Clinical trial NCT03575065
Conditions: HER2-negative Breast Cancer
Sponsor: BeiGene
Start date: 2018-06-22; Completion date: 2021-04-14
Enrollment: 88 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 2, open-label, multi-center study of BGB-290 administered orally (PO) twice daily (BID) in adult Chinese patients with advanced HER2(-) breast cancer harboring germline BRCA mutation, which have progressed despite standard therapy, or for which no standard therapy exists.

Detailed description:

Arms: arm 1: Locally advanced or metastatic TNBC arm 2: Locally advanced or metastatic Hormone receptor-positive(HR+) human epidermal growth factor receptor2 Negative(HER2-) breast cancer
Interventions: intervention 1: BGB-290
Intervention descriptions: intervention 1: Administered orally

Protocol documents:
Prot_000.pdf: 
BeiGene (Beijing) Co., Ltd. 
CONFIDENTIAL
BGB-290-201 
Protocol Amendment 1.0 
30 October 2018
 
Page 1 of 126 
 
Clinical Study Protocol 
Protocol Title:  
An Open Label, Multi-Center Phase 2 Study to 
Evaluate Efficacy and Safety of BGB-290 in the 
Treatment of Metastatic HER2-Negative Breast 
Cancer Patients with BRCA mutation in China 
Protocol Identifier: 
BGB-290-201 
Phase: 
2 
Date of Protocol: 
 
 
30 October 2018, Amendment 1.0 
Sponsor: 
BeiGene (Beijing) Co., Ltd 
No. 30, Science Park Rd. 
Zhong-Guan-Cun Life Science Park  
Changping District  
Beijing, China 102206 
Sponsor Medical Monitor: 
 
 
 
 
 
Confidentiality Statement 
This confidential information in this document is provided to you as an investigator or consultant 
for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics 
Committee. Your acceptance of this document constitutes agreement that you will not disclose 
the information contained herein to others without written authorization from the sponsor. 
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FINAL PROTOCOL APPROVAL SHEET 
An Open Label, Multi-Center Phase 2 Study to Evaluate Efficacy and Safety of BGB-290 
in the Treatment of Metastatic HER2-Negative Breast Cancer Patients with BRCA 
mutation in China 
BeiGene Approval: 
 
_______________________________________ 
 
Sponsor Medical Monitor  
 
___________________________________ 
Date 
 
 
 
 
 
 
 
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PROTOCOL AMENDMENT, VERSION 1.0 
The primary purpose of this amendment is to revise the dose modification algorithm for anemia. Content in the Notes to File to the 
original protocol were incorporated. Administrative updates, editorial changes, and/or style and formatting revisions were made to 
improve clarity and consistency throughout the document. Changes were made throughout the synopsis to match changes made in the 
protocol body. 
This amendment version number is Version 1.0.  
Key changes are summarized by section in the table below (where appropriate for clarity, additions may be in bold text and deletions 
may be in strikethrough text): 
Section 
Key Changes 
Rationale for change 
All sections 
 
Revised “BGB-290” to “pamiparib” 
To align with other 
protocols. 
Section 1.3: 
Biology of 
Germline BRCA-
mutant Breast 
Cancer and PARP 
Inhibitors 
 
Deleted “OlympiAD study has established the basis for approval of Olaparib in HER2(-) 
metastatic breast cancer patients.” 
 
Deleted “Two additional Phase 3 studies investigating a single-agent PARP inhibitor versus 
physician’s choice of chemotherapy in patients with germline BRCA1/2-mutated breast 
cancer are ongoing for niraparib and talazoparib.” 
 
Added a description of the EMBRACA study. 
 
Added “Both the OlympiAD and EMBRACA studies have consistently shown that a PARP 
inhibitor is a reasonable treatment option for patients with advanced TNBC or 
HR(+)/HER2(-) breast cancer with a germline BRCA1/2 mutation, since its use is associated 
with a PFS benefit, improvement in quality of life, and a favorable toxicity profile. Olaparib 
was approved in the US for patients with deleterious or suspected deleterious germline 
BRCA-mutant, HER2-negative metastatic breast cancer (Lynparza [olaparib] prescribing 
information).” 
To provide updated 
information regarding 
PARP inhibitors. 
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Section 
Key Changes 
Rationale for change 
Section 1.5 
Rationale for 
Selection of 
Pamiparib Dose 
 
Added “The BGB-290-102 Phase 1 study confirmed that the recommended dose for further 
investigation in Chinese patients was also 60 mg PO BID based on the following findings: 
o The AE profile observed from 15 female Chinese patients in the BGB-290-102 study 
was generally consistent with that from the BGB-290-AU-002 (Australia) study, and 
AEs could be managed clinically. 
o No DLTs and drug-related SAEs were observed across the dose range evaluated. 
o The average steady-state pamiparib plasma exposure (Cmax, AUC) at 60 mg BID in 
Chinese patients was approximately 35% higher than for Australian patients (BGB-290-
AU-002).  
In summary, pamiparib is an excellent candidate to determine the effects of PARP inhibition 
in advanced cancers.” 
To provide additional 
dose rationale 
information based on 
study results in Chinese 
patients. 
Section 3 Study 
Design 
 
Clarified study schema footnotes to “Key assessments during treatment phase: tumor 
assessments every 8 weeks  7 days in the first year and every 12 weeks  7 days in the 
second year and above.” 
To align with other 
sections of the 
protocol. 
Section 4.1 
Inclusion Criteria 
 
Inclusion Criterion 4d: Revised to “Prior therapy with an anthracycline and/or a taxane in 
neoadjuvant/adjuvant or metastatic setting” 
To clarify prior 
anthracycline and 
taxane therapy use. 
 
Inclusion Criterion 5: Added “Tumor lesions situated in a previously irradiated area, or in an 
area subjected to other loco-regional therapy, are usually not considered measurable unless 
there has been demonstrated progression in the lesion.” 
To clarify measurable 
disease definition. 
 
Inclusion Criterion 9: Revised to: 
Absolute neutrophil count ≥ 1,500/mL or ≥ 1.5 x 109/L 
Platelet count ≥ 75,000/mL or ≥ 75 x 109/L 
Hemoglobin ≥ 9 g/dL or ≥ 90 g/L (≥14 days after growth factor support or transfusion) 
To clarify values/units 
for adequate 
hematologic function 
per Note to File 001. 
To specify liver 
enzyme levels for 
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Section 
Key Changes 
Rationale for change 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN, if liver 
function abnormalities are due to liver metastasis, then AST and ALT ≤ 5 × ULN 
patients with liver 
metastasis. 
Section 4.2 
Exclusion Criteria 
 
Exclusion Criterion 3: Revised to: “Chemotherapy, hormonal therapy, radiotherapy, 
biologic therapy, immunotherapy, investigational agent, anticancer Chinese medicine, or 
anticancer herbal remedies ≤ 14 days (or ≤ 5 half-lives, if applicable, whichever is shorter) 
prior to Day 1 of Cycle 1” 
o Revised from “Bisphosphonate and denosumab use is permitted if the patient has already 
been receiving it at a stable dose for >28 days prior to the first dosing.” to 
“Bisphosphonate and RANK-L inhibitors are allowed for bone metastases if initiated 
before enrollment and at a stable dose.” 
To add hormonal 
therapy to exclusion 
criteria. To permit the 
use of any RANK-L 
inhibitor (not solely 
denosumab) and to 
specify requirements 
for bisphosphonate and 
RANK-L inhibitor use 
per Note to File 003. 
 
Exclusion Criterion 13: Revised to: “Females of childbearing potential require a negative 
urine or serum pregnancy test  7 days prior to Day 1 of Cycle 1” 
To allow flexibility in 
the method of 
pregnancy screening 
tests. 
Section 5.2 
Screening 
 
Added “Rescreening under limited conditions may be allowed after consultation with 
BeiGene, and it is allowed only once. Repeating screening assessments within the original 
screening window is allowed if the patient did not previously meet certain eligibility 
criteria.” 
To specify that 
rescreening may be 
permitted under certain 
circumstances. 
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Section 
Key Changes 
Rationale for change 
Section 5.6.2 End 
of Treatment Visit 
and Appendix 1, 
Table a Study 
Visit Schedule, 
Footnote 3 
 
Added “If discontinuation is due to unresolved toxicities for more than 28 days (56 days for 
anemia), the EOT visit should be conducted at the earliest day possible within 7 days after 
permanent discontinuation is determined.” 
To specify timing for 
the End of Treatment 
Visit if discontinuation 
is due to unresolved 
toxicities. 
 
Regarding tumor assessments or CT/MRI: Revised to “…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 disease progression.” 
To simplify when 
tumor assessments do 
not need to be repeated. 
Section 5.7.1 
Safety Follow-up 
and Appendix 1, 
Table a Study 
Visit Schedule, 
Footnote 4 
 
Added “If discontinuation is due to unresolved toxicities for more than 28 days, safety 
follow-up could be scheduled approximately 30 days after the last dose of study drug. If 
discontinuation is due to unresolved toxicities for more than 56 days for anemia, safety 
follow-up could be scheduled at the earliest day possible within 7 days after permanent 
discontinuation is determined.” 
To specify timing for 
safety follow-up if 
discontinuation is due 
to unresolved 
toxicities. 
Section 6.1.1 
Packaging and 
Labelling) 
 
Deleted “40-mg, or 60-mg capsules” 
Only 20-mg capsules 
will be supplied for this 
study. 
Section 6.1.3 
Dosage and 
Administration 
 
Revised from “The time difference between two consecutive doses should be at least 8 hours 
and generally not more than 12 hours.” to “The time difference between two consecutive 
doses will be approximately 12 hours with a window of ± 4 hours.” 
 
Added “However, to reduce gastrointestinal irritation that pamiparib may cause, patients are 
encouraged to take pamiparib with food.” 
 
Revised from “A dose of BGB-290 should be skipped if it is not taken within 2 hours of the 
scheduled time.” to “A dose of pamiparib should be skipped if it is not taken within the 
upper range of the scheduled time (ie, within 16 hours).” 
To clarify the time 
difference between 2 
consecutive doses and 
to specify how to 
reduce potential 
gastrointestinal 
irritation with dosing. 
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Section 
Key Changes 
Rationale for change 
Section 6.1.4 
Dose Hold and 
Modification 
 
Revised from “Dosing of BGB-290 can be withheld for up to 28 days consecutively.” to 
“Dosing of pamiparib can be withheld for up to 28 days consecutively for medical events 
(56 days for anemia).” 
 
Table 3 (Criteria for Modification of Pamiparib Dosing for Related Adverse Events):  
o Revised the dose modification algorithm for anemia. 
o Revised the dose modification algorithm for Grade 3 thrombocytopenia 
o Revised the dose modification algorithm for Grade 3 AST/ALT level increases 
o Revised the dose modification algorithm for cardiac – prolonged QTc interval 
o Revised the dose modification algorithm for Grade 3 cardiac events 
Revised guidance on 
dose 
reduction/modification 
to increase patient’s 
safety 
 
Table 3 (Criteria for Modification of Pamiparib Dosing for Related Adverse Events):  
o Deleted “(>20  ULN)” from Other AEs section of table 
o Revised footnote from “Dosing of BGB-290 can be withheld for up to 28 days 
consecutively.” to “Dosing of pamiparib can be withheld for up to 28 days consecutively 
for medical events (56 days for anemia).” 
Editorial changes. 
Section 6.2.2 
Prohibited 
Medications 
 
Revised from “Bisphosphonate and denosumab use is permitted if the patient has already 
been receiving it at a stable dose for >28 days prior to the first dosing.” to “Bisphosphonate 
and RANK-L inhibitors are allowed for bone metastases if initiated before enrollment and at 
a stable dose.” 
 
Added “Bisphosphonates are permitted during the study for a non-malignant indication.” 
To permit the use of 
any RANK-L inhibitor 
(not solely denosumab) 
and to specify 
requirements for 
bisphosphonate and 
RANK-L inhibitor use 
per Note to File 003. 
 
Revised from “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 permitted.” to “Please refer to the drugs/substances listed in Appendix 6 for a 
more complete list of medications that are not permitted.” 
Removed outdated 
reference. Appendix 6 
provides complete 
information. 
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Section 
Key Changes 
Rationale for change 
Section 7.4.2 
Physical 
Examination, 
Vital Signs, 
ECOG 
Performance 
Status, and 
Weight 
 
Revised to “A complete or limited physical examination, vital signs (systolic and diastolic 
blood pressure, pulse rate, oral, and temporal or tympanic temperature), weight, height, and 
ECOG performance status will be performed at time points specified in Appendix 1.” 
To allow flexibility in 
the method of 
obtaining patients’ 
temperature per Note to 
File 003. 
Section 7.5.2 
Chemistry and 
Appendix 2 
Clinical 
Laboratory 
Assessments 
 
Revised “blood urea nitrogen” to “blood urea nitrogen or urea”. 
 
Revised “phosphate” to “phosphate or phosphorus”. 
To clarify clinical 
chemistry assessments. 
Section 7.5.4 
Pregnancy 
Testing 
 
Updated from “During screening, a serum pregnancy test must be obtained within 7 days 
prior to Day 1 of Cycle 1. For subsequent pregnancy testing, if clinically indicated, urine 
pregnancy tests are allowed. If a urine pregnancy test is positive, a confirmatory serum 
pregnancy test is required.” to “During screening, for women of childbearing potential 
including those who have had a tubal ligation, a urine or serum pregnancy test must be 
performed and documented as negative within 7 days prior to Day 1 of Cycle 1, and urine 
pregnancy tests will be performed at each visit before dosing. A serum pregnancy test must 
be performed if the result of a urine pregnancy test is positive or equivocal.” 
To allow flexibility in 
the method of 
pregnancy tests. 
Section 7.6 
Pharmacokinetics 
 
Deleted “A 1 mL blood sample will be taken and discarded prior to collecting the blood 
sample for PK analysis.” 
Details of blood draw 
should be provided in 
the laboratory manual. 
Text only applies to 
situation where a 
catheter is placed 
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Section 
Key Changes 
Rationale for change 
(usually for serial 
blood draw) and does 
not apply when sparse 
blood draw is 
conducted with 
needles. 
Section 7.7 
Biomarkers 
 
Added “
from this sample will be stored and may be used at later time for 
 
testing including, but not limited to, 
 assays.” 
To allow for 
 
 
 in the 
future. 
 
Added “The most recent 
 is preferred.” 
To specify 
 
 requirements. 
Section 7.7 
Biomarkers and 
Appendix 1, 
Table a Study 
Visit Schedule, 
Footnote 17 
 
Revised from “Optional paired biopsy samples will be collected on Cycle 1 Day 1and Cycle 
2 Day 1 for the assessment of changes 
 
 in response to BGB-290.” to “Optional paired 
biopsy samples will be collected at baseline (any time before receiving the first dose of study 
drug on Cycle 1 Day 1) and Cycle 2 Day 1 for the assessment of changes in 
 
 in 
response to pamiparib.” 
Widened the collection 
window for the first 
 sample to allow 
more flexibility for 
study sites. 
Section 9.1.3 
Assessment of 
Causality 
 
Revised from “The investigator is obligated to assess the relationship between the study drug 
and the occurrence of each AE or SAE. The investigator will use clinical judgment to 
determine the relationship. 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 the study drug will be considered and investigated. The investigator will also 
consult the IB and/or product information for marketed products in the determination of 
his/her assessment.” to “The investigator is obligated to assess the relationship between the 
study drug and the occurrence of each AE or SAE using best clinical judgment. Alternative 
Revised for 
consistency with other 
pamiparib protocols. 
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Section 
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Rationale for change 
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 the study drug will be 
considered and investigated. The investigator should consult the Pamiparib Investigator’s 
Brochure in the determination of his/her assessment.” 
Section 9.1.4 
Follow-Up of 
Adverse Events 
 
Revised from “New or updated information will be recorded on the originally completed 
SAE report/eCRF, with all changes signed and dated by the investigator. The updated SAE 
report/eCRF should be resent to the sponsor within the time frames outlined in Section 
9.5.1.” to “New or updated information should be reported to the sponsor according to the 
SAE instructions provided by the sponsor within the time frames outlined in Section 9.5.1.” 
Revised for 
consistency with other 
pamiparib protocols. 
Section 9.1.5 
Laboratory Test 
Abnormalities 
 
Revised from “Abnormal laboratory findings (eg, hematology or chemistry) or other 
abnormal assessments (eg, ECGs or vital signs) that are judged by the investigator as 
clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE 
(as defined in Section 9.1.1) or an SAE (as defined in Section 9.2). Clinically significant 
abnormal laboratory findings or other abnormal assessments that are detected during the 
study or are present at baseline and significantly worsen following the start of the study will 
be reported as AEs or SAEs. However, clinically significant abnormal laboratory findings or 
other abnormal assessments that are associated with the disease being studied, unless judged 
by the investigator as more severe than expected for the patient’s condition, or that are 
present or detected at the start of the study and do not worsen, will not be reported as AEs or 
SAEs. They should be reported as AEs or SAEs if they induce clinical signs or symptoms, 
need active intervention, require a dose hold or permanent discontinuation, or are clinically 
significant in the opinion of the investigator. 
The investigator will exercise his/her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant.” 
to 
“Abnormal laboratory findings (eg, chemistry, hematology, or coagulation) or other 
abnormal assessments (eg, ECGs, x-rays, or vital signs) that are judged by the investigator as 
clinically significant will be recorded as AEs or SAEs. This includes clinically significant 
abnormal laboratory findings or other abnormal assessments that are present at baseline and 
Revised for 
consistency with other 
pamiparib protocols. 
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Section 
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Rationale for change 
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” 
Section 9.2 
Definition of a 
Serious Adverse 
Event 
 
Moved the following text to the end of the section and edited as shown: 
The following are NOT considered SAEs: 
o Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an SAE. 
o Hospitalization for social/convenience considerations is not considered an SAE. 
o Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience, is not considered an SAE. 
Revised for 
consistency with other 
pamiparib protocols. 
Section 9.3.1 
Adverse Event 
Reporting Period 
 
Revised from 
“After the ICF has been signed, but prior to initiation of study drug, only SAEs should be 
reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, 
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 study drug.” 
to 
“After the ICF has been signed, but prior to initiation of study drug, only SAEs should be 
reported to the sponsor. 
Revised for 
consistency with other 
pamiparib protocols. 
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Section 
Key Changes 
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After initiation of treatment, all AEs and SAEs, regardless of relationship to treatment, 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 drug treatment. 
After a patient is discontinued from the study, investigators are not obligated to actively 
seek AEs or SAEs from the former patients. However, if the investigator learns of any SAE, 
including a death, at any time, and considers the SAE related to pamiparib, the investigator 
will notify the sponsor.” 
Section 9.4 Study-
Specific 
Instructions for 
Recording 
Adverse Events 
and Serious 
Adverse Events 
 
Changed section heading to “Study-Specific Instructions for Recording Adverse Events and 
Serious Adverse Events” 
 
Deleted old subsections Section 9.4.1 Diagnosis versus Signs and Symptoms, Section 9.4.2 
Adverse Events Occurring Secondary to Other Events, Section 9.4.3 Persistent or Recurring 
Adverse Events, and Section 9.4.6 Myelodysplastic Syndrome and Acute Myeloid Leukemia 
 
Revised newly numbered Section 9.4.1 Disease Progression text from “Disease progression 
is measured as an efficacy endpoint and not considered to be an AE. However, if there are 
separate identifiable clinical sequelae that result from disease progression, those sequelae are 
reportable as AEs. For instance, a patient with pleural effusion presents with shortness of 
breath. The cause of the shortness of breath is a pleural effusion resulting from disease 
progression. The AE term should be reported as “pleural effusion” instead of disease 
progression or metastasis to lungs. If a patient has a seizure that is determined to be 
associated with a brain metastasis, the term “seizure” should be recorded as the AE instead 
of disease progression or brain metastasis. If a patient experienced multi-organ failure due to 
disease progression, the term “multi-organ failure” should be reported as the AE instead of 
disease progression. Deaths that are assessed by the investigator as solely due to disease 
progression should be recorded on study completion or early discontinuation eCRF as 
efficacy data. They should not be reported as an SAE. If deaths are assessed by the 
investigator as not solely due to disease progression, whether they are assessed as related or 
not related to the study drug, they should be reported as SAE immediately. 
If there is any uncertainty regarding whether an AE is due to disease progression, it should 
be reported as an AE.” 
Revised for 
consistency with other 
pamiparib protocols. 
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Section 
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to 
““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”.” 
 
Revised newly numbered Section 9.4.2 Death text from “When recording a death as an SAE, 
the AE that caused or contributed to fatal outcome should be recorded as the single medical 
concept. If the cause of death is unknown and cannot be ascertained at the time of reporting, 
record “unexplained death”.” 
to 
“Death is an outcome and not usually considered an event. If the only information available 
is death and the cause of death is unknown, then the death is reported as an event, eg, 
“death”, “death of unknown cause”, or “death unexplained”.” 
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Section 
Key Changes 
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Section 9.5.1 
Time Frames and 
Documentation 
Methods for 
Submitting 
Serious Adverse 
Events 
 
Revised section heading to “Time Frames and Documentation Methods for Submitting 
Serious Adverse Events” 
 
Revised to “SAEs will be reported promptly (within 24 hours) to the sponsor or designee as 
described in Table 4 once the investigator determines that the AE meets the protocol 
definition of an SAE.” 
 
Revised Table 4 title to “Time Frames and Documentation Methods for Submitting 
Serious Adverse Events” and table from 
Type of SAE 
Initial SAE Report 
Document 
All SAEs 
Within 24 hours of first 
knowledge of the AE 
eCRF/SAE form 
Abbreviations: AE, adverse event; eCRF, electronic case report form; SAE, serious 
adverse event. 
to  
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: SAE, serious adverse event. 
Revised for 
consistency with other 
pamiparib protocols. 
9.5.2 Completion 
and Transmission 
of the Serious 
 
Revised from “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 eCRF will always be completed as thoroughly as possible with all available details 
of the SAE, e-signed by the investigator, and forwarded to the sponsor or designee within 
Revised for 
consistency with other 
pamiparib protocols. 
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Adverse Event 
Report 
the designated time frames.  
The data alert letter will automatically be submitted to sponsor or designee immediately after 
investigator signature. If the investigator does not have all information regarding an SAE, 
he/she will not 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. 
In case the EDC is nonoperational, email or facsimile transmission of the paper SAE form is 
the preferred backup method to transmit this information to the project contact for SAE 
receipt. In rare circumstances and in the absence of facsimile equipment, notification by 
telephone or email is acceptable with a copy of the paper SAE form sent by overnight mail. 
Initial notification via the telephone does not replace the need for the investigator to 
complete and sign the paper SAE form within the time frames outlined in Section 9.5.1. 
After the EDC becomes operational again, the investigator will enter the information in the 
EDC system. 
The sponsor will provide a list of project contacts for SAE receipt, fax numbers, telephone 
numbers, and mailing addresses.” 
to 
“Once an investigator becomes aware that an SAE has occurred in a patient, he/she will 
report the information to the sponsor within 24 hours as outlined in Section 9.5.1. The SAE 
Report will always be completed as thoroughly as possible with all available details of the 
event and forwarded to the sponsor or designee within the designated time frames. 
If the investigator does not have all information regarding an SAE, he/she will not 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.” 
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Section 9.5.3 
Regulatory 
Reporting 
Requirements for 
Serious Adverse 
Events 
 
Revised from “The investigator will promptly report all SAEs to the sponsor in accordance 
with the procedures detailed in Section 9.5.2. The sponsor has a legal responsibility to 
notify, as appropriate, both the local regulatory authority and other regulatory agencies 
about the safety of a product under clinical investigation. Prompt notification of SAEs by 
the investigator to the appropriate project contact for SAE receipt is essential so that legal 
obligations and ethical responsibilities towards the safety of other patients are met. 
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. 
This protocol is being filed under an investigational new drug (IND) protocol amendment 
with the China Food and Drug Administration (CFDA). Once active, a given SAE may 
qualify as an IND safety report if the SAE is both attributable to the study drug and 
unexpected. In this case, all investigators filed to the IND (and associated INDs for the same 
compound) will receive an expedited investigator safety report, identical in content to the 
IND safety report submitted to the CFDA. 
Expedited investigator safety reports are prepared according to the sponsor’s policy and are 
forwarded to investigators as necessary. The purpose of the report is to fulfill specific 
regulatory and GCP requirements regarding the product under investigation. 
When a study center receives an initial or follow-up report or other safety information (eg, 
revised IB) from the sponsor, the responsible person according to local requirements is 
required to promptly notify his/her IRB or IEC.” 
to 
“The investigator will promptly report all SAEs to the sponsor in accordance with the 
procedures detailed in Section 9.5.2. The sponsor has a legal responsibility to notify, as 
appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation.  
The investigator, or responsible person according to local requirements, will comply with 
the applicable local regulatory requirements related to the reporting of SAEs to regulatory 
authorities and the IRB/IEC. 
All suspected unexpected serious adverse reactions (as defined in Section 9.6) will be 
submitted to all applicable regulatory authorities and investigators for pamiparib studies. 
When a study center receives an initial or follow-up safety report or other safety information 
(eg, revised Investigator’s Brochure) from the sponsor, the investigator or designated 
Revised for 
consistency with other 
pamiparib protocols. 
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Section 
Key Changes 
Rationale for change 
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. 
Section 9.6 
Suspected 
Unexpected 
Serious Adverse 
Reactions and 
Expedited 
Reporting 
 
Added new section titled “Suspected Unexpected Serious Adverse Reactions and Expedited 
Reporting” with the following text 
“A suspected unexpected serious adverse reaction is a serious adverse reaction that is both 
unexpected (ie, not present in the product’s Reference Safety Information in the 
Investigator’s Brochure) and assessed as related to pamiparib either by the investigator or 
the sponsor. The sponsor will promptly assess the expectedness for all SAEs against the list 
of expected serious adverse reactions in the Reference Safety Information and expeditiously 
submit suspected unexpected serious adverse reactions to regulatory authorities, 
investigators, IRBs, and IECs based on applicable legislation.” 
Added for consistency 
with other pamiparib 
protocols. 
Section 9.7 
Pregnancy 
Reporting 
 
Deleted “Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, follow-up will be no longer than 8 weeks following the estimated delivery date. 
Any premature termination of the pregnancy will be reported.” 
Deleted for consistency 
with other pamiparib 
protocols. 
Section 9 Safety 
Monitoring and 
Reporting 
 
Deleted old subsections Section 9.7 Post-study Adverse Event and Section 9.8 Expedited 
Reporting to Health Authorities, Ethics Committees and Investigators 
Deleted for consistency 
with other pamiparib 
protocols. 
Appendix 1, 
Table a Study 
Visit Schedule 
(continued) 
 
Hematology, Footnote 9: Added “Weekly hematology test should be done for the first 
3 cycles during the study. For all Grade 2 or higher anemia, hematology tests should be done 
weekly thereafter until adequate recovery. At the investigator’s discretion, weekly tests may 
take place at an alternate fixed hospital near the patient’s home. The investigator’s 
permission and choice of hospital should be documented in the patient chart and the medical 
monitor needs to be notified. Hematology results from this fixed hospital are acceptable.” 
To specify hematology 
testing requirements. 
 
