An Open Label, Multi-Center Phase I/II Study to Evaluate Efficacy and Safety of BGB-290 in Chinese Subjects With Advanced Ovarian Cancer, Fallopian Cancer, and Primary Peritoneal Cancer or Advanced Triple Negative Breast Cancer
Phase: PHASE1
Conditions: Advanced High-grade Ovarian Cancer, Triple Negative Breast Cancer
Sponsor: BeiGene

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Clinical Study Protocol 
Protocol Title:  
An Open Label, Multi-Center Phase I/II Study to 
Evaluate Efficacy and Safety of BGB-290 in Chinese 
Subjects with Advanced Ovarian Cancer, Fallopian 
Cancer, and Primary Peritoneal Cancer or Advanced 
Triple Negative Breast Cancer 
Protocol Number: 
 
 
BGB-290-102 
Date of Protocol: 
 
 
21 September 2018, Version 5.0 
Study Phase:  
 
1/2 
Sponsor: 
BeiGene (Beijing) Co., Ltd 
No. 30, Science Park Rd. 
Zhong-Guan-Cun Life Science Park  
Changping District 102206  
Beijing, China 
Sponsor Medical Monitor: 
 
 
 
 
 
 
 
 
 
 
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FINAL PROTOCOL APPROVAL SHEET 
An Open Label, Multi-Center Phase I/II Study to Evaluate Efficacy and Safety of BGB-290 
in Chinese Subjects with Advanced Ovarian Cancer, Fallopian Cancer, and Primary 
Peritoneal Cancer, or Advanced Triple Negative Breast Cancer 
BeiGene Approval: 
 
____________________________________ 
 
 
___________________ 
  
 
 
 
 
 
 
Date 
Sponsor Medical Monitor 
 
 
 
  
 
 
 
 
 
 
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PROTOCOL AMENDMENT, VERSION 5.0, RATIONALE 
The main purpose of this protocol amendment is to update the dose modification algorithm 
for anemia in the Phase 2 portion of this study. Meanwhile, content in the Note to Files to the 
last approved protocol amendment (version 4.0) were incorporated. In addition, some content 
was modified to improve the clarity of the document. Changes were made to the synopsis to 
match those in the protocol body. 
This amendment version number is version 5.0.  
Substantial changes from version 4.0 are summarized as below: 
 
Table 5 (Study Visit Schedule in Phase 1 Portion), changed column title “Cycle 4 and 
Subsequent Cycles (every 21 days for one Cycle)” to “Cycle 4 and Subsequent Cycles 
(every 21 days for 1 cycle in Year 1, every 12 weeks ± 7 days thereafter)” 
 
Section 4.1.2 (Phase 2 Portion), Table 5 Footnote 4, Table 7 Footnote 6 and 
Section 4.2.1 (Inclusion Criteria) #3-2)-a)-ii, updated the criteria to define 
platinum-sensitive from “if disease progression had occurred more than 6 months 
after their last dose of platinum treatment” to “≥ 6 months after their last dose of 
platinum treatment” 
 
Section 4.1.2.1 (Safety, Tolerability and Efficacy), added and specified “Dose 
interruption due to investigational drug-related anemia could be on hold for up to 
56 days consecutively” 
 
Section 4.1.3 (Follow-up for Toxicities), updated “If the levels have not recovered to 
NCI-CTCAE ≤ Grade 1 or baseline after 4 weeks” to “If the levels have not recovered 
to NCI-CTCAE ≤ Grade 1 or baseline after 8 weeks” 
 
Section 4.2.4 (Patient Discontinuation and Withdrawal) and Table 7 (Study Visit 
Schedule in Phase 2 Portion) Footnote 3, added “If discontinuation is due to 
unresolved toxicities for more than 21 days (56 days for anemia), EOT visit should be 
conducted at the earliest day as possible within 5 days after permanent discontinuation 
is determined”  
 
Table 5 (Study Visit Schedule in Phase 1 Portion) and Table 7 (Study Visit Schedule 
in Phase 2 Portion) 
- 
Added pregnancy test to visits of Cycle 2 and subsequent cycles, EOT, and Safety 
Follow-up in the assessment table 
- 
Updated Table 5 Footnote 14 and Table 7 Footnote 15 to “For women of 
childbearing potential including those who have had a tubal ligation, 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 prior to dosing. A serum pregnancy test must be performed if urine 
pregnancy test is positive or equivocal” 
 
Table 7 (Study Visit Schedule in Phase 2 Portion), 
- 
Footnote 3 and Section 4.2.4.2 (End of Treatment Visit), clarified the rule for the 
assessment of CT/MRI at EOT by deleting “within 14 days of the EOT visit” 
- 
Footnote 4, added “If discontinuation is due to unresolved toxicities for more than 
21 days, safety follow-up could be scheduled 30 ± 5 days after the last dose of 
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treatment. 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 5 days after permanent discontinuation is determined” 
- 
Footnote 9, added “Weekly hematology test should be done for the first 3 cycles 
during the study” 
 
