for the following: 
• TEAEs 


 
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• Treatment Related Grade 3 or higher TEAEs 
• Serious TEAEs 
• TEAEs that led to treatment discontinuation 
• TEAEs that led to dose modification 
TEAEs will also be summarized by PT in descending order. A listing of all AEs and AEs that led 
to treatment discontinuation will be provided. 
All deaths and causes of death will be provided in a listing, including those occurring during the 
study treatment period and those reported during the survival follow-up period after treatment 
completion/discontinuation.   
6.5.3 Laboratory Values 
Laboratory safety tests will be evaluated for selected parameters described in Table 4. 
Laboratory parameters that are graded in NCI CTCAE v.4.03 will be summarized by grade, and 
shift tables (baseline grade to maximum post-baseline grade) will be provided.  In the summary 
of laboratory parameters by CTCAE grade, parameters with CTCAE grading in both high and 
low directions will be summarized separately.  The number and percentage of patients with 
abnormal liver laboratory values will be summarized.   
Patient data listings of selected hematology, serum chemistry parameters and urinalysis will be 
provided.   
Table 4  Serum Chemistry and Hematology Laboratory Tests 
Serum Chemistry 
Hematology 
Alkaline phosphatase (ALP) 
Hemoglobin 
Alanine aminotransferase (ALT) 
Platelet counts 
Aspartate aminotransferase (AST) 
White blood cell (WBC) count 
Albumin 
Neutrophil (Absolute) 
Total bilirubin 
Lymphocyte (Absolute) 
Blood Urea Nitrogen 
 
Creatinine 
Chloride 
 
Phosphate 
 
Glucose 
 
Lactate dehydrogenase (LDH) 
 
Total Protein 
 
Potassium 
 
Sodium 
 
 


 
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6.5.4 ECOG Performance Status 
A shift table from baseline to worst post-baseline ECOG performance score will be summarized 
by cohort and overall for the Safety Analysis Set. ECOG scores will be summarized by visit.   
6.6 
PHARMACOKINETIC ANALYSIS 
BGB-290 concentrations after single-dose and at steady-state will be summarized by the 
sampling timepoint. Descriptive statistics will include means, medians, standard deviation, 
arithmetic coefficient of variation (ACV) and geometric coefficient of variation (GCV) as 
appropriate. ACV is calculated in original scale with the equation 100 × SD/AM 
and GCV is calculated in natural log-scale with the equation: √(e^(σ^2 ) −1) × 100, where σ2 
is the observed variance on the natural log scale. If a patient undergoes dose modification (e.g. 
dose reduction or study drug discontinuation) before steady-state PK collection, then that 
patient’s steady-state concentrations will be excluded from summary statistics.  
Population PK analysis may be carried out to include plasma concentrations from this study. 
Additional PK parameters such as CL/F of the drug from plasma and AUC0-12 may be derived 
from the population PK analysis if supported by data. 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by 
data. 
6.7 
BIOMARKER ANALYSIS 
Baseline blood samples for ctDNA analyses will be subjected to next generation sequencing. In 
addition, available archival tissue samples will be subjected to Myriad MyChoice testing for 
homologous recombination deficiency determination.  
7 
INTERIM ANALYSIS 
A non-binding interim futility analysis will be performed among the first 20 patients enrolled in 
Cohorts 1 and 2.  If the confirmed PSA response rate is < 30% (< 6 responses), enrollment will 
be halted, and safety and efficacy data will be further evaluated before making the decision of 
stopping enrollment permanently. The decision to continue the enrollment may be made at any 
time the 6 confirmed PSA responses in Cohorts 1 and 2 can be documented; enrollment of all 20 
patients is not required before determining further patient accrual.   
8 
CHANGES IN THE PLANNED ANALYSIS 
Due to upcoming changes in standard of care, changes in program strategy, slow enrolment and 
apparent lack of responses, the trial was terminated after enrolling 13 patients in cohort 1B and 
cohort 2B. The final clinical study report will not include all the planned analyses per protocol 
including the interim analysis because the milestone of enrolling 20 patients was not reached. 
For the final clinical study report, tables of patient disposition and reasons for discontinuation, 
demographics and baseline characteristics and prior anti-cancer therapies will be provided.  No 
efficacy related tables or analysis will be conducted. Tumor assessment result by investigator 
(target lesions by time point and bone lesions) will be listed but result by IRC will not be 


 
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included in the final clinical study report, because of the small number of patients enrolled and 
the fact that the majority of the patients did not had postbaseline tumor assessments. HRQoL 
data results will be listed.  Data from PSA assessments will be provided in listings and discussed 
in the clinical study report. Exposure data, safety analyses and PK analyses will be conducted as 
planned. ECOG performance shift table will not be conducted. The biomarker data will be 
provided as listings.  
9 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics. 1982 
Mar;38(1):29-41.   
 