Pregnancy test, Footnote 13: Updated from “Serum pregnancy test (for women of 
childbearing potential, including women who have had a tubal ligation) must be performed 
and documented as negative within 7 days prior to Cycle 1 Day 1. Urine pregnancy tests will 
To allow flexibility in 
the method of 
pregnancy tests. 
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Section 
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Rationale for change 
be performed as clinically indicated during treatment. A serum pregnancy test must be 
performed if the urine pregnancy test is positive.” to “For women of childbearing potential 
including those who have had a tubal ligation, a urine or serum pregnancy test must be 
performed and documented as negative within 7 days prior to Cycle 1 Day 1, and urine 
pregnancy tests will be performed at each visit before dosing. A serum pregnancy test must 
be performed if the result of a urine pregnancy test is positive or equivocal.” 
 
To clarify the timing of 
the sample collection 
on Cycle 1 Day 1. 
Appendix 1, 
Table b 
Pharmacokinetic 
Sampling 
 
Deleted columns that did not have assessments marked. 
 
Deleted footnote designator “1” from ECG and vital signs rows in table. 
 
General notes: Reorganized from “Thus, the sequence at a particular time point is: 
1) scheduled 12-lead ECGs; 2) vital sign measurements; 3) PK blood samples (to be 
performed at the precise protocol scheduled time); and 4) any other scheduled or 
unscheduled measurements at that time point.” to “Thus, the sequence at a particular time 
point is: 1) vital sign measurements; 2) scheduled 12-lead ECGs; 3) PK blood samples (to be 
performed at the precise protocol scheduled time); and 4) any other scheduled or 
unscheduled measurements at that time point.”  
 
General notes: Added “For sparse PK sampling, the sequence of collection at a particular 
timepoint may be determined by the sites based on feasibility.” 
To clarify timing of PK 
assessments and to 
reorder the sequence of 
other assessments in 
relation to PK blood 
draws. 
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Section 
Key Changes 
Rationale for change 
Appendix 2 
Clinical 
Laboratory 
Assessments 
 
Deleted from the footnote “and a random urine sample for total protein and creatinine to 
determine a protein to creatinine ratio”. 
To clarify urinalysis 
assessment. 
Appendix 4 
Chronic Kidney 
Disease 
Epidemiology 
Collaboration 
(CKD-EPI) 
Equation 
 
Revised from “The online calculator for CKD-EPI can be found here: 
https://www.niddk.nih.gov/health-information/health-communication-programs/nkdep/lab-
evaluation/gfr-calculators/Pages/gfr-calculators.aspx” to “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” 
Updated website link 
 
 
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SYNOPSIS 
Name of 
Sponsor/Company: 
BeiGene (Beijing) Co., Ltd 
Name of Finished 
Product: 
Pamiparib (BGB-290) Capsule 
Name of Active 
Ingredient: 
Pamiparib (BGB-290) 
Title of Study: 
 
An Open Label, Multi-Center Phase 2 Study to Evaluate Efficacy and 
Safety of BGB-290 in the Treatment of Metastatic HER2-Negative 
Breast Cancer Patients with BRCA mutation in China 
Protocol No: 
 
BGB-290-201 
Number of 
Patients: 
Approximately 75 patients will be enrolled. 
Study Centers: 
Approximately 25 study centers 
Study Phase: 
2 
Treatment 
Duration: 
Patients will receive treatment continuously during the study until 
occurrence of disease progression as assessed by the investigator, 
unacceptable toxicity, death, withdrawal of consent, lost to follow-up, 
or study termination by sponsor. 
Objectives: 
Primary: 
 
To evaluate the efficacy of pamiparib (also known as BGB-290) in patients with 
advanced triple negative breast cancer (TNBC) or hormone receptor-positive 
(HR[+])/human epidermal growth factor receptor 2-negative (HER2[-]) breast cancer 
harboring germline breast cancer susceptibility gene 1/2 (BRCA1/2) mutation, as 
measured by: 
o Objective response rate (ORR) according to Response Evaluation Criteria in 
Solid Tumors (RECIST), version 1.1, by independent radiology review (IRR) 
Secondary:  
 
To further evaluate the efficacy of pamiparib in patients with TNBC or 
HR(+)/HER2(-) breast cancer harboring germline BRCA1/2 mutation, as measured by: 
o ORR by investigator assessment 
o Progression-free survival (PFS) and duration of response (DOR) by 
independent radiology review and investigator assessment 
o Disease control rate (DCR), best overall response (BOR) and clinical benefit 
rate (CBR) assessment by independent radiology review and investigator 
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assessment 
o Overall survival (OS) 
 
To evaluate the safety and tolerability of pamiparib, as measured by: 
o Incidence, timing, and severity of treatment-emergent adverse events 
(TEAEs), graded according to the National Cancer Institute-Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03 
(Common Toxicity Criteria Version 4.03) or higher 
Exploratory: 
Study Design: 
This is a Phase 2, open-label, multi-center study of pamiparib administered orally (PO) twice 
daily (BID) in adult Chinese patients with advanced HER2(-) breast cancer harboring germline 
BRCA mutation, which have progressed despite standard therapy, or for which no standard 
therapy exists. In this study, the efficacy, safety, tolerability and PK profile of pamiparib will 
be further evaluated. All eligible patients will be enrolled into one of the below cohorts: 
1. Approximately 55 previously treated patients with locally advanced or metastatic 
TNBC with confirmed either deleterious or suspected deleterious germline BRCA1/2 
mutation 
2. Approximately 20 previously treated patients with locally advanced or metastatic 
HR(+)/HER2(-) breast cancer with confirmed either deleterious or suspected 
deleterious germline BRCA1/2 mutation  
In this study, all patients, including those with known germline BRCA1/2 mutation status, need 
to undergo germline BRCA mutation testing prior to pamiparib dosing. Patients with unknown 
mutation status must undergo germline BRCA1/2 testing in pre-screening phase prior to 
screening. Patients with known germline BRCA1/2 mutation can proceed to the screening 
phase once they have signed the pre-screening informed consent and submitted their blood 
samples for confirmatory germline BRCA1/2 mutation testing, but patients need to have 
germline BRCA1/2 mutation confirmed before the first dosing. 
Archival tumor tissues will be collected for all patients, if available. 
All patients will receive pamiparib BID continuously from Day 1 of Cycle 1 and in subsequent 
28-day cycles. Patients will receive treatment continuously during the study until occurrence of 
disease progression as assessed by the investigator, unacceptable toxicity, death, withdrawal of 
consent, lost to follow-up, or study termination by sponsor. Once the treatment phase has been 
completed, an end of treatment (EOT) visit will be conducted at the earliest day possible within 
7 days of the last dose of pamiparib, and a safety follow-up will be conducted for 
approximately 30 days after the last dose of pamiparib. All patients will be followed for 
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adverse events (AEs), serious adverse events (SAEs) and concomitant medications (including 
any new anticancer treatment) for 30 days following the last dose of pamiparib. 
All patients will be followed for safety, tolerability, and efficacy from the first dosing day to 
the 30 days after the last dose. 
Safety evaluations will be conducted at the clinical site as indicated in Appendix 1. Clinical 
laboratory evaluations should be conducted before dosing on visit days at the clinical sites. A 
12-lead electrocardiogram (ECG) will be performed as clinically indicated during treatment 
and at EOT visit. 
Tumor response will be assessed separately by IRR and Investigator’s review based on 
RECIST, version 1.1 (Appendix 5). Tumor response will be evaluated once every 8 weeks  
7 days in the first year and then once every 12 weeks  7 days starting in the second year. 
Study Schema 
 
 
Abbreviations: BC, breast cancer; BID, twice daily; HER2(-), human epidermal growth factor receptor 2 negative; 
HR(+), hormone receptor-positive; PD, progression disease; PO, oral; TNBC, triple negative breast cancer 
Note: Key assessments during treatment phase: tumor assessments every 8 weeks  7 days in the first year and once 
every 12 weeks  7 days in the second year and above. Hematology every 2 weeks in Cycle 1 and Cycle 2, then 
keep once every 4 weeks in subsequent cycles. Adverse events at each visit. Chemistry every 4 weeks until disease 
progression. Pamiparib is to be administered continuously. 
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Key Eligibility Criteria: 
The population under study is adult patients (≥18 years of age) with histologically or 
cytologically confirmed locally advanced or metastatic HER2(-) breast cancer (TNBC or 
HR[+]/HER2[-] breast cancer) harboring germline BRCA1/2 mutation. All patients are required 
to have received ≤2 prior lines of chemotherapy in the advanced or metastatic setting. Prior 
therapy with an anthracycline and/or a taxane in either neoadjuvant/adjuvant or metastatic 
setting are required. Prior platinum therapy is allowed as long as no breast cancer progression 
occurred on treatment, or if given in neoadjuvant/adjuvant setting, at least 6 months from last 
platinum to relapse. For HR(+)/HER2(-) breast cancer, patients must have received and 
progressed on at least one endocrine therapy either in adjuvant or metastatic setting, or have 
disease that the treating physician believes to be inappropriate for endocrine therapy. All 
patients will be required to undergo germline BRCA1/2 mutation testing prior to Day 1 of 
Cycle 1. Patients with diagnosis of myelodysplastic syndrome (MDS) are excluded. 
Test product, dose, 
and mode of 
administration: 
Pamiparib: 60 mg will be administered PO BID  
Dose Modifications: 
Dosing of pamiparib can be withheld for up to 28 days consecutively for medical events (56 
days for anemia). A maximum of 2 dose reductions is allowed before the patient will be 
permanently withdrawn from study drug. If drug is planned to be held > 28 days, the medical 
monitor should be contacted prior to permanent patient discontinuation from the study drug. 
Concomitant Therapy and Clinical Practice: 
All treatments and supportive care, including antiemetic therapy, hematopoietic growth factors, 
and/or red blood cell/platelet transfusions, that the investigator considers necessary for a 
patient’s welfare may be administered at the discretion of the investigator in keeping with the 
local standards of medical care. All concomitant medications, including all prescription and 
over-the-counter drugs, herbal supplements, and intravenous (IV) medications and fluids, taken 
by or administered to the patient within 28 days before the first dosing and 30 days after the 
last day of pamiparib will be recorded. 
Patients are not allowed to receive other anticancer therapy, including surgery, radiation 
therapy (except for palliative radiation therapy to non-targeted lesion), immunotherapy, 
investigational agents, cytotoxic, biologic or hormone therapy, anticancer Chinese medicine, or 
anticancer herbal remedies. Bisphosphonate and RANK-L inhibitors are allowed for bone 
metastases if initiated before enrollment and at a stable dose. Bisphosphonates are permitted 
during the study for a non-malignant indication. 
 
 
 
 
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Criteria for Evaluation: 
Efficacy: 
Tumor imaging studies will be reviewed for the purposes of eligibility determination and on-
study tumor monitoring. Disease assessment during the screening may be completed within 28 
days prior to the first dose of pamiparib. Afterward, disease assessments will be performed 
every 8 weeks (±7 days) in the first year and then every 12 weeks (±7 days) in the second year 
and subsequent years. Any measurable disease must be documented at screening and 
reassessed at each subsequent tumor evaluation. Patients who do not have disease progression 
at the time of pamiparib permanent discontinuation but meet other discontinuation criteria (eg, 
discontinued for AE and no new anticancer therapy) will continue to have tumor assessments 
per protocol. ORR will be assessed by IRR and by the investigator. PFS and DOR will be 
assessed by IRR and investigator using RECIST, version 1.1. The same imaging method(s) 
used at screening must be used throughout the study. A documented standard-of-care tumor 
assessment may be used as the screening assessment if it meets protocol requirements. Survival 
status of patients will be monitored through all phases of the study. 
Safety: 
Safety will be monitored throughout the study. Safety assessments include AE monitoring and 
reporting, physical examinations, vital sign measurements, ECGs, and clinical laboratory tests. 
Statistical Methods: 
Analysis Sets 
The Safety Analysis Set includes all patients who receive at least one dose of pamiparib. 
The Efficacy Analysis Set includes all patients in the Safety Analysis Set who have measurable 
disease at baseline per RECIST, version 1.1, and have at least one evaluable post baseline 
tumor assessment by IRR unless discontinued treatment due to clinical progression or death 
prior to tumor assessment. This is the primary analysis set for all the tumor response endpoints 
(ORR, BOR, DOR, etc). 
The Intent-to-Treat (ITT) Analysis Set is defined as all enrolled patients who receive any 
amount of study drug. This is the primary analysis set for OS. 
The PK Evaluable Analysis Set includes all patients for whom valid pamiparib PK parameters 
can be estimated. 
Statistical and Analytical Methods 
Efficacy and safety of pamiparib will be evaluated in two cohorts (TNBC and HR[+]/HER2[-] 
breast cancer) separately.  
Efficacy Analyses 
Primary Efficacy Analyses 
TNBC cohort 
Hypothesis testing of ORR by IRR will be performed in the patients with evaluable tumor 
assessment pre- and post-baseline. The primary analysis will be carried out using IRR data in 
the Efficacy Analysis Set. Efficacy endpoints based on investigator assessed tumor response 
will be presented as the sensitivity analysis. 
ORR of pamiparib per IRR is assumed as 46% in patients with TNBC. The historical rate in a 
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similar population is estimated as 25%. The null and alternative hypotheses are set as follows: 
H0:  ORR=25% 
Ha:  ORR >25% 
A binomial exact test will be performed for hypothesis testing in the Efficacy Analysis Set. If 
the obtained one-sided p-value is ≤ 0.025, it will be concluded that pamiparib monotherapy 
statistically significantly increases ORR compared with historical control. A two-sided 
binomial exact 95% confidence interval (CI) of ORR will be constructed to assess the precision 
of the rate estimate.  
The primary efficacy analysis will be conducted when mature response rate data have been 
observed, estimated as no more than 12 months after the last patient received the first dose of 
study drug. 
Sensitivity analysis of ORR will be carried out in the ITT analysis set. 
HR(+)/HER2(-) breast cancer Cohort 
ORR and its two-sided binomial exact 95% confidence interval (CI) will be calculated 
similarly as described above in the TNBC cohort. However, no statistical comparison to a 
specified historical rate is planned. 
Secondary Efficacy Analyses 
TNBC and HR(+)/HER2(-) breast cancer cohort 
As in the primary efficacy analyses, secondary efficacy analyses will be performed by cohort. 
Tumor response assessed by IRR and investigator will be summarized. 
BOR is defined as the best response recorded from the start of pamiparib until data cut or start 
of new anti-neoplastic treatment. The proportion of each response category (complete response 
[CR], partial response [PR], stable disease [SD], disease progression and not evaluable [NE]) 
will be presented in the Efficacy Analysis Set and ITT Analysis Set. 
DCR and CBR and their 95% CIs will be summarized by cohort in the Efficacy Analysis Set 
and ITT Analysis Set. 
Kaplan-Meier method will be used to estimate the key secondary endpoint, DOR, and 
corresponding quartiles (including the median) in the responders. A two-sided 95% CIs of 
median, if estimable, will be constructed with a generalized Brookmeyer and Crowley method.  
The DOR censoring rule will follow Food and Drug Administration (FDA) (Guidance for 
Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics 2007) 
Other time to event variables (PFS and OS) will be similarly analysed in the Efficacy Analysis 
Set using the Kaplan-Meier method as described above. The Kaplan-Meier estimates of PFS 
and OS will be plotted over time. The PFS time point estimates, defined as the percentages of 
patients in the analysis population who remain alive and progression-free at the specified time 
points (ie, 3 or 6 months), will be estimated using the Kaplan-Meier method along with the 
corresponding 95% CI constructed using Greenwood’s formula. The OS time point estimates 
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Exploratory Efficacy Analyses 
Safety 
Verbatim description of AEs will be mapped to the Medical Dictionary for Regulatory 
Activities (MedDRA) terms and graded according to the NCI-CTCAE, version 4.03. A TEAE 
is defined as an AE that had an onset date on or after the first dose of study drug up to 30 days 
following study drug discontinuation. All AEs will be included in the listings and only TEAEs 
will be included in the summary tables. SAEs, deaths, TEAEs with Grade 3 or above, related 
TEAEs and TEAEs that led to treatment discontinuation, dose reduction or dose interruption 
will be summarized. 
A patient will be counted only once by the highest grade according to NCI-CTCAE, version 
4.03, within a system organ class (SOC) and preferred term (PT), even if the patient 
experienced more than 1 TEAE within a specific SOC and PT. Clinical laboratory data with 
values outside of the normal ranges will be identified. Selected laboratory data will be 
summarized by grade. Vital signs and physical examination will also be summarized by visit.  
Pharmacokinetic Analysis 
Pamiparib concentrations after single-dose and at steady-state will be summarized by the 
sampling timepoint. Descriptive statistics will include means, medians, and standard 
deviations, as appropriate.  
Population PK analysis may be carried out to include plasma concentrations from this study. 
Additional PK parameters such as apparent clearance (CL/F) of the drug from plasma and area 
under the plasma concentration-time curve from 0 to 12 hours postdose (AUC0-12) may be 
derived from the population PK analysis if supported by data. 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by 
data. 
Sample Size 
A total of approximately 75 patients will be enrolled into one of the below cohorts.  
1) Approximately 55 evaluable patients will be enrolled into the TNBC cohort. In TNBC 
cohort, it is assumed that ORR is 46% in patients with pamiparib. There is an 90% 
power of demonstrating a statistical difference versus a historical response rate of 25% 
using a binomial exact test at an alpha of 0.025 in 55 evaluable patients. The 2-sided 
exact 95% CI is (32.0%, 59.5%) when the observed ORR is 46%. Additional patients 
may be enrolled to meet the required number of evaluable patients.  
2) 
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TABLE OF CONTENTS 
 
FINAL PROTOCOL APPROVAL SHEET ................................................................... 2 
PROTOCOL AMENDMENT, VERSION 1.0 ............................................................... 3 
SYNOPSIS ....................................................................................................................... 20 
TABLE OF CONTENTS ............................................................................................... 27 
LIST OF TABLES .......................................................................................................... 33 
LIST OF FIGURES ........................................................................................................ 33 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................. 34 
1. 
INTRODUCTION .................................................................................................... 36 
1.1 
METASTATIC BREAST CANCER .......................................................................... 36 
1.2 
POLY (ADP-RIBOSE) POLYMERASE INHIBITORS ................................................ 36 
1.3 
BIOLOGY OF GERMLINE BRCA-MUTANT BREAST CANCER AND PARP 
INHIBITORS .................................................................................................................... 37 
1.4 
PARP INHIBITOR PAMIPARIB ............................................................................. 40 
1.4.1 Nonclinical Data for Pamiparib ................................................................... 40 
1.4.2 Nonclinical Activity Data .............................................................................. 41 
1.4.3 Clinical Data for BGB-290 ........................................................................... 42 
1.5 
RATIONALE FOR SELECTION OF PAMIPARIB DOSE ............................................. 46 
1.6 
STUDY RATIONALE ............................................................................................ 46 
1.7 
BENEFIT-RISK ASSESSMENT .............................................................................. 47 
1.8 
STUDY CONDUCT ............................................................................................... 48 
2. 
STUDY OBJECTIVES ............................................................................................. 49 
2.1 
PRIMARY OBJECTIVE ......................................................................................... 49 
2.2 
SECONDARY OBJECTIVES ................................................................................... 49 
2.3 
EXPLORATORY OBJECTIVES ............................................................................... 49 
3. 
STUDY DESIGN ..................................................................................................... 50 
4. 
STUDY POPULATION ........................................................................................... 52 
4.1 
INCLUSION CRITERIA ......................................................................................... 52 
4.2 
EXCLUSION CRITERIA ........................................................................................ 53 
5. 
STUDY PHASES FROM SCREENING TO END OF STUDY ............................. 56 
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5.1 
PRE-SCREENING ................................................................................................. 56 
5.2 
SCREENING ........................................................................................................ 56 
5.3 
ENROLLMENT ..................................................................................................... 56 
5.4 
TREATMENT ....................................................................................................... 57 
5.5 
UNSCHEDULED VISIT ......................................................................................... 57 
5.6 
PERMANENT DISCONTINUATION OF STUDY DRUG ............................................. 57 
5.6.1 Reasons for Permanent Discontinuation of Pamiparib ................................ 57 
5.6.2 End of Treatment Visit .................................................................................. 58 
5.7 
FOLLOW-UP PHASE ............................................................................................ 58 
5.7.1 Safety Follow-up ........................................................................................... 58 
5.7.2 Long-term Follow-up .................................................................................... 59 
5.7.3 Lost to Follow-up .......................................................................................... 59 
5.8 
END OF STUDY ................................................................................................... 59 
6. 
STUDY TREATMENTS .......................................................................................... 61 
6.1 
STUDY DRUG ..................................................................................................... 61 
6.1.1 Packaging and Labelling .............................................................................. 61 
6.1.2 Handling and Storage ................................................................................... 61 
6.1.3 Dosage and Administration .......................................................................... 61 
6.1.4 Dose Hold and Modification ......................................................................... 62 
6.1.5 Compliance and Accountability .................................................................... 67 
6.1.6 Disposal and Destruction ............................................................................. 67 
6.2 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ............................... 67 
6.2.1 Permitted Medications and Supportive Care ................................................ 67 
6.2.2 Prohibited Medications ................................................................................. 68 
6.2.3 Medications to be used with Caution ............................................................ 68 
7. 
STUDY ASSESSMENTS ........................................................................................ 69 
7.1 
STUDY FLOW AND VISIT SCHEDULE .................................................................. 69 
7.2 
PATIENT DEMOGRAPHIC AND OTHER BASELINE ASSESSMENTS 
CHARACTERISTICS ......................................................................................................... 69 
7.2.1 Demographics ............................................................................................... 69 
7.2.2 Medical History and Prior Medications ....................................................... 69 
7.2.3 Other Baseline Characteristics ..................................................................... 69 
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7.3 
EFFICACY ........................................................................................................... 69 
7.3.1 Tumor Assessments ....................................................................................... 69 
7.3.2 Survival Assessments .................................................................................... 71 
7.4 
SAFETY .............................................................................................................. 72 
7.4.1 Adverse Events .............................................................................................. 72 
7.4.2 Physical Examination, Vital Signs, ECOG Performance Status, and Weight ..  
 