Table 8 (Pharmacokinetic Sampling in Phase 2 Portion) General note, added “For 
sparse PK sampling, the sequence of collection at a particular time point may be 
determined by the sites based on feasibility” 
 
Section 4.2.1 (Inclusion Criteria) #3-2)-a)-i, revised “patients must have received at 
least 2 lines of therapy in the advanced or metastatic setting” to “patients must have 
received at least 2 lines of standard chemotherapy” 
 
Section 4.2.2 (Exclusion Criteria)  
- 
#2, removed “surgical therapy” 
- 
#12, updated “a negative serum pregnancy test” to “a negative urine or serum 
pregnancy test” 
 
Section 5.2 (Dosage and Administration) Phase 2 Portion,  
- 
Clarified the dose administration interval 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 parmiparib may cause, 
patients are encouraged to take parmiparib with food”  
- 
Revise “A dose of pamiparib 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” 
 
Section 5.2.1 (Treatment interruption and treatment discontinuation), added “For 
reasons other than drug-related AEs, eg, safety concerns due to the poor health 
condition, if deemed necessary by the investigators, dose modifications could be 
applied after discussion with medical monitor” 
 
Table 9 (Criteria for interruption and re-initiation of Pamiparib due to treatment 
associated adverse event),  
- 
Revised the dose modification algorithm for anemia in the Phase 2 portion 
- 
Removed “Dosing of pamiparib can be withheld for up to 28 days consecutively” 
from the footnote 
 
Section 7.8 
 
 
.” 
 
Section 9.1.4 (Follow-Up of Adverse Events),  
- 
Deleted “Once resolved, the appropriate AE or SAE eCRF page(s) will be 
updated” 
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- 
Revised “new or updated information will be recorded on the originally completed 
SAE report/eCRF” 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 9.6.1” 
 
Section 9.3 (Suspected Unexpected Serious Adverse Reaction), revised “meet the 
definition of an SAE” to “meets the definition of a serious adverse drug reaction 
(SADR), the specificity or severity of which is not consistent with those noted in the 
IB” 
 
Section 9.5.1 (Disease Progression), revised “event(s)” to “adverse event(s)” 
 
Section 9.6.1 (Timeframes for Submitting Serious Adverse Events), specified prompt 
reporting by adding “within 24 hours” 
 
Table 10 (Time Frame for Reporting Serious Adverse Events to the Sponsor or 
Designee), revised the table by updating the Documentation Method and adding 
Reporting Method 
 
Section 9.6.2 (Completion and Transmission of the Serious Adverse Event Report), 
- 
Replaced “SAE eCRF” with “SAE Report” 
- 
Removed “The data alert letter will automatically be submitted to sponsor or 
designee immediately after investigator signature” 
- 
Removed the content specifying the transmission rules of paper SAE forms under 
the situation when EDC is non-operational.  
 
Appendix 2 (Clinical Laboratory Assessments),  
- 
Updated “Blood urea nitrogen” to “Blood urea nitrogen or urea” in Clinical 
Chemistry 
- 
Removed “and a random urine sample for total protein and creatinine to determine 
a protein to creatinine ratio” from the footnote 
 
Appendix 8 (Prohibited Medications), updated the food products among moderate 
CYP3A inhibitors from “grapefruit juice (citrus paradisi fruit juice)” to “grapefruit 
and juice (Citrus paradisi), Seville orange and juice (Citrus aurantium)” 
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SYNOPSIS 
Name of Sponsor/Company: 
BeiGene (Beijing) Co., Ltd 
Name of Finished Product: 
Pamiparib (BGB-290) Capsules 
Name of Active Ingredient: 
Pamiparib (BGB-290) 
Title of Study: 
An Open Label, Multi-Center Phase I/II Study to Evaluate Efficacy and Safety of 
BGB-290 in Chinese Subjects with Advanced Ovarian Cancer, Fallopian Cancer, and 
Primary Peritoneal Cancer or Advanced Triple Negative Breast Cancer 
Protocol No: 
BGB-290-102 
Study Centers: 
Phase 1: in 2 study centers 
Phase 2: in 25 to 35 study centers 
Study Duration: 
For Phase 1: Screening (up to 21 days), treatment cycle of 23 days (Cycle 1 only) and 
repeated treatment cycles of 21 days, safety follow-up (30 ± 5 days after the last dose of 
pamiparib [also known as BGB-290]). Patients will continue treatment until confirmed 
disease progression, intolerable toxicity, withdrawal of consent, or deemed unacceptable 
for further treatment at the discretion of the investigators, whichever occurs first. 
For Phase 2: Screening (up to 21 days), repeated treatment cycles of 21 days, safety 
follow-up (30 ± 5 days after the last dose of pamiparib). Patients will continue treatment 
until confirmed disease progression, intolerable toxicity, withdrawal of consent, or at the 
discretion of the investigators. 
Phase: 1/2  
Objectives: 
 
