Clinical trial NCT03994211
Conditions: Solid Tumor
Sponsor: BeiGene
Start date: 2019-05-29; Completion date: 2021-08-06
Enrollment: 25 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study was an open-label, parallel-group, fixed-sequence study in male and female cancer patients. The study consists of 2 phases: the Core Phase, which is divided into Part A and Part B, and the Extension Phase. Part A investigated the effect of CYP3A induction by rifampin on the single dose pharmacokinetics (PK) of pamiparib, and Part B investigated the effect of CYP3A inhibition by itraconazole on the single dose PK of pamiparib. Participants were offered participation in the Extension Phase, in which they received pamiparib until progression of disease, unacceptable toxicity, withdrawal of consent, or any other reason for discontinuation.

Detailed description:

Arms: arm 1: 60 mg pamiparib administered orally on Days 1 and 10 fasting 8 hours pre-dose 600 mg rifampin once a day from days 3 to 11 in the fasted state (at least 2 hours predose) arm 2: Single dose of 20 mg pamiparib orally in the fasted state (at least 8 hours predose) on days 1 and 7 200 mg itraconazole once a day approximately 30 minutes after completing a meal Day 3 to day 8 arm 3: 60 mg pamiparib orally twice a day in 28-day cycles until progression of disease
Interventions: intervention 1: pamiparib 60 mg intervention 2: pamiparib 20 mg intervention 3: itraconazole intervention 4: rifampin intervention 5: pamiparib
Intervention descriptions: intervention 1: Single dose of 60 mg pamiparib orally on Days 1 and 10 intervention 2: Single dose of 20 mg pamiparib orally on days 1 and 7 intervention 3: 200 mg itraconazole once a day al Day 3 to day 8 intervention 4: 600 mg rifampin once a day from days 3 to 11 intervention 5: 60 mg pamiparib orally twice a day in 28-day cycles

Protocol documents:
Prot_000.pdf: 
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PROTOCOL 
A Phase 1, Open-label, Parallel-group, Fixed-sequence Study to Investigate 
the Effect of the CYP3A Inducer Rifampin and the CYP3A Inhibitor 
Itraconazole on the Pharmacokinetics of Pamiparib (BGB-290) in Cancer 
Patients 
Original Protocol (Version 0.0): 24 January 2019 
Protocol Amendment (Version 1.0): 14 June 2019 
 
Study Drug: Pamiparib (BGB-290) 
 
Sponsor Reference Number: BGB-290-105 
 
EudraCT Number: 2019-000112-28 
 
 
 
 
 
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STUDY IDENTIFICATION 
Sponsor 
BeiGene, Ltd 
c/o BeiGene USA, Inc. 
2955 Campus Drive, Suite 200 
San Mateo, CA  94403 
USA 
Sponsor’s Study Contact 
, Manager, Clinical Operations 
BeiGene USA, Inc. 
55 Cambridge Parkway, Suite 700W  
Cambridge, MA  02142, USA 
(857) 327-8121 (Office Telephone) 
Sponsor’s Medical Contact 
. 
BeiGene, Ltd. 
c/o BeiGene USA, Inc. 
2955 Campus Drive, Suite 200 
San Mateo, CA  94403, USA  
(628) 239-0021 (Office Telephone) 
(628) 239-0021 (After-Hours Telephone) 
 
 
 
 
 
 
 
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SYNOPSIS 
 
Title of study: A Phase 1, Open-label, Parallel-group, Fixed-sequence Study to Investigate 
the Effect of the CYP3A Inducer Rifampin and the CYP3A Inhibitor Itraconazole on the 
Pharmacokinetics of Pamiparib (BGB-290) in Cancer Patients 
Objectives: 
The primary objectives of the study are: 
• To determine the effect of the strong cytochrome P450 (CYP)3A inducer rifampin on 
the pharmacokinetics (PK) of pamiparib in patients with advanced solid tumors 
• To determine the effect of the strong CYP3A inhibitor itraconazole on the PK of 
pamiparib in patients with advanced solid tumors 
 
The secondary objectives of the study are: 
 
• To evaluate the safety and tolerability of pamiparib when coadministered with rifampin 
or itraconazole in patients with advanced solid tumors 
 
• To further investigate the safety of oral pamiparib in patients with advanced solid 
tumors (Extension Phase) 
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Study design: 
This is an open-label, parallel-group, fixed-sequence study in patients with advanced solid 
tumors. The study consists of a Core Phase and an Extension Phase. The Core Phase is 
comprised of Part A and Part B, which will run in parallel (Figure 1). Part A will 
investigate the effect of CYP3A induction by rifampin on the pharmacokinetics (PK) of a 
single dose of pamiparib. Part B will investigate the effect of CYP3A inhibition by 
itraconazole on the PK of a single dose of pamiparib (Figure S-1). 
 
Figure S-1. Study Design 
 
Abbreviations: EOT = End-of-Treatment; PK = pharmacokinetic; PO = orally; QD = once a day.  
a PK Samples at: Predose; 0.5, 1, 2, 4, 6, 9, 12, 24, and 48 hours postdose. 
b End of Treatment (EOT) Visit (Core Phase, outpatient) to occur within 7 days of last dose of rifampin or itraconazole; 
assessments performed at this visit can be used as the assessments of the predose visit of the Extension Phase provided 
that they are performed within 7 days of the start of pamiparib dosing in the Extension Phase. 
c Safety Follow-up Visit (outpatient)/call to occur at the end of Core Phase only if patient does not continue into the 
Extension Phase; Safety Follow-up Visit (outpatient)/call to occur at the end of the Extension Phase. 
d Pamiparib will be given at 60 mg orally twice a day in 28-day cycles until progression of disease, unacceptable toxicity, 
withdrawal of consent, or any other reason for discontinuation. 
e  End-of-Treatment Visit (Extension Phase) to occur within 7 days of last dose of pamiparib. 
In Part A, all patients will receive the following treatments: 
• Day 1 and Day 10: A single dose of 60 mg pamiparib orally in the fasted state (at least 
8 hours predose).  On Day 10, 600 mg rifampin will be administered concomitantly.  
Fasting will continue for 4h postdose 
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• Day 3 to 9 and Day 11: 600 mg rifampin once a day in the fasted state (at least 2 hours 
predose).  Fasting will continue for 1h postdose 
In Part B, all patients will receive the following treatments: 
• Day 1 and Day 7: A single dose of 20 mg pamiparib orally in the fasted state (at least 
8 hours predose).  On Day 7, itraconazole will be administered concomitantly.  Fasting 
will continue for 4h postdose 
 
• Days 3 to 6 and Day 8: 200 mg itraconazole once a day approximately 30 minutes after 
completing a meal 
 
Patients enrolled in either part of the study will be admitted to the Clinical Research Unit 
(CRU) on Day -1 and will remain in the CRU for the duration of treatment until their 
discharge on Day 12 (patients enrolled on Part A) or Day 9 (patients enrolled on Part B). 
Patients will return to the CRU for an End of Treatment Visit within 7 days from the last 
dose of study drug. Patients who are discontinued early in the Core Phase or who will not 
participate in the Extension Phase will return 30 days (±7 days) after the last dose of study 
drug or before initiation of new anticancer therapy, whichever occurs first, for the Safety 
Follow-up Visit. 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 9.1.4 should be made. Patients who complete the Core Phase of 
the study or who discontinue treatment during the Core Phase may enter the Extension 
Phase and receive pamiparib twice a day (BID) until disease progression, unacceptable 
toxicity, withdrawal of consent, or any other reason for discontinuation. Patients will have 
an End-of-Treatment visit within 7 days of the last dose of pamiparib.  Thirty days (±7 
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. Clinical Study Reports (CSR) will be compiled 
based on data from the Core Phase (CSR A) and from the Extension Phase (CSR B). The 
two reports will then be combined as a final CSR. During the Extension Phase, scheduled 
assessments will be performed as shown in Appendix 1. 
Number of patients: 
A total of approximately 24 patients will be enrolled (approximately 12 in each part) to 
ensure that at least 20 patients (10 in each part) complete the study. 
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Inclusion criteria: 
Patients must meet all of the following criteria to be eligible for the study: 
1. 
Voluntarily agreed to participate by signing an informed consent form (ICF) 
2. 
Age ≥ 18 years 
3. 
Histologically or cytologically confirmed advanced or metastatic solid tumors that are 
refractory or resistant to standard therapy or for which no suitable effective standard 
therapy exists. 
4. 
Disease that is evaluable per RECIST Version 1.1 or PCWG-3  
5. 
ECOG performance status ≤ 1 (Appendix 2) 
6. 
Life expectancy ≥ 12 weeks 
7. 
Ability to swallow whole capsules 
8. 
Adequate hematologic and end-organ function, as defined by the following laboratory 
results (obtained ≤ 14 days before day 1): 
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
b. Platelet count ≥ 100 x 109/L  
c. Hemoglobin ≥ 9 g/dL (≥ 14 days after growth factor support or transfusion) 
d. Estimated glomerular filtration rate ≥ 50 mL/min/1.73 m2 by the Modification 
of Diet in Renal Disease study equation (MDRD STUDY EQ; 
www.mdrd.com) 
e. Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN) 
a. ≤ 4 × ULN, if Gilbert’s syndrome or if indirect bilirubin concentrations 
suggestive of extrahepatic source of elevation 
f. Aspartate and alanine aminotransferase (AST and ALT) ≤ 3 x ULN or ≤ 5 x 
ULN for patients with liver metastases 
9. 
Females of childbearing potential and nonsterile males must use a highly effective 
method of birth control (see Appendix 4) while in the Core Phase of the study and for 
at least 6 months after the Core Phase is completed. In the Extension Phase, females 
of childbearing potential and nonsterile males must use a highly effective method of 
birth control (see Appendix 4) for the duration of the study and for at least 6 months 
after the last dose of study drug. Females of childbearing potential and non-sterile 
males must also agree to not freeze/donate oocytes or sperm respectively. 
10. Willingness and ability to comply with the protocol for the duration of the study  
11. Body weight ≥ 60 Kg at screening 
Exclusion criteria: 
Patients will be excluded from the study for any of the following reasons: 
1. History of hypersensitivity to rifampin, any rifamycin or any of the components of 
the rifampin capsule (Part A).  
2. History of hypersensitivity to itraconazole or any of the components of the 
itraconazole capsule (Part B).  
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3. Unresolved acute effects from prior medications of ≥ Grade 2 (CTCAE v5.0) 
a. Except for adverse effects not considered a likely safety risk (eg, alopecia, 
neuropathy and specific laboratory abnormalities) 
4. Prior treatment with a PARP inhibitor at therapeutic doses is allowed, provided that 
such treatment was not the most recent therapy (PARP inhibitor must have been 
discontinued ≥ 3 months prior to the first dose of pamiparib)  
a. Patients who experienced prior severe toxicity to PARP inhibitors that in the 
opinion of the investigator precludes further treatment with PARP inhibitors 
should be excluded 
5. Major surgical procedure, open biopsy, or significant traumatic injury ≤ 4 weeks 
prior to Day 1 of pamiparib administration, or anticipation of need for major surgical 
procedure during the course of the study 
a. Placement of vascular access device is not considered major surgery 
6. Diagnosis of Myelodysplastic syndrome (MDS)  
7. Other diagnosis of malignancy 
a. Except for surgically excised non-melanoma skin cancer, adequately treated 
carcinoma in situ of the cervix, localized prostate cancer treated with curative 
intent, adequately treated low-stage bladder cancer, ductal carcinoma in situ 
treated surgically with curative intent, or a malignancy diagnosed > 2 years 
ago with no current evidence of disease and no therapy ≤ 2 years prior to 
Day 1  
8. Untreated leptomeningeal disease or brain metastasis.  Patients with previously 
treated brain metastases are eligible if the metastases have shown no progression on 
brain computed tomography (CT) or magnetic resonance imaging (MRI) over at least 
4 weeks prior to Day 1 of pamiparib administration, the patient has no symptoms due 
to the brain metastases, and the patient has been off corticosteroids for ≥ 2 weeks  
9. Active infection requiring systemic treatment 
10. Have known human immunodeficiency virus (HIV) infection or serologic status 
reflecting active viral hepatitis infection as follows: 
a. Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) 
carriers whose HBV DNA is > 500 IU/mL should be excluded.  Patients 
positive for anti HCV and positive for HCV PCR test are to be excluded.  
Note: Inactive HBsAg carriers, treated and stable hepatitis B (HBV DNA 
≤ 500 IU/mL) can be enrolled. 
11. 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 of pamiparib administration 
b. Symptomatic pulmonary embolism ≤ 28 days before Day 1 of pamiparib 
administration 
c. Any history of acute myocardial infarction ≤ 6 months before Day 1 of 
pamiparib administration 
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d. Any history of heart failure meeting New York Heart Association 
Classification III or IV (Appendix 5) ≤ 6 months before Day 1 of pamiparib 
• Patients with congestive heart failure or history of heart failure should be 
excluded from Part B (itraconazole) 
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before 
Day 1 of pamiparib administration 
f. Any history of cerebral vascular accident ≤ 6 months before Day 1 of 
pamiparib administration 
12. Previous complete gastric resection or lap-band surgery, chronic diarrhea, active 
inflammatory gastrointestinal disease, known diverticular disease or any other 
disease-causing malabsorption syndrome 
a. Gastroesophageal reflux disease under treatment with proton pump inhibitors 
is allowed. 
13. Active bleeding disorder, including gastrointestinal bleeding, as evidenced by 
hematemesis, significant hemoptysis, or melena ≤ 6 months before Day 1 of 
pamiparib administration 
14. Use or anticipated need for food or drugs known to be strong or moderate CYP3A 
inhibitors or strong CYP3A inducers ≤ 14 days (or ≤ 5 half-lives, if half- life is 
known) prior to Day 1 of pamiparib administration (Appendix 6) 
15. Pregnant or nursing females 
a. Females of childbearing potential require a negative serum pregnancy test 
≤ 7 days before Day 1 of pamiparib administration 
16. Known history of intolerance to the excipients of the pamiparib capsule 
17. Have known hereditary problems of galactose intolerance, the Lapp lactase 
deficiency or glucose-galactose malabsorption 
 