....................................................................................................................... 72 
7.4.3 Electrocardiogram ........................................................................................ 72 
7.5 
LABORATORY ASSESSMENTS ............................................................................. 73 
7.5.1 Hematology ................................................................................................... 73 
7.5.2 Chemistry ...................................................................................................... 73 
7.5.3 Urinalysis ...................................................................................................... 73 
7.5.4 Pregnancy Testing ........................................................................................ 73 
7.6 
PHARMACOKINETICS .......................................................................................... 73 
7.7 
BIOMARKERS ..................................................................................................... 74 
7.8 
APPROPRIATENESS OF MEASUREMENTS ............................................................. 75 
8. 
DATA HANDLING AND QUALITY ASSURANCE ............................................ 76 
8.1 
DATA COLLECTION ............................................................................................ 76 
8.2 
DATA MANAGEMENT/CODING ........................................................................... 76 
8.3 
QUALITY ASSURANCE AUDIT ............................................................................ 77 
9. 
SAFETY MONITORING AND REPORTING ....................................................... 78 
9.1 
ADVERSE EVENTS .............................................................................................. 78 
9.1.1 Definition and Reporting of an Adverse Event ............................................. 78 
9.1.2 Assessment of Severity .................................................................................. 78 
9.1.3 Assessment of Causality ................................................................................ 79 
9.1.4 Follow-Up of Adverse Events ....................................................................... 80 
9.1.5 Laboratory Test Abnormalities ..................................................................... 81 
9.2 
DEFINITION OF A SERIOUS ADVERSE EVENT ...................................................... 81 
9.3 
TIMING, FREQUENCY, AND METHOD OF CAPTURING ADVERSE EVENTS AND 
SERIOUS ADVERSE EVENTS ........................................................................................... 82 
9.3.1 Adverse Event Reporting Period ................................................................... 82 
9.3.2 Eliciting Adverse Events ............................................................................... 82 
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9.4 
STUDY-SPECIFIC INSTRUCTIONS FOR RECORDING ADVERSE EVENTS AND 
SERIOUS ADVERSE EVENTS ........................................................................................... 83 
9.4.1 Disease Progression ..................................................................................... 83 
9.4.2 Death ............................................................................................................. 83 
9.5 
PROMPT REPORTING OF SERIOUS ADVERSE EVENTS.......................................... 83 
9.5.1 Time Frames and Documentation Methods for Submitting Serious Adverse 
Events ....................................................................................................................... 83 
9.5.2 Completion and Transmission of the Serious Adverse Event Report ........... 84 
9.5.3 Regulatory Reporting Requirements for Serious Adverse Events................. 84 
9.6 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTIONS AND EXPEDITED 
REPORTING .................................................................................................................... 84 
9.7 
PREGNANCY REPORTING .................................................................................... 85 
10. 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ....................... 86 
10.1 
SAMPLE SIZE CONSIDERATIONS ......................................................................... 86 
10.2 
GENERAL CONSIDERATIONS FOR DATA ANALYSIS ............................................ 86 
10.2.1 
Analysis Sets.............................................................................................. 86 
10.2.2 
Interim Analysis ........................................................................................ 87 
10.2.3 
Patient Disposition.................................................................................... 87 
10.2.4 
Demographics and Other Baseline Characteristics ................................. 87 
10.2.5 
Prior and Concomitant Therapy ............................................................... 87 
10.3 
EFFICACY ANALYSES ......................................................................................... 88 
10.3.1 
Primary Efficacy Analyses ........................................................................ 88 
10.3.2 
Secondary Efficacy Analyses .................................................................... 88 
10.3.3 
Exploratory Efficacy Analyses .................................................................. 89 
10.4 
SAFETY ANALYSES ............................................................................................ 89 
10.4.1 
Adverse Event............................................................................................ 89 
10.4.2 
Laboratory Assessments............................................................................ 89 
10.4.3 
Physical Examinations .............................................................................. 90 
10.4.4 
Vital Signs ................................................................................................. 90 
10.4.5 
Extent of Exposure .................................................................................... 90 
10.5 
PHARMACOKINETIC ANALYSES.......................................................................... 90 
10.6 
BIOMARKER ANALYSES ..................................................................................... 90 
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11. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS .......... 91 
11.1 
REGULATORY AUTHORITY APPROVAL............................................................... 91 
11.2 
INVESTIGATOR RESPONSIBILITIES ...................................................................... 91 
11.2.1 
Good Clinical Practice ............................................................................. 91 
11.2.2 
Ethical Conduct of the Study and Ethics Approval ................................... 91 
11.2.3 
Informed Consent ...................................................................................... 92 
11.2.4 
Investigator Reporting Requirements ....................................................... 92 
11.2.5 
Confidentiality........................................................................................... 92 
11.2.6 
Electronic Case Report Forms.................................................................. 93 
11.2.7 
Drug Accountability .................................................................................. 93 
11.2.8 
Inspections ................................................................................................ 94 
11.2.9 
Protocol Adherence .................................................................................. 94 
11.3 
SPONSOR RESPONSIBILITIES ............................................................................... 94 
11.3.1 
Protocol Modifications ............................................................................. 94 
11.3.2 
Use of Information and Publication ......................................................... 94 
11.4 
STUDY AND STUDY CENTER CLOSURE ............................................................... 94 
11.5 
RECORDS RETENTION AND STUDY FILES ........................................................... 95 
11.5.1 
Study Files and Retention of Records ....................................................... 95 
11.5.2 
Provision of Study Results and Information to Investigators ................... 96 
11.6 
INFORMATION DISCLOSURE AND INVENTIONS ................................................... 97 
11.7 
JOINT INVESTIGATOR/SPONSOR RESPONSIBILITIES ............................................ 97 
11.7.1 
Access to Information for Monitoring....................................................... 97 
11.7.2 
Access to Information for Auditing or Inspections ................................... 98 
12. 
REFERENCES ..................................................................................................... 99 
13. 
APPENDICES .................................................................................................... 102 
APPENDIX 1 
SCHEDULE OF ASSESSMENTS ............................................................... 102 
APPENDIX 2 
CLINICAL LABORATORY ASSESSMENTS ............................................... 108 
APPENDIX 3 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE 
STATUS 
............................................................................................................. 109 
APPENDIX 4 
CHRONIC KIDNEY DISEASE EPIDEMIOLOGY COLLABORATION (CKD-EPI) 
EQUATION 
............................................................................................................. 110 
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APPENDIX 5 
THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 
GUIDELINES, VERSION 1.1 ........................................................................................... 111 
APPENDIX 6 
PROHIBITED MEDICATIONS .................................................................. 121 
APPENDIX 7 
MEDICATIONS TO BE USED WITH CAUTION .......................................... 122 
APPENDIX 8 
CONTRACEPTION GUIDELINES AND DEFINITIONS OF “WOMEN OF 
CHILDBEARING POTENTIAL”, “NO CHILDBEARING POTENTIAL”.................................. 123 
APPENDIX 9 
NEW YORK HEART ASSOCIATION FUNCTIONAL CLASSIFICATION ....... 125 
APPENDIX 10 
SIGNATURE OF INVESTIGATOR ......................................................... 126 
 
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LIST OF TABLES 
Table 1. 
PARP Enzyme Inhibition and DNA Trapping Activity of 
PARP Inhibitors ........................................................................................ 41 
Table 2. 
Dose Levels for Pamiparib........................................................................ 62 
Table 3. 
Criteria for Modification of Pamiparib Dosing for Related 
Adverse Events ......................................................................................... 63 
Table 4. 
Time Frames and Documentation Methods for Reporting 
Serious Adverse Events to the Sponsor or Designee ................................ 83 
 
 
LIST OF FIGURES 
Figure 1.  
Correlation of PAR Inhibition in Peripheral-blood 
Mononuclear Cells with Pamiparib Dose ................................................. 44 
Figure 2. 
Study Schema............................................................................................ 51 
 
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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-12h 
area under the plasma concentration-time curve from zero to 
12 hours post-dose 
BID 
twice daily 
BGB-290 
study drug code 
BOR 
best overall response 
BRCA1/2 
breast cancer susceptibility gene 1/2 
CBR 
clinical benefit rate 
CI 
confidence interval 
CL/F 
apparent clearance 
Cmax 
maximum observed plasma concentration 
CR 
complete response 
CT 
computed tomography 
ctDNA 
circulating tumor DNA 
CYP 
cytochrome P450 
DCR 
disease control rate 
DLT 
DNA 
dose-limiting toxicity 
deoxyribonucleic acid 
DOR 
duration of response 
EC50 
half maximal effective concentration 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
HER2(-) 
human epidermal growth factor receptor 2-negative 
HGOC 
High-grade non-mucinous ovarian cancer 
HR(+) 
hormone receptor-positive 
Hgb 
hemoglobin 
IC50 
half inhibitory concentration 
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Abbreviation 
Definition 
ICF 
informed consent form 
IEC 
independent ethics committee 
IRB 
institutional review board 
IRR 
independent radiology review 
ITT 
Intent-to-Treat 
MDS/AML 
myelodysplastic syndrome/acute myeloid leukemia  
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
NCI-CTCAE 
National Cancer Institute Common Toxicity Criteria for 
Adverse Events 
NE 
not evaluable 
ORR 
objective response rate 
OS 
overall survival 
pamiparib 
BGB-290 
PAR 
poly(ADP-ribose) 
PARP 
poly(ADP-ribose) polymerase 
PBMCs 
peripheral blood mononuclear cells 
PET 
positron emission tomography 
PFS 
Progression-free survival 
PK 
pharmacokinetic(s) 
PO 
orally 
PR 
partial response 
PT 
preferred term 
QTc 
QT interval corrected for heart rate 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SD 
stable disease 
SOC 
system organ class 
TEAE 
Treatment-emergent adverse event 
Tmax 
time of maximum plasma concentration 
TNBC 
triple negative breast cancer 
ULN 
upper limit of normal 
US 
United States 
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1. INTRODUCTION 
1.1 
Metastatic Breast Cancer 
Breast cancer is the most common cancer among women worldwide, with approximately 
1.7 million new cases and 520,000 deaths according to GLOBOCAN 2012. In China, 
breast cancer accounts for 17% (approximately 280,000) of all new cancer cases and 
approximately 65,000 cancer deaths in 2013, ranking as the top female malignancy and 
the 5th leading cause of cancer-related death (Chen et al 2017).  
Triple negative breast cancer (TNBC) is characterized by the absence of estrogen 
receptor, progesterone receptor, and HER2, and represents 15% to 20% of all breast 
cancers (Metzger-Filho et al 2012). In addition, HR(+) and HER2(-) tumors constitute 
approximately 65% to 70% of all breast cancers (Hart et al 2015).  Recurrences of TNBC 
typically occur during the first 3 years after diagnosis with a high rate of visceral 
metastases, particularly to the lungs and brain, and, less frequently, metastases to bone. 
(Haffty et al 2006). Once breast cancer becomes metastatic, it is generally considered 
incurable. The median survival for metastatic TNBC ranges from 6 months to 
13.3 months. (Dent et al 2007; Kassam et al 2009). The aim of systemic therapies for 
metastatic breast cancer is to optimize survival and quality of life, and to minimize the 
side effects of treatment. 
Women with TNBC do not benefit from endocrine therapy or trastuzumab. The only 
established therapeutic strategies for metastatic TNBC are cytotoxic chemotherapy, with 
no targeted therapies approved so far (Cardoso et al 2017; NCCN Guidelines 2017). 
Currently, there is no standard recommendation of chemotherapy for metastatic TNBC. 
Preferred single agents recommended by National Comprehensive Cancer Network 
guideline include anthracyclines, taxanes, anti-metabolites and other microtubule 
inhibitor, with objective response rates (ORRs) ranging from ~11% to 23% (Rugo et al 
2009; O'Shaughnessy et al 2010; Brufsky et al 2012; Curigliano et al 2013). Thus, further 
development of effective targeted treatment represents an important unmet medical need. 
1.2 
Poly (ADP-ribose) Polymerase Inhibitors 
Poly (ADP-ribose) polymerase (PARP) proteins are involved in DNA replication, 
transcriptional regulation, and DNA damage repair. DNA-bound PARP1/2 catalyzes the 
synthesis of poly (ADP ribose) (PAR) onto a range of DNA-associated proteins that 
mediate DNA repair. PARP1 also undergoes auto-PARylation, a molecular change that 
ultimately leads to its release from DNA. Inhibition of PARP converts common single-
strand DNA breaks (SSBs) 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 
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synthetic lethality of PARP inhibitors in BRCA-deficient cells and, more broadly, cells 
with homologous recombination deficiency, accumulation of unrepaired SSBs 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 SSBs (Pommier et al 2016; O'Connor 2015; Lord and 
Ashworth 2017). 
In clinical studies, PARP inhibitors, including olaparib, rucaparib, niraparib, and 
talazoparib, have demonstrated sustained antitumor responses as single agents in patients 
with BRCA1- or BRCA2-mutated tumors, while achieving a favorable safety profile. 
Olaparib has been approved in the United States (US) as single agent for the maintenance 
treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary 
peritoneal cancer, who are in a CR or PR to platinum-based chemotherapy, as well as for 
the treatment of adult patients with deleterious or suspected deleterious germline BRCA-
mutated advanced ovarian cancer who have been treated with three or more prior lines of 
chemotherapy. In 2016, rucaparib was approved for monotherapy for the treatment of 
patients with advanced ovarian cancer with deleterious BRCA mutation (germline and/or 
somatic) who have been treated with two or more chemotherapies. Niraparib was 
approved in 2017 for the maintenance treatment of adult patients with recurrent epithelial 
ovarian, fallopian tube, or primary peritoneal cancer who are in a CR or PR to platinum-
based chemotherapy (Lynparza [olaparib] prescribing information; Rubraca [rucaparib] 
prescribing information, Zejula [niraparib] prescribing information). 
Pamiparib (also known as BGB-290) is a potent and selective inhibitor of PARP1 and 
PARP2 (Pamiparib Investigator’s Brochure). It showed potent PARP-trapping activity 
and anti-proliferative activity against a number of cell lines harboring BRCA gene 
mutations or with homologous recombination deficiency. In combination studies, 
pamiparib demonstrated strong synergism with temozolomide in a number of small cell 
lung cancer and glioblastoma cell lines. 
1.3 
Biology of Germline BRCA-mutant Breast Cancer and PARP Inhibitors 
Breast cancer is a clinically and biologically heterogenous disease characterized by 
diverse genomic signatures and protein expression patterns. Up to 10% of TNBC and 
5% HR(+) breast cancers can be linked to germline mutations in BRCA1 and/or BRCA2 
genes (Lang et al 2017; Sun et al 2017; Welsch et al 1998). Both BRCA1 and BRCA2 are 
tumor suppressor genes, and, when mutated, can lead to a higher risk of cancer by 
disabling DNA repair processes called homologous recombination or homology-directed 
repair (Yoshida and Miki 2004; O’Sullivan et al 2014). BRCA1/2 mutations also sensitize 
cells to inhibition of PARP activity because it leads to chromosomal instability, cell-cycle 
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arrest, and subsequent apoptosis (Sonnenblick et al 2015). Approximately 70% of 
BRCA1-mutant and 20% of BRCA2-mutant breast tumors present as TNBC (Mavaddat et 
al 2017). 
Clinical studies support the use of platinum compounds for BRCA1/2-mutated breast 
cancers in the neoadjuvant and advanced setting, including TNBC (Gronwald et al 2009; 
Arun et al 2011;Telli 2014; Tutt et al 2015). The TNT study (Tutt et al 2015) 
demonstrated no difference in ORR or progression-free survival (PFS) with carboplatin 
treatment compared to docetaxel for an unselected population of patients with TNBC. 
However, carboplatin was associated with improved ORR in the subgroup of patients 
with germline BRCA1/2-mutated breast cancer.  
PARP inhibitors have been tested clinically in metastatic breast cancer patients with 
BRCA1/2. In a single-arm, open-label study, olaparib (400 mg or 100 mg oral [PO] twice 
daily [BID]) was administered to women with BRCA1- and/or BRCA2-mutant, advanced 
breast cancer (of which >50% were triple negative) (Tutt et al 2009). Patients in the 
400 mg BID treatment group had an ORR of 41% and PFS of 5.7 months. The most 
commonly reported Grade 3 AEs were fatigue, nausea, and vomiting.  
OlympiAD was a randomized, open-label, Phase 3 trial in which olaparib monotherapy 
was compared to physician’s choice chemotherapy (capecitabine, eribulin, or vinorelbine 
in 21-day cycles) in 302 patients with a germline BRCA mutation and HER2(-) metastatic 
breast cancer who had received no more than two previous chemotherapy regimens for 
metastatic disease (Robson et al 2017). In this trial, 205 patients were assigned to the 
olaparib group, and 97 patients were assigned to the physician’s choice group. The 
randomized, phase 3 OlympiAD trial showed that, among patients with HER2(-) 
metastatic breast cancer and a germline BRCA mutation, median PFS was significantly 
longer with oral olaparib monotherapy than with standard chemotherapy (7.0 months 
versus 4.2 months; hazard ratio for disease progression or death, 0.58; 95% confidence 
interval [CI], 0.43 to 0.80). The risk of disease progression or death was 42% lower and 
the median PFS was 2.8 months longer with olaparib than with standard therapy. The 
response rate in the olaparib group was approximately double the rate in the standard-
therapy group (59.9% versus 28.8%). Although no significant difference in OS was 
observed between olaparib treatment and standard therapy, this trial was not powered to 
assess differences in OS between treatment groups. Analysis of OS is also likely to be 
confounded by subsequent treatment, and more patients in the standard-therapy group 
than in the olaparib group received treatment with PARP inhibitors, platinum-based 
therapy, and cytotoxic chemotherapy after they had disease progression while receiving 
the assigned treatment (Robson et al 2017). 
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ABRAZO (NCT02034916) is a 2-cohort, 2-stage Phase 2 study of talazoparib (1 mg/d) 
following platinum-based therapy (Cohort 1) or ≥ 3 platinum-free cytotoxic-based 
regimens (Cohort 2) in patients with locally advanced or metastatic breast cancer and 
germline BRCA1/2 mutation (Turner et al 2017). The final results were reported at the 
2017 ASCO meeting. In this study, 84 patients were enrolled (Cohort 1, n = 49; Cohort 2, 
n = 35). ORR by independent radiology facility was 21% in Cohort 1 and 37% in 
Cohort 2, ORR by IRF for BRCA1/BRCA2 was 24%/34%, and ORR by independent 
radiology facility for TNBC/HR(+) was 26%/29%, respectively. Most common AEs were 
anemia (52%), fatigue (45%), nausea (42%), diarrhea (33%), thrombocytopenia (33%), 
and neutropenia (27%). AEs of ≥ Grade 3 were anemia (35%), thrombocytopenia (19%), 
and neutropenia (15%). This study showed talazoparib was exhibiting promising 
antitumor activity in cohort 1 and cohort 2. 
EMBRACA (NCT01945775) is a randomized, open-label, Phase 3 study comparing the 
efficacy and safety of talazoparib (1 mg once daily) with single-agent chemotherapy of 
physician’s choice (capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with 
advanced breast cancer and a germline BRCA1/2 mutation. Patients were randomized in a 
2:1 ratio; 287 were assigned to receive talazoparib and 144 were assigned to receive 
standard therapy. Median PFS was significantly longer in the talazoparib group than in 
the standard chemotherapy group (8.6 months versus 5.6 months; hazard ratio for disease 
progression or death, 0.54; 95% CI, 0.41 to 0.71; p < 0.001). The ORR was higher in the 
talazoparib group than in the standard-therapy group (62.6% versus 27.2%; odds ratio, 
5.0; 95% CI, 2.9 to 8.8; p < 0.001). The interim median hazard ratio for death was 
0.76 (95% CI, 0.55 to 1.06; p = 0.11 [57% of projected events]). Common AEs included 
anemia, fatigue, and nausea in the talazoparib group and nausea, fatigue, and neutropenia 
in the standard-therapy group. Hematologic Grade 3 to 4 AEs (primarily anemia) 
occurred in 55% of the patients who received talazoparib and in 38% of the patients who 
received standard therapy; nonhematologic Grade 3 AEs occurred in 32% and 38% of the 
patients, respectively (Litton et al 2018).  
Both the OlympiAD and EMBRACA studies have consistently shown that a PARP 
inhibitor is a reasonable treatment option for patients with advanced TNBC or 
HR(+)/HER2(-) breast cancer with a germline BRCA1/2 mutation, since its use is 
associated with a PFS benefit, improvement in quality of life, and a favorable toxicity 
profile. Olaparib was approved in the US for patients with deleterious or suspected 
deleterious germline BRCA-mutant, HER2-negative metastatic breast cancer (Lynparza 
[olaparib] prescribing information). 
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1.4 
PARP Inhibitor Pamiparib 
1.4.1 
Nonclinical Data for Pamiparib 
Pamiparib is a highly potent and selective inhibitor of PARP1 and PARP2 and is unique 
from other PARP inhibitors by combining potent PARP-trapping activity with good brain 
penetrance. In addition, pamiparib has shown anti-tumor activity against a number of cell 
lines, as well as in vivo models, harboring BRCA gene mutations or with homologous 
recombination deficiency. 
1.4.1.1 Nonclinical Safety Data 
The nonclinical toxicity and toxicokinetic profile of pamiparib was characterized in 
single and up to 91-day repeat-oral-dose studies in rats and dogs, and in a core battery of 
genotoxicity tests, including in vitro Ames and chromosomal aberration assays, and in 
vivo bone marrow micronucleus assays in rats. Safety pharmacology assessments 
included in vitro human ether-à-go-go related gene channel activity assays and in vivo 
studies of cardiovascular function in dogs, as well as central nervous system and 
respiratory system function tests in rats. 
The main toxicity findings were bone marrow inhibition that correlated with clinical 
pathology changes, and gastrointestinal toxicity that presented as emesis, decreased food 
consumption, and decreased body weight. The systemic exposure increased 
dose-proportionally without apparent sex differences or accumulation. 
 
 
  
Pamiparib was not mutagenic in the in vitro Ames (bacterial reverse mutation) assay, but 
clastogenic in the in vitro chromosomal aberration assay in mammalian Chinese hamster 
ovary cells, and in the in vivo bone marrow micronucleus assay in rats, which is 
consistent with its mechanism of action. PARP enzymes are involved in normal cellular 
homeostasis, such as DNA transcription, cell cycle regulation, and DNA damage repair. 
Pamiparib interacts with and inhibits the enzymatic repair machinery that carries out 
detection and repair of single-stranded binding proteins. 
In the general toxicity studies in rats and dogs with pamiparib, no gross lesions or 
histopathological changes were noted in male and female reproductive organs. No 
embryo-fetal toxicity studies were conducted or planned as it was not considered 
essential because of its genotoxicity and bone marrow inhibition. 
There was no apparent inhibition of pamiparib on 
 
 
. No effects on blood pressure, heart rate, 
or ECGs were noted in telemetry-instrumented conscious dogs. No effects on central 
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nervous system, or respiratory functions were noted in Sprague Dawley rats. No 
abnormal changes in the cardiovascular, central nervous system, and respiratory systems 
were identified in single- or repeat-dose toxicity studies in both rats and dogs. No QT 
interval prolongation was noted in cardiovascular function studies in conscious dogs and 
in 28-day and 91-day repeat-dose toxicity studies in dogs. Embryo-fetal toxicity studies 
were not conducted because of the already established genotoxicity of and bone marrow 
inhibition by pamiparib. 
In summary, all available toxicological studies and data are adequate to support clinical 
development of pamiparib for treatment of patients with advanced cancer.  
Please refer to the investigator’s brochure (IB) for additional information (Pamiparib 
Investigator’s Brochure).  
1.4.2 
Nonclinical Activity Data 
Pamiparib potently inhibits enzyme activity of PARP1 and PARP2, 
 
 Most PARP inhibitors are able to trap PARP enzymes at 
damaged DNA sites, and these trapped PARP-DNA complexes appear to be more 
cytotoxic than unrepaired DNA breaks caused by PARP inactivation (Section 1.2). The 
PARP-trapping activity of pamiparib was measured by a fluorescence polarization 
binding assay, similar to the method described in the literature (Murai et al 2012). 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
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Pamiparib as a single agent has demonstrated excellent in vitro activity against tumor cell 
lines with defects of the homologous repair pathway. In vivo, pamiparib showed strong 
anti-tumor activity against a BRCA1-mutant mouse xenograft model (MDA-MB-436 
breast cancer) and was 16-fold more potent than olaparib. In a PK/pharmacodynamic 
study, oral administration of pamiparib resulted in time- and dose-dependent inhibition of 
PARylation in MDA-MB-436 breast cancer xenografts in mice. Inhibition of PARylation 
in the tumor tissues correlated well with tumor drug concentrations of pamiparib. 
Please refer to the IB for additional information (Pamiparib Investigator’s Brochure).  
1.4.3 
Clinical Data for BGB-290 
Pamiparib is currently being studied in two Phase 1/2 studies: BGB-290-AU-002 in 
Australia, n=68 (as of 1 June 2017) and BGB-290-102 in China, n=15 (as of 25 
September 2017) (Lickliter et al 2017). There is one Phase 1b study, 
BGB-A317/BGB-290_Study_001, for the combination of pamiparib with BGB-A317, an 
anti-PD 1 antibody (n= 42; as of 27 January 2017). The study data from BGB-290-AU-
002 are the most mature, and key interim results are summarized below, as are 
preliminary safety and PK data for pamiparib in China patients (BGB-290-102). 
1.4.3.1 Pharmacokinetics Data for BGB-290-AU-002 
In the first-in-human Phase 1 study, interim PK data of pamiparib showed that pamiparib 
is rapidly absorbed and eliminated after oral administration. The maximum serum 
concentration (Cmax) and the drug exposure (the area under the concentration-time curve 
[AUC]) increased in a nearly dose-proportional manner from 2.5 mg BID to 120 mg BID 
both after the single dose administration and at the steady state. The terminal half-life 
was determined to be approximately 13 hours, with a range of 5.4 to 34 hours. At the 
steady state, from 2.5 mg BID to 120 mg BID, drug exposure was increased in a dose-
dependent manner, with an approximately 2-fold accumulation. 
1.4.3.2 Pharmacokinetics for BGB-290-102 in China 
In this Phase 1a study, the PK data were extracted based on samples obtained from 15 
enrolled patients. PK samples were taken on Cycle 1 Day 1 and Cycle 1 Day 10. On 
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Cycle 1 Day 1, samples were collected within 1 hour predose, and at 0.5, 1, 2, 4, 6, 9, 12, 
24, and 48 hours postdose. On Cycle 1 Day 10, samples were collected within 1 hour 
predose, and at 0.5, 1, 2, 4, 6, 9, and 12 hours postdose. Preliminary PK showed that 
Pamiparib plasma drug exposure (AUC) increased in a nearly dose proportional manner, 
with a plasma half-life of about 12 hours. In the 20-mg BID cohort, pamiparib steady 
state plasma maximum concentration (Cmax) and drug exposure (area under the plasma 
concentration-time curve from 0 to 9 hours postdose [AUC0-9]) were 1450 ng/mL and 
9361 ng/mL•h, respectively. In the 40-mg BID cohort, pamiparib steady state Cmax and 
AUC0-9 were 5340 ng/ml and 33545 ng/mL•h, respectively. In the 60-mg BID cohort, 
pamiparib steady state plasma Cmax and AUC0-9 were 6048 ng/ml and 39657ng/mL•h, 
respectively. Pamiparib steady state Cmax and AUC0-9 in the Phase 1 portion of the BGB-
290-102 study were about 35% higher than that in BGB-290-AU-002 study. Given the 
limited sample size in this study (n=4 each at 20 and 40 mg BID, n=7 at 60 mg BID), 
these differences represent a very preliminary result and need to be interpreted with 
caution. 
 