Phase 1 
Primary: 
 
To evaluate the safety and tolerability of pamiparib for advanced cancer in 
Chinese patients 
 
To determine the recommended Phase 2 dose (RP2D) of pamiparib  
Secondary: 
 
To characterize the pharmacokinetics (PK) of pamiparib in Chinese patients 
 
To evaluate the clinical anti-tumor activity of pamiparib in Chinese patients with 
triple negative breast cancer (TNBC) or high-grade epithelial, non-mucinous 
ovarian cancer (including fallopian cancer, or primary peritoneal cancer) 
 
To evaluate the relationship between pamiparib PK and clinical endpoints 
Exploratory: 
 
 
Phase 2 
Primary: 
 
To evaluate the efficacy of pamiparib as measured by objective response rate 
(ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST), 
version 1.1 (RECIST V 1.1), by independent radiology review (IRR) in patients 
with advanced platinum-sensitive or platinum-resistant high grade, non-mucinous, 
epithelial ovarian cancer (including fallopian cancer or primary peritoneal cancer), 
harboring germline breast cancer susceptibility gene 1/gene 2 (BRCA1/2) mutation 
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Secondary:  
 
To evaluate the efficacy of pamiparib as measured by progression free survival 
(PFS), duration of response (DOR) by both IRR and investigator review, and 
overall survival (OS) by investigator review 
 
To evaluate the efficacy of pamiparib as measured by the objective response rate 
by investigator review 
 
To evaluate the safety and tolerability of pamiparib  
 
To evaluate the efficacy of pamiparib as measured by disease control rate (DCR), 
best overall response (BOR) and clinical benefit rate (CBR) by both IRR and 
investigator review  
 
To evaluate the carcinoma antigen-125 (CA-125) response rate per Gynecological 
Cancer Intergroup (GCIG) criteria for CA-125 changes  
 
To further characterize the PK of pamiparib 
Exploratory: 
 
 
 
Methodology: 
This is a Phase 1/2, open-label, multi-center study of pamiparib administered orally (PO) 
twice daily (BID) to adult Chinese patients with advanced solid tumors, which have 
progressed despite standard therapy, or for which no standard therapy exists. The Phase 1 
portion of this study is designed to evaluate the safety, tolerability and PK profile of 
pamiparib in Chinese patients with advanced cancer and to determine the recommended 
Phase 2 dose (RP2D) of pamiparib for Chinese patients.  
In the Phase 2 portion of this study, approximately 100 evaluable Chinese patients will be 
evaluated for the efficacy, safety, tolerability, and PK profile of pamiparib: 
 
Eighty (80) previously treated platinum-sensitive patients and 20 previously 
treated platinum-resistant patients with advanced high grade, non-mucinous, 
epithelial ovarian cancer (including fallopian cancer, or primary peritoneal cancer) 
with either known deleterious or suspected deleterious germline BRCA1/2 
mutation  
In the Phase 1 portion of the study, fresh blood samples at baseline for all patients must be 
collected for the purposes of retrospective germline BRCA1/2 mutation testing. 
In the Phase 2 portion of the study, all patients, including those with known germline 
BRCA1/2 mutation status need to undergo centralized germline BRCA mutation testing and 
have germline BRCA1/2 mutation confirmed before being eligible for the study.  
Archival tumor tissues will be collected for all patients, if available. 
Phase 1 
Adult patients with advanced solid tumors which have progressed despite standard therapy 
or for which no standard therapy exists will be enrolled. Dose escalation will follow a 
modified 3+3 scheme: 
 
If no dose limiting toxicity (DLT) is observed in a cohort of 3-6 patients at a given 
dose level, the next cohort of 3-6 new patients may be enrolled at the next higher 
dose level. 
 
At least 3 patients will be enrolled into each cohort. Additional patient(s), up to a 
maximum of 6 patients in total, will be enrolled if more than 3 have been screened 
and are eligible for the cohort. The DLT assessment and dose escalation scheme 
will follow the same principle as stipulated for a standard 3+3 dose escalation 
design. For example, 3 additional patients will be enrolled if a DLT is observed in 
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1 of 3 patients; an additional 2 patients will be enrolled if a DLT is observed in 1 
of 4 patients; and an additional 1 patient will be enrolled if a DLT is observed in 1 
of 5 patients. No additional patients are required if a DLT is observed in 1 of 6 
patients. 
 