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Test products, dose, and mode of administration: 
Core Phase:  All doses will be administered in the morning with approximately 240 mL of 
water. On the days of PK sampling (Days 1 and 10 in Part A and Days 1 and 7 in Part B), 
patients are required to fast for at least 8 hours before and 4 hours after study drug 
administration.  Water is allowed during the fasting period, except 1h predose and 1 h 
postdose.  Rifampin (Part A) or itraconazole (Part B) will be administered first, followed 
within 5 minutes by pamiparib.  
Patients enrolled in Part A will receive rifampin in the fasted state (at least 2 hours predose) 
on Days 3 to 9 and Day 11. Patients will continue to fast for 1h postdose on those days. 
Patients enrolled in Part B will received itraconazole approximately 30 minutes after 
completing a meal on Days 3 to 6 and Day 8. 
Extension Phase:  
Patients may receive 60 mg pamiparib orally twice a day; doses should be taken 10 to 12 
hours apart with approximately 240 mL of water. Predose or postdose fasting is not 
required. 
Duration of treatment: 
Planned screening duration: Up to 28 days 
Length of clinic confinement: Days -1 to 12 for Part A and Days -1 to 9 for Part B 
Outpatient visits: Every month after discharge from the clinic until progression of disease, 
unacceptable toxicity, or other reason for discontinuation (eg, withdraw consent).  
Criteria for evaluation: 
Pharmacokinetics: 
Blood samples will be collected for the analysis of pamiparib plasma concentrations at the 
following timepoints: 30 minutes predose and 0.5, 1, 2, 4, 6, 9, 12, 24, and 48 hours 
postdose. Pamiparib PK parameters following dosing on Days 1 and 10 (Part A) and on 
Days 1 and 7 (Part B) will be calculated using standard non-compartmental methods. The 
following PK parameter endpoints will be calculated: area under the concentration-time 
curve (AUC) from time zero to time of last quantifiable concentration postdose (AUC0-t), 
from zero to 12 hour (AUC0-12) and from zero to infinity (AUC0-∞), maximum observed 
concentration (Cmax), time of the maximum observed concentration (tmax), apparent terminal 
elimination half-life (t1/2), apparent oral clearance (CL/F), and apparent volume of 
distribution (Vz/F). Additional PK parameters may also be reported. 
Safety: 
Safety endpoints for this study include assessment of adverse events (AEs) graded by 
CTCAE v5.0, and physical examinations, vital signs, clinical laboratory results, and 12-
lead electrocardiograms (ECGs). 
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Statistical methods: 
The sample size chosen for this study was based on precedent set by other PK studies of 
similar nature and was not based on power calculations. 
PK Analysis: 
The PK population will include all patients who received at least 1 dose of pamiparib and 
have evaluable PK data. A patient will be excluded from the PK summary statistics if the 
patient has an AE of vomiting that occurs at or before 2 x median tmax. 
The primary PK parameters are AUC0-∞, AUC0-12, AUC0-t, Cmax, tmax, t1/2, CL/F, and Vz/F 
for pamiparib following pamiparib dosing on Days 1 and 10 in Part A and Days 1 and 7 in 
Part B. Other PK parameters may be reported but will be regarded as secondary and will 
not be subjected to inferential statistical analysis. A linear mixed-model analysis will be 
applied to analyze the log-transformed primary PK parameters (AUC0-∞, AUC0-t and Cmax) 
for each part of the study. The model assumes a fixed effect for treatment and a random 
effect for patient. Estimates of geometric mean ratios together with the corresponding 90% 
confidence intervals will be derived for the comparisons of the PK parameters as follows: 
• Part A: Pamiparib plus rifampin (test) versus pamiparib alone (reference) 
• Part B: Pamiparib plus itraconazole (test) versus pamiparib alone (reference) 
Safety Analysis: 
The safety population will include all patients who received at least 1 dose of pamiparib. 
Safety will be assessed by monitoring and recording all AEs graded by the CTCAE v5.0. 
Laboratory values (CBC, clinical chemistry, coagulation, and urinalysis), vital signs, 
physical examinations, and ECG findings will also be used in determining safety. 
Descriptive statistics will be used to analyze all safety data in the Safety Population. 
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................4 
TABLE OF CONTENTS .........................................................................................................12 
LIST OF ABBREVIATIONS ..................................................................................................16 
1 
INTRODUCTION ...........................................................................................................17 
1.1 
PARP Inhibitors .....................................................................................................17 
1.2 
PARP Inhibitor Pamiparib .....................................................................................18 
1.2.1 
Clinical Data for Pamiparib .........................................................................18 
1.3 
Study Rationale ......................................................................................................20 
1.4 
Benefit-Risk Assessment .......................................................................................20 
2 
OBJECTIVES ..................................................................................................................21 
2.1 
Primary Objectives.................................................................................................21 
2.2 
Secondary Objectives.............................................................................................21 
3 
ENDPOINTS ...................................................................................................................21 
3.1 
Primary Endpoints .................................................................................................21 
3.2 
Secondary Endpoints .............................................................................................22 
4 
INVESTIGATIONAL PLAN ..........................................................................................23 
4.1 
Study Design ..........................................................................................................23 
4.2 
Discussion of Study Design ...................................................................................25 
5 
STUDY POPULATION ..................................................................................................27 
5.1 
Inclusion Criteria ...................................................................................................27 
5.2 
Exclusion Criteria ..................................................................................................28 
5.3 
Patient Number and Identification .........................................................................30 
5.4 
Patient Withdrawal and Replacement ....................................................................30 
5.5 
Study Termination .................................................................................................31 
5.6 
Data Entry in the eCRF ..........................................................................................31 
6 
STUDY TREATMENTS .................................................................................................32 
6.1 
Description, Storage, Packaging, and Labeling .....................................................32 
6.1.1 
Handling and Storage ...................................................................................32 
6.2 
Study Treatment Administration............................................................................32 
6.3 
Randomization .......................................................................................................33 
6.4 
Blinding..................................................................................................................33 
6.5 
Study Treatment Compliance ................................................................................33 
6.6 
Drug Accountability...............................................................................................33 
6.7 
Dose Holds and Modifications...............................................................................34 
7 
CONCOMITANT MEDICATIONS AND OTHER RESTRICTIONS ..........................39 
7.1 
Concomitant Medications ......................................................................................39 
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7.1.1 
Core Phase ...................................................................................................39 
7.1.2 
Extension Phase ...........................................................................................40 
7.2 
Contraception .........................................................................................................41 
8 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................42 
8.1 
Pharmacokinetic Assessments (Core Phase ONLY) .............................................42 
8.1.1 
Pharmacokinetic Blood Sample Collection and Processing ........................42 
8.1.2 
Analytical Methodology ..............................................................................42 
8.2 
Safety and Tolerability Assessments (Core and Extension Phases) ......................42 
8.2.1 
Adverse Events ............................................................................................42 
8.2.2 
Clinical Laboratory Evaluations ..................................................................43 
8.2.3 
Vital Signs ....................................................................................................43 
8.2.4 
12-Lead Electrocardiogram .........................................................................43 
8.2.5 
Physical Examination...................................................................................44 
8.2.6 
Tumor Assessments .....................................................................................44 
8.3 
End-of-Treatment Visit ..........................................................................................44 
8.4 
Safety Follow-up Visit/Call ...................................................................................44 
9 
SAFETY MONITORING AND REPORTING...............................................................45 
9.1 
Adverse Events ......................................................................................................45 
9.1.1 
Definition and Reporting of an Adverse Event ............................................45 
9.1.2 
Assessment of Severity ................................................................................45 
9.1.3 
Assessment of Causality ..............................................................................46 
9.1.4 
Follow-Up of Adverse Events .....................................................................47 
9.1.5 
Laboratory Test Abnormalities ....................................................................47 
9.2 
Definition of a Serious Adverse Event ..................................................................48 
9.3 
Timing, Frequency, and Method of Capturing Adverse Events and Serious Adverse 
Events .....................................................................................................................49 
9.3.1 
Adverse Event Reporting Period .................................................................49 
9.3.2 
Eliciting Adverse Events..............................................................................49 
9.4 
Study-Specific Adverse Event and Serious Adverse Event Reporting Instructions49 
9.4.1 
Disease Progression .....................................................................................49 
9.4.2 
Death ............................................................................................................50 
9.5 
Prompt Reporting of Serious Adverse Events .......................................................50 
9.5.1 
Timeframes for Submitting Serious Adverse Events...................................50 
9.5.2 
Completion and Transmission of the Serious Adverse Event Report ..........50 
9.5.3 
Regulatory Reporting Requirements for Serious Adverse Events ...............50 
9.6 
Suspected Unexpected Serious Adverse Reactions and Expedited Reporting ......51 
9.7 
Pregnancy Reporting ..............................................................................................51 
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10 DATA HANDLING AND QUALITY ASSURANCE ...................................................52 
10.1 
Data Collection ......................................................................................................52 
10.2 
Data Management/Coding .....................................................................................52 
10.3 
Quality Assurance ..................................................................................................53 
11 SAMPLE SIZE AND DATA ANALYSES .....................................................................54 
11.1 
Determination of Sample Size ...............................................................................54 
11.2 
Analysis Populations ..............................................................................................54 
11.2.1 
Pharmacokinetic Population ........................................................................54 
11.2.2 
Safety Population .........................................................................................54 
11.3 
Pharmacokinetic Analyses .....................................................................................54 
11.4 
Safety Analysis ......................................................................................................55 
12 REGULATORY, ETHICAL AND STUDY OVERSIGHT CONSIDERATIONS ........56 
12.1 
Regulatory Authority Approval .............................................................................56 
12.2 
Investigator Responsibilities ..................................................................................56 
12.2.1 
Regulatory and Ethical Considerations ........................................................56 
12.3 
Informed Consent...................................................................................................57 
12.4 
Confidentiality .......................................................................................................57 
12.5 
Inspections .............................................................................................................58 
12.6 
Protocol Adherence ................................................................................................58 
12.7 
Patient Data Protection ..........................................................................................58 
12.8 
Disclosure ..............................................................................................................58 
12.9 
Data Quality Assurance .........................................................................................58 
12.10 Principal Investigator Documentation Responsibilities .........................................59 
12.11 Sponsor Responsibilities ........................................................................................60 
12.11.1 Protocol Modifications.................................................................................60 
12.11.2 Use of Information and Publication .............................................................60 
12.11.3 Study and Study Center Closure ..................................................................61 
12.12 Records Retention and Study Files ........................................................................62 
12.12.1 Study Files and Retention of Records ..........................................................62 
12.12.2 Provision of Study Results and Information to Investigator ........................63 
12.13 Information Disclosure and Inventions ..................................................................63 
12.14 Joint Investigator/Sponsor Responsibilities ...........................................................64 
12.14.1 Access to Information for Monitoring .........................................................64 
12.14.2 Access to Information for Auditing or Inspections......................................64 
13 REFERENCES ................................................................................................................65 
14 APPENDICES .................................................................................................................67 
APPENDIX 1: ........................................................................... SCHEDULE OF ASSESSMENTS..68 
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APPENDIX 2:THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 
GUIDELINES, VERSION 1.1 ................................................................................................77 
APPENDIX 3: ......................................................................... ECOG PERFORMANCE STATUS..86 
APPENDIX 4: . CONTRACEPTION GUIDELINES AND DEFINITIONS OF “WOMEN OF 
CHILDBEARING POTENTIAL” AND “NO CHILDBEARING POTENTIAL” .................87 
APPENDIX 5: . NEW YORK HEART ASSOCIATION FUNCTIONAL CLASSIFICATION..90 
APPENDIX 6: ............................................................................... PROHIBITED MEDICATIONS..91 
APPENDIX 7: ..................................................... CLINICAL LABORATORY EVALUATIONS..93 
APPENDIX 8: ...................................................................................... TOTAL BLOOD VOLUME..94 
APPENDIX 9: ....... CHRONIC KIDNEY DISEASE EPIDEMIOLOGY COLLABORATION 
EQUATION .............................................................................................................................95 
APPENDIX 10: ..................................................................... SIGNATURE OF INVESTIGATOR..96 
 
 
LIST OF IN-TEXT TABLES AND FIGURES 
Table 1:  
Dose Levels for Pamiparib ...............................................................................34 
Table 2:  
Criteria for Modification of Pamiparib Dosing for Related Adverse Events ...35 
Table 3:  
Timeframes and Documentation Methods for Reporting Serious Adverse 
Events to the Sponsor or Designee ...................................................................50 
 
Figure 1: 
Correlation of PAR Inhibition in Peripheral Blood Mononuclear Cells with 
BGB-290 Dose .................................................................................................19 
Figure 2: 
Study Schematic ...............................................................................................24 
 
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1 
INTRODUCTION 
Pamiparib is a potent and selective inhibitor of poly (ADP-ribose) polymerase (PARP) proteins 
being developed by BeiGene USA Inc. (BeiGene) for the treatment of patients with various 
malignancies. Please refer to the Investigator’s Brochure for detailed information concerning the 
available pharmacology, toxicology, drug metabolism, clinical studies, and adverse event (AE) 
profile of pamiparib as well as a list of ongoing studies. 
1.1 
PARP 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 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 as a single agent in subjects with BRCA1- or 
BRCA2-mutant tumors, while achieving a favorable safety profile. Olaparib and rucaparib have 
been approved for the treatment of patients with advanced ovarian cancer that harbors germline 
or somatic/germline mutations in the BRCA gene (gBRCAm), respectively. Olaparib, rucaparib 
and niraparib have been approved as maintenance therapy for ovarian cancer. In addition, 
Olaparib was approved for the treatment of patients with human epidermal growth factor 
receptor-2 negative (HER2-) and gBRCAm breast cancer (Approved product package insert 
available online).  
Aside from BRCA1 or BRCA2 mutations, other alterations can also result in HRD, which is 
characterized by ‘BRCA-like” genomic scarring. HRD does not only make cancer cells sensitive 
to PARP inhibitors but also to platinum agents, and shared mechanisms of resistance suggest that 
both classes of drugs have similar antitumor effects in cancers with HRD (Edwards et al, 2008; 
Sakai et al, 2008; Sakai et al, 2009). This concept is supported by clinical data for the PARP 
inhibitor olaparib in patients with BRCA-mutated ovarian cancer demonstrating that platinum 
sensitivity correlated with response and platinum refractoriness with an almost complete lack of 
response to olaparib (Fong et al, 2010; Gelmon et al, 2011). In addition, rucaparib has been 
shown to be effective in platinum-sensitive ovarian cancer with BRCA-mutated patients deriving 
most benefit, followed by non-BRCA HRD and non-HRD patients (Swisher et al, 2017). 
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The strongest evidence that platinum sensitivity can predict clinical benefit from PARP 
inhibition is provided by 2 studies conducted in ovarian cancer patients.  The NOVA study for 
the PARP inhibitor niraparib in patients with platinum-sensitive ovarian cancer demonstrated 
that patients had significantly improved median progression-free survival (PFS) with niraparib 
compared with placebo, regardless of BRCA mutation or HRD status (Mirza et al, 2016). Median 
PFS for niraparib in patients with germline BRCA-mutations was 21.0 versus 5.5 months for 
placebo (Hazard Ratio [HR] 0.27; P < 0.001).  An exploratory analysis for patients who were 
biomarker negative (germline BRCA-wild-type and HRD negative) showed a median PFS of 
6.9 versus 3.8 months (HR 0.58, P = 0.02).  This led to the approval of niraparib for the 
maintenance treatment of patients who are in a complete response or partial response to 
platinum-based chemotherapy (Zejula [niraparib] prescribing information 2017).  Similar results 
were recently reported for rucaparib in the ARIEL3 study.  Median PFS for rucaparib in patients 
with BRCA-mutant (germline or somatic) ovarian cancers was 16.6 versus 5.4 months for 
placebo (HR 0.23; P < 0.0001).  In an exploratory analysis for patients who were biomarker 
negative (BRCA-wild-type and HRD negative), median PFS was 6.7 versus 5.4 months (HR 
0.58, P = 0.0049) (Coleman et al, 2017). 
 
1.2 
PARP Inhibitor Pamiparib 
Pamiparib is a potent and selective inhibitor of PARP1 and PARP2 with potent PARP-trapping 
activity and significant brain penetration in preclinical models. 
1.2.1 
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 in solid tumors), BGB-290-104 
(pamiparib in combination with radiation and/or temozolomide in glioblastoma), 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. 
1.2.1.1 
Pharmacokinetics Data for BGB-290-AU-002 
In the first-in-human Phase 1 study, interim pharmacokinetics (PK) data of pamiparib showed 
that pamiparib is rapidly absorbed and eliminated after oral administration. The maximum serum 
concentration and the drug exposure area under the concentration-time curve (AUC) increased in 
a nearly dose proportional manner from 2.5 to 120 mg twice a day both after the single-dose 
administration and at steady-state. The terminal half-life was determined to be approximately 13 
hours, with a range of 5.5 to 34 hours. At steady-state, from 2.5 to 120 mg twice a day, drug 
exposure was increased in a dose-dependent manner.  
A total of 13 patients in Study BGB-290-AU-002 contributed to serial plasma samples at 
predose, 0.5, 1, 2, 4, 7, 24 and 48 hours after a single 60 mg dose of pamiparib, either fasted or 
with high-fat breakfast, each followed by a 5-day washout for food-effect PK investigation.  
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When pamiparib was administered with food, a reduction of 15% in AUC and 41% in Cmax was 
observed, along with a delay of Tmax from 2 to 7 hours. 
The 15% reduction in AUC is not considered to be clinically relevant and falls well within the 
variability of pamiparib exposure of approximately 50% coefficient of variation. Therefore, food 
restrictions are not required with pamiparib administration. 
1.2.1.2 
Exploratory Biomarker Data 
The PAR formation from peripheral blood mononuclear cells (PBMCs) was detected by enzyme-
linked immunosorbent assay to explore the pharmacodynamic activity in the Phase 1 study BGB-
290-AU-002. Blood samples for PK and isolation of PBMCs were obtained at baseline on Day 1 
(predose) and 4 hours postdose on Days 1 and 17 of Cycle 1. The pharmacodynamic activity at 
4 hours postdose on Days 1 and 17 was reported as percentage of predose PAR inhibition. 
PK/pharmacodynamic correlation analyses were conducted in 30 patients who received doses of 
2.5, 5, 10, 20, 40, 60, 80, and 120 mg twice a day. Robust PAR inhibition in PBMCs was 
observed at the first dose level of 2.5 mg twice a day. The pharmacodynamic activity increased 
in a dose-dependent manner from 2.5 to 10 mg twice a day. Sustained PAR inhibition in PBMCs 
was observed at steady-state for patients treated at 10 mg twice a day or higher dose levels 
(Figure 1). 
Figure 1: 
Correlation of PAR Inhibition in Peripheral Blood Mononuclear Cells with 
BGB-290 Dose  
 
Abbreviations: BID = twice a day; h = hours. 
1.2.1.3 
Clinical Safety and Preliminary Efficacy for BGB-290-AU-002 
BGB-290-AU-002 is a first-in-human study evaluating pamiparib to characterize the safety, 
maximum tolerated dose (MTD), preliminary antitumor activity, and the PK of pamiparib given 
as a monotherapy in a 3+3 dose escalation scheme. Pamiparib was administered in doses ranging 
from 2.5 mg up to 120 mg orally twice a day. 
The study is being conducted in 5 Australian study centers and preliminary data for 81 patients 
are available (cut-off date of 01 December 2017).  
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The Dose Limiting Toxicity was Grade 2 nausea, which persisted despite optimal standard 
medical therapy and was observed in the 120 mg twice daily cohort (n = 2) and in the 40 mg and 
80 mg twice daily cohorts (1 patient each). The MTD of pamiparib was 80 mg orally twice a day. 
The most frequent treatment-emergent AEs occurring in ≥ 2 patients included nausea (64.4%), 
vomiting (35.6%), fatigue (33.3%), and diarrhea (28.9%). Anemia was the most frequent 
hematologic AE (33%), followed by neutropenia (11%). 
Twenty-six percent of the patients experienced a ≥ Grade 3 AE deemed related to pamiparib. The 
most frequent Grade 3 pamiparib related AEs were anemia (11.5%); neutropenia (7.7%); nausea, 
fatigue and diarrhea (2.6% each); and oral paresthesia, paresthesia, vomiting, hypophosphatemia, 
AT elevated, abdominal pain, and platelet counts decreased (1.3% each). Serious AEs reported 
as related to pamiparib included anemia (n = 2) and nausea (n = 2).  
Four patients experienced AEs with fatal outcome, which included worsening of pleural effusion, 
intestinal obstruction, gastric obstruction, and intestinal perforation.  
Three patients experienced AEs leading to discontinuation of pamiparib; 2 of those AEs were 
deemed related to pamiparib (Grade 1 paresthesia of hands and mouth, and Grade 2 vomiting). 
The third, not related AE was a serious event of Grade 3 traumatic hematoma due to fall. 
No fatal AE was deemed related to pamiparib. 
Fifty-four patients with gynecological cancers have been enrolled in the BGB-290-AU-002 study 
as of 01 December 2017. Seventeen patients achieved either complete (n = 5) or partial (n = 12) 
responses; and responses were observed across all dose levels including a partial response (PR) 
at 2.5 mg twice a day. 
Based upon the overall safety, efficacy, and PK profile of pamiparib, a dose of 60 mg orally 
twice a day was selected as the recommended phase 2 dose (RP2D) for further investigation.  
1.3 
Study Rationale 
Available human in-vitro metabolism data suggest that pamiparib is metabolized mainly by 
CYP3A; therefore, inducers and inhibitors of CYP3A have the potential to lower and raise 
pamiparib plasma concentrations, respectively. Given the theoretical potential for CYP3A 
inducers and inhibitors to alter the PK of pamiparib, a clinical drug interaction study is warranted 
to determine the extent of any interaction. This study is designed to determine the effect of 
CYP3A induction by rifampin and CYP3A inhibition by itraconazole on the PK of pamiparib. 
Rifampin and itraconazole are commonly used in drug interaction studies as a prototypical 
CYP3A inducer and inhibitor, respectively, (CDER Guidance; European Medicines Agency, 
CHMP).  
1.4 
Benefit-Risk Assessment 
Patients carrying HRD tumors may receive health benefit from participating in the Extension 
Phase of the study. Pamiparib has been studied in nonclinical toxicity and Phase 1 clinical studies 
and its toxicities are largely consistent with the safety profile shared by other PARP inhibitors, 
with the potential exception that pamiparib may cause less myelosuppression. Myelodysplastic 
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syndrome (MDS) and acute myeloid leukemia (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 PARPi 
therapy had a history of extensive previous chemotherapy and some had 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 drug reactions. Patients in this study will be 
monitored monthly for hematological toxicities, and events of MDS and AML will be reported 
as serious AEs (SAEs). The doses of rifampicin and itraconazole are the same as those 
previously used in other PARP inhibitor drug-drug interaction (DDI) studies. 
Based on the nonclinical and clinical collected data to date, pamiparib warrants further 
exploration in patients with advanced solid tumors and the overall risk-benefit ratio appears to be 
favorable. More information about the known and expected benefits, risks, and reasonably 
anticipated AEs associated with pamiparib may be found in the Investigator’s Brochure (IB) 
(Pamiparib [BGB-290] Investigator’s Brochure). More information about the known and 
expected benefits and risks of rifampin and itraconazole may be found in their respective 
prescribing information. 
2 
OBJECTIVES 
2.1 
Primary Objectives 
The primary objectives of the study are: 
• to determine the effect of the strong CYP3A inducer rifampin on the PK of pamiparib in 
cancer patients 
• to determine the effect of the strong CYP3A inhibitor itraconazole on the PK of 
pamiparib in cancer patients 
2.2 
Secondary Objectives 
The secondary objectives of the study are: 
• to evaluate the safety and tolerability of pamiparib when coadministered with rifampin or 
itraconazole/fluconazole in cancer patients 
• to further investigate the tolerability of oral pamiparib in patients with advanced solid 
tumors (Extension Phase). 
3 
ENDPOINTS 
3.1 
Primary Endpoints 
The PK outcome endpoints of pamiparib derived from the plasma concentration-time profiles 
following oral administration of pamiparib on Days 1 and 10 in Part A (rifampin interaction) and 
Days 1 and 7 in Part B (itraconazole interaction) are as follows: 
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• maximum observed concentration (Cmax) 
• AUC from time zero to time of last quantifiable concentration postdose (AUC0-t) 
• AUC from zero to infinity (AUC0-∞) 
• AUC from zero to 12 hours (AUC0-12) 
• time of the maximum observed concentration (tmax) 
• apparent terminal elimination half-life (t1/2) 
• apparent oral clearance (CL/F) 
• apparent volume of distribution (Vz/F) 
3.2 
Secondary Endpoints 
• incidence and severity of AEs 
• incidence of laboratory abnormalities, based on hematology, clinical chemistry, and 
urinalysis test results 
• vital sign assessments 
• 12-lead electrocardiogram (ECG) parameters 
• physical examinations 
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4 
INVESTIGATIONAL PLAN 
4.1 
Study Design 
This is an open-label, parallel-group, fixed-sequence study in male and female cancer patients. 
Part A will investigate the effect of CYP3A induction by rifampin on the single-dose PK of 
pamiparib, and Part B will investigate the effect of CYP3A inhibition by itraconazole on the 
single-dose PK of pamiparib.  
The study consists of two phases: the Core Phase, which is divided into Part A and Part B, and 
the Extension Phase. A total of approximately 24 patients will be enrolled (approximately 12 in 
each part) to ensure that at least 20 patients (10 in each part) complete the study. 
In Part A, all patients will receive the following treatments: 
• Day 1 and Day 10: single oral doses of 60 mg pamiparib 
• Days 3 to 11: oral doses of 600 mg rifampin once a day  
In Part B, all patients will receive the following treatments: 
• Day 1 and Day 7: single oral doses of 20 mg pamiparib  
• Days 3 to 8: oral doses of 200 mg itraconazole once a day 
An overview of the study design is shown in Figure 2. 
For both parts of the study, potential patients will be screened to assess their eligibility within 28 
days prior to the first dose administration. Patients enrolled in either part of the study will be 
admitted to the Clinical Research Unit (CRU) on Day -1 and will remain in the CRU for the 
duration of treatment until their discharge on Day 12 (patients enrolled on Part A) or Day 9 
(patients enrolled on Part B). Patients will return to the CRU for an EOT Visit within 7 days 
from the last dose of study drug. Patients who are discontinued early during the Core Phase or 
who will not participate in the Extension Phase will return for a Safety Follow-up Visit 30 days 
(±7 days) after the last dose of study drug or before initiation of new anticancer therapy, 
whichever occurs first. 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 
9.1.4 should be made. 
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Figure 2: 
Study Schematic 
 