 
 
Although all 3 demographic factors were inter-related and showed statistical significance 
in the forward-addition step, they were not retained in the backward elimination process 
of the covariate analysis. The apparent difference in plasma exposure observed between 
BGB-290-AU-002 and BGB-290-102 could ultimately be due to the difference in patient 
body weight, as the median weight from 15 female patients in BGB-290-102 (China) was 
61 kg, and the median body weight from 60 male and female patients in BGB-290-AU-
002 (Australia) was 71.5 kg. 
1.4.3.3 Exploratory Biomarker Data 
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1.4.3.4 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, the maximum tolerated dose, preliminary anti-tumor 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 PO BID up to 120 mg PO BID. 
The study is being conducted in 3 Australian study centers, and preliminary data for 
45 patients are available (cut-off date of 30 September 2016).  
The preliminary safety data indicates the most frequent AEs (≥ 10% of patients) assessed 
as related to pamiparib were nausea (51%, n=23), fatigue (29%, n=13), vomiting (18%, 
n=8), diarrhea (16%, n=7), and decreased appetite (11%, n=5). 
Hematologic AEs are of interest in this study. The most frequent hematologic AEs 
(≥ 10% of patients) assessed as related to pamiparib were anemia (22%, n=10) and 
neutropenia (11%, n=5). Hematologic AEs, regardless of relatedness, were reported in 
40% of patients (n=18). Anemia was most frequent (33%, n=15), followed by 
neutropenia (11%, n=5) and thrombocytopenia (2%, n=1). 
Twenty-six patients experienced Grade 3 AEs (regardless of relatedness), and no Grade 4 
AEs were reported. Eleven Grade 3 AEs in 9 patients (20%) were considered related to 
pamiparib: anemia (11%, n=5), neutropenia (7%, n=3), hypophosphatemia (2%, n=1), 
paresthesia (2%, n=1), nausea (2%, n=1) and fatigue (2%, n=1).  
Serious AEs (SAEs) were reported in 25 patients, and for 3 patients they were considered 
related to pamiparib: anemia (n=2) and nausea (n=1). Three patients discontinued study 
drug because of an AE: vomiting (n=1), oral paresthesia (n=1), and right neck cutaneous 
metastases (n=1). 
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Four patients experienced a fatal AE ≤28 days after the last pamiparib dose. All deaths 
were due to complications of the underlying malignancy, and none was considered 
related to pamiparib. 
Four patients experienced AEs that were considered dose limiting toxicities (DLTs): 
2 patients experienced Grade 2 nausea that persisted despite optimal standard medical 
therapy; 1 patient experienced Grade 2 anorexia and Grade 2 nausea, and 1 patient 
experienced Grade 2 nausea and Grade 2 paresthesia. Based on the encountered DLTs 
and the overall safety profile of pamiparib, the maximum tolerated dose of pamiparib was 
determined to be 80 mg PO BID (160 mg/day).  
MDS or acute myeloid leukemia (AML) are recognized AEs in patients receiving PARP 
inhibitors (Ricks et al 2015). To date, no cases of either MDS or AML have been 
observed in any study that includes pamiparib. 
Ten patients achieved either a complete (n=2) or partial (n=8) response; all responses 
were observed in patients with gynecological cancers. 
1.4.3.5 Clinical Safety and Preliminary Efficacy for BGB-290-102 in China 
The Phase 1 portion of Study BGB-290-102 evaluates the safety, tolerability, PK, and 
preliminary efficacy of pamiparib in Chinese patients with advanced high-grade non-
mucinous ovarian cancer (HGOC), including fallopian and primary peritoneal cancer, or 
TNBC. Three cohorts with BID dosing (20, 40, and 60 mg) were evaluated in the dose-
escalation phase. Preliminary data for 15 patients are available (HGOC: n=9; TNBC: 
n=6; as of 25 September 2017): n=4 for 20 mg, n=4 for 40 mg and n=7 for 60 mg.  
The most common related AEs were asthenia (n=12), nausea (n=12), decreased appetite 
(n=9), white blood cell count decreased (n=9), anemia (n=8) and neutrophil count 
decreased (n=7). Grade 3 AEs in ≥ 2 patients were anemia (n=5), decreased neutrophil 
count and decreased white blood cell count (n=2 each). No ≥ Grade 4 AEs were reported. 
All SAEs were not related to pamiparib (1 each of abdominal infection, ileus, and pleural 
effusion). No dose-limiting toxicities were reported; and the recommended Phase 2 dose 
was confirmed as 60 mg PO BID. 
Available preliminary efficacy data for 5 TNBC patients showed progressive disease for 
all 5 (BRCA1/2 mutation: n=1). Median duration of treatment for 9 HGOC patients was 
133 days (range: 8–260). Available preliminary efficacy data for 8 HGOC patients (all 
platinum-resistant/refractory) showed 2 patients with partial response (on treatment: n=2; 
BRCA1/2 mutation: n=1) and 6 with stable disease (on treatment: n=3; BRCA1/2 
mutation: n=4).   
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1.5 
Rationale for Selection of Pamiparib Dose 
Based upon the overall safety, efficacy, and PK profile of pamiparib, the dose of 
pamiparib 60 mg PO BID was selected using available clinical data from Studies BGB-
290-AU-002 and BGB-290-102 (Sections 1.4.3.4 and 1.4.3.5, respectively). Study BGB-
290-AU-002 determined the maximum tolerated dose of pamiparib to be 80 mg PO BID 
(160 mg/day). The dose of 60 mg BID was selected for further evaluation based on the 
following findings (refer to the IB [Pamiparib Investigator’s Brochure]): 
 
A linear PK profile observed up to 80 mg BID 
 
Similar toxicity profiles at 60 and 80 mg BID with the following exceptions: 
o Fewer patients at 60 mg BID experienced treatment-related AEs of anemia and 
neutropenia 
o There was a slightly higher rate of dose interruptions at 80 versus 60 mg BID 
for anemia and nausea 
 
Responses were observed across the dose range evaluated 
The recommended dose for further investigation in Chinese patients was also 
determined to be 60 mg PO BID. 
The BGB-290-102 Phase 1 study confirmed that the recommended dose for further 
investigation in Chinese patients was also 60 mg PO BID based on the following 
findings: 
 
The AE profile observed from 15 female Chinese patients in the BGB-290-102 
study was generally consistent with that from the BGB-290-AU-002 (Australia) 
study, and AEs could be managed clinically. 
 
No DLTs and drug-related SAEs were observed across the dose range evaluated. 
 
The average steady-state pamiparib plasma exposure (Cmax, AUC) at 60 mg BID 
in Chinese patients was approximately 35% higher than for Australian patients 
(BGB-290-AU-002).  
In summary, pamiparib is an excellent candidate to determine the effects of PARP 
inhibition in advanced cancers. 
1.6 
Study Rationale 
This is a Phase 2 study to evaluate the anti-tumor activity of pamiparib, its safety and PK 
profile in advanced or metastatic HER2(-) breast cancer patients with confirmed either 
deleterious or suspected deleterious germline BRCA1/2 mutations susceptible to 
treatment with a PARP inhibitor. Preliminary biomarkers for efficacy and resistance will 
also be explored. 
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Pamiparib is a potent and selective inhibitor of PARP1 and PARP2. It has excellent 
PARP-trapping activity that is likely to be more important for anti-tumor activity than 
catalytic PARP inhibition. In the clinic, pamiparib has shown favorable PK properties, 
has been well-tolerated and achieved maximum pharmacodynamic target modulation in 
PBMCs at a dose level well below the recommended Phase 2 dose (10 mg versus 60 mg 
BID). PK modeling predicts that the recommended Phase 2 dose of pamiparib can 
achieve brain concentrations required for anti-tumor activity. 
 
. 
Breast cancer is now the most common cancer among Chinese women, and 15-20% of 
them are TNBC. The prognosis of TNBC is poor, and effective treatment choices are 
limited. The 3rd ESO-ESMO International Consensus Guideline for advanced breast 
cancer recommends that genetic counseling and possibly BRCA testing should be 
discussed with TNBC patients, if the results can impact on treatment decisions and/or 
clinical trial entry. In China, there is currently no PARP inhibitor approved for the 
treatment of breast cancer. 
Data from the OlympiAD study support the use of PARP inhibitors as monotherapy in 
HER2(-) breast cancer patients with deleterious BRCA mutation.  
In summary, pamiparib is an attractive drug candidate to determine the effects of PARP 
inhibition in this unmet medical need of HER2(-) breast cancer patients with BRCA 
mutation. 
1.7 
Benefit-Risk Assessment 
Pamiparib has been studied in nonclinical toxicity and Phase 1 clinical studies, and 
pamiparib toxicities are largely consistent with the safety profile shared by other PARP 
inhibitors. 
MDS and AML have been reported in a small number (<1%) of patients treated with 
PARP inhibitors, especially in patients harboring a germline BRCA mutant (Ricks et al 
2015). Typically, patients who develop MDS and AML while on therapy with a PARP 
inhibitor have a history of extensive previous chemotherapy and some have a history of 
previous cancer or bone marrow abnormalities. To date, there have been no reports of 
MDS or AML in patients treated with pamiparib. Patients in this study will be monitored 
monthly for hematological toxicities, and events of MDS and AML will be reported as 
SAEs irrespective of time elapsed since end of study treatment. 
In this study, patients with advanced HER2(-) breast cancer harboring germline BRCA1/2 
mutation will be recruited. Given that PARP inhibitors have shown clinical benefit in this 
patient populations (Refer to Section 1.3), the risk of toxicities of the PARP inhibitor 
pamiparib appears acceptable. 
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1.8 
Study Conduct 
This study will be conducted in compliance with the protocol approved by the 
institutional review board (IRB) or Independent Ethics Committee (IEC), and in 
accordance with good clinical practice (GCP) standards. 
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2. STUDY OBJECTIVES 
2.1 
Primary Objective 
 To evaluate the efficacy of pamiparib in patients with advanced triple negative breast 
cancer or HR(+)/HER2(-) breast cancer harboring germline BRCA1/2 mutation, as 
measured by: 
o Objective response rate according to Response Evaluation Criteria in Solid 
Tumors, version 1.1, by independent radiology review 
2.2 
Secondary Objectives 
 To further evaluate the efficacy of pamiparib in patients with TNBC or 
HR(+)/HER2(-) breast cancer harboring germline BRCA1/2 mutation, as measured 
by: 
o Objective response rate by investigator assessment 
o Progression-free survival and duration of response by independent radiology 
review and investigator assessment 
o Disease control rate, best overall response and clinical benefit rate assessment 
by independent radiology review and investigator assessment 
o Overall survival 
 To evaluate the safety and tolerability of pamiparib, as measured by: 
o Incidence, timing, and severity of treatment-emergent adverse events, graded 
according to the National Cancer Institute-Common Terminology Criteria for 
Adverse Events, version 4.03 (Common Toxicity Criteria Version 4.03) or 
higher 
2.3 
Exploratory Objectives 
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3. STUDY DESIGN 
This is a Phase 2, open-label, multi-center study of pamiparib administered PO BID in 
adult Chinese patients with advanced HER2(-) breast cancer harboring germline BRCA 
mutation, which have progressed despite standard therapy, or for which no standard 
therapy exists. In this study, the efficacy, safety, tolerability and PK profile of pamiparib 
will be further evaluated. All eligible patients will be enrolled into one of the below 
cohorts: 
1. Approximately 55 previously treated patients with locally advanced or metastatic 
TNBC with confirmed either deleterious or suspected deleterious germline 
BRCA1/2 mutation 
2. Approximately 20 previously treated patients with locally advanced or metastatic 
HR(+)/HER2(-) breast cancer with confirmed either deleterious or suspected 
deleterious germline BRCA1/2 mutation 
Patients will be screened for eligibility up to 28 days prior to the first dose of pamiparib 
and will take pamiparib at 60 mg BID continuously for all cycles (28-day cycles) starting 
on Day 1 of Cycle 1. Patients will be instructed to swallow the capsules whole, in rapid 
succession, with water. Pamiparib can be administered with or without food. 
Tumor response will be assessed by IRR and investigators based on RECIST, version 1.1.  
Patients will be monitored for safety, tolerability, and efficacy throughout the study. 
Tumor assessments will be performed every 8 weeks ± 7 days in the first year, and then 
every 12 weeks ± 7 days thereafter, or as clinically indicated. 
Patients will continue treatment until occurrence of disease progression as assessed by the 
investigator, unacceptable toxicities, death, withdrawal of consent, lost to follow-up, or 
study termination by sponsor. 
Study procedures and assessments are detailed in Appendix 1. The study schema is 
provided in Figure 2. 
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Figure 2. 
Study Schema 
 
Abbreviations: BC, breast cancer; BID, twice daily; HER2(-), human epidermal growth factor receptor 2 
negative; HR(+), hormone receptor-positive; PD, progression disease; PO, oral; TNBC, triple negative 
breast cancer.  
Note: Key assessments during treatment phase: tumor assessments every 8 weeks  7 days in the first year 
and every 12 weeks  7 days in the second year and above. Hematology assessments every 2 weeks in 
Cycles 1 and 2, then every 4 weeks in subsequent cycles. Adverse events at each visit. Chemistry 
assessments every 4 weeks throughout the study. Pamiparib is to be administered continuously. 
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4. STUDY POPULATION 
4.1 
Inclusion Criteria 
Patients may be enrolled in the study only if they meet all of the following criteria: 
1. Signed informed consent form (ICF) 
2. Age ≥ 18 years on day of signed ICF 
3. Confirmed deleterious or suspected deleterious germline BRCA1 or BRCA2 mutation 
 Germline BRCA1/2 mutation testing in central laboratory prior to Day 1 of 
Cycle 1 
4. Locally advanced or metastatic breast cancer despite standard therapy and the 
following: 
a. Histologically or cytologically confirmed HER2(-) breast cancer (TNBC or 
estrogen receptor-positive and/or PR+) 
b. ≤ 2 prior lines of chemotherapy in advanced or metastatic setting 
c. Prior platinum therapy allowed as long as no disease progression while on 
treatment, or if given in neoadjuvant/adjuvant setting with ≥ 6 months from 
last platinum to relapse 
d. Prior therapy with an anthracycline and/or a taxane in neoadjuvant/adjuvant or 
metastatic setting 
e. Archival tumor tissues will be collected from all patients, if available 
f. For HR(+)/HER2(-) breast cancer only: patients must have received and 
progressed on at least one endocrine therapy either in adjuvant or metastatic 
setting, or have disease that the treating physician believes to be inappropriate 
for endocrine therapy  
5. Measurable disease as defined per RECIST, version 1.1 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to 
other loco-regional therapy, are usually not considered measurable unless there 
has been demonstrated progression in the lesion. 
6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 (Appendix 3) 
7. Ability to swallow whole capsules 
8. Ability to comply with study requirements independently 
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9. Adequate hematologic and organ function as defined by the following laboratory 
values (obtained  14 days before Day 1 of Cycle 1): 
 Absolute neutrophil count ≥ 1,500/mL or ≥ 1.5 x 109/L 
 Platelet count ≥ 75,000/mL or ≥ 75 x 109/L 
 Hemoglobin ≥ 9 g/dL or ≥ 90 g/L (≥14 days after growth factor support or 
transfusion) 
 Estimated glomerular filtration rate ≥30mL/min/1.73m2 by Chronic Kidney 
Disease Epidemiology Collaboration equation (CKD-EPI EQ; Appendix 4) 
 Total serum bilirubin ≤ 1.5 × upper limit of normal (ULN)  
 Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × 
ULN, if liver function abnormalities are due to liver metastasis, then AST and 
ALT  5  ULN 
10. For females of childbearing potential and nonsterile males, must practice highly 
effective methods of birth control (Appendix 8) for the duration of the study and for 
at least 6 months after last study drug  
4.2 
Exclusion Criteria 
Patients will not be enrolled in the study for any of the following reasons: 
1. Unresolved acute effects of prior therapy of ≥ Grade 2 
 
Except for AEs not considered a likely safety risk (eg, alopecia, neuropathy, and 
specific laboratory abnormalities) 
2. Prior treatment with a PARP inhibitor 
 
Subtherapeutic exposure to a PARP inhibitor for ≤ 28 days is permissible 
provided it was not the most recent prior therapy 
3. Chemotherapy, hormonal therapy, radiotherapy, biologic therapy, immunotherapy, 
investigational agent, anticancer Chinese medicine, or anticancer herbal remedies 
≤ 14 days (or ≤ 5 half-lives, if applicable, whichever is shorter) prior to Day 1 of 
Cycle 1 
 
Bisphosphonate and RANK-L inhibitors are allowed for bone metastases if 
initiated before enrollment and at a stable dose 
4. Major surgical procedure, open biopsy, or significant traumatic injury ≤ 14 days prior 
to Day 1 of Cycle 1, or anticipation of need for major surgical procedure during the 
course of the study 
 
Placement of vascular access device is not considered major surgery 
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5. Diagnosis of MDS 
6. Other diagnosis of malignancy 
 
Except for surgically excised nonmelanoma 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 ≥5 years ago 
with no current evidence of disease and no therapy ≥5 years prior to Day 1 of 
Cycle 1 
7. Untreated and/or active brain metastases  
a. A scan to confirm the absence of brain metastases is not required 
b. Patients with treated brain metastases must be off corticosteroids for ≥ 2 weeks 
and have no signs or symptoms of progressive brain metastases 
8. Active infection requiring systemic treatment, active viral hepatitis, or active 
tuberculosis  
9. Any of the following cardiovascular criteria:  
a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of 
daily living, ≤ 28 days prior to Day 1 of Cycle 1 
b. Symptomatic pulmonary embolism ≤ 28 days prior to Day 1 of Cycle 1 
c. Any history of acute myocardial infarction ≤ 6 months prior to Day 1 of Cycle 1 
d. Any history of heart failure meeting New York Heart Association Classification 
III or IV (see Appendix 9) ≤ 6 months prior to Day 1 of Cycle 1 
e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months prior to 
Day 1 of Cycle 1 
f. Any history of cerebral vascular accident ≤ 6 months prior to Day 1 of Cycle 1 
10. Previous complete gastric resection, chronic diarrhea, active inflammatory 
gastrointestinal disease, or any other disease causing malabsorption syndrome 
 
Gastroesophageal reflux disease under treatment with proton pump inhibitors is 
allowed. 
11. Active bleeding disorder, including gastrointestinal bleeding, as evidenced by 
hematemesis, significant hemoptysis, or melena  6 months prior to Day 1 of Cycle 1 
12. Use ≤ 10 days (or ≤ 5 half-lives, whichever is shorter), prior to Day 1 of Cycle 1, or 
anticipated need for food or drugs known to be strong or moderate 
 
s (Appendix 6) 
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13. Pregnancy or nursing 
a. Females of childbearing potential require a negative urine or serum pregnancy test 
 7 days prior to Day 1 of Cycle 1 
14. Significant intercurrent illness that may result in the patient’s death before death from 
breast cancer  
15. Known history of intolerance to the excipients of the pamiparib capsule 
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5. STUDY PHASES FROM SCREENING TO END OF STUDY 
5.1 
Pre-screening 
In this study, all patients including those with known germline BRCA1/2 mutation must 
undergo blood sampling for examination or confirmation of germline BRCA1/2 mutation 
prior to Day 1 of Cycle 1.  
Patients with unknown mutation status must undergo germline BRCA1/2 testing in pre-
screening phase prior to screening. The mutation testing will be performed in the 
qualified central laboratory. Patients with known germline BRCA1/2 mutation can 
proceed to the screening phase once they have signed the pre-screening informed consent 
and submitted their blood samples for confirmatory germline BRCA1/2 mutation testing, 
but patients need to have germline BRCA1/2 mutation confirmed before being eligible for 
the study. 
The following will be performed during pre-screening blood sample collection: 
 Obtain written pre-screening ICF from the patient 
 Prepare blood sample and ship to the qualified central laboratory for mutation 
analysis as specified in the laboratory manual 
5.2 
Screening 
A signed, written informed consent must be obtained prior to screening assessments and 
before any study-specific assessments are initiated. The study-specific assessments and 
procedures are shown in Table a of Appendix 1. The PK sampling time points are 
presented in Table b of Appendix 1. 
Rescreening under limited conditions may be allowed after consultation with BeiGene, 
and it is allowed only once. Repeating screening assessments within the original 
screening window is allowed if the patient did not previously meet certain eligibility 
criteria. 
5.3 
Enrollment 
After a patient is screened and the investigator determines the patient is eligible for 
enrollment, study site personnel will complete an eligibility form and email it to the 
medical monitor or designee to approve the enrollment in writing. Study site personnel 
should ensure that a medical monitor approved eligibility form is in the patient’s file 
before proceeding with study procedures. Each patient enrolled in this study will receive 
a unique patient number which will be assigned when the patient is enrolled in the study. 
Patients will be assigned in chronological order starting with the lowest number. Once a 
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patient number has been assigned to a patient, it cannot be reassigned to any other 
patient. 
5.4 
Treatment 
Day 1 of Cycle 1 is the first day of pamiparib administration. 
Study procedures of each clinic visit are outlined in Appendix 1. 
On days with PK assessments, pamiparib should be administered in the clinic in 
accordance with the schedule for the PK samples. Assessments should be obtained before 
study treatment unless stated otherwise in Appendix 1 and should be performed in order 
of least invasive to most invasive assessment. All safety-related assessments have to be 
reviewed and dose modifications, if necessary, be made by the investigator or 
sub-investigator before study treatment. 
5.5 
Unscheduled Visit 
Unscheduled visits may occur any time as necessary as per investigator’s decision, or 
patient’s request for reasons such as assessment or follow-up of AEs. Study activities of 
an unscheduled visit should be performed based on the reason for the unscheduled visit 
and are outlined in Appendix 1. If disease progression is suspected, imaging studies 
should be performed and blood for biomarkers should be obtained, as appropriate.  
5.6 
Permanent Discontinuation of Study Drug 
5.6.1 
Reasons for Permanent Discontinuation of Pamiparib 
The reason for discontinuation of pamiparib will be recorded in the electronic case report 
form (eCRF). These reasons include: 
 Disease progression 
 AE(s) 
 Pregnancy 
 Protocol violation 
 Patient withdrew consent for study treatment 
o Patients may voluntarily withdraw consent from study treatment at any 
time 
o Patients should be requested to participate in the follow-up phase, if a 
patient withdraws consent from the treatment phase only 
 Investigator’s discretion 
 Start of other anticancer therapy 
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Patients may discontinue pamiparib for other reasons but these will result in premature 
discontinuation from study (Section 5.8) and, consequently, result in lack of an EOT 
visit. 
5.6.2 
End of Treatment Visit 
The EOT visit should occur within 7 days after pamiparib has been permanently 
discontinued. Required assessments are listed in Appendix 1. If discontinuation is due to 
unresolved toxicities for more than 28 days (56 days for anemia), the EOT visit should be 
conducted at the earliest day possible within 7 days after permanent discontinuation is 
determined. The visit at which tumor assessments showed disease progression may be 
used as the EOT visit as long as all required assessments were performed. Tumor 
assessments do not have to be repeated if they were performed at a prior response 
evaluation that documented disease progression. For the other required assessments, if 
they were performed within 4 days of the EOT visit, they do not need to be repeated on 
EOT visit. ECG does not have to be repeated if it was performed within 14 days of the 
EOT visit. 
5.7 
Follow-Up Phase 
5.7.1 
Safety Follow-up 
All patients who discontinue study drug and have not initiated new anticancer therapy 
will be followed for AEs and SAEs as outlined in Section 9.3.1. A safety follow-up will 
occur with the safety assessments outlined in Appendix 1, until approximately 30 days 
after the last day of pamiparib or before initiation of new anticancer therapy, whichever 
occurs first. If new anticancer therapy is inadvertently initiated before this safety follow-
up (eg, without the knowledge of the study center team), a safety follow-up should be 
scheduled as soon as possible. If discontinuation is due to unresolved toxicities for more 
than 28 days, safety follow-up could be scheduled approximately 30 days after the last 
dose of study drug. If discontinuation is due to unresolved toxicities for more than 
56 days for anemia, safety follow-up could be scheduled at the earliest day possible 
within 7 days after permanent discontinuation is determined. 
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 AEs. If these attempts to contact 
are unsuccessful, the additional attempts detailed in Section 5.7.3 should be made. 
When treatment is interrupted or permanently discontinued due to an AE or abnormal 
laboratory value the patient will be followed at a frequency as medically indicated until 
resolution or stabilization of the event, whichever comes first. 
Patients who are discontinued from the study due to an unacceptable drug-related AE will 
be followed until the resolution of the AE to ≤ Grade 1 or stabilization. 
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If MDS/AML is diagnosed, treatment of pamiparib must be permanently discontinued. 
5.7.2 
Long-term Follow-up 
Patients will be followed for survival, further anticancer therapy, and diagnosis of MDS 
or AML via telephone contact or other means (eg, clinic visit) approximately every 
12 weeks (Appendix 1). 
Patients who were permanently discontinued from study drug for reasons other than 
disease progression and meet criteria otherwise (eg, discontinued for AE and no new 
anticancer therapy) will be followed with tumor assessments per protocol as outlined in 
Appendix 1 until disease progression or any other reason listed in Section 5.8, whichever 
occurs first. For efficacy assessments as per protocol, refer to Section 7.3 and Appendix 
1. If the patient refuses to return for these tumor assessments or is unable to do so, every 
effort should be made to contact the patient by telephone to determine the patient’s 
disease status and survival. 
5.7.3 
Lost to Follow-up 
Should attempts of telephone contact be unsuccessful, the following additional attempts 
should be made to obtain protocol-required follow-up information. The patient should be 
contacted by mail in a manner that provides proof of receipt by the patient. If 
unsuccessful, other contacts should be explored, such as referring physicians or relatives. 
Attempts of contact should be documented in the patient’s source documents. If a patient 
cannot be contacted despite all attempts, the patient will be considered lost to follow-up, 
and death information should be obtained through a public record search if local agencies 
permit. 
5.8 
End of Study 
Premature discontinuation from the study (without EOT and any follow-up visits) will 
occur under the following circumstances: 
 Patient withdrew consent for study participation 
o Patients may voluntarily withdraw consent from the study at any time 
 Investigator’s discretion 
 Lost to follow-up 
o Lost to follow-up should be recorded as such in the eCRF 
o The investigator should show due diligence by documenting in the source 
documents steps taken to contact the patient (Section 5.7.3) 
 Death 
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 Study termination by sponsor 
 Other, as per the discretion of the sponsor or health authority 
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6. STUDY TREATMENTS 
6.1 
Study Drug 
6.1.1 
Packaging and Labelling 
Pamiparib capsules will be provided in 20-mg capsules and in a child-resistant high-density 
polyethylene (HDPE) bottle with an induction seal and bottle label. The label will include at a 
minimum, drug name, dose strength, contents, sponsor, protocol number, lot number, 
directions for use, storage conditions, caution statements, retest or expiry date, and space 
to enter the patient number. 
The contents of the label will be in accordance with all applicable local regulatory 
requirements. 
6.1.2 
Handling and Storage 
The 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. 
Investigational pamiparib product must be dispensed or administered according to 
procedures described herein. Only patients enrolled in the study may receive pamiparib, 
in accordance with all applicable regulatory requirements. Only authorized study center 
personnel may supply or administer pamiparib. 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 investigational product-specific requirements. 
 