If DLT occurs in 2 patients in a cohort of up to 6 patients at a given dose level, 
then this dose level will be defined as the DLT dose level. All investigators will be 
informed, no additional patient(s) will be enrolled at the DLT dose level, and dose 
escalation will stop. 
To be included in a dose-escalation decision, an evaluable patient is defined as one who 
either experienced a DLT during the first 23-day treatment cycle (Cycle 1) or has not 
experienced a DLT and has been administered for at least 18 days (ie, at least 75% of the 
dose) and completed all safety evaluations required in Cycle 1. 
Dose escalation will continue until RP2D or maximum tolerated dose (MTD), if any, is 
reached.  
Starting dose and dose levels 
The starting dose for pamiparib will be 20 mg BID which was based on the doses evaluated 
in the on-going first-in-human (FIH) Phase 1 study of pamiparib in Australia, and is 
significantly lower than the highest safe dose that has been identified to date. The dose 
escalation phase of the FIH study has been completed. Doses levels of 2.5, 5, 10, 20, 40, 
60, 80 and 120 mg BID have been evaluated in 45 patients. Drug exposure is linear up to 
80 mg BID. Therefore, 80 mg BID was determined to be the MTD and 60 mg BID is the 
RP2D for the dose expansion phase in that study. 
Three dose levels of 20, 40 and 60 mg BID are planned for the dose escalation phase. An 
intermediate, not pre-defined, and not previously-evaluated dose or a less frequent dosing 
schedule could be evaluated in dose escalation phase if necessary. 
Dose-Limiting Toxicity  
Adverse events (AEs) will be evaluated according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.03. A DLT is defined 
as an AE or abnormal laboratory value that occurs during the DLT assessment window and 
is assessed as unrelated to disease progression, intercurrent illness, or concomitant 
medications that meets one of the following criteria: 
Hematologic: 
 
Grade 4 neutropenia lasting >7 days 
 
Febrile neutropenia 
 
Grade 3 neutropenic infection 
 
Grade 3 thrombocytopenia with bleeding 
 
Grade 4 thrombocytopenia 
 
Grade 4 anemia 
Non-hematologic: 
 
≥ Grade 3 nausea, vomiting and diarrhea despite optimal supportive care 
 
Any other clinically relevant ≥ Grade 3 non-hematologic toxicity (excluding 
asymptomatic biochemical abnormalities that are not clinically significant and 
resolve to ≤ Grade 2 in <7 days) 
 
Any toxicity grade which in the judgment of the investigator or sponsor is dose 
limiting 
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Monitoring for DLT (SMC meetings) 
Meetings or teleconferences between the sponsor or its designee and investigators (Safety 
Monitoring Committee [SMC]) will be held on a regular basis to review all safety data 
including DLTs. The dose for each new cohort will be determined by SMC at a 
dose-escalation meeting by evaluating all available safety (including AEs that are not 
DLTs), PK, pharmacodynamics, and efficacy data. The SMC consists of investigators, the 
sponsor’s medical delegate, safety delegate, and the contract research organization’s 
medical monitor. Ad hoc members will be consulted as needed and may include, but are 
not restricted to the biostatistician and pharmacokineticist. Whenever a DLT occurs (as 
defined below), the affected site must immediately inform the sponsor or its designee. The 
sponsor or its designee will then inform all other sites that a DLT has occurred and 
determine if a second DLT has occurred at any other site at the same dose. If two DLTs 
have occurred at the same dose level based on evaluation of the patients at all sites, further 
enrolment of new patients at that dose level will be suspended until a safety evaluation 
meeting takes place to determine if the MTD has been exceeded. 
Once a DLT level has been established at a safety evaluation meeting, additional patients 
can be enrolled at a lower dose level (ie, the presumptive MTD) until a total of 6 patients 
have been treated at that dose level. 
Maximum Tolerated Dose 
MTD is the dose level at which 0/6 or 1/6 patients experiences DLT, provided that ≥ 33% 
of patients experienced DLT (eg, 2 of 3 or 2 of 6) at the next higher dose level. Even 
though an MTD may have been reached, a RP2D may still be selected which will take into 
account the MTD as well as available information on lower dose grade of AEs, AEs 
occurring in later cycles, PK, pharmacodynamics, and efficacy data. This decision will be 
made at a SMC meeting or teleconference at the time that the dose for the dose expansion 
phase is decided. At least 6, and up to 10 patients could be treated at RP2D. 
Phase 2 
Based upon the overall safety, efficacy, and PK profile of pamiparib, the dose of pamiparib 
60 mg PO BID was confirmed as RP2D using available clinical data from study 
BGB-290-AU-002 and the Phase 1 portion of this study. 
The following patients will be evaluated at 60 mg BID of pamiparib for efficacy, safety and 
tolerability in this Phase 2 portion: 
 