Abbreviations: EOT = End-of-Treatment; PK = pharmacokinetic; PO = orally; QD = once a day.  
a PK Samples at: Predose; 0.5, 1, 2, 4, 6, 9, 12, 24, and 48 hours postdose. 
b End of Treatment Visit (Core Phase, outpatient) to occur within 7 days of last dose of study drug; assessments performed at this 
visit can be used as the assessments of the predose visit of the Extension Phase provided that they are performed within 7 days 
of the start of pamiparib dosing in the Extension Phase. 
c Safety Follow-up Visit (outpatient)/call to occur at the end of Core Phase only if patient does not continue into the Extension 
Phase; Safety Follow-up Visit (outpatient)/call to occur at the end of the Extension Phase. 
d Pamiparib will be given at 60 mg orally twice a day in 28-day cycles until progression of disease, unacceptable toxicity, 
withdrawal of consent, or any other reason for discontinuation. 
e  End-of-Treatment (Extension Phase) visit to occur within 7 days of last dose of pamiparib  
After completing the Core Phase, patients may participate in the Extension Phase, in which they 
will receive pamiparib twice a day in 28-day cycles until progression of disease, unacceptable 
toxicity, withdraw consent, or any other reason for discontinuation. Patients will have a Predose 
visit within 7 days of the first planned dose of pamiparib in the Extension Phase. Assessments 
performed at the EOT Visit of the Core Phase (performed within 7 days from last dose) can be 
used for the Predose visit and need not to be repeated provided they are performed within 7 days 
of the first planned dose of pamiparib on the Extension Phase. During the Extension Phase, 
patients will undergo assessments as delineated in Appendix 1. Patients will have an End-of-
Treatment visit within 7 days of the last dose of pamiparib and a Safety Follow-up Visit 
approximately 30 days after the last dose if they experienced clinical laboratory abnormalities in 
their last visit. Patients who did not experience such abnormalities, will be contacted by phone to 
collect any AEs or SAEs. Clinical Study Reports (CSR) will be compiled based on data from the 
Core Phase (CSR A) and from the Extension Phase (CSR B). The two reports will then be 
combined as a final CSR.  
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The Schedule of Assessments is presented in Appendix 1. 
4.2 
Discussion of Study Design 
This is an open label, non-randomized study designed to evaluate the effect of rifampin (a strong 
CYP3A inducer) and itraconazole (a strong CYP3A inhibitor) on the PK of pamiparib in cancer 
patients.  
A parallel-group design has been selected due to the potential for carryover of CYP induction 
following rifampin dosing, which can remain for several weeks following cessation of dosing 
(Reitman, et al) and would prolong the study duration to a significant degree if a crossover 
design were utilized. 
For the Core Phase, the total duration of study participation for each patient (from Screening 
through the EOT Visit) is anticipated to be approximately 48 days. 
Patients may participate in the Extension Phase during which they will receive pamiparib 
monotherapy until disease progression, unacceptable toxicity, withdrawal of consent, or any 
other reason for discontinuation. 
Rationale for selection of the pamiparib dose: 
 
A dose of 60 mg pamiparib has been chosen for the induction portion of the study (Part A), as 60 
mg twice daily was administered to patients in Phase 1 study BGB-290-AU-002 and was well 
tolerated. 
A dose of 20 mg pamiparib has been chosen for the inhibition portion of the study (Part B), as it 
is one-sixth of 120 mg, where 120 mg BID is the highest dose administered in the phase I trial.  
With an observed rate of accumulation of approximately 2-fold, this gives an approximate of 12- 
fold margin, which should be sufficient to cover the plasma exposure increase due to complete 
blockade of CYP3A by itraconazole after a single-dose administration of 20 mg pamiparib.  In 
addition, 20 mg is the lowest dose strength of pamiparib. 
Given the objective of determining whether a CYP3A inducer or inhibitor has an effect on the 
BGB-290 PK, these doses are considered to be adequate to achieve study objectives with 
minimal risk to subjects. 
 
Rationale for selection of the rifampin and itraconazole doses: 
 
A dose of 600 mg rifampin once a day has been selected for Part A, as this is the recommended 
daily dose for adults weighing 60 kg or above (10 mg/kg/day, to a maximum of 600 mg/day). It 
is also the most commonly selected rifampin dose in drug interaction studies (Xu, et al). In this 
study, to achieve induction of CYP3A, 600 mg rifampin once a day will be administered for 7 
days to reach steady state, coadministered with pamiparib on Day 10, and given for an additional 
day following pamiparib dosing to maintain steady state. 
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A dose of 200 mg itraconazole once a day has been selected for Part B, as this dose is standard in 
clinical practice and has been demonstrated to inhibit CYP3A (Liu, et al). In this study, to 
achieve sufficient inhibition of CYP3A, 200 mg itraconazole once a day will be administered for 
a 4-day run-in period (Days 3 to 6) to reach steady state, coadministered with pamiparib on Day 
7, and given for an additional day following pamiparib dosing to maintain CYP3A inhibition 
during the elimination phase of pamiparib.  
Doses of 600 mg rifampin once a day and 200 mg itraconazole once a day are considered to be 
safe and anticipated to provide sufficient CYP3A induction and inhibition, respectively, to fulfill 
the primary study objectives. 
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5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for the study: 
1. 
Voluntarily agreed to participate by signing an informed consent form (ICF) 
2. 
Age ≥ 18 years 
3. 
Histologically or cytologically confirmed advanced or metastatic solid tumors that are 
refractory or resistant to standard therapy or for which no suitable effective standard 
therapy exists. 
4. 
Disease that is evaluable per RECIST Version 1.1 or PCWG-3  
5. 
ECOG performance status ≤ 1 (Appendix 2) 
6. 
Life expectancy ≥ 12 weeks 
7. 
Ability to swallow whole capsules 
8. 
Adequate hematologic and end-organ function, as defined by the following laboratory 
results (obtained ≤ 14 days before day 1): 
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
b. Platelet count ≥ 100 x 109/L  
c. Hemoglobin ≥ 9 g/dL (≥ 14 days after growth factor support or transfusion) 
d. Estimated glomerular filtration rate ≥ 50 mL/min/1.73 m2 by the Modification of 
Diet in Renal Disease study equation (MDRD STUDY EQ; www.mdrd.com) 
e. Total serum bilirubin ≤ 1.5 x upper limit of normal (ULN) 
• ≤ 4 x ULN, if Gilbert’s syndrome or if indirect bilirubin concentrations 
suggestive of extrahepatic source of elevation 
f. Aspartate and alanine aminotransferase (AST and ALT) ≤ 3 x ULN or ≤ 5 x ULN 
for patients with liver metastases 
9. Females of childbearing potential and nonsterile males must use a highly effective 
method of birth control (see Appendix 4) while in the Core Phase of the study and for at 
least 6 months after the Core Phase is completed. In the Extension Phase, females of 
childbearing potential and nonsterile males must use a highly effective method of birth 
control (see Appendix 4) for the duration of the study and for at least 6 months after the 
last dose of study drug. Females of childbearing potential and non-sterile males must also 
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agree to not freeze/donate oocytes or sperm respectively. 
10. Willingness and ability to comply with the protocol for the duration of the study  
11. Body weight ≥ 60 Kg at screening 
5.2 
Exclusion Criteria 
Patients will be excluded from the study for any of the following reasons: 
1. History of hypersensitivity to rifampin, any rifamycin or any of the components of the 
rifampin capsule (Part A).  
2. History of hypersensitivity to itraconazole or any of the components of the itraconazole 
capsule (Part B).  
3. Unresolved acute effects from prior medications of ≥ Grade 2 (CTCAE v5.0) 
a. Except for adverse effects not considered a likely safety risk (eg, alopecia, 
neuropathy and specific laboratory abnormalities) 
4. Prior treatment with a PARP inhibitor at therapeutic doses is allowed, provided that such 
treatment was not the most recent therapy (PARP inhibitor must have been discontinued 
≥ 3 months prior to the first dose of pamiparib)  
a. Patients who experienced prior severe toxicity to PARP inhibitors that in the 
opinion of the investigator precludes further treatment with PARP inhibitors should 
be excluded 
5. Major surgical procedure, open biopsy, or significant traumatic injury ≤ 4 weeks prior to 
Day 1 of pamiparib administration, or anticipation of need for major surgical procedure 
during the course of the study 
a. Placement of vascular access device is not considered major surgery 
6. Diagnosis of Myelodysplastic syndrome (MDS)  
7. Other diagnosis of malignancy 
a. Except for surgically excised non-melanoma skin cancer, adequately treated 
carcinoma in situ of the cervix, localized prostate cancer treated with curative 
intent, adequately treated low-stage bladder cancer, ductal carcinoma in situ treated 
surgically with curative intent, or a malignancy diagnosed > 2 years ago with no 
current evidence of disease and no therapy ≤ 2 years prior to Day 1  
8. Untreated leptomeningeal disease or brain metastasis.  Patients with previously treated 
brain metastases are eligible if the metastases have shown no progression on brain 
computed tomography (CT) or magnetic resonance imaging (MRI) over at least 4 weeks 
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prior to Day 1 of pamiparib administration, the patient has no symptoms due to the brain 
metastases, and the patient has been off corticosteroids for ≥ 2 weeks  
9. Active infection requiring systemic treatment 
10. Have known human immunodeficiency virus (HIV) infection or serologic status 
reflecting active viral hepatitis infection as follows: 
a. Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) 
carriers whose HBV DNA is > 500 IU/mL should be excluded.  Patients positive for 
anti HCV and positive for HCV PCR test are to be excluded.  Note: Inactive HBsAg 
carriers, treated and stable hepatitis B (HBV DNA ≤500 IU/mL) can be enrolled 
11. 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 of pamiparib administration 
b. Symptomatic pulmonary embolism ≤ 28 days before Day 1 of pamiparib 
administration 
c. Any history of acute myocardial infarction ≤ 6 months before Day 1 of pamiparib 
administration 
d. Any history of heart failure meeting New York Heart Association Classification III 
or IV (Appendix 5) ≤ 6 months before Day 1 of pamiparib 
• Patients with congestive heart failure or history of heart failure should be 
excluded from Part B (itraconazole) 
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before Day 1 
of pamiparib administration 
f. Any history of cerebral vascular accident ≤ 6 months before Day 1 of pamiparib 
administration 
12. Previous complete gastric resection or lap-band surgery, chronic diarrhea, active 
inflammatory gastrointestinal disease, known diverticular disease or any other disease-
causing malabsorption syndrome 
a. Gastroesophageal reflux disease under treatment with proton pump inhibitors is 
allowed 
13. Active bleeding disorder, including gastrointestinal bleeding, as evidenced by 
hematemesis, significant hemoptysis, or melena ≤ 6 months before Day 1 of pamiparib 
administration 
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14. Use or anticipated need for food or drugs known to be strong or moderate CYP3A 
inhibitors or strong CYP3A inducers ≤ 14 days (or ≤ 5 half-lives if half-life is known) 
prior to Day 1 of pamiparib administration (Appendix 6) 
15. Pregnant or nursing females 
a. 
Females of childbearing potential require a negative serum pregnancy test ≤ 7 days 
before Day 1 of pamiparib administration 
16. Known history of intolerance to the excipients of the pamiparib capsule 
17. Have known hereditary problems of galactose intolerance, the Lapp lactase deficiency or 
glucose-galactose malabsorption 
5.3 
Patient Number and Identification 
After signing the ICF, patients will be assigned a unique screening number by the study site. 
Patients will be assigned a patient number at the time of the first dosing occasion. Assignment of 
numbers will be in ascending order and no numbers will be omitted (eg, Subjects 101, 102, 103).  
Enrolled patients will be identified by patient number only on all study documentation. A list 
identifying the patients by patient number and screening number will be kept in the Site Master 
File. 
5.4 
Patient Withdrawal and Replacement 
A patient is free to withdraw from the study at any time.  A patient may be withdrawn for any of 
the following reasons: 
a. Disease progression (PD) 
b. AEs 
c. Major protocol violation 
d. Patient withdrew consent for study treatment either during the Core Phase or during the 
Extension Phase 
• Patients may voluntarily withdraw consent from study treatment at any time 
e. Investigator’s discretion  
f. Start of new anticancer therapy 
If a patient is withdrawn from dosing, the Sponsor will be notified and the date and reason(s) for 
the withdrawal will be documented in the patient’s eCRF. If a patient is withdrawn, efforts will 
be made to perform all discharge assessments, if possible (Appendix 1). Other procedures may 
be performed at the principal investigator’s (PI’s) (or designee’s) and/or sponsor’s discretion. If 
the patient is in-house, these procedures should be performed before the patient is discharged 
from the clinic. The PI (or designee) may also request that the patient returns for an additional 
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Follow-up Visit. All withdrawn patients will be followed until resolution of all their AEs or until 
the unresolved AEs are judged by the PI (or designee) to have stabilized. 
Patients who withdraw during the Core Phase may be replaced following discussion between the 
PI and sponsor. 
5.5 
Study Termination 
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 
• Poor protocol adherence  
• Inaccurate or incomplete data recording  
• Good Clinical Practice (GCP) noncompliance 
• Study activity is completed (ie, the last patient accrued in the Extension Phase has been 
discontinued from the study due to intolerable toxicity, disease progression or voluntary 
withdrawal) 
The sponsor will notify the PI 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 (Core and Extension Phase).  
The PI may be informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the patient’s interests. The PI will be responsible for 
informing the EC of the early termination of the study.  
5.6 
Data Entry in the eCRF 
Data collection on the eCRF must follow the instructions described in the eCRF completion 
guidelines. 
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6 
STUDY TREATMENTS 
6.1 
Description, Storage, Packaging, and Labeling 
Pamiparib is provided in 20-mg or 60-mg capsules, based upon availability and approval status. 
Pamiparib capsules will be provided in 30-
 
.  
Itraconazole will be provided as 100 mg capsules in 60-count packs. 
Rifampin will be provided as 300 mg capsules in 60-count packs. 
Excipients contained in the pamiparib capsule are listed in the Investigator’s Brochure. 
Excipients contained in the rifampin and itraconazole capsules are listed in their respective 
product inserts. 
The contents of the labels will be in accordance with all applicable local regulatory requirements. 
Labels will include at a minimum: drug name, dose strength, contents, sponsor, protocol number, 
bottle number, directions for use, storage conditions, caution statements, retest or expiration date, 
and space to enter the patient number and name of investigator  
6.1.1 
Handling and Storage 
The instructions for drug ordering are in the pharmacy binder. Pamiparib will be dispatched to a 
study center only after receipt of the required documents in accordance with applicable 
regulatory requirements and the sponsor’s procedures. The investigator or pharmacist/designated 
personnel are responsible for maintaining the drug supply inventory and acknowledging receipt 
of all pamiparib shipments. Pamiparib must be stored in a secure area with access limited to the 
investigator and authorized study center personnel and under physical conditions that are 
consistent with pamiparib specific requirements.  
Pamiparib must be kept at the condition as specified on the labels. 
 
.  
Itraconazole should be stored below 25°C and rifampin should be stored below 30°C. 
6.2 
Study Treatment Administration 
Core Phase 
All doses should be administered in the morning.  
On the days of PK sampling (Days 1 and 10 in Part A and Days 1 and 7 in Part B), patients are 
required to fast for at least 8 hours before and 4 hours after study drug administration.  Water is 
allowed during the fasting period, except 1h predose and 1h postdose.  Rifampin (Part A) or 
itraconazole (Part B) will be administered first, followed within 5 minutes by pamiparib. Both 
study drugs should be taken with approximately 240 mL of water. 
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Patients enrolled in Part A will receive rifampin once a day on Day 3 to 9 and on Day 11 in the 
fasted state (at least 2 hours predose) and will continue to fast for 1h postdose. Water is allowed 
during the fasting period.   
Patients enrolled in Part B will receive itraconazole once a day on Days 3 to 6 and on Day 8 
approximately 30 minutes after completing a meal.  
 