Cleeland CS. The Brief Pain Inventory: User Guide. 2009 
  
Clopper, C. and Pearson, ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial, Biometrika 1934;26: 404-413.  
 
Collett D. Modelling survival data in medical research. New York: Chapman & Hall; 1994.  
Common Terminology Criteria for Adverse Events (CTCAE). Version 4.0. United States Department 
of Health and Human Services, National Institutes of Health, National Cancer Institute, Washington, 
DC, USA, May 28, 2009. 
 
EQ-5D-5L User Guide. EuroQol Research Foundation 2015. www.euroqol.org 
 
Food and Drug Administration Center for Drug Evaluation Research CDER and Center for Biologics 
Evaluation and Research. FDA Guidance for Industry Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics, 2018. 
 
Greenwood M. “The natural duration of cancer”. Reports on Public Health and Medical Subjects 
(London: Her Majesty’s Stationery Office). 1926; 33:1-26. 
 
Gordon John Sampson Rustin, etc. Definitions for Response and Progression in Ovarian Cancer 
Clinical Trials Incorporating RECIST 1.1 and CA 125 Agreed by the Gynecological Cancer 
Intergroup (GCIG). Int J Gynecol Cancer. 2011;21: 419-423.  
 
Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. 
Washington, DC: United States Food and Drug Administration; 2007.  
Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 
1958;53:457-81. 
 


 
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10 APPENDICES 
10.1 HANDLING MISSING DATE INFORMATION 
In general, missing or partial dates will not be imputed at data level. The following rules will apply 
for the specific analysis and summary purposes mentioned below only.   
10.1.1 Prior/Concomitant Medications, Disease and Medical History, Prior Therapy (Drug, 
Surgery/Procedure, Radiotherapy) 
When the start date or end date of a medication/therapy/procedure is partially missing, the date 
will be imputed to determine whether the medication/therapy/procedure is prior or concomitant. 
The following rules will be applied to impute missing or partial dates for medications 
/therapy/procedure: 
 
Missing 
Impute 
Exception 
Start Date 
Day 
01 
N/A 
 
Day/Month 
January 01 
N/A 
 
Day/Month/Year or 
Year only 
Do not impute 
N/A 
End Date 
Day 
Last day of the month 
N/A 
 
Day/Month 
December 31 
N/A 
 
Day/Month/Year or 
Year only 
Do not impute 
N/A 
 
If the imputed start date becomes after end date, then update start date same as end date. And if 
the imputed start date or end date becomes after death date, then set to death date. 
For disease history, medical history and prior therapy (ie Chemotherapy, hormonal therapy, 
biologic therapy, radionuclide therapy, immunotherapy, investigational agent, Chinese anticancer 
medicine, or herbal remedies), including relapse date, therapy date (start/end date), or surgery 
date, if the imputed start date or end date becomes after first dose date, then set to first dose date 
- 15.  For radiotherapy, if the imputed start date or end date becomes after first dose date, then set 
to first dose date - 22. 
10.1.2 Initial Diagnosis and Most Recent Progression  


 
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For initial diagnosis date and most recent progression date, which has no duration and only start 
date is available, impute the date using the following rule: 
 
 
Missing 
Impute 
Exception 
Initial Diagnosis Date/ 
Most Recent Progression 
Date 
Day 
01 
N/A 
Day/Month 
January 01 
N/A 
Day/Month/Year or 
Year only 
Do not impute 
N/A 
If the imputed initial diagnosis date or most recent progression date is on or after the treatment 
start date, then set to treatment start date - 1. 
10.1.3 Adverse Events 
The imputation rule for the safety analyses will be used to address the issues with partial dates. 
When the start date or end date of an adverse event is partially missing, the date will be imputed 
to determine whether the adverse event is treatment-emergent. When in doubt, the adverse event 
will be considered treatment emergent by default. The following rules will be applied to impute 
missing or partial dates for adverse events: 
 
Missing 
Impute 
Exception 
Start Date 
Day 
01 
If Month and Year = Month 
and Year of treatment start 
date, the set to treatment start 
date 
 