High grade (Grade 2 or Grade 3 endometrioid epithelial cancer is acceptable too), 
non-mucinous, epithelial ovarian cancer (including fallopian cancer, or primary 
peritoneal cancer), with either known deleterious or suspected deleterious 
germline BRCA1/2 mutation: approximately 80 evaluable patients with platinum-
sensitive high grade ovarian cancer (HGOC) and 20 evaluable patients with 
platinum-resistant HGOC 
Study Plan 
Only for the Phase 1 dose escalation portion, the patient will take a single dose of 
pamiparib on Cycle 1 Day1. On Day 3, after a one-day treatment-free period, patients will 
receive pamiparib BID continuously from Days 3 to 23, of Cycle 1 and in subsequent 
21-day cycles. For Phase 2 portion, 21-day period of repeated drug administration (Days 1 
to 21, BID) starts from Cycle 1. 
Patients may continue treatment with pamiparib until the patient experiences disease 
progression or unacceptable toxicity that preclude any further treatment, or is discontinued 
from treatment at the discretion of investigator, or the patient withdraws consent from the 
study. An end of treatment (EOT) visit will be conducted at the earliest day possible within 
5 days of the last dose of pamiparib, and a safety follow-up will be conducted 
approximately 30 days after the last dose of pamiparib. All patients will be followed for 
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AEs, serious adverse events (SAEs) and concomitant medications (including any new 
cancer treatment) for 30 days following the last dose of pamiparib. 
Assessment 
All patients will be followed for safety, tolerability, and efficacy from the first dosing day 
to the 30 days after the last dose. 
Safety evaluation 
For the Phase 1 portion, safety evaluation (eg, AE, physical examinations, clinical 
laboratory assessments, vital signs) will be performed at the time points specified in Table 
5. Electrocardiograms (ECGs) will be assessed with matching PK time points from Cycle 1 
to Cycle 3. Subsequent ECG evaluations are outlined in Table 6 for the Phase 1 portion.  
For the Phase 2 portion, safety evaluation will be conducted at the clinical site on Day 1 of 
each cycle. Clinical laboratory evaluation should be conducted before dosing on visit days 
at the clinical sites. 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 8 
Efficacy assessment 
For the Phase 1 portion, tumor response will be assessed by investigators based on 
RECIST, version 1.1. For the Phase 2 portion, tumor response will be assessed separately 
by IRR and investigator’s review based on RECIST, version 1.1. Tumor response will be 
evaluated once every 6 weeks ± 7 days for the first 18 weeks, thereafter once every 
9 weeks ± 7 days for the remaining period in the first year, and then once every 12 weeks 
± 7 days starting with the second year. For patients with a first response of complete 
response (CR) or partial response (PR), a response confirmation will need to be performed 
during the following 4-6 weeks, then patients will keep original tumor assessments 
schedule per protocol. 
Planned 
Number of 
Patients: 
Phase 1: Approximately 14-18 evaluable patients for the dose escalation until RP2D 
determination 
Phase 2: Approximately 100 evaluable HGOC patients.  
Diagnosis and 
Main Criteria 
for Inclusion: 
Patients may be enrolled in the study only if they meet all of the following criteria: 
1. Patients have voluntarily agreed to participate by giving written informed consent. 
2. Age 18 years (including 18 years) on the day of signing informed consent. 
3. Patients meet the following eligibility criteria for the corresponding part of the 
study: 
1) In Phase 1 portion: 
a) The patients must have a histologically or cytologically confirmed locally 
advanced or metastatic cancer, either TNBC or epithelial, non-mucinous, 
HGOC (including fallopian cancer, or primary peritoneal cancer), for 
which no effective standard therapy is available. 
b) BRCA1 and BRCA2 mutations are not required but enrichment of this 
patient population is preferred. 
c) Patients must agree to retrospective germline BRCA testing using blood 
samples. 
d) Archival tumor tissues will be collected, if available. 
2) In Phase 2 portion: 
a) Patients who have histologically or cytologically confirmed high-grade 
(Grade 2 or Grade 3 endometrioid epithelial cancer is acceptable too), 
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non-mucinous, epithelial ovarian cancer (including fallopian cancer or 
primary peritoneal cancer), harboring germline BRCA1/2 mutation and 
must meet the following criteria: 
i. 
Patients must have received at least 2 lines of standard 
chemotherapy, currently with relapsed/progressive disease or have 
withdrawn due to unacceptable toxicity from most recent standard 
treatment 
ii. 
Platinum-sensitive, or platinum-resistant patients  
(Patients are defined as platinum-sensitive if disease progression by 
RECIST, version 1.1 criteria, had occurred ≥ 6 months after their last 
platinum treatment, while platinum-resistant is defined if disease 
progression occurred < 6 months after the last platinum treatment) 
iii. 
If mixed histology, >50% of the primary tumor had to be confirmed 
to be high-grade (Grade 2 or Grade 3 endometrioid epithelial cancer 
is acceptable too), non-mucinous, epithelial ovarian cancer 
b) All patients will be required to undergo germline BRCA1/2 mutation 
testing using blood samples prior to enrolment. 
c) Archival tumor tissues will be collected from all patients, if available. 
4. Patients must have measurable disease as defined per the RECIST, version 1.1. 
5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 
(Appendix 3) 
6. Life expectancy ≥ 12 weeks 
7. Patients must have adequate organ function as indicated by the following 
laboratory values: 
 