Extension Phase 
During the Extension Phase, pamiparib capsules will be administered orally at 60 mg, twice a 
day 10 to 12 hours apart on Days 1 to 28 of a 28-day cycle. 
6.3 
Randomization 
This is a nonrandomized study. The study has a fixed treatment sequence. 
6.4 
Blinding 
This is an open-label study. 
6.5 
Study Treatment Compliance 
During the Core Phase of the study, the following measures will be employed to ensure treatment 
compliance: 
• All doses will be administered under the supervision of suitably qualified study site staff. 
• Immediately after dose administration, visual inspection of the mouth and hands will be 
performed for each patient. 
• At each dosing occasion, a predose and postdose inventory of pamiparib (Parts A and B), 
rifampin (Part A) and itraconazole (Part B) will be performed. 
6.6 
Drug Accountability 
The investigator (or designee) will maintain an accurate record of the receipt of pamiparib 
capsules received, including the date in which they were received. One copy of this receipt will 
be returned to the Sponsor when the contents of the shipment have been verified. In addition, an 
accurate drug disposition record will be kept, specifying the amount dispensed to each subject; 
subject identification number; date of dispensing; and lot number(s) pamiparib, rifampin, and 
itraconazole. This drug accountability record will be available for inspection at any time. At the 
completion of the study, the original drug accountability record will be available for review by 
the Sponsor upon request. 
For each batch of unit doses, the empty used unit dose containers will be discarded upon 
satisfactory completion of the compliance and accountability procedures. Any unused assembled 
unit doses will be retained until completion of the study. A record of quantities destroyed or 
returned to BeiGene shall also be documented. 
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At the completion of the study, all unused pamiparib capsules will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 
Rifampin and itraconazole will also be subject to accountability procedures, and the CRU staff 
will not destroy unused supplies of rifampin and itraconazole until drug accountability and 
reconciliation has been performed by the Study Monitor. 
6.7 
Dose Holds and Modifications  
AEs should be assessed as best as possible regarding their relatedness to study drug. 
Investigators should make every effort to maintain dose intensity in patients.  
Core Phase 
Patients who experience AEs that require dose holds should be discontinued from the Core 
Phase.  Patients who experience AEs deemed related to rifampin or itraconazole are eligible to 
enter the Extension Phase. 
Extension Phase 
Dosing of pamiparib can be withheld for up to 28 days consecutively (up to 56 days 
consecutively for investigational drug-related anemia). If drug is planned to be held > 28 days (> 
56 days for investigational drug-related anemia), the medical monitor should be contacted before 
permanent patient discontinuation from the study drug. 
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 or placebo should be managed according to standard medical practice. 
A maximum of 2 dose reductions is allowed before the patient must be permanently withdrawn 
from study drug. Dose levels for pamiparib are summarized in Table 1. Pamiparib will be dose 
modified as outlined in Table 2. 
Table 1:  
Dose Levels for Pamiparib  
Dose Level 
Pamiparib 
1 
60 mg PO BID 
-1 
40 mg PO BID 
-2 
20 mg PO BID 
Abbreviations: PO = oral; BID = twice daily. 
Pamiparib may be dose-reduced for a maximum of 2 dose reductions. 
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Table 2:  
Criteria for Modification of Pamiparib Dosing for Related Adverse Events 
Toxicity 
Recommended Dose Modification a 
Hematologic 
Anemia (hemoglobin, Hgb) 
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. 
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Toxicity 
Recommended Dose Modification a 
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. 
Neutropenia (ANC) 
Grade 3  
(ANC < 1.0 - 0.5  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 (ANC <0.5  109/L) 
Hold pamiparib until resolved to Grade ≤ 1 or baseline and 
 pamiparib by 1 dose level 
Febrile neutropenia (ANC < 1.0  
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 (PLT) 
Grade 3 (PLT < 50 - 25  109/L) 
Hold pamiparib until resolved to Grade ≤ 1 or baseline  
and  pamiparib by 1 dose level 
Grade 4 (PLT < 25  109/L) 
Hold pamiparib until resolved to Grade ≤ 1 or baseline and  
pamiparib by 1 dose level 
Renal 
Estimated glomerular filtration rate (MDRD STUDY EQ; www.mdrd.com or Appendix 9) 
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  
Hepatic 
Bilirubin 
Grade 2 (> 1.5 - 3.0  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 
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Toxicity 
Recommended Dose Modification a 
Grade 3 (> 3.0 - 10.0  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 
Grade 4 (> 10.0  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 (AST) and/or alanine aminotransferase (ALT) 
Grade 3 (> 5 and ≤ 20  ULN) 
Hold pamiparib until AST and/or ALT resolved to ≤ 5  ULN or 
baseline 
• 
If not resolved within 7 days to ≤ 5  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  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 
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  
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Toxicity 
Recommended Dose Modification a 
Other AEs 
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: AE = adverse event; ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = 
aspartate aminotransferase; BID = twice daily; Hgb = hemoglobin; MDRD = Modification of Diet in Renal Disease; 
PLT = platelet (count); QTc = QT interval corrected for heart rate; 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 (up to 56 days consecutively for 
investigational drug-related anemia). 
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7 
CONCOMITANT MEDICATIONS AND OTHER RESTRICTIONS 
7.1 
Concomitant Medications 
All concomitant medications, including all prescription and over-the-counter drugs, supplements, 
and intravenous medications and fluids, taken by or administered to the patient within 28 days 
before Day 1 should be recorded in the source documents and eCRF.  
The PI will instruct the patient to notify the study site about any new medical treatment taken 
during the Extension Phase.  
7.1.1 
Core Phase 
Patients will refrain from use of any prescription or nonprescription medications/products during 
the study through the EOT Visit, unless the investigator and/or sponsor have given their prior 
consent. 
Acetaminophen (2 g/day for up to 3 consecutive days) is an acceptable concomitant medication. 
Acetaminophen can be taken as specified above at any time relative to the administration of 
study drug. The administration of any other concomitant medications during the study is 
prohibited without prior approval of the investigator, unless its use is deemed necessary in a 
medical emergency. Any medication taken by a subject during the course of the study and the 
reason for its use will be documented in the source data. 
7.1.1.1 
Diet 
While confined at the study site, patients will receive a standardized diet at scheduled times that 
do not conflict with other study-related activities.  
Foods and beverages containing poppy seeds, grapefruit, or Seville oranges will not be allowed 
from 72 hours prior to Check-in (Day -1) until discharge on Day 12 (Part A) and Day 9 (Part B). 
Caffeine-containing foods and beverages will not be allowed from 72 hours prior to Check-in 
(Day -1) until discharge on Day 12 in Part A and Day 9 in Part B. 
Consumption of alcohol will not be permitted from 72 hours prior to Check-in (Day -1) until 
discharge on Day 12 (Part A) and Day 9 (Part B), and alcohol intake will be limited to a 
maximum of 2 units/day on all other days while patients are not in the CRU, from Screening 
through the EOT Visit (end of Core Phase). 
On days 3 to 9 and 11, patients should be given rifampin in the fasted state (at least 2 hours); 
patients should continue to fast for 1h postdose. 
On Days 3 to 6 and 8, patients should be given itraconazole 30 minutes after a meal. 
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7.1.1.2 
Smoking  
Use of tobacco- or nicotine-containing products will not be permitted from Screening until the 
EOT Visit (end of Core Phase). 
7.1.1.3 
Exercise  
Patients are required to refrain from strenuous exercise from 72 hours before Check-in (Day -1) 
until the EOT Visit (end of Core Phase) and will otherwise maintain their normal level of 
physical activity during this time (ie, will not begin a new exercise program nor participate in 
any unusually strenuous physical exertion). 
7.1.1.4 
Blood Donation 
Patients are required to refrain from donation of blood from 56 days prior to Screening, plasma 
from 30 days prior to Screening, or platelets from 6 weeks prior to Screening until 3 months after 
the EOT Visit (end of Core Phase). 
7.1.2 
Extension Phase 
Supportive therapy considered necessary for the patients’ welfare may be given at the discretion 
of the PI. This includes, but is not limited to analgesics, anticonvulsants, anti-emetics, 
antidiarrheal treatment, laxatives, opiates, and transfusion of blood products. 
7.1.2.1 
Prohibited Medications  
Patients are not allowed to receive other anticancer therapy, including surgery; radiation therapy; 
immunotherapy; investigational agents; cytotoxic, biologic, or hormone therapy; anticancer 
Chinese medicine; or herbal remedies  14 days (or  5 half-lives, if applicable) before Day 1 of 
the Core Phase and during the study, including the Extension Phase. Hormone replacement 
therapy use is allowed during the Extension Phase.  
Use of bisphosphonate and denosumab 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 during the Core 
and Extension Phase.  
Please refer to the drugs/substances listed in Appendix 6 and to 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ for a more complete list of medications that 
are not allowed. Consumption of grapefruit and Seville oranges or their juices are not allowed 
throughout the study. No other dietary restrictions will apply. 
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7.1.2.2 
Medications to Be Used with Caution (Core and Extension Phases) 
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 6 and these should be used cautiously with 
drug concentration monitoring where appropriate. 
In addition to CYP3A, pamiparib can also be metabolized by 
in human liver 
microsomes, but to a lesser extent. See Appendix 6 for medications that should be used with 
caution for that reason. 
7.2 
Contraception 
Please refer to Appendix 4. 
 
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8 
STUDY ASSESSMENTS AND PROCEDURES 
Every effort will be made to schedule and perform the procedures as closely as possible to the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, and 
the other procedures to be performed at the same timepoint. 
The order of priority for scheduling procedures around a timepoint is (in descending order of 
priority): 
• 
dosing 
• 
blood samples 
• 
any other procedures (ECGs will be scheduled before vital sign measurements) 
8.1 
Pharmacokinetic Assessments (Core Phase ONLY) 
8.1.1 
Pharmacokinetic Blood Sample Collection and Processing  
Blood samples (approximately 1 x 2 mL for pamiparib) will be collected by venipuncture or 
cannulation at the times indicated in the Schedule of Assessments in Appendix 1. Procedures for 
collection, processing, and shipping of PK blood samples will be detailed in the laboratory 
manual. Plasma samples remaining after bioanalysis of pamiparib may be used to qualitatively or 
quantitatively characterize any metabolites of pamiparib. 
8.1.2 
Analytical Methodology 
Plasma concentrations of pamiparib will be determined using a validated analytical procedure. 
Specifics of the analytical method will be provided in a separate document. 
8.2 
Safety and Tolerability Assessments (Core and Extension Phases) 
8.2.1 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs are detailed in Section 9. The condition of each patient will be monitored from the time of 
signing the Informed Consent Form (ICF) to the end of the study. Patients will be observed for 
any signs or symptoms and asked about their condition by open questioning, such as “How have 
you been feeling since you were last asked?” at least once each day while a resident at the study 
site and at each study visit. Patients will also be encouraged to spontaneously report AEs 
occurring at any other time during the study. Any AEs, SAEs, and remedial action required will 
be recorded in the patient’s source data. The nature, time of onset, duration, and severity will be 
documented, together with a PI’s (or designee’s) opinion of the relationship to study drug. 
Adverse events recorded during the course of the study will be followed-up, where possible, until 
resolution. This will be completed at the PI’s (or designee’s) discretion.  
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8.2.2 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including clinical 
chemistry, hematology, urinalysis, and serology) at the times indicated in the Schedule of 
Assessments in Appendix 1. Clinical laboratory evaluations are listed in Appendix 7. Blood 
volume required is listed in Appendix 8. 
Patients will be asked to provide urine samples for a drugs of abuse screen and undergo an 
alcohol breath test at the times indicated in the Schedule of Assessments in Appendix 1.  For all 
female subjects, a pregnancy test will be performed at the times indicated in the Schedule of 
Assessments in Appendix 1. 
The Investigator (or designee) will perform a clinical assessment of all clinical laboratory data. 
8.2.3 
Vital Signs 
Supine blood pressure, supine pulse rate, respiratory rate, and body temperature will be assessed 
at the times indicated in the Schedule of Assessments in Appendix 1. Vital signs may also be 
performed at other times if judged to be clinically appropriate or if the ongoing review of the 
data suggests a more detailed assessment of vital signs is required. 
All measurements will be performed singly and repeated once if outside the relevant clinical 
reference range. 
Patients must be supine for at least 5 minutes before blood pressure, heart rate, and temperature 
measurements. During the in-house period of the Core Phase, blood pressure, heart rate, and 
temperature measurements should be conducted in the morning.  When scheduled at the same 
time, vital sign assessments are to be performed prior to PK blood draws, with blood draws to 
occur as close to the nominal times as possible except for Screening and Day -1. 
8.2.4 
12-Lead Electrocardiogram 
Resting 12-lead ECGs will be recorded after the patient has been supine and at rest for at least 5 
minutes at the times indicated in the Schedule of Assessments in Appendix 1.  
Single 12-lead ECGs will be repeated once if either of the following criteria apply postdose: 
• QTcF > 500 msec 
• QTcF change from the baseline (predose) is > 60 msec 
Additional 12-lead ECGs may be performed at other times if judged to be clinically appropriate 
or if the ongoing review of the data suggests a more detailed assessment of ECGs is required. 
The investigator (or designee) will perform a clinical assessment of each 12-lead ECG.  When 
numerous assessments are scheduled at the same time, ECGs are to be performed prior to vital 
sign assessments and PK blood draws, with PK blood draws to occur as close to the nominal 
times as possible except for Screening and Day -1. 
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8.2.5 
Physical Examination 
Complete and limited physical examinations will be performed at the timepoints specified in the 
Schedule of Assessments in Appendix 1.  A complete physical examination includes a review of 
the following systems: head/neck/thyroid; eyes/ears/nose/throat; respiratory; cardiovascular; 
lymph nodes; abdomen; skin; musculoskeletal; and neurological. A limited physical examination 
includes an assessment of the patient’s general appearance, skin, thorax/lungs, cardiovascular, 
and abdomen. 
8.2.6 
Tumor Assessments 
Tumor imaging (CT or magnetic resonance imaging [MRI], with preference for CT) will be 
performed at Screening and every 8 weeks (± 7 days) or as per standard of care. At the PI’s 
discretion, CT or MRI scans may be repeated at any time if disease progression (PD) is 
suspected. The same imaging technique should be used for each patient throughout the study. 
8.3 
End-of-Treatment Visit 
EOT Visit should occur within 7 days after the last dose of rifampin/itraconazole (Core Phase) or 
pamiparib (Extension Phase). 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. During the 
Extension Phase, the visit at which tumor assessments showed PD may be used as the EOT visit 
providing 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. 
8.4 
Safety Follow-up Visit/Call  
The Safety Follow-Up visit will occur 30 days (±7 days) after the last dose of study drug or 
before initiation of new anticancer therapy, whichever occurs first. The Safety Follow-up in the 
Core Phase is only to be conducted if the patient does not continue to the Extension Phase.  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 9.1.4 should be made. 
 
 
 
 
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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 study 
drug, whether considered related to study drug or not.  
Examples of AEs include:  
• Worsening of a chronic or intermittent pre-existing condition including an increase in 
severity, frequency, duration, and/or has an association with a significantly worse 
outcome 
• New conditions detected or diagnosed after study drug administration even though it may 
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 study drug 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 prior to submission to the sponsor. 
9.1.2 
Assessment of Severity 
The investigator will assess the severity for each AE and SAE reported during the study. AEs 
and SAEs should be assessed and graded based upon the NCI-CTCAE v5.0. 
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 
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• Grade 4: Life-threatening consequences; urgent intervention indicated 
• 
Grade 5: Death related to AE 
Note: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity 
(for example, 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 9.2. 
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 
• An AE should be considered “related” to pamiparib if any of the following are met, 
otherwise the event should be assessed as “not related”: 
o There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out 
o There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely 
o There is some evidence to suggest a causal relationship (eg, the AE occurred 
within a reasonable time after administration of pamiparib). However, the 
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influence of other factors may have contributed to the AE (eg, the patient’s 
clinical condition or other concomitant AEs). 
o 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 SAE form changes signed and dated by the investigator. The updated SAE 
follow-up report/eCRF should be re-sent to the sponsor within the time frames outlined in 
Section 9.5.1. 
If a patient is lost to follow-up, study center personnel must do their utmost to re-establish contact 
with the patient. 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. 
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 
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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 
• 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 were 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: 
o Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
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baseline 
o Hospitalization for social/convenience considerations 
o Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
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 prior to the administration of the study drug, only SAEs should 
be reported to the sponsor. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to pamiparib or 
placebo, will be reported until 30 days after the last dose of study drug 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 treatment. 
After a patient is discontinued from the study, investigators are not obligated to actively seek 
AEs or SAEs from the former patient. 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”. 
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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.” 
9.5 
Prompt Reporting of Serious Adverse Events 
9.5.1 
Timeframes for Submitting Serious Adverse Events 
If serious adverse events are identified by or reported to the investigator or study team, the SAEs 
will be reported within 24 hours of first knowledge of the SAEs to the sponsor or designee as 
described in Table 3 once the investigator determines that the AE meets the protocol definition 
of an SAE. 
Table 3:  
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 SAE and 
forwarded to the sponsor or designee within the designated timeframes. The paper SAE form, 
signed by the investigator, should be scanned and faxed and/or e-mailed to IQVIA. The original 
SAE form should then be filed appropriately, along with proof of reporting. 
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 
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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. 
When a study center receives an initial or follow-up safety report or other safety information (eg, 
revised IB) 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 IB) 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 a female patient or the partner of a male patient becomes pregnant while receiving study drug 
or within 6 months after completion of the last dose of study drug, 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 study 
drug should be recorded and reported as an SAE.  
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10 
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. 
10.1 
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 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. 
10.2 
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. 
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. 
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 monitor will review the eCRFs and evaluate them for completeness and consistency. The 
eCRF will be compared with the source documents to ensure that there are no discrepancies 
between critical data. All entries, corrections, and alterations are to be made by the responsible 
investigator or his/her designee. The monitor cannot enter data in the eCRFs. Once clinical data 
have been entered into the eCRF, any corrections or alterations to the data fields will be traceable 
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via an audit trail, meaning that the reason for change, the name of the person who performed the 
change, together with time and date will be logged. Roles and rights of the study center 
personnel responsible for entering the clinical data into the eCRF will be determined in advance. 
If additional corrections are needed, the responsible monitor or data manager will raise a query in 
the EDC application. The appropriate study center personnel will respond to any queries raised. 
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. 
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. 
The eCRF records will be automatically appended with the identification of the creator by means 
of their unique User ID. Specified records will be electronically signed by the investigator to 
document his/her review of the data and acknowledgement that the data are accurate. This will 
be facilitated by means of the investigators unique User ID and password; date and time stamps 
will be added automatically at the time of the electronic signature. If an entry on an eCRF 
requires change, the correction should be made in accordance with the relevant software 
procedures. All changes will be fully recorded in a protected audit trail, and a reason for the 
change will be required. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) Version 
20.10 or higher. Concomitant medications will be coded using the World Health Organization 
Drug Dictionary. Concomitant diseases/medical history will be coded using the MedDRA 
Version 20.10 or higher. 
10.3 
Quality Assurance 
To ensure compliance with GCP 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. 
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11 
SAMPLE SIZE AND DATA ANALYSES 
11.1 
Determination of Sample Size 
Approximately 24 patients (approximately 12 in each part) will be enrolled to ensure that 
20 patients (10 in each part) complete the study. 
The sample size chosen for this study was based on precedent set by other PK studies of similar 
nature and was not based on power calculations. 
11.2 
Analysis Populations 
11.2.1 
Pharmacokinetic Population 
The PK population will include all patients who received at least 1 dose of pamiparib and have 
evaluable PK data. A patient will be excluded from the PK summary statistics and statistical 
analysis if the patient has an AE of vomiting that occurs at or before 2 x median tmax. 
11.2.2 
Safety Population 
The safety population will include all patients who received at least 1 dose of pamiparib. 
11.3 
Pharmacokinetic Analyses 
The plasma PK parameters of pamiparib following pamiparib dosing on Days 1 and 10 in Part A 
and Days 1 and 7 in Part B will be calculated from pamiparib concentration-time profiles using 
standard noncompartmental methods. Leftover plasma samples may be analyzed for 
metabolite(s) of interest. 
The primary PK parameters are AUC0-t, AUC0-∞, AUC0-12, Cmax, tmax, t1/2, CL/F, and Vz/F for 
pamiparib. Other PK parameters may be reported but will be regarded as secondary and will not 
be subject to inferential statistical analysis.  
A linear mixed-model analysis will be applied to analyze the log-transformed primary PK 
parameters (AUC0-t, AUC0-∞, and Cmax) for each part of the study. The model assumes a fixed 
effect for treatment and a random effect for patient. 
Estimates of geometric mean ratios together with the corresponding 90% confidence intervals 
will be derived for the comparisons of the PK parameters as follows: 
• Part A: pamiparib plus rifampin (test) versus pamiparib alone (reference) 
• Part B: pamiparib plus itraconazole (test) versus pamiparib alone (reference) 
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11.4 
Safety Analysis 
All AEs will be listed and summarized using descriptive methodology. The incidence of AEs for 
each treatment will be presented by severity and by association with the study drugs, as 
determined by the investigator. Each AE will be coded using MedDRA. Observed values for 
clinical laboratory evaluations data, 12-lead ECGs, and vital signs will be listed and summarized 
descriptively. 
 