Day / Month 
January 01 
If Year = Year of treatment 
start date, then set to treatment 
start date 
 
Day / Month / Year or Year 
only 
Do not impute 
If AE End Date > treatment 
start date, then set to treatment 
start date   
End Date 
Day 
Last day of the month N/A 
 
Day / Month 
December 31 
N/A 


 
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Day / Month / Year or Year 
only 
Do not impute 
N/A 
If the imputed AE start date becomes after AE end date, then update AE start date same as AE end 
date. And if the imputed start date or end date becomes after death date, then set to death date. 
The following rule will be applied to impute missing toxicity grade of AE:   
1. The highest grade will be used from patient’s AEs with the same preferred term.   
2. If patient has no AEs with the same preferred terms, the highest grade of the AEs with the 
same SOC will be used. 
3. If patient has no same SOC, the highest grade of all AEs from that patient will be used.  
4. If it is the single AE reported for that patient, no imputation for the missing grade will be 
done. 
10.1.4 Deaths 
In case complete death dates are not recorded, impute as follows: 
• If both month and day are missing, then the imputed month and day will be 01Jan or the 
last date of the last date of patient known to be alive + 1, whichever is later. 
• If only day is missing, the death will be assumed to be on the first day of the month or the 
last date of patient known to be alive +1, whichever is later.  
10.1.5 New Anticancer therapy 
If the start day of a subsequent anticancer therapy is incomplete or missing, impute as follows:  
• if both month and day are missing,  
1) impute the date as 31Dec, if the year is earlier than the year of the first PD date + 1 
or the treatment end date + 1, whichever is later 
2) impute the date as 01Jan, if the year is later than the year of the first PD date or the 
treatment end date + 1, whichever is later 
3) impute the date as the first PD date + 1 or the treatment end date + 1, whichever is 
later, if the year is the same year of first PD date + 1 or the treatment end date + 1, 
whichever is later 
• if only day is missing, 
1) impute the date as the first day of the month if year and month are available and 
partial new anticancer therapy date still could indicate it is at least one month later 
than the first PD date +1 or the treatment end date +1, whichever is later.  


 
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2) impute the date as the last day of the month if year and month are available and 
partial new anticancer therapy date still could indicate it is at least one month earlier 
than the first PD date +1 or the treatment end date +1, whichever is later. 
3) Impute the date as the first PD date +1 or the treatment end date +1, whichever is 
later, if the year and month are the same year and month of first PD date +1 or the 
treatment end date +1, whichever is later. 
10.2 CENSORING RULES 
Table 5 shows the primary censoring rules for the derivation of rPFS.   
Table 5  Censoring Rules for Analysis of rPFS 
No. Situation 
Date of Progression or Censoring 
Outcome 
1 
No baseline tumor assessments or no 
post-baseline tumor assessment 
Reference start date 
Censored 
2 
Progression documented on scheduled 
visit or between scheduled visits 
Date of first radiologic PD 
assessment 
Progressed 
3 
No progression at the time of data cutoff 
or withdrawal from study 
Date of last adequate radiologic 
assessment prior to or on date of data 
cutoff or withdrawal from study 
Censored 
4 
Treatment discontinuation for 
undocumented progression 
Date of last radiological assessment 
of measured lesions 
Censored 
5 
New anticancer treatment started 
Date of last radiological assessment 
of measured lesions prior to or on 
date of new anticancer treatment 
Censored 
6 
Death before first PD assessment 
Date of death 
Progressed 
7 
Death between adequate assessment 
visits* 
Date of death 
Progressed 
8 
Death or PD after two or more 
consecutive missed visit** 
Date of last adequate radiologic 
assessment before missed tumor 
assessments 
Censored 
9 
A patient meets the criteria for more than 
1 censoring rule 
Date of the earliest censoring date 
among all events 
Censored 
Abbreviations: CR=complete response, PD=progressive disease, PR=partial response, SD=stable disease. 
*Adequate tumor assessment is a radiologic assessment of CR, PR, SD, non-CR/non-PD or PD as determined by investigators or 
by IRC.  
**More than one missed visit is defined if the duration between the last tumor assessment and death or PD is longer than 2 scheduled 
visits. 
 
 


 
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10.3 PROS:  INSTRUMENTS AND SCORING METHODS 
 
 
 
 
 
 
 
 


 
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Signature Page for VV-CLIN-035845 v2.0
Signature Page for VV-CLIN-035845 v2.0
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Approval
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