Absolute neutrophil count (ANC) ≥ 1,500/mm3 or 1.5 x 109/L 
 
Platelets ≥ 75,000/mm3 or 75 x 109/L 
 
Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L 
(If transfusion is used, at least 14 days should pass before re-test for 
hematology is performed at the screening visit) 
 
Estimated glomerular filtration rate (eGFR) ≥ 30 mL/1.73m2 by Chronic Kidney   
Disease Epidemiology Collaboration Equation (CKD-EPI EQ; Appendix 6)  
 
Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN)  
 
Aspartate aminotransferase and alanine aminotransferase ≤ 3 x ULN  
8. Females of childbearing potential and nonsterile males (only for Phase 1 portion), 
must practice highly effective method of birth control (Appendix 11) for the 
duration of the study and for at least 6 months after the last study drug 
administration  
Main criteria 
for Exclusion: 
Patients will not be entered in the study for any of the following reasons: 
1. Patients who have been treated with chemotherapy, biologic therapy, 
immunotherapy, investigational agent, anti-cancer Chinese medicine, or anti-
cancer herbal remedies ≤ 14 days (or ≤5 half-lives, whichever is shorter) prior to 
starting study drug, or who have not adequately recovered from the side effects of 
such therapy. 
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2. Patients who have undergone major surgery for any cause ≤ 4 weeks prior to 
starting study drug. Patients must have adequately recovered from the previous 
treatment and have a stable clinical condition before entering the study. 
3. Patients who have undergone radiotherapy for any cause ≤ 14 days prior to 
starting study drug. Patients must have adequately recovered from the previous 
treatment and have a stable clinical condition before entering the study. 
4. Untreated and/or active brain metastases. 
 
A scan to confirm the absence of brain metastases is not required. 
 
Patients with treated brain metastases must be off corticosteroids for ≥ 14 days 
and have no signs or symptoms of progressive brain metastases.  
5. Prior therapies targeting poly (ADP-ribose) polymerase (PARP). 
6. Inability to swallow oral medications (capsules and tablets) without chewing, 
breaking, crushing, opening or otherwise altering the product formulation.  
7. Patients with any of the following cardiovascular criteria: 
• 
Cardiac chest pain, defined as moderate pain that limits instrumental activities 
of daily living, ≤ 28 days prior to Day 1 
• 
Evidence of symptomatic pulmonary embolism within 4 weeks prior to Day 1 
• 
Acute myocardial infarction ≤ 6 months prior to Day 1 
• 
Heart failure of New York Heart Association Classification III or IV (see 
Appendix 12) ≤ 6 months prior to Day 1 
• 
≥ Grade 2 ventricular arrhythmia ≤ 6 months prior to Day 1 
• 
Cerebrovascular accident ≤ 6 months prior to Day 1 
8. Patients with other malignant cancer  
 
Except for surgically excised non-melanoma skin cancer, adequately treated 
carcinoma in situ of the cervix, 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 
9. Diagnosis of myelodysplastic syndrome (MDS) 
10. Known human immunodeficiency virus (HIV) infection, active viral hepatitis, or 
active tuberculosis 
11. Use ≤ 10 days (or ≤ 5 half-lives, whichever is shorter), prior to Day 1, or 
anticipated need for food or drugs known to be strong or moderate cytochrome 
P450 (CYP) 3A inhibitors or strong CYP3A inducers (Appendix 8) 
12. Pregnancy or nursing: 
 
Females of childbearing potential require a negative urine or serum pregnancy 
test ≤ 7 days before Day 1. 
13. Significant intercurrent illness that may result in the patient’s death prior to death 
from HGOC, or TNBC (only for Phase 1 portion). 
14. Known history of intolerance to the excipients of the pamiparib capsule 
15. Previous complete gastric resection, chronic diarrhea, active inflammatory 
gastrointestinal disease, or any other disease-causing malabsorption syndrome. 
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 
Gastroesophageal reflux disease under treatment with proton pump inhibitors is 
allowed. 
16. Active bleeding disorder, including gastrointestinal bleeding, as evidenced by 
hematemesis, significant hemoptysis, or melena ≤ 6 months before Day 1 
17. Any illness that investigator thinks makes the patient unsuitable for entry into the 
study. 
18. Unsolved acute effects of prior therapy of ≥ Grade 2 
 