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12 
REGULATORY, ETHICAL AND STUDY OVERSIGHT 
CONSIDERATIONS 
12.1 
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. 
12.2 
Investigator Responsibilities 
12.2.1 
Regulatory and Ethical Considerations 
This study will be conducted by the principal investigator and the study center in accordance 
with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
• Applicable International Conference on Harmonisation (ICH) GCP Guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, IB, and other relevant documents must be submitted to 
an Ethics Committee (EC) by the PI and reviewed and approved by the EC, and also approved by 
the regulatory authority (as applicable by local law and regulation), before the study is initiated.  
Any substantial protocol amendments, likely to affect the safety of the patients or the conduct of 
the study, will require EC and regulatory authority (as locally required) approval before 
implementation of changes made to the study design, except for changes necessary to eliminate 
an immediate hazard to study patients or any non-substantial changes, as defined by regulatory 
requirements. 
The PI will be responsible for the following: 
• Providing written summaries of the status of the study to the EC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the EC 
• Notifying the EC of SAEs or other significant safety findings as required by EC 
procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 Code of Federal Regulations (CFR), ICH guidelines, the EC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local regulations 
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The study will additionally be approved by the Administration of Radioactive Substances 
Advisory Committee. 
12.3 
Informed Consent  
Prior to starting participation in the study, each patient will be provided with a study-specific ICF 
giving details of the study drugs, procedures, and potential risks of the study. Patients will be 
instructed that they are free to obtain further information from the PI (or designee) and that their 
participation is voluntary, and they are free to withdraw from the study at any time. Patients will 
be given an opportunity to ask questions about the study prior to providing consent for 
participation. 
Following discussion of the study with CRU personnel, patients will sign 3 copies of the ICF in 
the presence of a suitably trained member of staff to indicate that they are freely giving their 
informed consent. One copy will be given to the patient, one placed in the site file, and the other 
will be maintained in the patient’s records. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
12.4 
Confidentiality 
Information on maintaining patient confidentiality in accordance to 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 US, a 
study-center specific HIPAA consent may be used). The investigator must assure that patients’ 
anonymity will be strictly maintained and that their identities are protected from unauthorized 
parties. Only patient initials, date of birth, and an identification code (ie, not names) should be 
recorded on any form or biological 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 IB, this protocol, eCRFs, the Investigational New Drug (IND), 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 site to any third party or otherwise 
into the public domain. 
If a written contract for the conduct of the study includes confidentiality provisions inconsistent 
with this section is executed, that contract’s provisions shall apply to the extent they are 
inconsistent with this section. 
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12.5 
Inspections 
The investigator should understand that the facilities used for this trial and all 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. 
12.6 
Protocol Adherence 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators assert they will apply due 
diligence to avoid protocol deviations and shall report all protocol deviations to sponsor. 
12.7 
Patient Data Protection 
Patients will be assigned a unique identifier and will not be identified by name in eCRFs, study-
related forms, study reports, or any related publications. Patient and PI personal data will be 
treated in compliance with all applicable laws and regulations. In the event the study protocol, 
study report, or study data are included in a public registry, all identifiable information from 
individual patients or PI will be redacted according to applicable laws and regulations.  
The patient must be informed that their personal study-related data will be used by the sponsor in 
accordance with local data protection law. The level of disclosure must also be explained to the 
patient. The patient must also be informed that their study-related data may be examined by 
sponsor or Contract Research Organization (CRO) auditors or other authorized personnel 
appointed by the sponsor, by appropriate EC members, and by inspectors from regulatory 
authorities. 
12.8 
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The PI (or designee) 
agrees not to disclose such information in any way without prior written permission from the 
Sponsor. 
12.9 
Data Quality Assurance 
The following data quality steps will be implemented: 
• All patient data relating to the study will be recorded on eCRFs unless directly 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The PI is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF. 
• The PI must maintain accurate documentation (source data) that supports the information 
entered in the eCRF. 
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• The PI must permit study-related monitoring, audits, EC review, and regulatory agency 
inspections and provide direct access to source data documents. 
• CRO is responsible for the data management of this study including quality checking of 
the data. Predefined, agreed risks, monitoring thresholds, quality tolerance thresholds, 
controls, and mitigation plans will be documented in a risk management register. 
Additional details of quality checking to be performed on the data may be included in a 
Data Management Plan.  
• A study monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and verifiable 
rom source documents; that the safety and rights of patients are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the PI in the study site archive for at least 25 years after the end of 
the study unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party 
without written notification to the sponsor. 
12.10 
Principal Investigator Documentation Responsibilities 
All individual, patient-specific study data will also be entered into a 21 CFR Part 11-compliant 
electronic data capture (EDC) system on an eCRF in a timely fashion.  
All data generated from external sources (eg, laboratory and bioanalytical data), and transmitted 
to the sponsor or designee electronically, will be integrated with the patient’s eCRF data in 
accordance with the Data Management Plan. EDC data will be transmitted to the sponsor at the 
end of the study as well.  
An eCRF must be completed for each patient who signs an ICF, undergoes screening procedures, 
and is not a screen failure in accordance with the eCRF completion instructions. The Sponsor, or 
CRO, will review the supporting source documentation against the data entered into the eCRFs 
to verify the accuracy of the electronic data.  
The PI will ensure that corrections are made to the eCRFs and that data queries are resolved in a 
timely fashion by the study staff. The PI will sign and date the eCRF via the EDC system’s 
electronic signature procedure. These signatures will indicate that the PI reviewed and approved 
the data on the eCRF, data queries, and site notifications. 
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12.11 
Sponsor Responsibilities 
12.11.1 
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. 
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. 
12.11.2 
Use of Information and Publication 
A CSR will be prepared and provided to the regulatory agency(ies) of participating countries. 
BeiGene will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be 
prepared in certain cases. 
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 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 
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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. 
12.11.3 
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 study drug(s) 
• 
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 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 study drug(s) 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. 
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12.12 
Records Retention and Study Files 
12.12.1 
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.  
The sponsor will inform the investigator of the time period 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 25 years. 
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 the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, arrangements must be made between the investigator and BeiGene to store these 
in secure containers outside of the study center so that they can be returned 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. 
Biological samples at the conclusion of this study may be retained as outlined in the agreement 
with the CRO managing the biological samples, for the shorter of: a period of up to 10 years or 
as allowed by the site’s IRB/IEC.  
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12.12.2 
Provision of Study Results and Information to Investigator 
When the CSR is completed, the sponsor will provide the major findings of the study to the 
investigator. 
The sponsor will not routinely inform the investigator or patient of any exploratory biomarker 
tests 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. 
12.13 
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) is 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 which becomes publicly available through no fault of the investigator or 
study center personnel 
• Information which is necessary to disclose in confidence to an IEC/IRB solely for the 
evaluation of the study 
• Information which is necessary to disclose in order to provide appropriate medical care to 
a patient 
• Study results that may be published as described in Section 12.11.2 
If a written contract for the conduct of the study which includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 
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12.14 
Joint Investigator/Sponsor Responsibilities 
12.14.1 
Access to Information for Monitoring 
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the data recorded in the eCRFs for 
consistency. 
The monitor is responsible for routine review of the CRFs 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. 
12.14.2 
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. 
 
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13 
REFERENCES 
Pamiparib (BGB-290) – Investigator’s Brochure (Version 4.0, 07 June 2018). 
Coleman RL, Oza AM, Lorusso D, et al. ARIEL3 investigators. Rucaparib maintenance 
treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a 
randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;pii: 0140-
6736(17)32440-6. 
Center for Drug Evaluation and Research (CDER). Draft Guidance for Industry. Dated October 
24, 2017.  Clinical Drug Interaction Studies — Study Design, Data Analysis, and Clinical 
Implications. Accessible at: https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf.  
Accessed on December 19, 2018. 
Edwards SL, Brough R, Lord CJ, et al. Resistance to therapy caused by intragenic deletion in 
BRCA2. Nature. 2008;451:1111-1115. 
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. 
European Medicines Agency, Committee for Human Medicinal Products (CHMP). CHMP 
(2012) Guideline on the Investigation of Drug Interactions. Accessible at: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/07/WC500
129606.pdf.  Accessed on December 19, 2018. 
Fong PC, Yap TA, Boss DS, et al. Poly(ADP)-ribose polymerase inhibition: frequent durable 
responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 
2010;28(15):2512-2519. 
Gelmon KA, Tischkowitz M, Mackay H, et al. Olaparib in patients with recurrent high-grade 
serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, 
multicentre, open-label, non-randomised study. Lancet Oncol. 2011;12:852-861. 
Liu L, Bello A, Dresser MJ, et al. Best practices for the use of itraconazole as a replacement or 
ketoconazole in drug-drug interaction studies. J Clin Pharmacol. 2016;56(2):143-151. 
Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science. 2017; Mar 
17;355(6330):1152-1158. 
Lynparza (olaparib) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. 
Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive, 
recurrent ovarian cancer. N Engl J Med. 2016;375(22):2154-2164. 
O’Connor MJ. Targeting the DNA damage response in cancer. Mol Cell. 2015; Nov 
19;60(4):547-560. 
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Oken MM, Creech RH, Tormey DC, et al. Toxicity in response of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 
Pommier Y, O’Connor MJ, de Bono J. Laying a trap to kill cancer cells: PARP inhibitors and 
their mechanisms of action. Sci Transl Med. 2016; Oct 26;8(362):362ps17.  
Reitman ML, Chu X, Cai X, et al. Rifampin’s acute inhibitory and chronic inductive drug 
interactions: Experimental and model-based approaches to drug-drug interaction trial design. 
Clin Pharmacol Ther. 2011;89(2):234-242. 
Ricks TK, Chiu HJ, Ison G, et al. Successes and Challenges of PARP inhibitors in cancer 
therapy. Front Oncol. 2015; Oct 14;5:222. 
Rubraca (rucaparib) [package insert]. Boulder, CO: Clovis Oncology, Inc.; 2017. 
Sakai W, Swisher EM, Jacquemont C, et al. Functional restoration of BRCA2 protein by 
secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma. Cancer Res. 
2009;69(16):6381-6386. 
Sakai W, Swisher EM, Karlan BY, et al. Secondary mutations as a mechanism of cisplatin 
resistance in BRCA2-mutated cancers. Nature. 2008;451(7182):1116-1120. 
Swisher EM, Lin KK, Oza AM, et al. Rucaparib in relapsed, platinum-sensitive high-grade 
ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. 
Lancet Oncol. 2017 Jan;18(1):75-87. 
Xu Y, Zhou Y, Hayashi M, et al. Simulation of clinical drug-drug interactions from hepatocyte 
CYP3A4 induction data and its potential utility in trial designs. Drug Metab Dispos. 
2011;39(7):1139-1148. 
Zejula (niraparib) [package insert]. Waltham, MA: Tesaro, Inc.; 2017. 
 
 
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14 
APPENDICES 
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Appendix 1: Schedule of Assessments 
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Schedule of Assessments: Part A 
 
Study Procedures 
Screening 
Core Phase 
Safety Follow-up 
Visit (≤30 days 
after last dose) p 
Day of Phase 
Days -28 
to -1n 
Day 
-1 
Day 1 
Days 2 to 11 
Day 12 
Core Phase 
EOT Visit (≤7 
days after last 
dose) 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
Confirm eligibility 
(laboratory values) a 
 
X 
 
 
 
 
 
Demographic data b 
X 
 
 
 
 
 
 
Medical history c 
X 
 
 
 
 
 
 
ECOG Performance 
Status 
X 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
Serum pregnancy 
test/FSH d 
X (Days -7 to -1) 
 
 
 
 
 
Height, BMI e 
X 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
Serology (HBV, HCV) f 
X 
 
 
 
 
 
 
Study residence 
 
Check-in 
 
X 
 
 
 
 
 
Check-out 
 
 
 
 
X o 
 
 
Non-residential visit 
 
 
 
 
 
X 
 
Study drug administration g 
 
Pamiparib Dosing 
 
 
X 
Day 10 
 
 
 
Rifampicin Dosing 
 
 
 
Days 3 to 11 
 
 
 
Pharmacokinetics 
 
Blood samples for 
pamiparib concentration 
 
 
X (30 min predose, 
0.5, 1, 2, 4, 6, 9, 12, 
24, and 48 hours 
postdose) 
Day 10: 30 min predose, 
0.5, 1, 2, 4, 6, 9, 12, 24, 
and 48 hours postdose 
 
 
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Schedule of Assessments: Part A (Continued) 
Study Procedures 
Screening 
Core Phase 
Safety Follow-Up 
Visit (≤30 days 
after last dose) p 
Day of Phase 
Days -28 
to -1n 
Day 
-1 
Day 1 
Days 2 to 11 
Day 12 
Core Phase 
EOT Visit (≤7 
days after last 
dose) 
Safety and tolerability 
Adverse event recording  X 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
medication recording 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry, 
hematology and 
urinalysis h 
X 
X 
 
 
X 
X 
X 
Vital signs i 
X 
X 
X (30 min predose and 
1, 2, 4, and 24 hours 
postdose 
Day 10: 30 
min predose 
and 1, 2, 4, 
and 24 hours 
postdose 
X 
X 
X 
12-lead ECG j 
X 
 
X (30 min predose and 
2 hours postdose) 
Day 10: 30 
min predose 
and 2 hours 
postdose 
X 
X 
 
Complete physical 
examination k 
X 
X 
 
 
 
 
 
Limited physical 
examination l 
 
 
X 
X (Day 10) 
X 
X 
X 
CT or MRI m 
X 
 
 
 
 
 
 
Abbreviations: BMI = body mass index; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; ECG = electrocardiogram; EOT: 
end of treatment; FSH = follicle-stimulating hormone; MRI = magnetic resonance imaging; PK = pharmacokinetic; SAE = serious adverse event. 
a. 
Confirmation of eligibility: all laboratory values obtained on Day -1 must meet eligibility criteria.  
b. Demographic data: Date of birth, gender, ethnicity, and race must be recorded.  
c. 
Medical History/Current Medical Conditions:  General and disease specific medical history including a history of past and current medical conditions. 
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d. For females of childbearing potential, a highly sensitive serum pregnancy test must be performed at a central or local laboratory within 7 days before 
Day 1. For subsequent pregnancy testing, highly sensitive urine pregnancy tests, performed at a central or local laboratory, are allowed.  If a urine 
pregnancy test is positive, a confirmatory serum pregnancy test is required. 
e. 
Height will be measured at Screening only for BMI calculation. 
f. 
Serology: hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B Core antibody, and hepatitis C antibody 
g. On Day 1 and Day 10, patients are required to fast for at least 8 hours before and 4 hours after pamiparib and rifampin administration.  Water is 
allowed during the fasting period.  On Day 10, rifampin will be administered first, followed within 5 minutes by pamiparib. On Days 3-9 and Day 
patients are required to fast for 2 hours before and 1 hour after rifampin administration. 
h. Blood samples for clinical laboratory evaluations (clinical chemistry, hematology, and urinalysis) will be collected after at least an 8-hour fast. If 
Screening urinalysis and chemistry and hematology laboratory evaluations were performed within 3 days of Day-1, they do not need to be repeated on 
Day-1. 
i. 
Vital signs include supine blood pressure, supine pulse rate, respiratory rate, and body temperature.  Patients are to remain supine for at least 5 minutes 
prior to blood pressure and pulse rate measurements.  When scheduled at the same time, vital sign assessments are to be performed prior to PK blood 
draws, with blood draws to occur as close to the nominal times as possible except for Screening and Day -1. 
j. 
Patients are to remain supine for at least 5 minutes prior to ECG assessments.  When numerous assessments are scheduled at the same time, ECGs are 
to be performed prior to vital sign assessments and PK blood draws, with PK blood draws to occur as close to the nominal times as possible except for 
Screening and Day -1. 
k. Complete physical examination at Screening and Day -1.   
l. 
Limited physical examination to occur on Days 1, 10 and 12, EOT and Safety Follow-up includes assessment of general appearance and additional 
examination of symptomatic systems or those affected by the patient’s disease.  
m. A computed tomography (CT) or MRI scan of the thorax, abdomen, and pelvis plus other relevant evaluations as appropriate will be performed at 
Screening. 
n. All assessments obtained within 3 days of Day -1 do not have to be repeated on Day -1. 
o. Check-out takes place on Day 12 after all procedures have been completed. 
p. All patients, including those who withdraw early from the study, will have an EOT visit within 7 days after the last dose of rifampicin.  Safety Follow-
up in the Core Phase is only to be conducted if the patient does not continue to the Extension Phase.  All patients who permanently discontinue study 
drug will have a Safety follow-up approximately 30 days after the last day of study drug or before initiation of new anticancer therapy, whichever 
occurs first.  AEs and SAEs will be collected; clinical laboratory assessment should only be conducted if the patient had an ongoing clinical laboratory 
abnormality in the previous visit, which the PI considers to be related to study drug.  If no laboratory assessments are required, the patient should be 
contacted by telephone for a review of AEs/concomitant medications and the limited physical exam will not be performed. 
 