. 
6.1.3 
Dosage and Administration 
The patients will take pamiparib at 60 mg BID from Day 1 of Cycle 1 (with no treatment-
free or rest period). Pamiparib capsules will be administered PO BID, once in the 
morning and once in the evening. The time difference between two consecutive doses 
will be approximately 12 hours with a window of ± 4 hours. Patients will be instructed to 
swallow the capsules whole, in rapid succession, with water. Pamiparib can be 
administered with or without food. However, to reduce gastrointestinal irritation that 
pamiparib may cause, patients are encouraged to take pamiparib with food. 
A dose of pamiparib should be skipped if it is not taken within the upper range of the 
scheduled time (ie, within 16 hours). An extra dose of pamiparib should not be taken to 
make up for a missed dose. If vomiting occurs during the course of treatment, no re-
dosing of the patient is allowed before the next scheduled dose.  
On days with PK assessments, the morning dose of pamiparib should be administered in 
the clinic in accordance with the schedule for the PK samples.  
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6.1.4 
Dose Hold and Modification 
AEs should be assessed as best as possible regarding their relatedness to pamiparib. 
Regardless of discontinuation of pamiparib, patients should continue on study with 
follow-up as outlined in Sections 5.6 and 5.7. 
Investigators should make every effort to maintain dose intensity in patients. Dosing of 
pamiparib can be withheld for up to 28 days consecutively for medical events (56 days 
for anemia). If drug is planned to be held > 28 days, the medical monitor should be 
contacted prior to permanent patient discontinuation from the study drug.  
Study treatment should be stopped at least 3 days prior to planned surgery. After surgery, 
study treatment can be restarted when the wound has healed. No stoppage of study 
treatment is required for any biopsy procedure. Study treatment should be discontinued 
for a minimum of 3 days before a patient undergoes radiation treatment. Study treatment 
should be restarted within 4 weeks as long as any bone marrow toxicity has recovered. 
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 
sponsor medical monitor and the best clinical judgment at that time; any decisions should 
be documented. Any toxicities related to pamiparib should be managed according to 
standard medical practice. 
A maximum of 2 dose reductions is allowed before the patient must be permanently 
withdrawn from study drug. Dose levels for pamiparib are summarized in Table 2. 
Pamiparib will be dose modified as outlined in Table 3. 
Table 2. 
Dose Levels for Pamiparib 
Dose Level 
Pamiparib 
1 
60 mg PO BID 
-1 
40 mg PO BID 
-2 
20 mg PO BID 
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Table 3. 
Criteria for Modification of Pamiparib Dosing for Related Adverse 
Events 
Toxicity 
Recommended Dose Modificationa 
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:  
 Continue pamiparib without interruption with 
appropriate supportive care based on clinical 
assessment OR 
 Hold pamiparib and treat as medically indicated to 
get Hgb to ≥ 9 g/dL, then restart at reduced dose 
level OR 
 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:  
 Continue pamiparib without interruption with 
appropriate supportive care based on clinical 
assessment OR 
 Hold pamiparib and treat as medically indicated to 
get Hgb to ≥ 9 g/dL, then restart at reduced dose 
level OR 
 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 
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Toxicity 
Recommended Dose Modificationa 
Grade 4 (life-threatening 
consequences; urgent 
intervention indicated) 
 
Second occurrence following dose reduction for 
anemia:  
 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:  
 Discontinue pamiparib if anemia is not caused by 
any other confounding event, eg gastrointestinal 
hemorrhage. 
 Hold pamiparib and treat as medically indicated to 
get Hgb to ≥ 9 g/dL, then restart at reduced dose 
level. 
Note: 
1) Weekly hematology test should be done for the first 3 cycles during the study. For 
all Grade 2 or higher anemia, hematology tests 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 (absolute neutrophil count, 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 
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Toxicity 
Recommended Dose Modificationa 
Thrombocytopenia (platelet count, 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 (CKD-EPI EQ; Appendix 4) 
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 
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 
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Toxicity 
Recommended Dose Modificationa 
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 ECGs (2 to 3 minutes apart) ~1 
hour after initial ECG  
 
If mean QTcF >500 ms or mean change in QTc 
interval > 60 msec, hold pamiparib until evaluation 
of ECGs by cardiologist  
o Cardiology evaluation as soon as practical but 
within 7 days of initial abnormal ECG  
 
If mean QTcF >500 ms or mean change in QTc 
interval > 60 msec 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  
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 
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Toxicity 
Recommended Dose Modificationa 
Grade 4  
Permanently discontinue pamiparib 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANC, absolute neutrophil count; 
AST, aspartate aminotransferase; CKD-EPI: Chronic Kidney Disease Epidemiology Collaboration 
equation; ECG, electrocardiogram; Hgb, hemoglobin; 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 for medical events 
(56 days for anemia). 
6.1.5 
Compliance and Accountability 
Compliance will be assessed by the investigator and/or study personnel at each patient 
visit and information provided by the patient. 
The investigator and/or study personnel will keep accurate records of the quantities of 
capsules dispensed and used by each patient. This information must be captured in the 
source document at the end of each cycle. The investigator is responsible for pamiparib 
accountability, reconciliation, and record maintenance. In accordance with all applicable 
regulatory requirements, the investigator or designated study center personnel must 
maintain pamiparib accountability records throughout the course of the study. This 
person will document the amount of pamiparib received from the sponsor, the amount 
supplied, and/or administered to and returned by patients, if applicable. 
6.1.6 
Disposal and Destruction 
After completion of the study, all unused pamiparib will be inventoried and packaged for 
return shipment by the hospital unit pharmacist or other designated study center 
personnel. The inventoried supplies can be destroyed on site or at the depot according to 
institutional policies after receiving written sponsor approval. 
6.2 
Concomitant Medications and Non-drug Therapies 
6.2.1 
Permitted Medications and Supportive Care 
All treatments and supportive care, including antiemetic therapy, hematopoietic growth 
factors, and/or red blood cell/platelet transfusions, that the investigator considers 
necessary for a patient’s welfare may be administered at the discretion of the investigator 
in keeping with the local standards of medical care. 
All concomitant medications, including all prescription and over-the-counter drugs, 
herbal supplements, and IV medications and fluids, taken by or administered to the 
patient within 28 days before Day 1 of Cycle 1 and 30 days after the last day of 
pamiparib will be recorded. 
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6.2.2 
Prohibited Medications 
Patients are not allowed to receive other anticancer therapy, including surgery, radiation 
therapy (except for palliative radiation therapy to non-targeted lesion), immunotherapy, 
investigational agents, cytotoxic, biologic or hormone therapy, anticancer Chinese 
medicine or anticancer herbal remedies. Bisphosphonate and RANK-L inhibitors are 
allowed for bone metastases if initiated before enrollment and at a stable dose. 
Bisphosphonates are permitted during the study for a non-malignant indication. 
 
 
 
. 
Grapefruit juice is not allowed at any time during the study. No other dietary restrictions 
will apply. 
6.2.3 
Medications to be used with Caution 
Based on preliminary in vitro screening assays, pamiparib is not a strong inhibitor of 
other human 
 tested. It is a moderate inhibitor of 
 Investigators should be aware that pamiparib has the 
potential to interfere with the appropriate metabolism of medications that rely on 
. Investigators should follow the prescribing information recommendations for 
use with 
. Examples of these medications include, but are not limited 
to, medications presented in Appendix 6 and these should be used cautiously with the 
monitoring of drug concentrations where appropriate. 
, pamiparib can also be metabolized by
 
, but to a lesser extent. The compounds/substances presented in Appendix 7 
are associated with possible interactions with pamiparib through the
 
 and should also be used cautiously. 
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7. STUDY ASSESSMENTS 
7.1 
Study Flow and Visit Schedule 
The study-specific assessments and procedures with allowed time windows are outlined 
in Appendix 1. Assessments of efficacy will occur as outlined in Section 7.3. 
Assessments of safety will be based on AE monitoring and reporting (including 
attribution of AEs and SAEs), physical examinations, vital signs, ECGs, and clinical 
laboratory tests as outlined in Section 7.4. 
7.2 
Patient Demographic and Other Baseline Assessments Characteristics 
7.2.1 
Demographics  
Demographic data will include date of birth, race, height (in cm), body weight (in kg), 
and body mass index (in kg/m2). For height and weight measurements, the patient will be 
allowed to wear indoor daytime clothing with no shoes. These data will be captured in the 
eCRF. 
7.2.2 
Medical History and Prior Medications 
Clinically significant medical history findings (eg, previous diagnoses, diseases, or 
surgeries) which started prior to signing the ICF, will be collected and captured, 
including baseline severity, if ongoing, in the eCRF. Clinically significant is defined as 
any events, diagnoses, or laboratory values requiring treatment, follow-up or the presence 
of signs or symptoms that require medical intervention. Concurrent medical signs and 
symptoms must be documented to establish baseline severities. 
For breast cancer history, the date of initial diagnosis and current disease status, staging, 
sites of disease, prior anticancer therapies and dates administered, responses, and duration 
of response to these treatments will also be recorded. 
7.2.3 
Other Baseline Characteristics 
Having given consent, patients will be required to undergo a medical screen to determine 
whether they are eligible to participate in the study according to the criteria listed in 
Section 4. Screening assessments will be completed within 28 days prior to the first dose 
of the pamiparib. Screening assessments completed within 4 days of administration can 
be used as Cycle 1 Day 1 assessments as indicated in Appendix 1.  
All the baseline data will be captured in the source documents and in the eCRF.  
7.3 
Efficacy 
7.3.1 
Tumor Assessments 
Tumor imaging studies will be reviewed for the purposes of eligibility determination and 
on-study tumor monitoring. Following the screening tumor assessment, tumor 
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assessments will occur at the schedule of every 8 weeks ± 7 days after the first dose of 
pamiparib in the first year, then every 12 weeks ± 7 days afterwards. Any measurable 
disease must be documented at screening and reassessed at each subsequent tumor 
evaluation. The same imaging method(s) used at screening must be used throughout the 
study. Patients who did not have disease progression at the time of pamiparib 
discontinuation and meet criteria (eg, discontinued for AE and no new anticancer 
therapy) will continue to have tumor assessments per protocol as outlined in Appendix 1, 
until 1) commencement of new treatment, 2) disease progression, 3) death, or 4) 
termination of the study. ORR, PFS, OS and DOR will be assessed by IRR and 
investigator using RECIST, version 1.1 (Appendix 5).   
7.3.1.1 Screening Tumor Assessment 
The baseline tumor assessment should include the following: 
 
Diagnostic-quality, computed tomography (CT) scans of the chest, abdomen, and 
pelvis  
(Day -28 to -1) 
o To be suitable for RECIST, version 1.1, assessments, CT scans should have a 
maximum thickness of 5 mm and no gaps. 
o CT is the preferred imaging method for tumor assessments of the chest, 
abdomen, and pelvis. 
o If a positron-emission tomography (PET)/CT scan is performed, the CT portion 
should meet the CT scan requirements described above.  
o In patients for whom the preferred CT scans are contraindicated because of, for 
example, a CT IV contrast allergy, a CT of the chest without contrast and 
magnetic resonance imaging (MRI) of the abdomen and pelvis with contrast are 
recommended. 
o MRI scans may be performed in lieu of CT scans. At screening, tumor 
assessments should include a diagnostic quality, contrast enhanced MRI scan of 
the chest, abdomen, and pelvis. To be suitable for RECIST Version 1.1 
assessments, MRI scans should ideally have a maximum thickness of 5 mm and 
minimal gaps. 
 
For all patients, a bone scan (Technetium-99m [TC-99m] or NaF-PET) at 
screening is required (Day -28 to -1) 
 
CT scan of the neck, if clinically indicated (Day -28 to -1) 
o Only to be performed at screening if the patient has known or suspected 
metastases in this area 
o MRI scan of the neck may be substituted for CT scan of the neck. 
 
MRI scan of the brain, if clinically indicated (Day -28 to -1) 
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o Only to be performed at screening if the patient has symptoms that could be due 
to brain metastases 
o MRI is the preferred imaging method for tumor assessments of the brain. 
o In patients for whom MRI of the brain is not available or who are 
claustrophobic, a CT scan of the brain with IV contrast may be performed. 
7.3.1.2 On-study Tumor Assessments 
All target and nontarget lesions must be assessed with the same imaging method used at 
baseline.  
 
Diagnostic-quality, CT scans of the chest, abdomen, and pelvis (every 8 weeks 
±7 days, as calculated by the date of the first administration of pamiparib) in the 
first year, and then every 12 weeks ±7 days thereafter until progression  
o CT scan with IV contrast is preferred but the imaging method at screening 
determines the imaging method of subsequent tumor assessments and must be 
used. 
 
Imaging of all other known sites of disease (every 8 weeks ±7 days, as calculated 
by the date of the first administration of pamiparib) in the first year and every 
12 weeks ±7 days thereafter until progression  
 
If bone metastases are present at screening and cannot be seen on CT or MRI 
scans, or if clinically indicated, TC-99m or NaF-PET bone scans should be 
repeated when CR is identified in target disease, or when progression in bone is 
suspected. 
In addition to the protocol-specified tumor assessments, CT scans or other imaging 
studies may be performed at the investigator’s discretion at any time as clinically 
indicated. If an unscheduled assessment was performed and the patient has not 
progressed, every attempt should be made to perform the subsequent assessments at their 
scheduled visits. 
After first documentation of response (CR or PR), confirmation of response should be 
obtained no sooner than 4 weeks following the initial evaluation and be better to occur at 
the next regularly scheduled assessment (4 weeks later, if possible).  
7.3.2 
Survival Assessments 
Following completion of the treatment and safety follow-up periods, all patients will be 
followed for survival status in the survival follow-up period specified by the protocol. 
Patients will have their survival status assessed approximately every 12 weeks by either a 
telephone or in-person contact until study completion or termination by the sponsor. No 
other data (eg, subsequent therapies, performance status, etc) beyond survival will be 
collected during these calls/visits. 
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Survival status of patients will be monitored throughout the study as outlined in 
Appendix 1. The date and cause of death will be recorded. 
7.4 
Safety 
7.4.1 
Adverse Events 
Safety assessments should be performed at the study center visits indicated in Appendix 
1. 
All AEs and SAEs, regardless of their relationship to study treatment, will be collected in 
the fashion and for the time periods outlined in Section 9. The accepted regulatory 
definition of AEs and important additional requirements for SAE reporting are outlined in 
Section 9. 
7.4.2 
Physical Examination, Vital Signs, ECOG Performance Status, and Weight 
A complete or limited physical examination, vital signs (systolic and diastolic blood 
pressure, pulse rate, and temperature), weight, height, and ECOG performance status will 
be performed at time points specified in Appendix 1. 
A complete physical examination should include an evaluation of head, eyes, ears, nose 
and throat, neck, heart, chest (including lungs), abdomen, extremities, skin, lymph nodes, 
cardiovascular status, and neurological status. A limited physical examination should be 
directed at the evaluation of symptoms or specific safety issues. Changes from baseline 
abnormalities should be recorded at each subsequent physical examination. New or 
worsened abnormalities should be recorded as AEs if appropriate. 
ECOG performance status will be determined as outlined in Appendix 3. 
7.4.3 
Electrocardiogram 
Single 12-lead ECGs with assessment of PR interval, QRS duration, and QT interval 
corrected for heart rate (QTc) will be obtained at screening and EOT visit. Additional 
ECGs will be performed if clinically indicated. To minimize postural variability, it is 
important that patients are resting and in a supine position for 5 minutes prior to each 
ECG measurement. Blood draws and other procedures should be avoided during the 
period immediately before ECG measurement, and activity should be controlled as much 
as possible to minimize variability because of the effects of physiologic stress. Screening 
ECG must be performed within 14 days prior to Day 1 of Cycle 1. For the scheduled 
ECG assessment at the EOT visit, ECG does not have to be repeated if it was performed 
within 14 days of the EOT visit. 
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7.5 
Laboratory Assessments 
Local laboratory assessments on serum chemistry, hematology, and urinalysis will be 
conducted, of which certain elements will be collected in eCRF as specified in Appendix 
2. 
Laboratory assessments should be performed at a local certified laboratory on Day 1 of 
Cycle 1 before pamiparib administration. Screening blood tests must be performed within 
14 days of Day 1 of Cycle 1. Laboratory assessments need not be repeated on Day 1 
Cycle 1 if these assessments were completed for screening within 4 days of the first 
administration. Required assessments are listed in Appendix 2. 
Clinical chemistry, hematology, and urinalysis will be performed at the time points 
specified in Appendix 1. 
7.5.1 
Hematology 
Hematology includes hemoglobin, lymphocyte count, neutrophil count, platelet count, 
and white blood cell count. 
7.5.2 
Chemistry 
Chemistry includes ALT, alkaline phosphatase, AST, albumin, blood urea nitrogen or 
urea, creatinine, chloride, glucose, lactate dehydrogenase, phosphate or phosphorus, 
potassium, total bilirubin, total protein, and sodium. 
7.5.3 
Urinalysis 
Urinalysis includes glucose, ketones, occult blood, pH, protein, red blood cells, specific 
gravity, and white blood cells. 
7.5.4 
Pregnancy Testing 
The Clinical Trials Facilitation Group recommendations related to contraception and 
pregnancy testing in clinical studies include for women with childbearing potential the 
use of highly effective forms of birth control (Appendix 8). During screening, for women 
of childbearing potential including those who have had a tubal ligation, a urine or serum 
pregnancy test must be performed and documented as negative within 7 days prior to 
Day 1 of Cycle 1, and urine pregnancy tests will be performed at each visit before dosing. 
A serum pregnancy test must be performed if the result of a urine pregnancy test is 
positive or equivocal. 
7.6 
Pharmacokinetics 
Blood samples (2 mL for determination of pamiparib concentration) for PK analysis will 
be collected according to the laboratory manual. Plasma will be separated and immediately 
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frozen. Samples must remain frozen at or below -70°C and in a box with dry ice during 
shipping. 
Samples will be shipped to the central laboratory where all samples will be analyzed for 
plasma pamiparib concentrations using a validated method. 
Time points of PK sampling are specified in Table b of Appendix 1. PK sampling will be 
conducted according to the laboratory manual. The actual time that each sample was 
collected at will be captured to the nearest minute in the eCRF and recorded in the 
database. The time of the last dose administration of pamiparib prior to PK sampling 
should also be recorded in the database. 
For details on collection and handling of PK blood samples, please refer to laboratory 
manual. If there is any inconsistency in blood sample collection and handling between 
protocol and laboratory manual, laboratory manual will take priority.  
Four blood samples (2 mL each) will be collected on Cycle 1 Day 1 and Cycle 2 Day 1 
(± 3 days) at the following time points: pre-dose (within 1 hour before pamiparib 
administration) and 2 hours post-dose for sparse PK sample collection. 
7.7 
Biomarkers 
A blood sample for all patients will be collected for germline BRCA mutation test. The 
blood sample should be collected prior to screening and will be processed according to the 
laboratory manual and sent to central laboratory for testing. DNA from this sample will be 
stored and may be used at later time for biomarker testing including, but not limited to, 
bridging to candidate companion diagnostic assays. 
Archival tumor tissues will be collected, if available. Either a formalin-fixed, paraffin 
embedded block with tumor tissue (preferred) or approximate 10 unstained slides are 
acceptable for the baseline archived tumor tissue. The most recent tumor block is 
preferred. 
Instructions for the processing, storage, and shipping of samples will be provided in the 
study laboratory manual. 
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7.8 
Appropriateness of Measurements 
All safety and PK assessments used in this study are standard, ie, widely used and 
generally recognized as reliable, accurate, and relevant. 
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8. DATA HANDLING AND QUALITY ASSURANCE 
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures, working practice documents, and applicable regulations 
and guidelines. Study center audits may be made periodically by the sponsor’s or the 
contract research organization’s qualified compliance auditing team, which is an 
independent function from the study team responsible for conduct of the study. 
8.1 
Data Collection 
Data will be entered into the eCRFs in an electronic data capture (EDC) system that is 
compliant with all regulatory requirements.  
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. 
8.2 
Data Management/Coding 
All final patient data, both eCRF and external data (eg, laboratory data), collected 
according to the protocol, will be stored at BeiGene at the end of the study.  
Standard procedures (including following data review guidelines, computerized 
validation to produce queries, and maintenance of an audit file which includes all 
database modifications) will be followed to support accurate data collection. Data will be 
reviewed for outliers, logic, data inconsistencies, and completeness. 
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. 
AEs will be coded using the MedDRA®, version 20.0 or higher. Concomitant 
medications will be coded using the World Health Organization Drug Dictionary 
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(WHODRUG). Concomitant diseases/medical history will be coded using the MedDRA, 
version 20.0 or higher. 
8.3 
Quality Assurance Audit 
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 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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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 an AE include:  
 
Worsening of a chronic or intermittent preexisting condition including an increase 
in severity, frequency, duration, and/or has an association with a significantly 
worse outcome 
 
New conditions detected or diagnosed after 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 the 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, version 4.03 
or higher. 
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  
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 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living  
 
Grade 4: Life-threatening consequences; urgent intervention indicated  
 
Grade 5: Death related to AE  
Note: The terms “severe” and “serious” are not synonymous. Severity is a measure of 
intensity (eg, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 
3], or life-threatening [Grade 4]); whereas, seriousness is classified by the criteria based 
on the regulatory definitions. Seriousness serves as the guide for defining regulatory 
reporting obligations from the sponsor to applicable regulatory authorities as described in 
Section 9.5. 
9.1.3 
Assessment of Causality 
The investigator is obligated to assess the relationship between the study drug 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 the study drug 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 since 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.  
Investigators must also systematically assess the causal relationship of AEs to study drug 
(including any other non-study drugs, radiation therapy, etc) using the following 
definitions:  
 Definitely related: There is clear evidence to suggest a causal relationship that 
there is reasonable temporal relationship; the positive of de-challenge result 
(when necessary the positive of re-challenge result); the occurrence of AE that 
could be attributed to the pharmacological effect of study drug.  
 Probably related: This causality assessment will be applied for AE that is regarded 
by the investigator as highly positive related to the study drug that: there is 
reasonable temporal relationship; the occurrence of AE could not be explained by 
the subject’s medical history, concurrent medical condition, or other the subject’s 
signs or symptoms; the positive of de-challenge result; the positive of re-
challenge result.  
 Possibly related: There is some evidence to suggest a causal relationship (eg, the 
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AE occurred within a reasonable time after administration of the study drug). 
However, the influence of other factors may have contributed to the AE (eg, the 
subject’s clinical condition, other concomitant AEs).  
 Unlikely related: There is little evidence to suggest there is a causal relationship. 
There is another reasonable explanation for the AE.  
 Unrelated: An AE will be considered “not related” to the use of study drug if any 
of the following tests are met:  
o An unreasonable temporal relationship between administration of study 
drug and the onset on the AE (eg, the AE occurred either before, or too 
long after administration of study drug for it to be considered drug-
related);  
o A causal relationship between study drug and the AE is biologically 
implausible (eg, death as a passenger in an automobile accident);  
o A clearly more likely alternative explanation for the AE is present (eg, 
typical adverse reaction to a concomitant drug and/or typical disease-
related AE). 
The causality for cases assessed with 5-point scale will be mapped to 2-point scale during 
aggregate safety data analysis according to the BeiGene latest mapping rule. 
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, 
histopathological 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. 
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New or updated information should be reported to the sponsor according to the SAE 
instructions provided by the sponsor within the time frames outlined in Section 9.5.1. 
9.1.5 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, chemistry, hematology, or coagulation) or other 
abnormal assessments (eg, ECGs, x-rays, or vital signs) that are judged by the 
investigator as clinically significant will be recorded as AEs or SAEs. This includes 
clinically significant abnormal laboratory findings or other abnormal assessments that are 
present at baseline and significantly worsen during the study. The definition of clinically 
significant is entrusted to the judgment of the investigator. In general, these are the 
abnormalities that: 
 
Are associated with clinical signs or symptoms, or 
 
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, which 
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, 
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influenza, and accidental trauma (eg, sprained ankle), which may interfere or prevent 
everyday life functions, but do not constitute a substantial disruption.  
 
Is a congenital anomaly/birth defect 
 
Is considered a significant medical AE by the investigator based on medical 
judgment (eg, may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above). 
The following are NOT considered SAEs: 
 
Hospitalization for elective treatment of a preexisting condition that did not 
worsen from baseline 
 
Hospitalization for social/convenience considerations 
 
Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
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 initiation of study drug, only SAEs should be 
reported to the sponsor. 
After initiation of treatment, all AEs and SAEs, regardless of relationship to treatment, 
will be reported until 30 days after the last dose of 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 drug treatment. 
After a patient is discontinued from the study, investigators are not obligated to actively 
seek AEs or SAEs from the former patients. However, if the investigator learns of any 
SAE, including a death, at any time, and considers the SAE related to pamiparib, the 
investigator will notify the sponsor. 
9.3.2 
Eliciting Adverse Events 
The investigator or designee will ask patients about AEs by asking the following standard 
questions: 
 
How are you feeling?  
 
Have you had any medical problems since your last visit?  
 
Have you taken any new medicines since your last visit?  
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9.4 
Study-Specific Instructions for Recording Adverse Events and Serious 
Adverse Events 
9.4.1 
Disease Progression 
“Disease progression” (including fatal disease progression), which is expected in this 
study population and measured as an efficacy endpoint, should not be reported as an 
event term. Instead, the symptoms, signs, or clinical sequelae that result from disease 
progression should be reported as the event terms. 
For example, a patient presents with pleural effusion resulting from disease progression 
of metastasis to lungs. The event term should be reported as “pleural effusion” instead of 
disease progression. If a patient experienced a fatal multiorgan failure due to disease 
progression, the term “multiorgan failure” should be reported as the SAE with death as 
outcome instead of reporting “fatal disease progression” or “death due to disease 
progression”. 
9.4.2 
Death 
Death is an outcome and not usually considered an event. If the only information 
available is death and the cause of death is unknown, then the death is reported as an 
event, eg, “death”, “death of unknown cause”, or “death unexplained”. 
9.5 
Prompt Reporting of Serious Adverse Events 
9.5.1 
Time Frames and Documentation Methods for Submitting Serious Adverse 
Events 
SAEs will be reported promptly (within 24 hours) to the sponsor or designee as described 
in Table 4 once the investigator determines that the AE meets the protocol definition of 
an SAE. 
Table 4. 
Time Frames 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. 
 
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9.5.2 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she will 
report the information to the sponsor within 24 hours as outlined in Section 9.5.1. The 
SAE Report will always be completed as thoroughly as possible with all available details 
of the event and forwarded to the sponsor or designee within the designated time frames.  
If the investigator does not have all information regarding an SAE, he/she will not wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form. The form will be updated when additional information is received. 
The investigator will always provide an assessment of causality at the time of the initial 
report as described in Section 9.1.3. 
The sponsor will provide contact information for SAE receipt. 
9.5.3 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the 
procedures detailed in Section 9.5.2. The sponsor has a legal responsibility to notify, as 
appropriate, both the local regulatory authority and other regulatory agencies about the 
safety of a product under clinical investigation.  
The investigator, or responsible person according to local requirements, will comply with 
the applicable local regulatory requirements related to the reporting of SAEs to regulatory 
authorities and the IRB/IEC. 
All suspected unexpected serious adverse reactions (as defined in Section 9.6) will be 
submitted to all applicable regulatory authorities and investigators for pamiparib studies. 
When a study center receives an initial or follow-up safety report or other safety 
information (eg, revised Investigator’s Brochure) from the sponsor, the investigator or 
designated responsible person is required to promptly notify his/her IRB or IEC. The 
investigator should place copies of Safety Reports from the sponsor in the Investigator 
Site File. 
9.6 
Suspected Unexpected Serious Adverse Reactions and Expedited 
Reporting 
A suspected unexpected serious adverse reaction is a serious adverse reaction that is both 
unexpected (ie, not present in the product’s Reference Safety Information in the 
Investigator’s Brochure) and assessed as related to pamiparib either by the investigator or 
the sponsor. The sponsor will promptly assess the expectedness for all SAEs against the 
list of expected serious adverse reactions in the Reference Safety Information and 
expeditiously submit suspected unexpected serious adverse reactions to regulatory 
authorities, investigators, IRBs, and IECs based on applicable legislation. 
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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 the completion of the last dose of study drug, a 
pregnancy report form should be completed and expeditiously submitted to the sponsor to 
facilitate outcome follow-up.  
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 the study drug should be recorded and reported as an SAE. 
 