Except for AEs not considered a likely safety risk (eg, alopecia, neuropathy, 
and specific laboratory abnormalities)  
Test Product, 
Dose, and Mode 
of 
Administration: 
Pamiparib oral 10 mg and 40 mg capsules for Phase 1 
Pamiparib oral 20 mg capsules for Phase 2 
Phase 1: BID, except for single administration on Day 1 of Cycle 1 and treatment-free on 
Day 2 of Cycle 1 
Level 1: pamiparib, 20 mg PO BID 
Level 2: pamiparib, 40 mg PO BID 
Level 3: pamiparib, 60 mg PO BID 
The proposed dose levels may be further modified and additional doses may be added 
based on the safety, tolerability, and efficacy observed during the dose escalation. 
Phase 2: 60 mg 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. 
Endpoints:  
Phase 1 
Primary Endpoints: 
 
Incidence of AE, overall and by severity, and incidence of SAE according to 
NCI-CTCAE, version 4.03; laboratory abnormalities; changes in laboratory 
assessments, ECGs, and assessment of physical examinations 
Secondary Endpoints: 
 
PK parameters of pamiparib and possibly its major metabolite(s) at selected time 
points: area under the plasma concentration-time curve from 0 to the last 
measurable concentration (AUClast), maximum observed plasma concentration 
(Cmax), and time to reach Cmax (Tmax); elimination half-life (t1/2), apparent clearance 
(CL/F), and apparent volume of distribution during terminal phase (Vz/F) 
 
Efficacy assessment by investigator based on the RECIST, version 1.1: 
o 
ORR is defined as the proportion of patients who had confirmed CR or PR  
o 
DOR is defined as the time from the first determination of a confirmed 
overall response until the first documentation of progression or death, 
whichever comes first 
o 
DCR is defined as a BOR of CR, PR and stable disease (SD) 
o 
CBR is defined as a BOR of CR, PR and SD lasting ≥ 24 weeks 
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o 
PFS is defined as the time from first dose of study medication to the first 
documented disease progression or death due to any cause, whichever occurs 
first 
Exploratory Endpoints: 
 
 
 
 
Phase 2 
Primary Endpoint: 
 
ORR as defined above in advanced HGOC patients by IRR 
Secondary Endpoints:  
 
DOR is defined as the time from the first determination of a confirmed overall 
response until the first documentation of progression or death, whichever comes 
first 
 
PFS is defined as the time from first dose of study medication to the first 
documented disease progression or death due to any cause, whichever occurs first 
 
OS is defined as time from the first dose of study treatment to the date of death 
due to any cause 
 
ORR as defined above in advanced HGOC patients by investigator review 
 
CA-125 response rate per GCIG criteria for CA-125 changes 
 
Incidence of AEs, overall and by severity, and incidence of SAEs; laboratory 
abnormalities; changes in laboratory assessments, ECGs, and assessment of 
physical examinations such as vital signs 
 
PK parameters of pamiparib and possibly its major metabolite(s) at selected time 
points: AUClast, Cmax, and Tmax 
 
For patients participating in intensive PK sample collection: AUC0-12h, Cmax, Cmin, 
and Tmax 
 
DCR and CBR as defined above 
Exploratory Endpoints: 
 
 
Statistical 
methods: 
 
Populations 
The Safety Population (SP) includes all patients who received at least one dose of 
pamiparib. 
The Efficacy Evaluable Population (EEP) includes all patients in the SP who had 
measurable disease at baseline per RECIST, version 1.1 and had at least one post baseline 
tumor assessment unless discontinued treatment due to clinical progression or death prior 
to tumor assessment. 
The DLT Population includes all patients who received at least 75% of pamiparib or who 
experienced a DLT event during the DLT observation period (Cycle 1). 
The PK Population includes all patients for whom valid pamiparib PK parameters can be 
estimated. 
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The Evaluable for CA-125 Response Population is defined as the subset of subjects in the 
SP with baseline CA-125 ≥ 2 x ULN (Rustin et al 2004). This will be the primary analysis 
set for the analysis of CA-125 response rate. 
 
Statistical and Analytical Methods 
Evaluation of safety and tolerability of pamiparib in Chinese patients is the primary 
objective of the Phase 1 portion of the trial. Descriptive statistics will be used to summarize 
the data according to the dose level tested. In Phase 2 portion, efficacy and safety of 
pamiparib will be evaluated in HGOC patients. The analysis methods described in this 
section are directed to Phase 2 portion of the study. However, they will be applied to Phase 
1 portion of data analysis whenever appropriate.  
Efficacy Analyses 
Primary Efficacy Analyses (Phase 2) 
Hypothesis testing of ORR will only be performed in the patients with platinum-sensitive 
ovarian cancer (PSOC). The primary analysis will be carried out using IRR data in EEP. 
Efficacy endpoints based on investigator assessed tumor response will be presented as the 
sensitivity analysis. 
ORR of pamiparib per IRR is assumed as 52% in patients with recurrent PSOC. The 
historical rate in a similar population is estimated as 30%. The null and alternative 
hypotheses are set as follows: 
 H0:  ORR=30% 
 Ha:  ORR > 30% 
A binomial exact test will be performed for hypothesis testing in the recurrent PSOC EEP. 
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 SP. 
ORR in evaluable recurrent platinum-resistant ovarian cancer (PROC), as well as in all 
evaluable recurrent HGOC, will be summarized descriptively. 
Secondary Efficacy Analyses (Phase 2)  
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) 
(FDA 2007). 
Other time to event variables (PFS and OS) will be similarly analyzed in the SP 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 
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corresponding 95% CI constructed using Greenwood’s formula. The OS time point 
estimates will be calculated similarly.  
BOR is defined as the best response recorded from the start of pamiparib until data cut off 
or start of new anti-neoplastic treatment. The proportion of each response category (CR, 
PR, SD, progressive disease [PD] and not evaluated [NE]) will be presented in the EEP and 
SP. 
Data will be summarized by platinum status and overall. Data assessed by IRR and 
investigator will be summarized. 
DCR and CBR and their 95% CIs will be summarized in the EEP and SP.  
Exploratory Efficacy Analyses (Phase 2)  
 