 
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Schedule of Assessments: Part B 
Study Procedures 
Screening 
Core Phase 
Safety 
Follow-
Up 
Visit (≤30 
days after 
last dose) 
p 
Day of Phase 
Days -28  
to -1n 
Day -
1 
Day 1 
Days 2 to 8 
Day 9 
Core Phase 
EOT Visit 
(≤7 days 
after last 
dose) 
Informed consent 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
Confirm eligibility 
(laboratory values) a 
 
X 
 
 
 
 
 
Demographic data b 
X 
 
 
 
 
 
 
Medical history c 
X 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
Alcohol breath test 
X 
X 
 
 
 
 
 
Serum pregnancy test/ FSH d 
X (Days -7 to -1) 
 
 
 
 
 
Height, BMI e 
X 
 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
 
 
Serology (HBV, HCV) f 
X 
 
 
 
 
 
 
Study residence 
 
Check-in 
 
X 
 
 
 
 
 
Check-out 
 
 
 
 
Xo 
 
 
Non-residential visit 
 
 
 
 
 
X 
 
Study drug administration g 
 
Pamiparib Dosing 
 
 
X 
Day 7 
 
 
 
Itraconazole Dosing 
 
 
 
Days 3 to 8 
 
 
 
Pharmacokinetics 
 
Blood samples for pamiparib 
concentration 
 
 
X (30 min 
predose, 0.5, 1, 2, 
4, 6, 9, 12, 24, 
and 48 hours 
postdose) 
Day 7:30 min predose, 0.5, 1, 2, 
4, 6, 9, 12, 24, and 48 hours 
postdose 
 
 
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Schedule of Assessments: Part B (Continued) 
Study Phase 
Screening 
Core Phase  
Safety 
Follow-
Up Visit 
(≤30 days 
after last 
dose) p 
Day of Phase 
Days -28  
to -1n 
Day -
1 
Day 1 
Days 2 to 8 
Day 9 
Core Phase 
EOT Visit 
(≤7 days 
after last 
dose) 
Safety and tolerability 
Adverse event recording  
X 
X 
X 
X 
X 
X 
X 
Prior/concomitant 
medication recording 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry, 
hematology and urinalysis h 
X 
X 
 
 
X 
X 
X 
Vital signs i 
X 
X 
X (30 min predose 
and 1, 2, 4, and 24 
hours postdose 
Day 7: 30 min 
predose and 1, 2, 
4, and 24 hours 
postdose 
X 
X 
X 
12-lead ECG j 
X 
 
X (30 min predose 
and 2 hours 
postdose) 
Day 7: 30 min 
predose and 2 
hours postdose 
X 
X 
 
Complete physical 
examination k 
X 
X 
 
 
 
 
 
Limited physical 
examination l 
 
 
X 
X (Day 7) 
X 
X 
X 
CT or MRI m 
X 
 
 
 
 
 
 
Abbreviations: BMI = body mass index; CT = computed tomography ECG = electrocardiogram; EOT: end of treatment; FSH = follicle-stimulating 
hormone; MRI = magnetic resonance imaging; PK = pharmacokinetic; SAE = serious adverse event. 
a. 
Confirmation of eligibility: all laboratory values obtained on Day -1 must meet eligibility criteria.  
b. Demographic data: Date of birth, gender, ethnicity, and race must be recorded.  
c. 
Medical History/Current Medical Conditions:  General and disease specific medical history including a history of past and current medical conditions. 
d. For females of childbearing potential, a highly sensitive serum pregnancy test must be performed at a central or local laboratory within 7 days before 
Day 1.  For subsequent pregnancy testing, highly sensitive urine pregnancy tests, performed at a central or local laboratory, are allowed.  If a urine 
pregnancy test is positive, a confirmatory serum pregnancy test is required. 
e. 
Height will be measured at Screening only for BMI calculation. 
f. 
Serology: hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B Core antibody, and hepatitis C antibody 
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g. On Day 1 and Day 7, patients are required to fast for at least 8 hours before and 4 hours after pamiparib and itraconazole administration.  Water is 
allowed during the fasting period.  Itraconazole will be administered approximately 30 minutes after completing a meal on Days 3 to 6 and 8.  On Day 
7, itraconazole will be administered first, followed within 5 minutes by pamiparib.  
h. Blood samples for clinical laboratory evaluations (clinical chemistry, hematology, and urinalysis) will be collected after at least an 8-hour fast. If 
Screening urinalysis and chemistry and hematology laboratory evaluations were performed within 3 days of Day-1, they do not need to be repeated on 
Day-1. 
i. 
Vital signs include supine blood pressure, supine pulse rate, respiratory rate, and body temperature.  Patients are to remain supine for at least 5 minutes 
prior to blood pressure and pulse rate measurements.  When scheduled at the same time, vital sign assessments are to be performed prior to PK blood 
draws, with blood draws to occur as close to the nominal times as possible except for Screening and Day -1. 
j. 
Patients are to remain supine for at least 5 minutes prior to ECG assessments.  When numerous assessments are scheduled at the same time, ECGs are 
to be performed prior to vital sign assessments and PK blood draws, with PK blood draws to occur as close to the nominal times as possible except for 
Screening and Day -1. 
k. Complete physical examination at Screening and Day -1.   
l. 
Limited physical examination to occur on Days 1, 7 and 9, EOT and Safety Follow-up includes assessment of general appearance and additional 
examination of symptomatic systems or those affected by the patient’s disease.  
m. A computed tomography (CT) or MRI scan of the thorax, abdomen, and pelvis plus other relevant evaluations as appropriate will be performed at 
screening 
n. All assessments obtained within 3 days of Day -1 do not have to be repeated on Day- 1. 
o. Check-out takes place on Day 9 after all procedures have been completed. 
p. All patients, including those who withdraw early from the study, will have an EOT visit within 7 days after the last dose of itraconazole. Safety 
Follow-up visit in the Core Phase is only to be conducted if the patient does not continue to the Extension Phase.  All patients who permanently 
discontinue study drug will have a Safety follow-up approximately 30 days after the last day of study drug or before initiation of new anticancer 
therapy, whichever occurs first.  AEs and SAEs will be collected; clinical laboratory assessment should only be conducted if the patient had an ongoing 
clinical laboratory abnormality in the previous visit, which the PI considers to be related to study drug.  If no laboratory assessments are required, the 
patient should be contacted by telephone for a review of AEs/concomitant medications and the limited physical exam will not be performed. 
 
 
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Schedule of Assessments Extension Phase 
Study Procedures 
Predose Visit 
(≤ 7 days prior 
to Cycle 1 
Day 1) e 
Cycles 1 and 2 
Cycle ≥ 3 f 
EOT visit g 
Safety Follow-
up 
Visit 
(≤30 days after 
last dose) h 
 
 
Day 1 i 
Day 15 
Day 1 
 
 
Allowed time window (days) 
 
± 2 
± 2 
± 2 
 
 
Body Weight 
X 
X 
 
X 
X 
 
ECOG performance status 
 
X 
 
X 
X 
 
Urinalysis 
X 
 
 
 
X 
 
Vital Signs a 
X 
 
 
 
X 
 
12-Lead ECG b 
X 
 
 
 
X 
 
Limited Physical examination c 
X 
X 
 
X 
X 
X 
Clinical chemistry and 
hematology 
X 
X 
X 
X 
X 
X j 
Pregnancy test 
X 
X 
 
X 
X 
 
Pamiparib administration d 
 
X (60 mg PO twice daily) 
 
 
Tumor assessments (CT or MRI 
scan) 
X (every 8 weeks ± 7 days) 
 
 
Adverse event recording  
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
Abbreviations: CT = computed tomography ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT: end of treatment; MRI = 
magnetic resonance imaging; PO = orally. 
a. 
Vital Signs: Blood pressure, heart rate, and temperature must be measured after the patient has been supine for 5 minutes at Screening and EOT. 
b. Single 12-lead ECGs will be repeated once if outside the clinical reference range, or there is other clinically significant finding. Repeat ECGs will be 
recorded in triplicate at least 2 minutes apart. ECGs will be recorded after the patient has been supine for 5 minutes. 
c. 
Limited physical examination: includes assessment of general appearance and additional examination of symptomatic systems or those affected by the 
patient’s disease. For the follow-up visit, the limited physical examination is only to be done if this visit is conducted while the patient is attending the 
clinic. 
d. Dosing: Pamiparib capsules should be administered continuously from Cycle 1 Day 1 (60 mg twice daily), until patients are discontinued from 
treatment. 
e. 
Predose visit: Assessments performed in the Core Phase Follow-up visit for Part 1 may be used as the predose visit for the Extension Phase if it occurs 
≤ 7days prior to the start of pamiparib treatment in Extension Phase.  
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f. 
Cycle 3+:Cycles will continue as long as the patient is experiencing clinical benefit, or until occurrence of progressive disease (PD), unacceptable 
toxicity, pregnancy, death, withdrawal of consent, lost to follow-up, major protocol violation which in the opinion of the sponsor would have 
significant impact on the study or its outcome, start of new anticancer therapy, withdrawal by the PI, or study termination by sponsor. 
g. End-of-Treatment (EOT) Visit: To occur within 7 days after the last day of study drug administration. A visit should be scheduled as soon as possible, 
but may occur later after discussion with the medical monitor for specific circumstances, such as prolonged hospitalization. An ECG does not need to 
occur at the EOT Visit if one was performed within 14 days prior to the visit. 
h. Safety Follow-up Visit: To occur approximately 30 days after the last day of study drug administration or before initiation of new anticancer therapy, 
whichever occurs first. If new anticancer therapy is initiated before this safety follow-up, a safety follow-up should be scheduled as soon as possible. 
Clinical laboratory evaluations are only required if the patient had an ongoing clinical laboratory abnormality at the previous visit that the principal 
investigator considered to be related to study drug. For patients who do not want to or cannot return to the clinic for the safety follow-up, the patient 
should be contacted by telephone for a review of adverse events.  
i. 
Cycle 1 Day 1: Assessments will be conducted prior to first dosing in the Extension Phase. 
j. 
Follow-up assessments: only to be conducted if the patient has an ongoing laboratory abnormality at the previous visit that the PI considers to be 
related to the study drug. 
 
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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 exam (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 the presence or disappearance of bone lesions. 
• 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 
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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 
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sum 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 P10 mm 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) in order 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, in order 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 time points 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. 
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 
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concept applies 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 FDG-PET (PET scanning with the tracer fluorine-18 [F-18]fluorodeoxyglucose [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-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 
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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 time points (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 time 
point 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)’ time point 
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 time point 
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 stable disease or PD are the primary endpoints, 
confirmation of response is not required since it will not add value to the interpretation of trial 
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results. However, elimination of the 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 
Stable disease 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 stable disease varies in different studies and diseases. If 
the proportion of patients achieving stable disease 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 two measurements for determination of stable disease. 
Note: The duration of response and stable disease 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-disease performance without restriction. 
(Karnofsky 90-100) 
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). 
(Karnofsky 70-80) 
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.  
(Karnofsky 50-60) 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
(Karnofsky 30-40) 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
(Karnofsky 10-20) 
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” and “No Childbearing Potential” 
Females of childbearing potential and nonsterile males must use a highly effective method of 
birth control while in either Phase of the study (Core Phase/Extension Phase) and for at least 6 
months after the last dose of pamiparib. In addition to a highly effective method of birth control, 
nonsterile males must also use a condom during intercourse while in either Phase of the study 
and for an additional 6 months after the last dose of pamiparib, even if the female partner of the 
male patient is already pregnant. 
Contraception Guidelines 
This study includes the use of the strong cytochrome P450 CYP3A inducer rifampin and the 
strong CYP3A inhibitor itraconazole, which may interact with hormonal contraceptives. Patients 
are not allowed to use hormonal contraceptives during the Core Phase of this study and for an 
additional 30 days after the last dose of either strong CYP3A inhibitor/inducer. 
The following highly effective methods of contraception are accepted during the Core Phase and 
for the additional 30 days following the end of Core Phase: 
 
• Non-hormonal intrauterine device (IUD) 
• Bilateral tubal occlusion 
• Vasectomized male partner 
• 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. 
After the 30 days following the last dose of either strong CYP3A inhibitor/inducer, patients are 
allowed to use hormonal contraceptives as listed below. Patients should be educated on how to 
transition from one birth control method to another, especially when initiating hormonal 
contraceptives while in the study. 
 
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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 
o oral 
o intravaginal 
o transdermal 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation  
o oral 
o injectable 
o implantable* 
• Intrauterine device (IUD)* 
• Intrauterine hormone-releasing system (IUS)* 
• Bilateral tubal occlusion* 
• Vasectomized male partner* 
• 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. 
*For this study, it is recommended the use of one of the contraception methods described above 
marked with an asterisk (*) as they are considered to have low user dependency. 
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Definitions of “Women of Childbearing Potential", “Women of No Childbearing Potential” 
As defined in this protocol, “women of childbearing potential” are female patients who are 
physiologically capable of becoming pregnant.  
Conversely, “women of no childbearing potential” are defined as female patients meeting > 1 of 
the following criteria: 
• Surgically sterile (ie, through bilateral salpingectomy, bilateral oophorectomy, or 
hysterectomy) 
• 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 
 
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 
Cardiac disease, but no symptoms and no limitation in ordinary physical 
activity, eg, no shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, eg, walking short distances (20-100 m). Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
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 FDA’s “Guidance for Industry, Drug Interaction Studies;” 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664 htm 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 
Medications to be Used with Caution  
Sensitive CYP2C9 Substrates or CYP2C9 Substrates with Narrow Therapeutic Index 
Celecoxiba 
Phenytoinb 
Warfarinb 
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a. Sensitive substrates: Drugs that exhibit an area under the concentration-time curve (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 
Data compiled from the FDA’s “Guidance for Industry, Drug Interaction Studies” 
(http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm09366
4 htm);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: Clinical Laboratory Evaluations 
Clinical Chemistry: 
Hematology: 
Urinalysis: 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Albumin 
Total bilirubin 
Direct bilirubin 
Blood urea nitrogen or urea 
Potassium 
Phosphorus 
Sodium 
Corrected calcium a 
Calcium 
Creatinine 
Glucose 
Lactate dehydrogenase 
Total protein 
 
Hematocrit 
Hemoglobin 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC differential: 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
Blood 
Glucose 
Ketones 
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic  
examination  
 
Viral Serology: b 
Urinary drug screen: c 
Hormone panel 
(females only): 
Hepatitis B surface antigen 
Hepatitis B surface antibody 
Hepatitis B Core antibody 
Hepatitis C antibody 
 
Including but not limited to: 
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/cannabinoids 
Alcohol breath test d 
Follicle-stimulating 
hormone b,e 
Serum pregnancy test 
(human chorionic 
gonadotropin) f 
a. 
Corrected calcium= calcium corrected for hypoalbuminemia (Serum calcium (mg/dL) + 0.8* (4-serum albumin 
[g/dL]). 
b. Analyzed at Screening only; for patients with known chronic but controlled hepatitis B or C, or with panel 
results unclear or suggestive of infection, a PCR test for viral DNA should be conducted to evaluate DNA 
levels. 
c. 
Analyzed at Screening and Day 1. 
d. Performed at Screening and Day 1. 
e. 
Postmenopausal females only as per Appendix 4. 
f. 
Performed at Screening and Check-in for all females. 
 