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10. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
10.1 Sample Size Considerations 
A total of approximately 75 patients will be enrolled into one of the below cohorts.  
 
Approximately 55 evaluable patients will be enrolled into the TNBC cohort. In 
TNBC cohort, it is assumed that ORR is 46% in patients with pamiparib. There is 
an 90% power of demonstrating a statistical difference versus a historical 
response rate of 25% using a binomial exact test at an alpha of 0.025 in 55 
evaluable patients. The 2-sided exact 95% CI is (32.0%, 59.5%) when the 
observed ORR is 46%. Additional patients may be enrolled to meet the required 
number of evaluable patients. 
 
10.2 General Considerations for Data Analysis 
Data will be listed and summarized using SAS®, version 9.4 or higher (SAS Institute, 
Inc., Cary, North Carolina) according to sponsor agreed reporting standards, where 
applicable. Complete details will be documented in the statistical analysis plan. 
The following descriptive statistics will be used to summarize the trial data on the basis 
of their nature unless otherwise specified: 
 Continuous variables: number of evaluable observations, number of missing, mean, 
standard deviation, coefficient of variation as appropriate, median, minimum, and 
maximum. 
 Categorical variables: frequencies and percentages. 
 Time to event variables: number of non-missing observations, median, minimum and 
maximum. Kaplan Meier median times, 25th and 75th percentiles and associated 95% 
CIs will also be provided for specific time to event variables. 
All data will be presented by cohorts. The analysis methods described in this section are 
directed to both cohorts in general  
Further description of the statistical methods and analyses will be provided in the 
statistical analysis plan. 
10.2.1 Analysis Sets 
The Safety Analysis Set includes all patients who receive at least one dose of pamiparib. 
The Efficacy Analysis Set includes all patients in the Safety Analysis Set who have 
measurable disease at baseline per RECIST, version 1.1, and have at least one evaluable 
post baseline tumor assessment by IRR unless discontinued treatment due to clinical 
progression or death prior to tumor assessment. This is the primary analysis set for all the 
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tumor response endpoints (ORR, BOR, DOR, etc). 
The ITT Analysis Set is defined as all enrolled patients who receive any amount of study 
drug. This is the primary analysis set for OS. 
The PK Evaluable Analysis Set includes all patients for whom valid pamiparib PK 
parameters can be estimated. 
10.2.2 Interim Analysis 
No formal interim analysis is planned. 
10.2.3 Patient Disposition 
The number of patients enrolled, treated, discontinued from study drug and those with 
major protocol deviations will be counted. The primary reason for study drug 
discontinuation will be summarized according to the categories in the eCRF. The end of 
study status (alive, death, withdrew consent, or lost to follow-up) at the data cutoff date 
will be summarized using the data from the eCRF. 
Major protocol deviations will be summarized and listed by each category. 
10.2.4 Demographics and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized in the Safety 
Analysis Set using descriptive statistics. Continuous variables include age, weight, vital 
signs, time since initial cancer diagnosis, time since metastatic disease diagnosis; 
categorical variables include age group, race, disease stage, ECOG-PS, and prior line of 
therapy in the metastatic setting. 
10.2.5 Prior and Concomitant Therapy 
Concomitant medications will be assigned an 11-digit code using the World Health 
Organization Drug Dictionary drug codes. Concomitant medications will be further 
coded to the appropriate Anatomical Therapeutic Chemical (ATC) code indicating 
therapeutic classification. Prior and concomitant medications will be summarized and 
listed by drug and drug class in the clinical study report for this protocol. Prior 
medications will be defined as medications that stopped before the first dose of study 
drug. Concomitant medications will be defined as medications that (1) started before the 
first dose of study drug and were continuing at the time of the first dose of study drug, or 
(2) started on or after the date of the first dose of study drug up to 30 days after the 
patient’s last dose. A listing of prior and concomitant medications will be included in the 
clinical study report of this protocol. 
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10.3 Efficacy Analyses 
10.3.1 Primary Efficacy Analyses 
TNBC cohort 
Hypothesis testing of ORR by IRR will be performed in the patients with evaluable tumor 
assessment pre- and post-baseline. The primary analysis will be carried out using IRR 
data in the Efficacy Analysis Set. Efficacy endpoints based on Investigator assessed 
tumor response will be presented as the sensitivity analysis. 
ORR of pamiparib per IRR is assumed as 46% in patients with TNBC. The historical rate 
in a similar population is estimated as 25%. The null and alternative hypotheses are set as 
follows: 
 H0:  ORR= 25% 
 Ha:  ORR > 25% 
A binomial exact test will be performed for hypothesis testing in the Efficacy Analysis 
Set. If the obtained one-sided p-value is ≤ 0.025, it will be concluded that pamiparib 
monotherapy statistically significantly increases ORR compared with historical control. 
A two-sided binomial exact 95% CI of ORR will be constructed to assess the precision of 
the rate estimate.  
The primary efficacy analysis will be conducted when mature response rate data have 
been observed, estimated as no more than 12 months after the last patient received the 
first dose of study drug. 
Sensitivity analysis of ORR will be carried out in the ITT analysis set. 
HR(+)/HER2(-) breast cancer cohort 
ORR and its two-sided binomial exact 95% CI will be calculated similarly as described 
above in the TNBC cohort. However, no statistical comparison to a specified historical 
rate is planned. 
10.3.2 Secondary Efficacy Analyses 
TNBC and HR(+)/HER2(-) breast cancer cohort 
As in the primary efficacy analyses, secondary efficacy analyses will be performed by 
cohort. Tumor response assessed by IRR and investigator will be summarized. 
BOR is defined as the best response recorded from the start of pamiparib until data cut or 
start of new anti-neoplastic treatment. The proportion of each response category (CR, PR, 
SD, disease progression and NE) will be presented in the Efficacy Analysis Set and ITT 
Analysis Set. 
DCR and CBR and their 95% CIs will be summarized by cohort in the Efficacy Analysis 
Set and ITT Analysis Set. 
Kaplan-Meier method will be used to estimate the key secondary endpoint, DOR, and 
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corresponding quartiles (including the median) in the responders. A two-sided 95% CIs 
of median, if estimable, will be constructed with a generalized Brookmeyer and Crowley 
method.  
The DOR censoring rule will follow FDA (Guidance for Industry Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics 2007). 
Other time to event variables (PFS and OS) will be similarly analysed in the Efficacy 
Analysis Set using the Kaplan-Meier method as described above. The Kaplan-Meier 
estimates of PFS and OS will be plotted over time. The PFS time point estimates, defined 
as the percentages of patients in the analysis population who remain alive and 
progression-free at the specified time points (ie, 3 or 6 months), will be estimated using 
the Kaplan-Meier method along with the corresponding 95% CI constructed using 
Greenwood’s formula. The OS time point estimates will be calculated similarly.  
10.3.3 Exploratory Efficacy Analyses 
10.4 Safety Analyses 
Pamiparib exposure will be summarized, including duration, dosage, and dose intensity. 
Safety will be assessed by monitoring and recording of all AEs. Laboratory values 
(hematology, clinical chemistry, and urinalysis), vital signs, physical examination, and 
ECG findings will also be used in determining the safety. Descriptive statistics will be 
used to analyze all safety data in the Safety Analysis Set. 
10.4.1 Adverse Event 
Verbatim description of AEs will be mapped to the MedDRA terms and graded according 
to the NCI-CTCAE, version 4.03. A TEAE is defined as an AE that had an onset date on 
or after the first dose of study drug up to 30 days following study drug discontinuation. 
All AEs will be included in the listings and only TEAEs will be included in the summary 
tables. SAEs, deaths, TEAEs Grade 3 or above, related TEAEs and TEAEs that led to 
treatment discontinuation, dose reduction or dose interruption will be summarized. 
A patient will be counted only once by the highest grade according to NCI-CTCAE, 
version 4.03, within a SOC and PT, even if the patient experienced more than 1 TEAE 
within a specific SOC and PT. 
10.4.2 Laboratory Assessments 
Clinical laboratory (eg, hematology and chemistry) values to be evaluated will be 
specified in the statistical analysis plan and collected in the EDC system. Analyzed 
laboratory values that are abnormal will be flagged and identified as outside (above or 
below) the normal range.  
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Laboratory parameters that are graded in NCI-CTCAE, version 4.03, or higher will be 
summarized by NCI-CTCAE grade. Shift tables will be provided as appropriate  
10.4.3 Physical Examinations 
Physical examination results collected in association with an AE will be listed and 
summarized.  
10.4.4 Vital Signs 
Specific vital signs, eg, blood pressure and temperature, will be summarized and listed. 
The change from baseline will also be presented. 
10.4.5 Extent of Exposure 
Extent of exposure to pamiparib will be calculated for each patient. Duration of 
treatment, total dosages taken, and dose intensity will be summarized by cohort. Dose 
interruption, reduction and discontinuation will be summarized by frequency. 
10.5 Pharmacokinetic Analyses 
Pamiparib concentrations after single-dose and at steady-state will be summarized by the 
sampling timepoint. Descriptive statistics will include means, medians, and standard 
deviations, as appropriate.  
Population PK analysis may be carried out to include plasma concentrations from this 
study. Additional PK parameters such as CL/F of the drug from plasma and AUC0-12 may 
be derived from the population PK analysis if supported by data. 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported 
by data. 
10.6 Biomarker Analyses 
All patients will have blood samples collected for germline BRCA1/2 mutation test. 
The baseline tumor biomarker analysis includes but is not limited to somatic mutation 
analysis. 
Predictive biomarkers of efficacy include but not limited to BRCA1/2 mutation. 
 
 
 
 
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11. STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS 
11.1 Regulatory Authority Approval 
The sponsor will obtain approval to conduct the study from the appropriate regulatory 
agency in accordance with any applicable country-specific regulatory requirements or file 
the protocol to appropriate regulatory agency before the study is initiated at a study center 
in China. 
11.2 Investigator Responsibilities 
11.2.1 Good Clinical Practice 
The investigator will ensure that this study is conducted in accordance with the principles 
of the “Declaration of Helsinki” International Conference of Harmonisation (ICH) 
guidelines, and that the basic principles of “GCP” as outlined in 21 Code of Federal 
Regulations (CFR) 312, Subpart D, “Responsibilities of Sponsors and Investigators,” 
21 CFR, Part 50, and 21 CFR, Part 56, are adhered to. 
Investigators and all sub-investigators must provide documentation of their financial 
interest or arrangements with BeiGene, or proprietary interests in the drug being studied. 
This documentation must be provided before participation of the investigator and any 
sub-investigator. The investigator and sub-investigator agree to notify BeiGene or its 
authorized representative of any change reportable interests during the study and for 
1 year following completion of the study. Study completion is defined as the date that the 
last patient has completed the protocol-defined activities. 
11.2.2 Ethical Conduct of the Study and Ethics Approval 
This study will be conducted in accordance with GCP and all applicable regulatory 
requirements, including, where applicable, the current version of the Declaration of 
Helsinki. 
The investigator (or sponsor, where applicable) is responsible for ensuring that this 
protocol, the study center’s ICF, and any other information that will be presented to 
potential patients (eg, advertisements or information that supports or supplements the 
ICF) are reviewed and approved by the appropriate IEC/IRB. 
The IEC/IRB must be constituted in accordance with all applicable regulatory 
requirements. The sponsor will provide the investigator with relevant document(s)/data 
that are needed for IEC/IRB review and approval of the study. 
Before the study drug(s) can be shipped to the study center, the sponsor or its authorized 
representative must receive copies of the IEC/IRB approval, the approved ICF, and any 
other information that the IEC/IRB has approved for presentation to potential patients. 
If the protocol, the ICF, or any other information that the IEC/IRB has approved for 
presentation to potential patients is amended during the study, the investigator is 
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responsible for ensuring the IEC/IRB reviews and approves, where applicable, these 
amended documents. The investigator must follow all applicable regulatory requirements 
pertaining to the use of an amended ICF including obtaining IEC/IRB approval of the 
amended form before new patient consent to take part in the study using this version of 
the form. Copies of the IEC/IRB approval of the amended ICF/other information and the 
approved amended ICF/other information must be forwarded to the sponsor promptly. 
11.2.3 Informed Consent 
The investigator is responsible for obtaining written informed consent from each 
individual participating in this study after adequate explanation of the aims, methods, 
objectives, and potential hazards of the study and before undertaking any study-related 
procedures. The investigator must utilize an IRB/IEC-approved ICF for documenting 
written informed consent. Each ICF will be appropriately signed and dated by the patient 
or the patient’s legally authorized representative and the person obtaining consent. 
Informed consent will be obtained before the patient can participate in the study. The 
contents and process of obtaining informed consent will be in accordance with all 
applicable regulatory requirements. 
11.2.4 Investigator Reporting Requirements 
As indicated in Section 9.5, the investigator (or sponsor, where applicable) is responsible 
for reporting SAEs to the IEC/IRB, in accordance with all applicable regulations. 
Furthermore, the investigator may be required to provide periodic safety updates on the 
conduct of the study at his/her study center and notification of study closure to the 
IEC/IRB. Such periodic safety updates and notifications are the responsibility of the 
investigator and not of the sponsor. 
11.2.5 Confidentiality 
Information on maintaining patient confidentiality in accordance 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, 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 
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employees or agents directly involved in the conduct of the study or as required by law) 
without prior written consent from BeiGene. The investigator further agrees to take all 
reasonable precautions to prevent the disclosure by any employee or agent of the study 
center to any third party or otherwise into the public domain. 
11.2.6 Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed and signed by the principal 
investigator or sub-investigator within a reasonable time period after data collection. This 
also applies to records for those patients those patients who discontinue the study early. If 
a patient withdraws from the study, the reason must be noted on the eCRF. If a patient is 
withdrawn from the study because of a treatment-limiting AE, thorough efforts should be 
made to clearly document the outcome. 
The eCRFs exist within an EDC system with controlled access managed by BeiGene or 
its authorized representative for this study. Study staff will be appropriately trained in the 
use of eCRFs and applications of electronic signatures before the study start and before 
being given access to the EDC system. Original data and any changes of data will be 
recorded using the EDC system, with all changes tracked by the system and recorded in 
an electronic audit trail. The investigator attests that the information contained in the 
eCRFs is true by providing an electronic signature within the EDC system. After final 
database lock, the investigator will receive a copy of the patient data on CD-ROMs for 
archiving the data at the study center.  
11.2.7 Drug Accountability 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate 
accountability of all used and unused study drug. This includes acknowledgment of 
receipt of each shipment of study drug (quantity and condition), patient dispensing 
records, and returned or destroyed study drug. Dispensing records will document 
quantities received from BeiGene and quantities dispensed to patients, including lot 
number, date dispensed, patient identifier number, patient initials, and the initials of the 
person dispensing the medication. 
At study initiation, the monitor will evaluate the study center’s standard operating 
procedure for study drug disposal/destruction in order to ensure that it complies with 
BeiGene requirements. At the end of the study, following final drug inventory 
reconciliation by the monitor, the study center will dispose of and/or destroy all unused 
study drug supplies, including empty containers, according to these procedures. If the 
study center cannot meet BeiGene’s requirements for disposal, arrangements will be 
made between the study center and BeiGene or its representative for destruction or return 
of unused study drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and 
verified by the study monitor over the course of the study. 
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11.2.8 Inspections 
The investigator should understand that source documents for this study should be made 
available to appropriately qualified personnel from BeiGene or its representatives, to 
IRBs/IECs, or to regulatory authority or health authority inspectors. 
11.2.9 Protocol Adherence 
The investigator is responsible for ensuring 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. 
11.3 Sponsor Responsibilities 
11.3.1 Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study patients, 
may be initiated only by BeiGene. All protocol modifications must be submitted to 
regulatory authorities and the IRB/IEC together with, if applicable, a revised model ICF 
in accordance with local requirements. As applicable by local requirements, written 
documentation of regulatory authorities, IRB/IEC, and required study center approval 
must be obtained by the sponsor before changes can be implemented. 
Information on any change in risk and/or change in scope must be provided to patients 
already actively participating in the study, and they must read, understand, and sign each 
revised ICF confirming his/her willingness to remain in the study. 
11.3.2 Use of Information and Publication 
A clinical study report will be prepared and provided to the regulatory agency(ies) of 
participating countries. The sponsor will ensure that the report meets the standards set out 
in the ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3). Note 
that an abbreviated report may be prepared in certain cases. 
The sponsor recognizes the importance of communicating medical study data, and 
therefore, encourages their publication in reputable scientific journals and at seminars or 
conferences. The details of the processes of producing and reviewing reports, 
manuscripts, and presentations based on the data from this study will be described in the 
clinical study agreement. 
If a written contract for the conduct of the study, which includes publication provisions 
inconsistent with this statement, is executed that contract’s publication provisions shall 
apply rather than this statement. 
11.4 Study and Study Center Closure 
Upon completion of the study, the monitor will conduct the following activities in 
conjunction with the investigator or study center personnel, as appropriate: 
 
Return of all study data to the sponsor 
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 
Resolve and close all 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. 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 
prior to it taking 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 be returned to the sponsor. In 
addition, arrangements will be made for all unused study drug in accordance with the 
applicable sponsor procedures for the study. 
Financial compensation to investigators and/or institutions will be in accordance with the 
agreement established between the investigator and the sponsor. 
11.5 Records Retention and Study Files 
11.5.1 Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into at least the following 2 categories: (1) investigator’s 
study file and (2) patient clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query 
forms, IRB/IEC, and governmental approval with correspondence, ICF, drug records, 
staff curriculum vitae and authorization forms, and other appropriate documents and 
correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include (although not be 
limited to) the following: patient hospital/clinic records, physician’s and nurse’s notes, 
appointment book, original laboratory reports, ECG, electroencephalogram, x-ray, 
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pathology and special assessment reports, consultant letters, screening and enrollment 
log, etc. 
Following closure of the study, the investigator must maintain all study records in a safe 
and secure location. The records must be maintained to allow easy and timely retrieval, 
when needed (eg, audit or inspection), and, whenever feasible, to allow any subsequent 
review of data in conjunction with assessment of the facility, supporting systems, and 
personnel. Where permitted by local laws/regulations or institutional policy, some or all 
of these records can be maintained in a format other than hard copy (eg, microfiche, 
scanned, or electronic); however, caution needs to be exercised before such action is 
taken. The investigator must assure that all reproductions are legible, are a true and 
accurate copy of the original, and meet accessibility and retrieval standards, including 
regenerating a hard copy, if required. Furthermore, the investigator must ensure there is 
an acceptable back up of these reproductions and that an acceptable quality control 
process exists for making these reproductions. 
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 15 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 the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study center for any 
or all of the documents, special arrangements must be made between the investigator and 
BeiGene to store these in sealed containers outside of the study center so that they can be 
returned sealed to the investigator in case of a regulatory audit. When source documents 
are required for the continued care of the patient, appropriate copies should be made for 
storage outside of the study center. 
Biological samples at the conclusion of this study may be retained in storage by the 
sponsor as outlined in the study manual. 
11.5.2 Provision of Study Results and Information to Investigators 
When the clinical study report is completed, the sponsor will provide the major findings 
of the study to the investigator. 
The sponsor will not routinely inform the investigator or patient the test results because 
the information generated from this study will be preliminary in nature and the 
significance and scientific validity of the results will be undetermined at such an early 
stage of research. 
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11.6 Information Disclosure and Inventions 
All information provided by the sponsor and all data and information generated by the 
study center as part of the study (other than a patient’s medical records) 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 11.3.2 
If a written contract for the conduct of the study that includes provisions inconsistent with 
this statement is executed, that contract’s provisions shall apply rather than this 
statement. 
11.7 Joint Investigator/Sponsor Responsibilities 
11.7.1 Access to Information for Monitoring 
In accordance with 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 eCRFs at regular intervals 
throughout the study to verify adherence to the protocol and the completeness, 
consistency, and accuracy of the data being entered on them. The monitor should have 
access to any patient records needed to verify the entries on the eCRFs. The investigator 
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agrees to cooperate with the monitor to ensure that any problems detected in the course of 
these monitoring visits are resolved. 
11.7.2 Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of BeiGene may conduct inspections or 
audits any time during or after completion of this clinical study. If the investigator is 
notified of an inspection by a regulatory authority the investigator agrees to notify the 
sponsor or its designee immediately. The investigator agrees to provide to representatives 
of a regulatory agency or BeiGene access to records, facilities, and personnel for the 
effective conduct of any inspection or audit. 
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Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 
O'Shaughnessy J, Romieu G, Diéras V, et al. Abstract P6-12-03: Meta-Analysis of Patients with 
Triple-Negative Breast Cancer (TNBC) from Three Randomized Trials of First-Line 
Bevacizumab (BV) and Chemotherapy Treatment for Metastatic Breast Cancer (MBC). Cancer 
Res. 2010;70(24 Suppl): Abstract nr P6-12-03. 
O’Sullivan CC, Moon DH, Kohn EC, et al. Beyond breast and ovarian cancers: PARP inhibitors 
for BRCA mutation-associated and BRCA-like solid tumors. Front Oncol. 2014;4:42. 
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): ps17.  
Prescribing information: Lynparza (olaparib) US. 2014 
Prescribing information: Rubraca (rucaparib) US. 2016 
Prescribing information: Zejula (niraparib) US. 2017 
Ricks TK, Chiu HJ, Ison G, et al. Successes and Challenges of PARP Inhibitors in Cancer 
Therapy. Front Oncol. 2015; Oct 14;5: 222. 
Robson M, Im SA, Senkus E, et al. Olaparib for Metastatic Breast Cancer in Patients with a 
Germline BRCA Mutation. N Engl J Med. 2017;377(6):523-533. 
Rugo HS, Roche H, Thomas E, et al. Ixabepilone plus capecitabine vs capecitabine in patients 
with triple negative tumors: a pooled analysis of patients from two large phase III clinical studies. 
Cancer Res. 2009;69(2 Suppl):Abstract nr 3057. 
Sonnenblick A, de Azambuja E, Azim HA Jr, et al. An update on PARP inhibitors--moving to the 
adjuvant setting. Nat Rev Clin Oncol. 2015;12(1):27-41. 
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Sun J, Meng H, Yao L, et al. Germline Mutations in Cancer Susceptibility Genes in a Large 
Series of Unselected Breast Cancer Patients. Clin Cancer Res. 2017 Jul 19. 
Telli M, Optimizing chemotherapy in triple-negative breast cancer: the role of platinum. 2014 
ASCO education book. Asco.org/edbook. 
Turner NC, Telli ML, Rugo HS, et al. Final results of a phase 2 study of talazoparib (TALA) 
following platinum or multiple cytotoxic regimens in advanced breast cancer patients (pts) with 
germline BRCA1/2 mutations (ABRAZO). J Clin Oncol. 2017. 
Tutt A, Robson M, Garber JE, et al. Phase II trial of the oral PARP inhibitor olaparib in BRCA-
deficient advanced breast cancer. J Clin Oncol 2009;27:18s, (suppl; abstr CRA501). 
Tutt A, Ellis P, Kilburn L, et al. The TNT trial: A randomized phase III trial of carboplatin (C) 
compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple 
negative or BRCA1/2 breast cancer. AACR; Cancer Res. 2015;75(9 Suppl): Abstract nr S3-01. 
Welsch PL, Schubert EL, King MC. Inherited breast cancer: an emerging picture. Clin Genet. 
1998;54(6):447-58. 
Yoshida K, Miki Y. Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and 
cell cycle in response to DNA damage. Cancer Sci. 2004;95(11):866-71.
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13. APPENDICES 
Appendix 1 
Schedule of Assessments 
Table a.  
Study Visit Schedule 
Assessments7 
Pre- 
screening1 
Screen-
ing1 
Cycle 1 
(28 days) 
Cycle 2 
(28 days) 
Cycle 3 and 
subsequent 
Cycles 
(28 days for 
one cycle) 
Unscheduled 
Visit2 
EOT 
Visit3 
Safety 
Follow-
up4 
Long-term 
Follow-up5 
Day of Cycle 
 
D -28 to -1 
D1 
D15 
D1 
D1
5 
D1 
Varies 
≤7 days 
after last 
dose 
~30 days 
after last 
dose 
Every 
12 weeks 
Allowed time 
window 
 
 
 
±3 
days 
±3 days 
±3 days 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
 
Baseline 
demographics 
 
X 
 
 
 
 
 
 
 
 
 
Medical 
history/treatment 
history6 
 
X 
 
 
 
 
 
 
 
 
 
Concomitant 
medications8 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Complete physical 
examination 
 
X 
 
 
 
 
 
 
X 
 
 
Limited physical 
examination 
 
 
X 
 
X 
 
X 
X 
 
 
 
Vital signs and 
weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
ECOG performance 
status 
 
X 
X 
 
X 
 
X 
X 
X 
 
 
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Assessments7 
Pre- 
screening1 
Screen-
ing1 
Cycle 1 
(28 days) 
Cycle 2 
(28 days) 
Cycle 3 and 
subsequent 
Cycles 
(28 days for 
one cycle) 
Unscheduled 
Visit2 
EOT 
Visit3 
Safety 
Follow-
up4 
Long-term 
Follow-up5 
Day of Cycle 
 
D -28 to -1 
D1 
D15 
D1 
D1
5 
D1 
Varies 
≤7 days 
after last 
dose 
~30 days 
after last 
dose 
Every 
12 weeks 
Allowed time 
window 
 
 
 