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Appendix 8: Total Blood Volume  
The following blood volume are the maximum planned to be withdrawn for each patient. 
Core Phase 
 
Volume per 
blood sample 
(mL) 
Maximum 
estimated 
number of blood 
samples 
Total amount 
of blood 
(mL) 
Clinical chemistry 
4.7 
5 
23.5 
Hematology 
2.7 
5 
13.5 
Serology 
7.5 
1 
7.5 
Glucose 
2.7 
5 
13.5 
Plasma for pamiparib 
concentration 
4 
20 
80.0 
Total: 
138.0 
Extension Phase 
Volume per 
blood sample 
(mL) 
Maximum estimated 
number of blood 
samples per visit 
Total amount of 
blood (mL) per 
visit 
Predose, End of 
treatment, 
and Safety 
Follow-up 
visits 
Clinical chemistry 
4.7 
1 
4.7 
Hematology 
2.7 
1 
2.7 
Glucose 
2.7 
1 
2.7 
Total:  
 
 
10.1 
Volume per 
blood sample 
(mL) 
Maximum estimated 
number of blood samples 
per cycle 
Total amount 
of blood (mL) 
per cycle 
Cycle 1 and Cycle 2 
Clinical chemistry 
4.7 
2 
9.4 
Hematology 
2.7 
2 
5.4 
Glucose 
2.7 
2 
5.4 
Cycles 3+ 
Clinical chemistry 
4.7 
1 
4.7 
Hematology 
2.7 
1 
2.7 
Glucose 
2.7 
1 
2.7 
Total: 
 
 
30.3 
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Appendix 9: Chronic Kidney Disease Epidemiology Collaboration 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) 
equation and the Modification of Diet in Renal Disease Study equation. The National Kidney 
Disease Education Program calculators rely on creatinine determinations, which are isotope 
dilution mass spectrometry traceable. All laboratories should be using creatinine methods 
calibrated to be isotope dilution mass spectrometry traceable.  
This CKD-EPI equation calculator should be used when Scr is reported in mg/dL. This equation 
is recommended when estimated GFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 x min (Scr /κ, 1)α x max(Scr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 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/communication-
programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-calculators/ckd-epi-adults-
conventional-units 
MDRD  
This IDMS-traceable MDRD study equation calculator should be used when Scr is reported in 
µmol/L. This equation should not be used when eGFR values above 60 mL/min/1.73 m² are 
desired. 
GFR (mL/min/1.73 m²) = 175 x (Scr/88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if 
African American) (SI units) 
Online calculator:  https://www.niddk.nih.gov/health-information/communication-
programs/nkdep/laboratory-evaluation/glomerular-filtration-rate-calculators/mdrd-adults-si-units 
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Appendix 10: Signature of Investigator 
 
Protocol Title: 
A Phase 1, Open-label, Parallel-group, Fixed-sequence Study 
to Investigate the Effect of the CYP3A Inducer Rifampin and 
the CYP3A Inhibitor Itraconazole on the Pharmacokinetics of 
Pamiparib (BGB-290) in Cancer Patients 
 
Protocol Identifier: 
BGB-290-105 
 
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: 
___________________________ 
 
 
___________________________ 
 
 
___________________________ 
 
 
___________________________ 
 
 
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Statistical Analysis Plan
BEI001PC-170016
Protocol: BGB-290-105
Version Date: 19 Dec 2019
EDSREP 009 T 01 E
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2.0 Table of Contents
1.0 Approvals ................................................................................................................................................1 
2.0 Table of Contents....................................................................................................................................2 
3.0 Introduction .............................................................................................................................................4 
4.0 Changes from Previous Version of Approved SAP ................................................................................4 
5.0 Study Objectives and Endpoints.............................................................................................................4 
5.1 Objectives ...........................................................................................................................................4 
5.1.1 Primary Objectives.......................................................................................................................4 
5.1.2 Secondary Objectives ..................................................................................................................4 
5.2 Endpoints ............................................................................................................................................4 
5.2.1 Primary Endpoints........................................................................................................................4 
5.2.2 Secondary Endpoints...................................................................................................................5 
6.0 Study Design...........................................................................................................................................5 
6.1 Sample Size Considerations...............................................................................................................6 
6.2 Randomization ....................................................................................................................................6 
7.0 Overview of Planned Analysis ................................................................................................................6 
7.1 Changes from Protocol .......................................................................................................................6 
7.2 Interim Analysis...................................................................................................................................6 
7.3 Final Analysis......................................................................................................................................6 
8.0 Data Review............................................................................................................................................7 
8.1 Data Management...............................................................................................................................7 
8.2 Acceptance of Data for Summarization ..............................................................................................7 
9.0 Definitions and General Analysis Methods .............................................................................................7 
9.1 Analysis Data Presentation.................................................................................................................7 
9.1.1 Rounding......................................................................................................................................7 
9.1.2 Imputation ....................................................................................................................................7 
9.1.3 Descriptive Statistics....................................................................................................................7 
9.1.4 Pooling .........................................................................................................................................7 
9.1.5 Unscheduled Measurements .......................................................................................................8 
9.2 Analysis Data Definitions ....................................................................................................................8 
9.2.1 Baseline Definition .......................................................................................................................8 
9.2.2 Treatment/Patient Grouping.........................................................................................................8 
9.2.3 Other Definitions ..........................................................................................................................8 
9.2.4 ADaM Datasets............................................................................................................................8 
9.3 Software ..............................................................................................................................................9 
9.4 Statistical Methods..............................................................................................................................9 
9.4.1 Statistical Outlier Determination...................................................................................................9 
9.4.2 Predetermined Covariates and Prognostic Factors.....................................................................9 
9.4.3 Hypothesis Testing.......................................................................................................................9 
9.5 TFL Layout ..........................................................................................................................................9 
10.0 Analysis Sets.........................................................................................................................................9 
10.1 Safety Population..............................................................................................................................9 
10.2 Pharmacokinetic Population .............................................................................................................9 
11.0 Patient Disposition ................................................................................................................................9 
12.0 Protocol Deviations and Violations .....................................................................................................10 
13.0 Demographic and Baseline Characteristics........................................................................................10 
13.1 Demographics.................................................................................................................................10 
13.2 Medical History................................................................................................................................10 
13.3 Anti-Cancer Treatments and Procedures .......................................................................................10 
13.4 Other Baseline Characteristics .......................................................................................................10 
14.0 Prior and Concomitant Medications/Procedures ................................................................................10 
15.0 Treatment Compliance and Exposure ................................................................................................10 
16.0 Pharmacokinetic Analyses..................................................................................................................11 
16.1 Pharmacokinetic Variables..............................................................................................................11 
 
 
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16.2 Estimation of Pharmacokinetic Parameters....................................................................................11 
16.3 Pharmacokinetic Concentrations ....................................................................................................13 
16.4 Statistics of Pharmacokinetic Parameters ......................................................................................13 
17.0 Tumor Assessment .............................................................................................................................14 
18.0 Safety Analyses ..................................................................................................................................14 
18.1 Safety Variables..............................................................................................................................14 
18.1.1 Adverse Events........................................................................................................................14 
18.1.2 Deaths and Serious Adverse Events .......................................................................................15 
18.1.3 Laboratory Data .......................................................................................................................15 
18.1.4 Vital Signs ................................................................................................................................16 
18.1.5 Electrocardiograms ..................................................................................................................16 
18.1.6 Other Observations Related to Safety .....................................................................................16 
19.0 References..........................................................................................................................................16 
Appendix 1: Glossary of Abbreviations.......................................................................................................17 
Appendix 2: Schedule of Assessments.......................................................................................................18 
Appendix 3: List of End of Text Outputs .......................................................Error! Bookmark not defined. 
Document History........................................................................................................................................27 
 
 
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3.0 Introduction
This Statistical Analysis Plan (SAP) describes the statistical methods that will be used during the analysis 
and reporting of data collected under BeiGene, Ltd, Protocol BGB-290-105.
This SAP should be read in conjunction with the study protocol and case report form (CRF). This version 
of the plan has been developed using the protocol amendment 1 dated 14 Jun 2019 and the final CRF(s) 
dated 19 Aug 2019.
An approved and signed SAP is a requirement for database lock. This SAP only covers the results that will
be processed by the PRA Early Development Services (EDS) Biostatistics Department.
PRA EDS will perform the Pharmacokinetic (PK) and Safety evaluations. 
This SAP supersedes the statistical considerations identified in the protocol; where considerations are 
substantially different, they will be so identified. Any post-hoc or unplanned analyses, or significant changes 
from the planned analysis in this SAP performed to provide results for inclusion in the clinical study report 
(CSR) but not included in this SAP, will be clearly identified in the CSR. Changes to planned analyses do 
not require an updated SAP but should be included in the CSR if significant.
4.0 Changes from Previous Version of Approved SAP
This is the first version of the SAP.
5.0 Study Objectives and Endpoints
5.1 Objectives
5.1.1 Primary Objectives
x
To determine the effect of the strong cytochrome P450 (CYP)3A inducer rifampin on the 
pharmacokinetics (PK) of pamiparib in patients with advanced solid tumors 
x
To determine the effect of the strong CYP3A inhibitor itraconazole on the PK of pamiparib in 
patients with advanced solid tumors 
5.1.2 Secondary Objectives
x
To evaluate the safety and tolerability of pamiparib when coadministered with rifampin or 
itraconazole in patients with advanced solid tumors 
x
To further investigate the safety of oral pamiparib in patients with advanced solid tumors (Extension 
Phase) 
5.2 Endpoints
5.2.1 Primary Endpoints
The PK outcome endpoints of pamiparib derived from the plasma concentration-time profiles following oral 
administration of pamiparib on Days 1 and 10 in Part A (rifampin interaction) and Days 1 and 7 in Part B 
(itraconazole interaction) are as follows:
x
maximum observed concentration (Cmax)
x
AUC from time zero to time of last quantifiable concentration postdose (AUC0-t)
x
AUC from zero to infinity (AUC0-)
x
AUC from zero to 12 hours (AUC0-12)
x
AUC from zero to 9 hours (AUC0-9)  
 
 
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x
x
time of the maximum observed concentration (tmax)
x
apparent terminal elimination half-life (t1/2)
x
apparent oral clearance (CL/F) 
x
apparent volume of distribution (Vz/F) 
5.2.2 Secondary Endpoints
x
incidence and severity of AEs 
x
incidence of laboratory abnormalities, based on hematology, clinical chemistry, and urinalysis test 
results 
x
vital sign assessments 
x
12-lead electrocardiogram (ECG) parameters 
x
physical examinations 
6.0 Study Design
This is an open-label, parallel-group, fixed-sequence study in male and female cancer patients. Part A will 
investigate the effect of CYP3A induction by rifampin on the single-dose PK of pamiparib, and Part B will 
investigate the effect of CYP3A inhibition by itraconazole on the single-dose PK of pamiparib. 
The study consists of two phases: the Core Phase, which is divided into Part A and Part B, and the 
Extension Phase. A total of approximately 24 patients will be enrolled (approximately 12 in each part) to 
ensure that at least 20 patients (10 in each part) complete the study. 
In Part A, all patients will receive the following treatments: 
x
• Day 1 and Day 10: single oral doses of 60 mg pamiparib 
x
• Days 3 to 11: oral doses of 600 mg rifampin once a day 
In Part B, all patients will receive the following treatments: 
x
• Day 1 and Day 7: single oral doses of 20 mg pamiparib 
x
• Days 3 to 8: oral doses of 200 mg itraconazole once a day 
After completing the Core Phase, patients may participate in the Extension Phase, in which they will receive 
pamiparib twice a day in 28-day cycles until progression of disease, unacceptable toxicity, withdraw 
consent, or any other reason for discontinuation.
 
 
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6.1 Sample Size Considerations
Approximately 24 patients (approximately 12 in each part) will be enrolled to ensure that 20 patients (10 
in each part) complete the study. 
The sample size chosen for this study was based on precedent set by other PK studies of similar nature 
and was not based on power calculations. 
6.2 Randomization
This is a nonrandomized study. The study has a fixed treatment sequence 
7.0 Overview of Planned Analysis
7.1 Changes from Protocol
There are no changes from protocol.
7.2 Interim Analysis
Primary and secondary endpoints from the core phase (part A and B) will be analyzed taking into 
consideration all data from all available patients for this phase.
7.3 Final Analysis
The final analysis will be performed once the extension phase of the study is complete, i.e. once all patients
have completed all study procedures. 
Final analysis will include safety data collected in the extension phase. For continuity reasons, core phase
safety data will be listed and summarized again for final analysis.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
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8.0 Data Review
8.1 Data Management
Data handling and transfer will take place under the Data Management Plan for the study.
8.2 Acceptance of Data for Summarization
Programming of analysis datasets and TFLs may be ongoing during the data management of the study. 
However, programming of analysis datasets and TFLs will be completed and quality controlled (QC’d) after 
clean data extraction for the core phase and after database lock for the extension phase. Only quality 
assured (QA’d) results released by the Bioanalytical Laboratories, or other external data source will be used 
for the programming of analysis datasets and TFLs for the final report. Any data values requiring
investigation or corrections that are identified while programming the analysis datasets and TFLs will be 
sent to the project Data Manager. Database will not be locked until the identified issues are resolved. 
9.0 Definitions and General Analysis Methods
9.1 Analysis Data Presentation
9.1.1 Rounding
In listings, data will be presented with the same precision as the original data.  Derived data will be rounded 
for presentation purposes. 
PK parameters will be as calculated in the datasets. For presentation purpose, PK parameters will be 
rounded to 3 significant digits for t1/2 and Tmax, and 4 significant digits for everything else for listings and 
tables.
Summary statistics will be calculated using individual parameter values before rounding.
For all safety summaries, the mean and median will be presented to one decimal place greater than the 
data, standard deviation to two greater than the data, and the minimum and maximum will be presented to 
the same number of decimal places as the data. 
Frequency percentages will be presented with one decimal.
9.1.2 Imputation
Unless otherwise noted data will not be imputed.
9.1.3 Descriptive Statistics
Unless otherwise indicated, continuous variables will be summarized with the following descriptive 
statistics: n (number of observations), (arithmetic) mean, standard deviation (SD), minimum (min) value, 
median, and maximum (max) value.
Where calculated, Geometric CV (%) = sqrt(exp(S2) - 1) x 100, where S2 is the sample variance of PK 
parameters in the logarithmic scale.
Categorical data will be summarized with frequencies and percentages. Percentages by categories will be 
based on the number of patients exposed within a category of interest.
For categorical data the categories will be presented in the tables exactly as they appear in the CRF / 
Database. No data manipulation will be done for presentation purposes.
9.1.4 Pooling
No data pooling will be performed.
 
 
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Disposition data including date of informed consent and end of treatment will be listed.
12.0 Protocol Deviations and Violations
Protocol deviations/violations will be listed.
13.0 Demographic and Baseline Characteristics
13.1 Demographics
Patient demographics will be summarized descriptively for all patients by part. The summary will include 
the patients’ age at informed consent (in years), gender, race, ethnicity, weight (in kg) at baseline, height 
(in cm), and BMI (in kg/m2) at baseline. Demographics will be summarized for the safety analysis set.
Associated person’s demographics will be listed.
13.2 Medical History
Medical history will be listed by part.
Disease history will be listed by part.
13.3 Anti-Cancer Treatments and Procedures
The following listings will be provided: 
x
listing of previous anti-cancer therapy 
x
listing of previous anti-cancer radiotherapy
x
listing of post treatment discontinuation anti-cancer therapy
These will include all collected data from the corresponding CRF pages.
13.4 Other Baseline Characteristics
The following baseline characteristics will be listed:
x
Non-compliance to inclusion or exclusion criteria (if any)
x
The results of alcohol screen 
x
The results of urine drug screen
x
The results of HBV/HCV tests
x
Viral load assessments
14.0 Prior and Concomitant Medications/Procedures
Prior and concomitant medication and procedures will be listed by part. Medications with an end date prior 
to the first dose of study drug will be considered prior medications. If a partial date allows a medication to 
be considered concomitant it will be categorized as such.
15.0 Treatment Compliance and Exposure
Exposure data will be listed.
The number of patients receiving doses of pamiparib, rifampin or itraconazole will be summarized 
separately for the core phase.
The following variables will be summarized using extension phase data only: 
•
The number of cycles initiated
•
Duration of treatment 
 
 
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The plasma PK parameters of pamiparib following pamiparib dosing on Days 1 and 10 in Part A and Days 
1 and 7 in Part B will be calculated from pamiparib concentration-time profiles using standard 
noncompartmental methods. with WinNonlin®.
In estimating the PK parameters, BQL values at the beginning of the profile will be set to zero. BQL values 
that occur after the first quantifiable point will be set to missing. Values that are embedded between BQLs, 
or quantifiable values occurring after two or more BQLs, may be set to missing at the discretion of the 
pharmacokineticist. Actual sampling times, rather than scheduled sampling times, will be used in all 
computations involving sampling times. If the actual time or dose time is missing, the scheduled time may 
be substituted in order to calculate the PK parameter. In the event the PK draw occurs during the start or 
end of daylight savings time, the time will be adjusted to reflect the actual time from when the study drug 
was taken rather than the time on the clock.
As appropriate, additional PK parameters may be calculated and reported.
16.3 Pharmacokinetic Concentrations
Plasma concentrations below the quantifiable limit (BQL) will be set to 0 in the computation of concentration 
summary statistics. 
Descriptive statistics, including number (N), number for higher or equal values of Lower Limit of 
quantification (N>=LLOQ), arithmetic mean, standard deviation (SD), coefficient of variation (%CV), 
standard error of the mean (SEM), minimum, median, maximum, and geometric mean will be used to 
summarize the plasma concentrations at each scheduled time point. As BQL results are set to 0, statistics 
will be calculated with 0 for BQL results, i.e. minimum will be displayed as 0, and the respective patient will 
be included in counting the number of patients with results, but excluded in counting the number of patients
with higher or equal values of LLOQ. Zero concentrations will be considered as missing in geometric mean 
calculations. If more than half of the patients have values BQL, the summary descriptive statistics will not 
be performed for that time point. 
Linear and semi-logarithmic plots of the arithmetic mean (+/-SD) plasma concentration by scheduled 
sampling time will be provided. These plots will show time in hours. The plots will match the summary table 
results and will not have an observation at a given time point if more than half of the patients have values 
BQL.
Linear and semi-logarithmic plots of the individual plasma concentration by actual sampling time will be 
provided by patient (one patient per page). These plots will show time in hours. In individual plots 
concentrations BQL will not be shown.
All individual patient plasma concentration data will be listed.
16.4 Statistics of Pharmacokinetic Parameters
Statistical analyses will be performed to assess the effect of steady-state itraconazole and rifampin on the 
PK of pamiparib using the treatment in combination with pamiparib as test and the treatment with pamiparib 
only as reference.
Summary statistics will include number (N), arithmetic mean, standard deviation (SD), %CV, standard error 
of the mean (SEM), minimum, median, maximum, and geometric mean. For Tmax, only n, median, min and 
max will be presented.
Data for each treatment part will be analyzed separately. 
A linear mixed model with a fixed effect for treatment and a random effect for patient will be used on the 
natural log-transformed parameters Cmax, AUC0-last, and AUC0-inf. A point estimate and the corresponding 
90% CI for the difference between least squares means of Test and Reference treatment (Test –
Reference) will be calculated. The antilogarithm of this value will be calculated to obtain the point estimate 
and the 90% CI for the ratio (Test/Reference) of the geometric means on the untransformed scale. For each 
 
 
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parameter selected for analysis, patients who do not have valid parameters in both periods will not be 
included for analysis.
The SAS PROC MIXED code is as follows:
proc mixed data = adpp;
by parameter;
class treatment patient;
model ln(aval) = treatment;
random patient;
lsmeans treatment / alpha = 0.1;
estimate “Pamiparib only vs Pamiparib with Itraconazole/Rifampin”
treatment -1 1 / e cl alpha=0.1;
run;
For parameters Cmax, AUC0-last, and AUC0-inf a listing of the individual patient ratios (Test/Reference) will 
be provided.
A forest plot of the geometric LS mean ratios of Cmax, AUC0-last, and AUC0-inf will be provided for a visual 
representation of the data.
All plasma PK parameters will be listed by patient. 
17.0 Tumor Assessment
Tumor identification and assessment will be listed..
18.0 Safety Analyses
18.1 Safety Variables
The following safety variables will be summarized:
x
Adverse Events (AEs)
x
Vital Signs, including weight
x
Electrocardiograms (ECG)
x
Clinical Laboratory Evaluations
All summaries will be by treatment within a part/treatment arm.
18.1.1 Adverse Events
Adverse events will be classified using the Medical Dictionary for Regulatory Activities (MedDRA) 
classification system. 
All adverse events (including non-treatment-emergent events) recorded on the CRF will be listed.
All AE summaries will include only treatment-emergent adverse events. Treatment-emergent adverse 
events are those AEs with an onset date on or after the date of first dose of study medication until the date 
of last study medication dose plus 30 days.
AEs will be categorized according to the following:
x
Prior to Day 1 (thus not summarized, just listed)
x
From Day 1 to the day prior to start rifampin or itraconazole dosing (category = pamiparib only)
x
Part A: The day of start of rifampin dosing to the day prior to combined pamiparib and rifampin 
dosing (category = rifampin)
x
Part A: At or after the day of coadministration until date of last dosing in core phase plus 30 days
and before the administration of pamiparib in the Extension Phase (category = pamiparib with 
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x
Part B: The day of start of itraconazole dosing to the day prior to combined pamiparib and 
itraconazole dosing (category = itraconazole)
x
Part B: At or after the day of coadministration until date of last dosing in core phase plus 30 days
and before the administration of pamiparib in the Extension Phase (category = pamiparib with 
itraconazole) 
x
Extension Phase AEs
An overview of all AE will present the following frequencies by treatment and part:
•
All treatment-emergent AEs
•
Grade 3 or greater treatment-emergent AEs
•
Treatment-related, treatment-emergent AEs
•
Serious treatment-emergent AEs
•
Serious, treatment-related treatment-emergent AEs
•
Treatment-emergent AEs with an outcome of death
•
Treatment-emergent AEs leading to discontinuation of study treatment
A breakdown of the number and percentage of patients reporting each adverse event, categorized by body 
system and preferred term, will be presented. Counting will be done by patient only, not by event; patients
will only be counted once within each body system or preferred term.
A summary of drug related events reported, categorized by relationship to either study drug, will be 
provided. Patients with multiple events within a particular body system or preferred term will be counted 
once for a relation to study drug within that body system or preferred term.
A summary of events reported, categorized by toxicity grade (CTCAE version 5.0), will be provided. If a 
patient experiences multiple occurrence of the same AE with different intensity toxicity grades, the patient 
will be counted once for the maximum (most severe) toxicity grade. AEs with a missing intensity will be 
presented in the summary table with a toxicity grade of “Missing”. For each toxicity grade, the number and 
percentage of patients with at least 1 treatment emergent AE of the given grade will be summarized. 
A listing of adverse events leading to treatment discontinuation will be provided.
The following missing data will be imputed as defined (for calculations only / will not be presented):
•
Missing AE start times for the determination of treatment emergence will be assumed to occur after 
treatment unless partial date documents the AE as happening prior to treatment
•
Missing or partial AE start date will be assumed to be after treatment for the determination of TEAE 
unless the start or end date is prior to treatment
18.1.2 Deaths and Serious Adverse Events
A listing of deaths and other serious adverse events will be provided.
18.1.3 Laboratory Data
All laboratory data will be listed. A separate listing, including results with CTCAE (version 5.0) grade 3 or 
higher will also be provided. For listings, normal ranges will be used directly from the clinical laboratory.
For summaries, clinical laboratory data will be presented using Système International (SI) units (also used 
in the SDTM Controlled Terminology). Data will be standardized for units while site specific reference 
ranges for normal results will be maintained (in the standardized unit). 
Hematology (including coagulation) and serum chemistry values at baseline, post-baseline and changes 
from baseline for each scheduled timepoint will be summarized. 
 
 
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For parameters with CTCAE grading, for all post-baseline results (scheduled and unscheduled) the shift to 
worst CTCAE grade after baseline grade will be identified per parameter and patient. This worst post 
baseline grade will be used in shift tables to summarize shifts from baseline using patient counts and 
percentages by treatment.
Pregnancy tests will be listed.
18.1.4 Vital Signs
Descriptive statistics will be provided to summarize vital signs and changes from baseline at each 
scheduled time and presented separately for each treatment group. All Vital Signs, including repeats in 
response to abnormalities, will be listed.
18.1.5 Electrocardiograms
Descriptive statistics will be provided to summarize ECG parameters and changes from baseline at 
scheduled time and presented separately for each treatment group, and overall.
ECG parameters will be listed.
18.1.6 Other Observations Related to Safety
ECOG Performance Status will be listed and summarized descriptively .
Physical examination data will be listed by patient
19.0 References
Clinical Study Protocol. A Phase 1, Open-label, Parallel-group, Fixed-sequence Study to Investigate the 
Effect of the CYP3A Inducer Rifampin and the CYP3A Inhibitor Itraconazole on the Pharmacokinetics of 
Pamiparib (BGB-290) in Cancer Patients. Version 1.0, Final, 14 Jun 2019.
 
 
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Appendix 2: Schedule of Assessments
Schedule of Assessments: Part A 
Study Procedures
Screening
Core Phase
Safety Follow-up
9LVLW  GD\V DIWHU
last dose) p
Day of Phase
Days -28 to 
-1n
Day 
-1
Day 1
Days 2 to 11
Day 12
Core Phase EOT 
9LVLW  GD\V
after last dose)
Informed consent
X
Inclusion/exclusion 
criteria
X
Confirm eligibility 
(laboratory values) a
X
Demographic data b
X
Medical history c
X
ECOG Performance Status X
Urine drug screen
X
X
Alcohol breath test
X
X
Serum pregnancy test/FSH 
d
X (Days -7 to -1)
Height, BMI e
X
Weight
X
X
X
Serology (HBV, HCV) f
X
Study drug administration g
Pamiparib Dosing
X
Day 10
Rifampicin Dosing
Days 3 to 11
Pharmacokinetics
Blood samples for 
pamiparib concentration
X (30 min predose, 0.5, 1, 
2, 4, 6, 9, 12, 24, and 48 
hours postdose)
Day 10: 30 min predose, 0.5, 
1, 2, 4, 6, 9, 12, 24, and 48 
hours postdose
Safety and tolerability
Adverse event recording
X
X
X
X
X
X
X
 
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Prior/concomitant 
medication recording
X
X
X
X
X
X
X
 
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Schedule of Assessments: Part A (Continued)
Study Procedures
Screening
Core Phase
Safety Follow-
Up
9LVLW  GD\V
after last dose) p
Day of Phase
Days -28 to -
1n
Day -
1
Day 1
Days 2 to 11
Day 
12
Core Phase EOT 
9LVLW  GD\V DIWHU
last dose)
Clinical chemistry, 
hematology and urinalysis h
X
X
X
X
X
Vital signs i
X
X
X (30 min predose and 
1, 2, 4, and 24 hours 
postdose
Day 10: 30 min predose
and 1, 2, 4, and 24 hours 
postdose
X
X
X
12-lead ECG j
X
X (30 min predose and 
2 hours postdose)
Day 10: 30 min predose 
and 2 hours postdose
X
X
Complete physical 
examination k
X
X
Limited physical 
examination l
X
X (Day 10)
X
X
X
CT or MRI m
X
Abbreviations: BMI = body mass index; CT = computed tomography; ECG = electrocardiogram; EOT: end of treatment; FSH = follicle-stimulating hormone; MRI = 
magnetic resonance imaging; PK = pharmacokinetic; SAE = serious adverse event.
a.
Confirmation of eligibility: all laboratory values obtained on Day -1 must meet eligibility criteria. 
b.
Demographic data: Date of birth, gender, ethnicity, and race must be recorded. 
c.
Medical History/Current Medical Conditions:  General and disease specific medical history including a history of past and current medical conditions.
d.
For females of childbearing potential, a highly sensitive serum pregnancy test must be performed at a central or local laboratory within 7 days before Day 1. 
For subsequent pregnancy testing, highly sensitive urine pregnancy tests, performed at a central or local laboratory, are allowed.  If a urine pregnancy test is 
positive, a confirmatory serum pregnancy test is required.
e.
Height will be measured at Screening only for BMI calculation.
f.
Serology: hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B Core antibody, and hepatitis C antibody
g.
On Day 1 and Day 10, patients are required to fast for at least 8 hours before and 4 hours after pamiparib and rifampin administration.  Water is allowed during 
the fasting period.  On Day 10, rifampin will be administered first, followed within 5 minutes by pamiparib. On Days 3-9 and Day patients are required to fast for 
2 hours before and 1 hour after rifampin administration.
h.
Blood samples for clinical laboratory evaluations (clinical chemistry, hematology, and urinalysis) will be collected after at least an 8-hour fast. If Screening 
urinalysis and chemistry and hematology laboratory evaluations were performed within 3 days of Day-1, they do not need to be repeated on Day-1.
i.
Vital signs include supine blood pressure, supine pulse rate, respiratory rate, and body temperature.  Patients are to remain supine for at least 5 minutes prior 
to blood pressure and pulse rate measurements.  When scheduled at the same time, vital sign assessments are to be performed prior to PK blood draws, with 
blood draws to occur as close to the nominal times as possible except for Screening and Day -1.
 
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j.
Patients are to remain supine for at least 5 minutes prior to ECG assessments.  When numerous assessments are scheduled at the same time, ECGs are to 
be performed prior to vital sign assessments and PK blood draws, with PK blood draws to occur as close to the nominal times as possible except for 
Screening and Day -1.
k.
Complete physical examination at Screening and Day -1.  
l.
Limited physical examination to occur on Days 1, 10 and 12, EOT and Safety Follow-up includes assessment of general appearance and additional 
examination of symptomatic systems or those affected by the patient’s disease. 
m. A computed tomography (CT) or MRI scan of the thorax, abdomen, and pelvis plus other relevant evaluations as appropriate will be performed at Screening.
n.
All assessments obtained within 3 days of Day -1 do not have to be repeated on Day -1.
o.
Check-out takes place on Day 12 after all procedures have been completed.
p.
All patients, including those who withdraw early from the study, will have an EOT visit within 7 days after the last dose of rifampicin. Safety Follow-up in the 
Core Phase is only to be conducted if the patient does not continue to the Extension Phase.  All patients who permanently discontinue study drug will have a 
Safety follow-up approximately 30 days after the last day of study drug or before initiation of new anticancer therapy, whichever occurs first.  AEs and SAEs 
will be collected; clinical laboratory assessment should only be conducted if the patient had an ongoing clinical laboratory abnormality in the previous visit, 
which the PI considers to be related to study drug.  If no laboratory assessments are required, the patient should be contacted by telephone for a review of 
AEs/concomitant medications and the limited physical exam will not be performed.
 
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Schedule of Assessments: Part B
Study Procedures
Screening
Core Phase
Safety 
Follow-Up
9LVLW 
days after 
last dose) p
Day of Phase
Days -28 to -1n
Day -1
Day 1
Days 2 to 8
Day 9
Core Phase 
(27 9LVLW 
days after last 
dose)
Informed consent
X
Inclusion/exclusion criteria
X
Confirm eligibility (laboratory 
values) a
X
Demographic data b
X
Medical history c
X
ECOG Performance Status 
X
Urine drug screen
X
X
Alcohol breath test
X
X
Serum pregnancy test/ FSH d
X (Days -7 to -1)
Height, BMI e
X
Weight
X
X
X
Serology (HBV, HCV) f
X
Study drug administration g
Pamiparib Dosing
X
Day 7
Itraconazole Dosing
Days 3 to 8
Pharmacokinetics
Blood samples for pamiparib 
concentration
X (30 min predose,
0.5, 1, 2, 4, 6, 9, 12, 
24, and 48 hours 
postdose)
Day 7:30 min predose, 0.5, 1, 2, 4, 6, 
9, 12, 24, and 48 hours postdose
Safety and tolerability
Adverse event recording
X
X
X
X
X
X
X
Prior/concomitant medication 
recording
X
X
X
X
X
X
X
 
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Schedule of Assessments: Part B (Continued)
Study Phase
Screening
Core Phase 
Safety 
Follow-Up
Visit
 GD\V
after last 
dose) p
Day of Phase
Days -28 to -1n
Day -1
Day 1
Days 2 to 8
Day 9
Core Phase 
(27 9LVLW 
days after last 
dose)
Clinical chemistry, hematology 
and urinalysis h
X
X
X
X
X
Vital signs i
X
X
X (30 min predose and 
1, 2, 4, and 24 hours 
postdose
Day 7: 30 min 
predose and 1, 2, 4, 
and 24 hours 
postdose
X
X
X
12-lead ECG j
X
X (30 min predose and 
2 hours postdose)
Day 7: 30 min 
predose and 2 hours 
postdose
X
X
Complete physical examination k
X
X
Limited physical examination l
X
X (Day 7)
X
X
X
CT or MRI m
X
Abbreviations: BMI = body mass index; CT = computed tomography ECG = electrocardiogram; EOT: end of treatment; FSH = follicle-stimulating hormone; MRI = 
magnetic resonance imaging; PK = pharmacokinetic; SAE = serious adverse event.
a.
Confirmation of eligibility: all laboratory values obtained on Day -1 must meet eligibility criteria. 
b.
Demographic data: Date of birth, gender, ethnicity, and race must be recorded. 
c.
Medical History/Current Medical Conditions:  General and disease specific medical history including a history of past and current medical conditions.
d.
For females of childbearing potential, a highly sensitive serum pregnancy test must be performed at a central or local laboratory within 7 days before Day 1.  
For subsequent pregnancy testing, highly sensitive urine pregnancy tests, performed at a central or local laboratory, are allowed.  If a urine pregnancy test is 
positive, a confirmatory serum pregnancy test is required.
e.
Height will be measured at Screening only for BMI calculation.
f.
Serology: hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B Core antibody, and hepatitis C antibody
g.
On Day 1 and Day 7, patients are required to fast for at least 8 hours before and 4 hours after pamiparib and itraconazole administration.  Water is allowed 
during the fasting period.  Itraconazole will be administered approximately 30 minutes after completing a meal on Days 3 to 6 and 8.  On Day 7, itraconazole 
will be administered first, followed within 5 minutes by pamiparib. 
h.
Blood samples for clinical laboratory evaluations (clinical chemistry, hematology, and urinalysis) will be collected after at least an 8-hour fast. If Screening 
urinalysis and chemistry and hematology laboratory evaluations were performed within 3 days of Day-1, they do not need to be repeated on Day-1.
 
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i.
Vital signs include supine blood pressure, supine pulse rate, respiratory rate, and body temperature.  Patients are to remain supine for at least 5 minutes prior 
to blood pressure and pulse rate measurements.  When scheduled at the same time, vital sign assessments are to be performed prior to PK blood draws, with 
blood draws to occur as close to the nominal times as possible except for Screening and Day -1.
j.
Patients are to remain supine for at least 5 minutes prior to ECG assessments.  When numerous assessments are scheduled at the same time, ECGs are to 
be performed prior to vital sign assessments and PK blood draws, with PK blood draws to occur as close to the nominal times as possible except for 
Screening and Day -1.
k.
Complete physical examination at Screening and Day -1.  
l.
Limited physical examination to occur on Days 1, 7 and 9, EOT and Safety Follow-up includes assessment of general appearance and additional examination 
of symptomatic systems or those affected by the patient’s disease. 
m. A computed tomography (CT) or MRI scan of the thorax, abdomen, and pelvis plus other relevant evaluations as appropriate will be performed at screening
n.
All assessments obtained within 3 days of Day -1 do not have to be repeated on Day- 1.
o.
Check-out takes place on Day 9 after all procedures have been completed.
p.
All patients, including those who withdraw early from the study, will have an EOT visit within 7 days after the last dose of itraconazole. Safety Follow-up visit in 
the Core Phase is only to be conducted if the patient does not continue to the Extension Phase.  All patients who permanently discontinue study drug will have 
a Safety follow-up approximately 30 days after the last day of study drug or before initiation of new anticancer therapy, whichever occurs first.  AEs and SAEs 
will be collected; clinical laboratory assessment should only be conducted if the patient had an ongoing clinical laboratory abnormality in the previous visit, 
which the PI considers to be related to study drug.  If no laboratory assessments are required, the patient should be contacted by telephone for a review of 
AEs/concomitant medications and the limited physical exam will not be performed.
 
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Statistical Analysis Plan
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Version Date: 19 Dec 2019
EDSREP 009 T 01 E
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Schedule of Assessments Extension Phase
Study Procedures
3UHGRVH 9LVLW  7
days prior to Cycle 
1 Day 1) e
Cycles 1 and 2
&\FOH  3 f
EOT visit g
Safety Follow-up
Visit
 GD\V DIWHU ODVW
dose) h
Day 1 i
Day 15
Day 1
Allowed time window (days)
± 2
± 2
± 2
Body Weight
X
X
X
X
ECOG performance status
X
X
X
Urinalysis
X
X
Vital Signs a
X
X
12-Lead ECG b
X
X
Limited Physical examination c
X
X
X
X
X
Clinical chemistry and hematology
X
X
X
X
X
X j
Pregnancy test
X
X
X
X
Pamiparib administration d
X (60 mg PO twice daily)
Tumor assessments (CT or MRI 
scan)
X (every 8 weeks ± 7 days)
Adverse event recording 
X
X
X
X
X
X
Concomitant medication
X
X
X
X
X
X
Abbreviations: CT = computed tomography ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT: end of treatment; MRI = magnetic 
resonance imaging; PO = orally.
a.
Vital Signs: Blood pressure, heart rate, and temperature must be measured after the patient has been supine for 5 minutes at Screening and EOT.
b.
Single 12-lead ECGs will be repeated once if outside the clinical reference range, or there is other clinically significant finding. Repeat ECGs will be recorded 
in triplicate at least 2 minutes apart. ECGs will be recorded after the patient has been supine for 5 minutes.
c.
Limited physical examination: includes assessment of general appearance and additional examination of symptomatic systems or those affected by the 
patient’s disease. For the follow-up visit, the limited physical examination is only to be done if this visit is conducted while the patient is attending the clinic.
d.
Dosing: Pamiparib capsules should be administered continuously from Cycle 1 Day 1 (60 mg twice daily), until patients are discontinued from treatment.
e.
Predose visit: Assessments performed in the Core Phase Follow-up visit for Part 1 may be used as the predose visit for the Extension Phase if it occurs 
 7days prior to the start of pamiparib treatment in Extension Phase. 
f.
Cycle 3+:Cycles will continue as long as the patient is experiencing clinical benefit, or until occurrence of progressive disease (PD), unacceptable toxicity, 
pregnancy, death, withdrawal of consent, lost to follow-up, major protocol violation which in the opinion of the sponsor would have significant impact on the 
study or its outcome, start of new anticancer therapy, withdrawal by the PI, or study termination by sponsor.
 
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Statistical Analysis Plan
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Version Date: 19 Dec 2019
EDSREP 009 T 01 E
Page 26 of 27
g.
End-of-Treatment (EOT) Visit: To occur within 7 days after the last day of study drug administration. A visit should be scheduled as soon as possible, but may 
occur later after discussion with the medical monitor for specific circumstances, such as prolonged hospitalization. An ECG does not need to occur at the EOT
Visit if one was performed within 14 days prior to the visit.
h.
Safety Follow-up Visit: To occur approximately 30 days after the last day of study drug administration or before initiation of new anticancer therapy, whichever 
occurs first. If new anticancer therapy is initiated before this safety follow-up, a safety follow-up should be scheduled as soon as possible. Clinical laboratory 
evaluations are only required if the patient had an ongoing clinical laboratory abnormality at the previous visit that the principal investigator considered to be 
related to study drug. For patients who do not want to or cannot return to the clinic for the safety follow-up, the patient should be contacted by telephone for a 
review of adverse events. 
i.
Cycle 1 Day 1: Assessments will be conducted prior to first dosing in the Extension Phase.
j.
Follow-up assessments: only to be conducted if the patient has an ongoing laboratory abnormality at the previous visit that the PI considers to be related to the 
study drug.
 
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Signature Page for VV-CLIN-083944 v1.0
Approval
Biometrics
16-Mar-2022 16:58:07 GMT+0000
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