±3 
days 
±3 days 
±3 days 
Hematology9 
 
-14 to -1 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical chemistry 
 
-14 to -1 
X 
X 
 
X 
 
X 
X 
X 
 
 
Urinalysis10 
 
-14 to -1 
X 
X 
 
 
 
 
X 
X 
 
 
12-lead ECG11 
 
-14 to -1 
X 
 
 
 
 
 
X 
X 
 
 
Disease assessment12 
 
X 
EVERY 8 WEEKS ± 7 DAYS in first 
year  
EVERY 12 WEEKS ± 7 DAYS in second 
year and later 
 
 
 
X 
Adverse events 
(including serious) 
 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
Pregnancy test13 
 
-7 to -1 
X 
 
 
X 
 
X 
X 
X 
X 
 
Blood sample 
collection for 
BRCA1/2 mutation 
testing14 
X 
 
 
 
 
 
 
 
 
 
 
PK blood sampling15 
 
 
X 
 
X 
 
 
 
 
 
 
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Assessments7 
Pre- 
screening1 
Screen-
ing1 
Cycle 1 
(28 days) 
Cycle 2 
(28 days) 
Cycle 3 and 
subsequent 
Cycles 
(28 days for 
one cycle) 
Unscheduled 
Visit2 
EOT 
Visit3 
Safety 
Follow-
up4 
Long-term 
Follow-up5 
Day of Cycle 
 
D -28 to -1 
D1 
D15 
D1 
D1
5 
D1 
Varies 
≤7 days 
after last 
dose 
~30 days 
after last 
dose 
Every 
12 weeks 
Allowed time 
window 
 
 
 
±3 
days 
±3 days 
±3 days 
Tumor Tissues16 
 
X 
 
 
 
 
 
 
 
 
 
Optional paired 
biopsies17 
 
 
X 
 
X 
 
 
 
 
 
 
Investigational 
product 
administration18 
 
 
CONTINUOUS 
X 
 
 
 
Bone Scan19 
 
X 
 
 
 
 
 
 
X 
 
 
X 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: CT, computed tomography; D, Day; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, end of treatment; MRI, magnetic 
resonance imaging; PK, pharmacokinetic; X, to be performed. 
1. Screening assessments will be completed within 28 days prior to the first dose of pamiparib. Pre-screening for germline BRCA mutation test (blood sample) 
can be completed prior to screening. A separate pre-screening informed consent must be obtained. 
2. Unscheduled visits may occur any time as necessary as per investigator decision or patient’s request for reasons such as assessment or follow-up of adverse 
events. Study activities, as indicated by ‘X,’ should be performed based on the reason for the unscheduled visit. If disease progression is suspected, imaging 
studies should be performed and blood for biomarkers should be obtained as appropriate. 
3. EOT visit should be conducted at the earliest day within 7 days of the last dose of pamiparib, if possible. If discontinuation is due to unresolved toxicities for 
more than 28 days (56 days for anemia), the EOT visit should be conducted at the earliest day possible within 7 days after permanent discontinuation is 
determined. The CT/MRI does not have to be repeated if it was performed at a prior response evaluation that documented progressive disease. ECG do not 
have to be repeated if it was performed within 14 days of the EOT visit, For the other required assessments, if they were performed within 4 days of the EOT 
visit, they do not need to be repeated on EOT visit. 
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4. A safety follow-up will occur with the outlined safety assessments, until approximately 30 days after the last day of pamiparib. If new anticancer therapy is 
initiated before this safety follow-up, a safety follow-up should be scheduled as soon as possible ideally before other anticancer treatment starts. If 
discontinuation is due to unresolved toxicities for more than 28 days, safety follow-up could be scheduled approximately 30 days after the last dose of study 
drug. If discontinuation is due to unresolved toxicities for more than 56 days for anemia, safety follow-up could be scheduled at the earliest day possible 
within 7 days after permanent discontinuation is determined. For patients who do not want to or cannot return to the clinic for the safety follow-up, the 
patient should be contacted by phone for a review of AEs. 
5. Patients will be followed for survival, further anticancer therapy, and diagnosis of myelodysplastic syndrome or acute myeloid leukemia via phone contact or 
other means (eg, clinic visit) approximately every 12 weeks. 
Patients who were permanently discontinued from study drug for reasons other than disease progression and meet criteria otherwise (eg, discontinued for AE 
and no new anticancer therapy) will be followed with tumor assessments per protocol until disease progression or any other reason listed in Section 5.8, 
whichever occurs first. For efficacy assessments as per protocol, refer to Section 7.3. If the patient refuses to return for these tumor assessments or is unable 
to do so, every effort should be made to contact the patient by telephone to determine the patient’s disease status and survival. 
6. Date of and response to last platinum treatment must be documented (unless no platinum treatment has been received).  
7. All assessments, unless stated otherwise, must be performed before investigational product administration in each cycle. 
8. All concomitant medications taken by or administered to the patient within 28 days before the first dosing and 30 days after the last dose of study drug will 
be recorded. Concomitant medications include subsequent anticancer therapy information acquired during the long-term follow-up phase. 
9. Weekly hematology test should be done for the first 3 cycles during the study. For all Grade 2 or higher anemia, hematology tests should be done weekly 
thereafter until adequate recovery. At the investigator’s discretion, weekly tests may take place at an alternate fixed hospital near the patient’s home. The 
investigator’s permission and choice of hospital should be documented in the patient chart and the medical monitor needs to be notified. Hematology results 
from this fixed hospital are acceptable. 
10. Screening urine tests must be performed within 14 days of Cycle 1 Day1 and at the EOT visit. If they were performed within 4 days of Cycle 1 Day 1, they 
do not need to be repeated on Cycle 1 Day 1. Urine tests will be performed as clinically indicated during treatment and at safety follow-up. If urine protein is 
≥ 2+, a 24-hour urine sample for total protein will be obtained and evaluated.  
11. A single 12-lead ECG will be performed during screening within 14 days of Cycle 1 Day1 and at the EOT visit. A 12-lead ECG will be performed as 
clinically indicated during treatment and at safety follow-up. For ECG test during the PK sample collection, follow instructions in Table b.  
12. Disease assessment during the screening may be completed up to 28 days prior to pamiparib administration. Afterwards, disease assessments will be 
performed once every 8 weeks ± 7 days after the first dose of pamiparib in the first year, then every 12 weeks ±7 days afterwards. A CT scan or MRI scan of 
the chest, abdomen, and pelvis will be performed. Patients with treatment terminated prior to documentation of disease progression shall be subject to 
CT/MRI radiographic assessments according to the previous visit assessment scheme, until 1) commencement of new treatment, 2) disease progression, 
3) death or 4) termination of the study.  
13. For women of childbearing potential including those who have had a tubal ligation, a urine or serum pregnancy test must be performed and documented as 
negative within 7 days prior to Cycle 1 Day 1, and urine pregnancy tests will be performed at each visit before dosing. A serum pregnancy test must be 
performed if the result of a urine pregnancy test is positive or equivocal. 
14. Pre-screening for germline BRCA1/2 mutation will be performed prior to study eligibility screening (pre-screening phase). Blood sample will be taken for 
each patient. Patients with known germline BRCA1/2 mutation can proceed to the screening phase once they have signed the pre-screening informed consent 
and submitted their blood samples for confirmatory germline BRCA1/2 mutation testing, but patients need to have germline BRCA1/2 mutation confirmed 
before being eligible for the study. 
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15. The PK blood samples will be collected at the time points specified in Table b. 
16. Archival tumor tissues will be collected, if available. 
17. Optional paired biopsy samples will be collected at baseline (any time before receiving the first dose of study drug on Cycle 1 Day 1) and on Cycle 2 Day 1 
for the assessment of changes in tumor microenvironment and other markers (PARP inhibition) in response to pamiparib. A separate informed consent must 
be obtained for paired biopsy. Specific instructions for tissue collection and shipment are provided in the laboratory manual. 
18. BID dosing of pamiparib starts from Cycle 1 Day 1. 
19. Bone scan (Technetium-99m [TC-99m]) at baseline is required. Only bone lesion confirmed by CT/MRI or X ray should be recorded as non-target lesion 
and should be followed with the same method of examination. If bone metastases are present at screening or if clinically indicated, TC-99m bone scans 
should be repeated when a complete response is identified in target lesion or when progression in bone is suspected. 
20.
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Table b.  
Pharmacokinetic Sampling 
Procedure 
Cycle 1 
Cycle 2 
Days 
Day 1 
Day 1±3 
Hours 
Pre-dose 
2  
Pre-dose 
2 
ECGs 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
Sparse PK 
sampling2 
X1 
X1 
X1 
X1 
 
Abbreviations: ECG, electrocardiogram, PK, pharmacokinetic. 
General note: It is important that PK sampling occurs as close as possible to the scheduled time. In order to achieve this, some of the other assessments scheduled 
at the same time need to be initiated prior to or after the time point to allow for completion of these measurements in enough time for the PK sampling to be taken 
at the designated time point. Thus, the sequence at a particular time point is: 1) vital sign measurements; 2) scheduled 12-lead ECGs; 3) PK blood samples (to be 
performed at the precise protocol scheduled time); and 4) any other scheduled or unscheduled measurements at that time point. 
For sparse PK sampling, the sequence of collection at a particular timepoint may be determined by the sites based on feasibility. 
1. The window period is within 1 hour before the morning dose and, ±20 min for the samples 2 hours post dose. 
Note: About 2 mL blood sample will be taken for each sample. 
2. Sparse PK sampling will be collected in this study from sites that are able to adequately perform PK sampling, handling, and processing procedures as 
outlined in the Laboratory Manual. 
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Appendix 2 
Clinical Laboratory Assessments 
 
Clinical Chemistry 
Hematology 
Urinalysis 
ALT 
 
Hemoglobin (Hgb) 
24-hour protein1 
Alkaline phosphatase 
Lymphocyte count 
Glucose 
AST 
Neutrophil count 
Ketones 
Albumin 
Platelet count  
Occult blood 
Blood urea nitrogen or urea 
White blood cell count  
pH 
Creatinine 
 
Protein1 
Chloride 
 
Red blood cells 
Glucose  
 
Specific gravity 
Lactate dehydrogenase 
 
White blood cells 
Phosphate or phosphorus 
 
 
Potassium 
 
 
Total bilirubin 
 
 
Total protein 
 
 
Sodium 
 
 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; pH, negative of the 
logarithm to base 10 of the activity of the (solvated) hydronium ion. 
1. On routine urinalysis, if urine protein is ≥2+ by dipstick, obtain a 24-hour urine sample for total 
protein.
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Appendix 3 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-diseases 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 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 
Equation 
In adults, the most widely-used equations for estimating glomerular filtration rate (GFR) 
from serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation1 and the Modification of Diet in Renal Disease (MDRD) Study 
equation. The National Kidney Disease Education Program (NKDEP) calculators rely on 
creatinine determinations which are isotope dilution mass spectrometry (IDMS) 
traceable.  All laboratories should be using creatinine methods calibrated to be IDMS 
traceable.  Read more about creatinine standardization. 
This CKD-EPI equation calculator should be used when Scr reported in mg/dL.  This 
equation is recommended when eGFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 
1.159 [if black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 
1.73 m2 body surface area, which is an accepted average adult surface area. 
 
The online calculator for CKD-EPI can be found here: https://www.niddk.nih.gov/health-
information/communication-programs/nkdep/laboratory-evaluation/glomerular-filtration-
rate-calculators 
 
 
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Appendix 5 
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 magnetic resonance imaging 
(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. 
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 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as 
CT or 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 × 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. 
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A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all 
target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then as noted above, only the short axis is added into 
the sum. The baseline sum 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). 
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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. 
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. 
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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. 
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”. 
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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 concept apply here as noted above, however, in this instance there is no 
measurable disease assessment to factor into the interpretation of an increase in 
nonmeasurable disease burden. Because worsening in nontarget disease cannot be easily 
quantified (by definition: if all lesions are truly nonmeasurable) a useful test that can be 
applied when assessing patients for unequivocal progression is to consider if the increase 
in overall disease burden based on the change in nonmeasurable disease is comparable in 
magnitude to the increase that would be required to declare PD for measurable disease: 
ie, an increase in tumor burden representing an additional 73% increase in “volume” 
(which is equivalent to a 20% increase diameter in a measurable lesion). Examples 
include an increase in a pleural effusion from “trace” to “large”, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as 
“sufficient to require a change in therapy”. If “unequivocal progression” is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal 
to have objective criteria to apply to nonmeasurable disease, the very nature of that 
disease makes it impossible to do so; therefore, the increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some 
comments on detection of new lesions are important. There are no specific criteria for the 
identification of new radiographic lesions; however, the finding of a new lesion should be 
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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 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 
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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. 
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 
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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 ‘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 results. However, elimination of the requirement 
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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 6 
Prohibited Medications 
Data compiled from the FDA’s “Guidance for Industry, Drug Interaction Studies;” 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/uc
m093664 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 
Medications to be used with Caution 
 
 
 
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Appendix 8 
Contraception Guidelines and Definitions of “Women of Childbearing 
Potential”, “No Childbearing Potential” 
Contraception Guidelines 
The Clinical Trials Facilitation Group’s recommendations related to contraception and 
pregnancy testing in clinical trials include the use of highly effective forms of birth 
control. These methods include the following: 
 
Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with the inhibition of ovulation (oral, intravaginal, or transdermal) 
o Progestogen-only hormonal contraception associated with the inhibition of 
ovulation (oral, injectable, or implantable) 
 
Intrauterine device 
 
Intrauterine hormone-releasing system 
 
Bilateral tubal occlusion 
 
Vasectomized male partner 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of exposure associated with the study treatment) 
NOTE: Total sexual abstinence should only be used as a contraceptive    
method if it is in line with the patient’s usual and preferred lifestyle.  
Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation 
methods), declaration of abstinence for the duration of exposure to study drug, 
and withdrawal are not acceptable methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without 
spermicide) is not considered a highly effective method of contraception and if used, this 
method must be combined with another acceptable method listed above. 
Definitions of “Women of Childbearing Potential", “Women of No Childbearing 
Potential” 
As defined in this protocol, “women of childbearing potential” are 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 
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postmenopausal follicle-stimulating hormone concentration >30 IU/mL 
 
 
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Appendix 9 
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 10 Signature of Investigator 
Protocol Title: 
An Open Label, Multi-Center Phase 2 Study to Evaluate 
Efficacy and Safety of BGB-290 in the Treatment of Metastatic 
HER2-Negative Breast Cancer Patients with BRCA mutation in 
China 
 
Protocol Identifier: 
 
BGB-290-201 
 
This protocol is a confidential communication of BeiGene, Ltd. I confirm that I have read this 
protocol, I understand it, and I will work according to this protocol.  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. 
 
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 or its designee. 
 
I have read the entire protocol and agree to carry out the study according to this protocol. 
 
Investigator’s Signature:  
 
_____________________________ 
 
Investigator’s Printed Name:               _____________________________ 
Date (dd mmm yyyy):                           _____________________________ 
Name of the center in which  
the study will be conducted:                  _____________________________  
 
 
 
 
 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-290-201 
Study Protocol 
Title: 
An Open Label, Multi-Center Phase 2 Study to Evaluate Efficacy and 
Safety of BGB-290 in the Treatment of Metastatic HER2-Negative 
Breast Cancer Patients with BRCA mutation in China 
Date: 
OCT 13, 2020 
Version: 
1.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
1 
INTRODUCTION 
7 
2 
STUDY OVERVIEW 
7 
3 
STUDY OBJECTIVES 
8 
3.1 
Primary Objectives 
8 
3.2 
Secondary Objectives 
9 
3.3 
Exploratory Objectives 
9 
4 
STUDY ENDPOINTS 
9 
4.1 
Primary Endpoints 
9 
4.2 
Secondary Endpoints 
9 
4.3 
Exploratory Endpoints 
10 
5 
SAMPLE SIZE CONSIDERATIONS 
10 
6 
STATISTICAL METHODS 
10 
6.1 
Analysis Populations 
10 
6.2 
Data Analysis General Considerations. 
11 
6.2.1 
Definitions and Computations 
11 
6.2.2 
Conventions 
11 
6.2.3 
Handling of Missing Data 
12 
6.2.4 
Adjustment for Covariates 
12 
6.2.5 
Multiplicity Adjustment 
12 
6.2.6 
Data Integrity 
12 
6.3 
Subject Characteristics 
12 
6.3.1 
Subject Disposition 
12 
6.3.2 
Protocol Deviations 
13 
6.3.3 
Demographic and Other Baseline Characteristics 
13 
6.3.4 
Prior Anti-Cancer Drug Therapies, Surgeries and 
Radiotherapies 
13 
6.3.5 
Prior and Concomitant Medications 
13 
6.3.6 
Medical History 
13 
6.4 
Efficacy Analysis 
14 
6.4.1 
Primary Efficacy Endpoints 
14 
6.4.2 
Secondary Efficacy Endpoints 
14 
6.4.3 
Subgroup Analyses 
16 
6.4.4 
Exploratory Efficacy Endpoints 
16 
6.5 
Safety Analyses 
16 
6.5.1 
Extent of Exposure 
17 
6.5.2 
Adverse Events 
17 
6.5.3 
Laboratory Values 
18 
6.5.4 
Vital Signs 
19 
6.5.5 
Electrocardiograms 
19 
6.5.6 
ECOG Performance Status 
19 
6.6 
Pharmacokinetic Analyses 
19 
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6.7 
Ad hoc Analyses 
19 
7 
INTERIM ANALYSIS 
20 
8 
CHANGES IN THE PLANNED ANALYSIS 
20 
9 
REFERENCES 
20 
10 
APPENDIX 
21 
10.1 
IMPUTATION OF PARTIAL DATES FOR 
AES/MEDICATIONS/THERAPIES/PROCEDURES 
21 
10.2 
PRE- AND POST- PROTOCOL AMENDMENT (PA) HEMATOLOGICAL 
ANALYSES 
22 
10.3 
PROGRAMMING RULE 
23 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
AUC 
area under the plasma concentration-time curve 
AUC0-12h 
area under the plasma concentration-time curve from zero to 
12 hours post-dose 
BC 
breast cancer 
BID 
twice daily 
BGB-290 
study drug code 
BOR 
best overall response 
BP 
blood pressure 
BRCA 
breast cancer susceptibility gene  
CBR 
clinical benefit rate 
CD8 
cluster of differentiation 8 
CI 
confidence interval 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
CR 
complete response 
DCR 
disease control rate 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOT 
end of treatment 
FDA 
Food and Drug Administration 
HER2(-) 
human epidermal growth factor receptor 2-negative 
HR(+) 
hormone receptor-positive 
ICF 
informed consent form 
IRC 
independent radiology review 
MDS/AML 
myelodysplastic syndrome/acute myeloid leukemia  
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI-CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse 
Events 
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NE 
not evaluable 
ORR 
objective response rate 
OS 
overall survival 
PA 
protocol amendment 
PARP 
 
poly(ADP-ribose) polymerase 
PD-L1 
programmed death-ligand 1 
PFS 
Progression-free survival 
PK 
pharmacokinetic(s) 
PO 
orally 
PR 
partial response 
PT 
preferred term 
QTc 
QT interval corrected for heart rate 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
system organ class 
TEAE 
Treatment-emergent adverse event 
TNBC 
triple negative breast cancer 
TTR 
time to response 
WBC 
white blood cell 
WHO DD 
World Health Organization Drug Dictionary 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for BGB-290-201: An Open Label, Multi-
Center Phase 2 Study to Evaluate Efficacy and Safety of BGB-290 in the Treatment of Metastatic 
HER2-Negative Breast Cancer Patients with BRCA mutation in China. The focus of this SAP is 
for the planned analysis specified in the study protocol. 
The analysis details for Pharmacokinetic (PK), Pharmacodynamics, Pharmacogenomics and 
Biomarker analyses are not described within this SAP.  
Reference materials for this statistical plan include the protocol BGB-290-201 (30OCT2018) and 
Case Report Forms (1JUN2020). If the protocol or case report forms are amended or updated, then 
appropriate adjustments to the SAP may be made if they are related to the planned analyses. 
The SAP described hereafter is an a priori plan. This is an open label study and the SAP will be 
finalized and approved prior to database lock. Statistical programming may occur as study data 
accumulate to have analysis programs ready at the time of study end. 
2 
STUDY OVERVIEW 
This is a Phase 2, open-label, multi-center study of BGB-290 administered PO BID in adult 
Chinese patients with advanced HER2(-) breast cancer harboring germline BRCA mutation, which 
have progressed despite standard therapy, or for which no standard therapy exists. In this study, 
the efficacy, safety, tolerability, and PK profile of BGB-290 will be further evaluated. All eligible 
patients will be enrolled into one of the below cohorts: 
1. Approximately 55 evaluable previously treated patients with locally advanced or metastatic 
TNBC with confirmed either deleterious or suspected deleterious germline BRCA1/2 
mutation 
2. Approximately 20 previously treated patients with locally advanced or metastatic 
HR(+)/HER2(-) breast cancer with confirmed either deleterious or suspected deleterious 
germline BRCA1/2 mutation 
Patients will be screened for eligibility up to 28 days prior to the first dose of BGB-290 and will 
take BGB-290 at 60 mg BID continuously for all cycles (28-day cycles) starting on Day 1 of Cycle 
1. Patients will be instructed to swallow the capsules whole, in rapid succession, with water. BGB-
290 can be administered with or without food. 
Tumor response will be assessed by independent radiology review (IRC) and investigators based 
on Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).  
Patients will be monitored for safety, tolerability, and efficacy throughout the study. Tumor 
assessments will be performed every 8 weeks f 7 days in the first year, and then every 12 weeks 
± 7 days thereafter, or as clinically indicated. 
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Patients will continue treatment until occurrence of disease progression as assessed by the 
investigator, unacceptable toxicities, death, withdrawal of consent, lost to follow-up, or study 
termination by sponsor. 
Figure 1. Study Schema 
 
Abbreviations: BC, breast cancer; BID, twice daily; HER2(-), human epidermal growth factor receptor 2 negative; 
HR(+), hormone receptor-positive; PD, progression disease; PO, oral; TNBC, triple negative breast cancer. 
Note: Key assessments during treatment phase: tumor assessments every 8 weeks r 7 days in the first year and every 
12 weeks r 7 days in the second year and above. Hematology assessments every 2 weeks in Cycles 1 and 2, then every 
4 weeks in subsequent cycles. Adverse events at each visit. Chemistry assessments every 4 weeks throughout the 
study. BGB-290 is to be administered continuously. 
3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVES  
x To evaluate the efficacy of BGB-290 in patients with advanced triple negative breast cancer 
or HR(+)/HER2(-) breast cancer harboring germline BRCA1/2 mutation, as measured by 
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Overall Response Rate (ORR) according to RECIST v1.1 by IRC.  
3.2 
SECONDARY OBJECTIVES  
x To further evaluate the efficacy of BGB-290 in patients with TNBC or HR(+)/HER2(-) 
breast cancer harboring germline BRCA1/2 mutation, as measured by ORR according to 
RECIST v1.1 by investigator assessment; Progression-free survival (PFS) and duration of 
response (DOR) by IRC and investigator assessment; Disease control rate (DCR), best 
overall response (BOR) and clinical benefit rate (CBR) assessment by IRC and investigator 
assessment; Overall survival (OS). 
x To evaluate the safety and tolerability of BGB-290.  
3.3 
EXPLORATORY OBJECTIVES 
4 
STUDY ENDPOINTS 
4.1 
PRIMARY ENDPOINTS 
x 
ORR is defined as the proportion of patients who achieved a best overall response of 
complete response (CR) or partial response (PR), assessed by IRC per RECIST v1.1. 
Secondary Endpoints 
x 
ORR is defined as the proportion of patients who achieved a best overall response of CR or 
PR, assessed by investigator per RECIST v1.1. Both confirmed and unconfirmed ORR will 
be summarized. 
x 
PFS is defined as the time from first dose of BGB-290 to the first documented disease 
progression assessed by IRC and investigator per RECIST v1.1 or death due to any cause. 
x 
DOR is defined as the time from first determination of a confirmed best overall response 
until the first documentation of progression or death, whichever comes first, assessed by 
IRC and investigator per RECIST v1.1. 
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x 
BOR is defined as the best overall response recorded from the start of the treatment until 
disease progression/recurrence, assessed by IRC and investigator per RECIST v1.1. Both 
confirmed and unconfirmed BOR will be summarized. 
x 
DCR is defined as the proportion of patients who achieved a confirmed BOR of CR, PR, or 
stable disease (SD) assessed by IRC and investigator per RECIST v1.1.  
x 
CBR is defined as proportion of patients with confirmed CR or confirmed PR or a durable 
SD (SD lasting ≥ 24 weeks) assessed by IRC and investigator per RECIST v1.1. 
x OS is defined as time from the first dose of BGB-290 to the date of death due to any cause.  
x Incidence, timing, and severity of treatment-emergent adverse events graded according to 
the National Cancer Institute-Common Terminology Criteria for Adverse Events, version 
4.03 (Common Toxicity Criteria Version 4.03) or higher; changes in vital signs, physical 
findings, and clinical laboratory results. 
4.2 
EXPLORATORY ENDPOINTS 
x 
5 
SAMPLE SIZE CONSIDERATIONS 
A total of approximately 75 patients will be enrolled into one of the below cohorts.  
x 
Approximately 55 evaluable patients will be enrolled into the TNBC cohort. In TNBC 
cohort, it is assumed that ORR is 46% in patients with BGB-290. There is an 90% power of 
demonstrating a statistical difference versus a historical response rate of 25% using a 
binomial exact test at an alpha of 0.025 in 55 evaluable patients. The 2-sided exact 95% CI 
is (32.0%, 59.5%) when the observed ORR is 46%. Additional patients may be enrolled to 
meet the required number of evaluable patients. 
x 
Approximately 20 patients will be enrolled into the HR(+)/HER2(-) breast cancer cohort. 
This is an exploratory cohort. 
6 
STATISTICAL METHODS 
All analyses in this section will be presented by cohort side by side, unless otherwise specified. 
6.1 
ANALYSIS SETS 
Safety Analysis Set: includes all patients who receive at least one dose of BGB-290. 
Efficacy Evaluable Analysis Set: includes all patients in the safety population who have 
measurable disease at baseline per RECIST v1.1 by IRC and have at least one evaluable post 
baseline tumor assessment by IRC unless discontinued treatment due to clinical progression or 
death prior to tumor assessment.  
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PK Analysis Set: includes all patients in the safety population who have at least 1 quantifiable PK 
sample for BGB-290.  
6.2 
DATA ANALYSIS GENERAL CONSIDERATIONS. 
6.2.1 Definitions and Computations 
Study day: Study day will be calculated in reference to the date of the first dose of study drug.  
For assessments conducted on or after the date of the first dose of study drug, study day will be 
calculated as (assessment date – date of first dose of study drug + 1). For assessments conducted 
before the date of the first dose of study drug, study day is calculated as (assessment date – date 
of first dose of study drug). There is no study day 0.  
In the situation where the event date is partial or missing, the date will appear partial or missing in 
the listings. Study day and any corresponding durations will be presented based on the imputations 
specified in Appendix 10.1. 
Treatment duration: The treatment duration will be calculated as (date of the last non-zero dose of 
study drug – date of first dose of study drug + 1).  
Baseline: the non-missing value most recently collected before the first dose. 
All calculations and analyses will be conducted using SAS version 9.4 or higher. 
6.2.2 Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses: 
x 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
decimal place. 
x 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded up to 
1 decimal place. 
x Age will be calculated as the integer part of (date of informed consent – date of birth + 
1)/365.25 
x P-values will be rounded to 4 decimal places.  P-values that round to 0.0000 will be 
presented as ‘< 0.0001’ and p-values that round to 1.000 will be presented as ‘> 0.9999’.   
x Time-to-event or duration-of-event endpoints will be based on the actual date the radiograph 
was obtained rather than the associated visit date. 
x Missing efficacy or safety data will not be imputed unless otherwise specified. 
x For laboratory results collected as < or >, a numeric value, 0.0000000001 will be subtracted 
or added, respectively, to the value. 
x For by-visit observed data analyses, percentages will be calculated based on the number of 
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patients with nonmissing data as the denominator, unless otherwise specified. 
x For continuous endpoints, summary statistics will include n, mean, standard deviation, 
median, Q1, Q3 and range (minimum and maximum). 
6.2.3 Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in the SAP. Missing dates 
or partially missing dates will be imputed conservatively for adverse events and prior/concomitant 
medications. Specific rules for handling of missing or partially missing dates for adverse events 
and prior/concomitant medications/procedures are provided in Appendix 10.1. 
In the situation where the event date is partial or missing, the date will appear partial or missing in 
the listings. 
By-visit endpoints will be analyzed using observed data, unless otherwise specified. For observed 
data analyses, missing data will not be imputed and only the observed records will be included. 
At the time of efficacy analysis, if death or disease progression is not observed from a patient, 
corresponding censoring rules for OS, DOR and PFS will be followed.  
6.2.4 Adjustment for Covariates 
No adjustments for covariates are planned for primary, secondary and exploratory analyses in the 
study.  
6.2.5 Multiplicity Adjustment 
No multiplicity adjustments will be made in this study. Two-sided 95% confidence interval will 
be used to describe the precision of the rate estimate whenever appropriate. 
6.2.6 Data Integrity 
Before pre-specified final statistical analysis begins, the integrity of the data will be reviewed to 
assure fit-for-purpose.  The data set for analysis will be an accurate and complete representation 
of the subjects' relevant outcomes from the clinical database.  All data will be complete and 
reviewed up to a pre-specified cutoff date.  Consistency checks and appropriate source data 
verification will be complete. 
6.3 
SUBJECT CHARACTERISTICS 
6.3.1 Subject Disposition 
The number (percentage) of patients treated, discontinued from study treatment, entered survival 
follow-up, discontinued from study (including those who discontinued study treatment and did not 
enter survival follow-up, and those discontinued from the survival follow-up) and duration of 
follow-up will be summarized. The primary reason for study drug discontinued will be 
summarized according to the categories in the eCRF. The survival end of study status (alive, death, 
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withdrew consent or lost to follow-up) at the data cutoff date will be listed using the data from the 
eCRF. 
6.3.2 Protocol Deviations 
Major protocol deviation criteria will be established and patients with major protocol deviations 
will be identified and documented before the database lock. 
Major protocol deviations will be summarized for all patients in the safety analysis set. They will 
also be listed by each category. 
6.3.3 Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized in the safety analysis set, using 
descriptive statistics. 
Continuous demographic and baseline variables include age, BMI, body weight, and height; 
categorical variables include age group (< 50 years, 50 – 65 years, > 65 years), race, ECOG 
performance status at study entry. In addition, disease characteristics include types of cancer, 
tumor staging, tumor diagnosis, metastasis status, germline BRCA mutation type and time from 
initial diagnosis.  
6.3.4 Prior Anti-Cancer Drug Therapies, Surgeries and Radiotherapies 
The number of line, type, best response and duration of prior systemic treatment will be 
summarized in safety analysis set. The therapies with the same line number are counted as one 
prior therapy.  
Previous anticancer medication will be summarized in the World Health Organization Drug 
Dictionary (WHO DD) preferred term.. 
6.3.5 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using WHO DD and will be further classified to 
the appropriate Anatomical Therapeutic Chemical (ATC) code.  
The number (percentage) of patients reporting prior and concomitant medications will be 
summarized by ATC medication class and WHO DD preferred term by phase in the safety analysis 
set. Prior medications are defined as medications that stopped before the first dose date. 
Concomitant medications will be defined as medications that (1) started before the first dose of 
study drug and were continuing at the time of the first dose of study drug, or (2) started on or after 
the date of the first dose of study drug up to 30 days after the patient’s last dose or  initiation of a 
new anticancer therapy, whichever occurs first. A listing of prior and concomitant medications 
will be provided. 
6.3.6 Medical History 
Medical/disease history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, version 22.0 or higher). The number (percentage) of patients reporting a history of any 
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medical condition, as recorded on the eCRF, will be summarized by system organ class and 
preferred term in the safety analysis set. A listing of medical history will be provided. 
6.4 
EFFICACY ANALYSIS 
6.4.1 Primary Efficacy Endpoints 
ORR by IRC is defined as the proportion of patients who achieves a best overall response of 
complete response (CR) or partial response (PR), assessed by IRC per RECIST v1.1.  
TNBC cohort 
Hypothesis testing of ORR by IRC will be performed in the Efficacy Analysis Set. 
ORR of BGB-290 per IRC is assumed as 46% in patients with TNBC. The historical rate in a 
similar population is estimated as 25%. The null and alternative hypotheses are set as follows: 
 H0:  ORR= 25% 
 Ha:  ORR > 25% 
A binomial exact test will be performed for hypothesis testing in the Efficacy Analysis Set. If the 
obtained one-sided p-value is ≤ 0.025, it will be concluded that BGB-290 monotherapy statistically 
significantly increases ORR compared with historical control. A two-sided binomial exact 95% CI 
of ORR will be constructed to assess the precision of the rate estimate.  
The primary efficacy analysis will be conducted when mature response rate data have been 
observed, estimated at 6th month after the last patient received the first dose of study drug. In 
addition, the duration of treatment will be presented in swimmer plot. The tumor size change from 
baseline will be presented as in a waterfall plot in the efficacy evaluable analysis set. 
HR(+)/HER2(-) breast cancer cohort 
ORR by IRC and its two-sided binomial exact 95% CI will be calculated similarly as described 
above in the TNBC cohort. However, no statistical comparison to a specified historical rate is 
planned. 
6.4.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be analyzed in the TNBC and HR(+)/HER2(-) cohorts. Kaplan-
Meier method will be used to estimate the DOR by IRC and DOR by INV, and corresponding 
quartiles (including the median) in the responders. A two-sided 95% CIs of median, if estimable, 
will be constructed with a generalized Brookmeyer and Crowley method.   
Duration of response analysis will only include responders. Censoring rule for DOR will follow 
PFS censoring rule which will follow FDA Guidance for Industry Clinical Trial Endpoints for 
the Approval of Cancer Drugs and Biologics (2018). 
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Table 2 shows the primary censoring rules for the derivation of PFS using RECIST v1.1 criteria 
based upon tumor assessment.  
Table 2. Censoring Rules for Analysis of Progression-Free Survival  
No. Situation 
Date of Progression or Censoring 
Outcome 
1 
No baseline tumor assessments 
Reference start date    
Censored 
2 
Progression documented on scheduled 
visit or between scheduled visits 
Date of first radiologic PD 
assessment  
Progressed 
3 
No progression at the time of data cutoff 
or withdrawal from study 
Date of last adequate radiologic 
assessment prior to or on date of 
data cutoff or withdrawal from study 
Censored 
4 
Treatment discontinuation for 
undocumented progression 
Date of last radiological assessment 
of measured lesions 
Censored 
5 
New anticancer treatment started 
Date of last radiological assessment 
of measured lesions prior to or on 
date of new anticancer treatment 
Censored 
6 
Death before first PD assessment 
Date of death 
Progressed 
7 
Death between adequate assessment 
visits* 
Date of death 
Progressed 
8 
Death or progression after two or more 
consecutive missed visit** 
Date of last adequate radiologic 
assessment before missed tumor 
assessments 
Censored 
Abbreviations: CR = complete response, PD = progressive disease, PR = partial response, SD = stable disease, 
* Adequate tumor assessment is a radiologic assessment of CR, PR, SD, non-CR/non-PD or PD as determined by 
investigators. 
**More than one missed visit is defined if the duration between the last tumor assessment and death or PD is longer than 2 
scheduled visits + one time window. 
 
Other time-to-event analysis endpoints (PFS by IRC, PFS by INV and OS) will be analyzed in the 
safety analysis set using the Kaplan-Meier method. The Kaplan-Meier estimates of PFS and OS 
will be plotted over time. The PFS time point estimates, defined as the percentages of patients in 
the analysis population who remain alive and progression-free at the specified time point (eg, 3 or 
6 months), will be estimated using the Kaplan-Meier method along with the corresponding 95% 
CI constructed using Greenwood’s formula. The OS time point estimates will be calculated 
similarly. For OS analysis, patients with no death date in the database will be censored at the last 
date the patient was known to be alive before/on cutoff date. 
BOR is defined as the best response recorded from the start of BGB-290 until data cutoff or start 
of new antineoplastic treatment. BOR and their 95% CIs will be summarized in the efficacy 
evaluable analysis set. Sensitivity analysis of BOR will be carried out in the safety analysis set. 
The proportion of each response category (CR, PR, SD, PD and NE) will be presented for both 
efficacy evaluable analysis set and safety analysis set. 
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DCR and CBR and their 95% CIs will be summarized for the efficacy evaluable analysis set and 
safety analysis set.  
Time to response (TTR) is defined as the time from first dose date to the date of earliest confirmed 
response (CR or PR) assessed using RECIST V1.1. TTR will be summarized descriptively.  
All the efficacy endpoints will be summarized by cohort. Assessments by IRC and investigator 
will be summarized separately. The concordance rate between IRC and INV assessed BOR and 
ORR will be evaluated. 
6.4.3 Subgroup Analyses 
Subgroup analyses of ORR will be conducted separately for both TNBC and HR(+)/HER2(-) 
cohorts. Table and forest plot of subgroup analysis in ORR will be provided based on the 
following subgroups:  
x Age group (< 50 years vs. 50 – 65 years vs.  > 65 years)      
x Baseline ECOG performance status (0 vs. 1) 
x BRCA mutation type (BRCA1 vs. BRCA2) 
x Number of prior chemotherapy lines (0 vs. 1 vs. ≥2) 
x Prior Platinum-based Systemic Chemotherapy (Yes vs. No) 
x Number of metastatic sites (1 vs 2 vs ≥3) 
x Visceral metastasis (Yes vs No) 
x Brain metastasis (Yes vs No) 
For the HR(+)/HER2(-) cohort, an additional subgroup analysis will be conducted. 
x ER/PgR status (ER or PgR ≥10% vs ER and PgR <10% vs ER or PgR Unknown) 
These planned subgroup analyses may not be explored if enough samples cannot be achieved for 
certain subgroups. The subgroup variables and the cutoff values are subject to change if 
warranted to better represent the data. 
6.4.4 Exploratory Efficacy Endpoints 
6.5 
SAFETY ANALYSES 
All safety analyses will be performed by cohort based on the safety analysis set. The incidence of 
treatment-emergent adverse events (TEAEs) and SAEs will be summarized. Laboratory test 
results, vital signs, ECG and their changes from baseline will be summarized using descriptive 
statistics (e.g., n, mean, standard deviation, median, Q1, Q3, minimum, maximum for continuous 
variables; n [%] for categorical variables). Abnormal values will be flagged. 
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6.5.1 Extent of Exposure 
The number (and percentage) of patients requiring dose reductions, dose interruption, and 
treatment discontinuation will be summarized.  
The duration of treatment (months) will be summarized with descriptive statistics. It will be 
calculated as (Date of last non-zero dose – Date of first dose + 1) / 30.4375.  
Number of patients with dose reductions and treatment discontinuation and their reasons, as well 
as number of patients with any dose modification will be summarized by counts and percentages 
according to study medication data. In addition, frequency of dose reductions and dose interruption 
will be summarized by categories (0, 1, ≥2).  
Average dose intensity per patient (in mg/day) and relative dose intensity (total dose received / 
total dose planned) per patient will be summarized. Average dose intensity is calculated as the 
total dose (mg) taken by a patient divided by overall duration of exposure (= Date of last non-zero 
dose – Date of first dose + 1) for individual patient. Relative dose intensity is calculated as the 
total dose (mg) taken by a patient divided by the total dose planned for the patient by study design, 
e.g. 60 mg BID.  
Patient data listings will be provided for all dosing records. 
6.5.2 Adverse Events  
AEs will be graded by the investigators using CTCAE version 4.03 or above. The AE verbatim 
descriptions (investigator terms from the CRF) will be classified into standardized medical 
terminology using MedDRA. Adverse events will be coded to the MedDRA, version 22.0 or higher, 
lower level term closest to the verbatim term. The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) are also captured in the database. 
A TEAE is defined as an AE that had an onset date or was worsening in severity from baseline 
(pretreatment)on or after the first dose of study drug up to 30 days following study drug 
discontinuation. All AEs will be included in the listings and only TEAEs will be included in the 
summary tables. SAEs, deaths, TEAEs with Grade 3 or higher, treatment-related TEAEs and 
TEAEs that led to treatment discontinuation, dose reduction or dose interruption will be 
summarized. 
The attribution of TEAEs to the study drug are categorized by investigators according to the 5-
item scales, including not related, unlikely related, possibly, probably related and definitely related. 
The primary definition of the treatment-related TEAEs uses the 3 to 2 mapping, including those 
events considered by the investigator to be possibly or probably or definitely- related to study drug 
or with missing assessment of the causal relationship. The 4 to 1 mapping will also be explored in 
addition to the primary definition in the compliance with the agency requirements. In the 4 to 1 
mapping, the TEAEs assessed by the investigator to be unlikely related to the study drug will also 
be considered treatment related. 
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An overview table, including the incidence and the number of patients with TEAEs, treatment-
emergent serious adverse events (SAEs), TEAEs with Grade 3 or higher, treatment-related 
treatment-emergent SAEs, TEAEs that led to death, and TEAEs that led to treatment 
discontinuation, dose reduction or dose interruption will be provided. The above analyses will 
repeat for the treatment-related TEAEs defined in either the 3 to 2 or the 4 to 1 mapping. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and PT. A patient will be counted only once by the highest severity grade according to 
CTCAE version 4.03 within an SOC and PT, even if the patient experienced more than 1 TEAE 
within a specific SOC and PT.  
The number (percentage) of patients with treatment-emergent SAEs, TEAEs with Grade 3 or 
higher, TEAEs that led to death, and TEAEs that led to treatment discontinuation, dose reduction 
or dose interruption will be summarized by SOC and PT. The treatment-related TEAEs will also 
be summarized by SOC and PT for the above categories. TEAEs and treatment related TEAE with 
grade 3 or higher will also be summarized by PT in descending order.  
Patient data listings of all AEs, SAEs, treatment-related AEs, grade 3 or higher AEs, AEs that led 
to death and AEs that led to treatment discontinuation will be provided. 
6.5.3 Laboratory Values 
Laboratory safety tests (hematology, which is reviewed prior to BGB-290 administration, serum 
chemistry assessed on Day 1 of every cycle, and pregnancy test assessed at screening and EOT) 
will be assessed in the study. 
Laboratory results will be summarized using Système International (SI) units, as appropriate.  For 
all quantitative parameters listed in Table 3, the actual value and the change from baseline to each 
postbaseline visit and to the end of treatment will be summarized by visit using descriptive 
statistics. Qualitative parameters listed in Table 3 will be summarized using frequencies (number 
and percentage of patients), and changes from baseline to each postbaseline visit and to end of 
treatment will be reported using shift tables. Percentages will be based on the number of patients 
with non-missing baseline and relevant postbaseline results. 
Laboratory parameters will be categorized according to NCI CTCAE version 4.03 grades and shifts 
from baseline CTCAE grades to maximum and the last postbaseline grades will be assessed. 
Laboratory parameters will be summarized by worst postbaseline CTCAE grade as well. For the 
lab tests with both high and low abnormality, separate records of worst CTCAE grade (for high 
and low) will be generated. 
Table 1. Serum Chemistry and Hematology Laboratory Tests 
Serum Chemistry 
Hematology 
Alkaline phosphatase (ALP) 
Hemoglobin 
Alanine aminotransferase (ALT) 
Platelet counts 
Aspartate aminotransferase (AST) 
White blood cell (WBC) count 
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Albumin 
Neutrophil (Absolute) 
Total bilirubin 
Lymphocyte (Absolute) 
Creatinine 
 
Phosphate 
 
Glucose 
 
Potassium 
 
Sodium 
 
Urea 
 
Total protein 
 
Blood urea nitrogen 
 
Chloride 
 
Lactate dehydrogenase 
 
6.5.4 Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure [BP], pulse 
rate, temperature, and respiratory rate) and changes from baseline for all pre-dose assessments 
will be presented by visit. Vital signs will be listed by patients, visits and timepoints. 
6.5.5 Electrocardiograms 
ECG will be performed at baseline and the end of treatment visit. Patient listing of ECG will be 
provided for all ECG recordings with the indicator whether the abnormality is clinical significance. 
6.5.6 ECOG Performance Status 
ECOG scores will be summarized by visit. 
6.6 
PHARMACOKINETIC ANALYSES 
BGB-290 concentrations after single-dose and at steady-state will be summarized by the 
sampling timepoint. Descriptive statistics will include means, medians, and standard deviations, 
as appropriate.  
6.7 
AD HOC ANALYSES 
Protocol version 1.0 was released on 30 October 2018, which was in the middle of study conduct. 
The new version of the protocol provided a more proactive dose modification algorithm and closer 
hematology monitoring in early stage of drug administration to improve hematological safety 
management.  
The analysis of hematological safety data comparison of BGB-290 between pre- and post- protocol 
amendment (PA) is proposed. Post-PA subgroup is defined as patients signed the first ICF under 
protocol version 1.0 and Pre-PA subgroup includes patients who signed first ICF under at least 
one previous protocol version. The detailed description of the analysis is in Appendix 10.2. 
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6.8 
COVID-19 IMPACT ANALYSIS 
Impact of the COVID-19 on the study conduct will be summarized and listed.  
The COVID-19 impact on the patient disposition, including treatment and study discontinuation, 
will be summarized. The delay or missing of study visit, lab assessments due to COVID-19 will 
also be summarized. The missed and delayed tumor assessment as well as tumor assessment done 
at auxiliary sites will be summarized. For the safety analysis, the modification and discontinuation 
of study drug as well as COVID-19-related AE will be summarized if applicable.  In addition, the 
major protocol deviation due to COVID-19 will be listed. 
7 
INTERIM ANALYSIS 
No formal interim analysis is planned. 
8 
CHANGES IN THE PLANNED ANALYSIS 
No changes are identified.  
9 
REFERENCES 
Brookmeyer R, Crowley J. A Confidence interval for the median survival time. Biometrics. 1982; 
38: 29-41. 
Clopper, C. and Pearson, ES. The use of confidence or fiducial limits illustrated in the case of the 
binomial, Biometrika 1934;26: 404-413.  
Collett D. Modelling survival data in medical research. New York: Chapman & Hall; 1994.  
Common Terminology Criteria for Adverse Events (CTCAE).  Version 4.0.  United States 
Department of Health and Human Services, National Institutes of Health, National Cancer 
Institute, Washington, DC, USA, May 28, 2009. 
Eisenhauer EA, Therasse P, Bogaerts J Schwartz LH, Sargent D, Ford R, et al.  New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J Cancer. 
2009;45:228-47. 
Food and Drug Administration Center for Drug Evaluation Research CDER and Center for 
Biologics Evaluation and Research. FDA Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics, 2007. 
Greenwood M. “The natural duration of cancer”. Reports on Public Health and Medical Subjects 
(London: Her Majesty’s Stationery Office). 1926; 33:1-26. 
Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics.  
Washington, DC: United States Food and Drug Administration; 2007. 
Kaplan E, Meier P.  Nonparametric estimation from incomplete observations.  J Am Stat Assoc. 
1958;53:457-81. 
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10 APPENDIX 
10.1 IMPUTATION OF PARTIAL DATES FOR AES/MEDICATIONS/THERAPIES/PROCEDURES 
IMPUTATION FOR AES WITH MISSING OR PARTIAL DATES 
If AE start/end date are missing or partial missing, the following imputation rules apply.  
If end date of an adverse event is partially missing, impute as follows: 
• 
If both month and day are missing, then set to December 31 
• 
If only day is missing, then set to last day of the month 
• 
If the imputed end date > death date, then set to death date 
If year of the end date is missing or end date is completely missing, do not impute. 
 
If start date of an adverse event is partially missing, impute as follows: 
• 
If both month and day are missing and year = year of treatment start date, then set to 
treatment start date 
• 
If both month and day are missing and year ≠ year of treatment start date, then set to 
January 01 
• 
If day is missing and month and year = month and year of treatment start date, the set to 
treatment start date 
• 
If day is missing and month and year ≠ month and year of treatment start date, the set to 
first of the month 
If year of the start date is missing or start date is completely missing, do not impute.  
If the imputed start date > death date, then set to death date. If the imputed start date > the end 
date (or the imputed end date), set the imputed start date = end date (or the imputed end date).  
 
IMPUTATION FOR MEDICATIONS/THERAPIES/PROCEDURES WITH MISSING OR PARTIAL 
DATES 
 
When the start date or end date of a medication/therapy/procedure is partially missing, the date 
will be imputed to determine whether the medication/therapy/procedure is prior or concomitant. 
The following rules will be applied to impute partial dates for medication/therapy/procedure: 
If start date of a medication/therapy/procedure is partially missing, impute as follows: 
x If both month and day are missing, then set to January 01 
x If only day is missing, then set to the first of the month 
x If the imputed start date > death date, then set to death date 
If end date of a medication/therapy/procedure is partially missing, impute as follows: 
• 
If both month and day are missing, then set to December 31 
• 
If only day is missing, then set to last day of the month 
• 
If the imputed end date > death date, then set to death date 
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• 
For prior anticancer therapy (radiotherapy, systemic therapy), the imputed end date 
should be the first dose date – 15 at the latest after imputation. 
If the year of start date or year of end date of a medication/therapy/procedure is missing, or the 
start date or end date is completely missing, do not impute. 
For detailed imputation rule for new anti-cancer therapy and death date, etc., please refer to a 
separate document “Standard Definitions and Derivation Rules of Key Variables_V1”. 
 
10.2 PRE- AND POST- PROTOCOL AMENDMENT (PA) HEMATOLOGICAL ANALYSES 
The following safety data is considered for this analysis of comparison between pre- and post-PA: 
C1. Summary of Hematology Laboratory Values 
The hematological laboratory values at baseline will be summarized descriptively. The incidence 
of abnormal hematology values at baseline and any postbaseline visits, and number of patients (%) 
with shifts in hematology results of ≥ 2 toxicity grades from baseline to worst postbaseline grade 
will be summarized. The hematological laboratory parameters (unit) of interest for these 
summaries are: Hemoglobin (g/L), Leukocytes (109/L), Lymphocytes (109/L), Neutrophils 
(109/L), Platelets (109/L). 
C2. Summary of Hematological TEAEs  
An overall summary of hematological TEAEs will summarize the number (%) of patients.  
Summaries of the following hematological TEAEs will be provided:    
x All hematological TEAEs by preferred terms 
x Hematological TEAEs grade 3 or higher by preferred terms 
x Serious hematological TEAEs by preferred terms 
Hematological TEAE preferred terms are Anemia, Leukopenia, White blood cell count 
decreased, Neutropenia, Neutrophil count decreased, Thrombocytopenia, Platelet count 
decreased, Lymphopenia, Lymphocyte count decreased, Haemoglobin decreased, Erythropenia, 
Red blood cell count decreased, Bone marrow failure, and Febrile neutropenia. 
 
C3. Extent of Exposure and Dose Modification 
The following measures of overall extent of study drug exposure in patients between pre- and post-
PA will be summarized: 
x Duration of treatment (months), defined as (earlier of date of last nonzero dose and data 
cutoff date – date of first dose + 1) / 30.4375  
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x Number (%) of patients in each treatment duration category 
x Number (%) of patients with dose modification (interruption and reduction)   
x Number (%) of patients with dose interruptions and reasons of dose interruptions 
x Number (%) of patients with dose reductions and reasons of dose reductions 
x Time to first dose reduction (weeks), defined as (earlier of date of first nonzero dose date 
– date of first dose + 1) / 30.4375 for patients with dose reduction 
C4. Concomitant Medications for Anemia 
Erythropoietin and Red Blood Cell Transfusion related concomitant medications coded by the 
WHO-DD drug codes are identified as concomitant medications to cure anemia and will be 
further classified to the grouping drug name for this analysis of comparison on patients between 
pre- and post-PA. The number (%) of patients reporting concomitant medications for anemia will 
be summarized by two grouping drug names and its corresponding WHO-DD preferred terms as 
following: 
EPO (Erythropoietin) 
x Erythropoietin Human  
x Erythropoietin  
x Epoetin Beta 
  
Red Blood Cell Transfusion 
x Red Blood cells, Concentrated 
x Human Red Blood Cells 
x Blood, Whole 
x Red Blood Cells 
x Erythrocyte 
x Red Blood Cells, Leucocyte Depleted 
 
10.3 PROGRAMMING RULE 
For detailed programming rule, please refer to a separate document “Standard Definitions and 
Derivation Rules of Key Variables_V1”. 
 
 
 
 
 
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