Safety 
Pamiparib exposure will be summarized, including duration, dosage, and dose intensity.  
Verbatim description of AEs will be mapped to the Medical Dictionary for Regulatory 
Activities (MedDRA) terms and graded according to the National Cancer Institute 
Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.03. A treatment 
emergent adverse event (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, or was 
worsening in severity from baseline (pre-treatment). 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. 
DLT events will be summarized by dose level in Phase 1 dose escalation portion. 
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.  
Sample Size 
Approximately 14-18 evaluable patients will be enrolled in Phase 1 portion of the trial. In 
Phase 2 portion of the trial, approximately 100 evaluable patients will be enrolled.  
In recurrent HGOC patients, it is assumed that ORR is 52% in previously treated 
platinum-sensitive patients with BRCA mutation. There is an 98% power of demonstrating 
a statistical difference versus a historical response rate of 30% using a binomial exact test 
at an alpha of 0.025 in 80 evaluable patients. The 2-sided exact 95% CI is (40.5%, 63.3%) 
when the observed ORR is 52%. Approximately 20 patients will be enrolled to the 
platinum-resistant HGOC patients. 
Hence, approximately 118 patients will be enrolled to obtain 14-18 evaluable patients in 
Phase 1 and 100 evaluable patients in Phase 2. 
 
 
 
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TABLE OF CONTENTS 
FINAL PROTOCOL APPROVAL SHEET .......................................................................... 2 
PROTOCOL AMENDMENT, VERSION 5.0, RATIONALE ............................................ 3 
SYNOPSIS ................................................................................................................................ 6 
LIST OF TABLES ................................................................................................................. 22 
LIST OF FIGURES ............................................................................................................... 22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .................................... 23 
1 
INTRODUCTION ........................................................................................................... 26 
1.1 Background and Pharmacology ............................................................................... 26 
1.2 PARP Inhibitors in the Treatment of Breast Cancer and Ovarian Cancer ............... 26 
1.3 Nonclinical Data on Pamiparib ................................................................................ 29 
1.3.1 Nonclinical Safety Data for Pamiparib ........................................................ 29 
1.3.2 Nonclinical Anti-tumor Activity Data for Pamiparib .................................. 30 
1.4 Clinical Data for Pamiparib ..................................................................................... 31 
1.4.1 Pharmacokinetics of BGB-290-AU-002 and BGB-290-102 Phase 1 
studies ...................................................................................................... 31 
1.4.2 
 ........................................................................ 32 
1.4.3 Clinical Safety and Preliminary Efficacy for BGB-290-AU-002 and BGB-
290-102 Phase 1 study ............................................................................. 33 
1.5 Study Rationale ........................................................................................................ 34 
1.6 Benefit-Risk Assessment ......................................................................................... 36 
1.7 Study Conduct .......................................................................................................... 37 
2 
STUDY OBJECTIVES .................................................................................................... 38 
2.1 Phase 1 Portion ........................................................................................................ 38 
2.1.1 Primary Objectives....................................................................................... 38 
2.1.2 Secondary Objectives................................................................................... 38 
2.1.3 Exploratory Objectives ................................................................................ 38 
2.2 Phase 2 Portion ........................................................................................................ 38 
2.2.1 Primary Objectives....................................................................................... 38 
2.2.2 Secondary Objectives................................................................................... 38 
2.2.3 Exploratory Objectives ................................................................................ 38 
3 
STUDY ENDPOINTS ..................................................................................................... 39 
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3.1 Phase 1 Portion ........................................................................................................ 39 
3.1.1 Primary Endpoint ......................................................................................... 39 
3.1.2 Secondary Endpoints ................................................................................... 39 
3.1.3 Exploratory Endpoint ................................................................................... 39 
3.2 Phase 2 Portion ........................................................................................................ 39 
3.2.1 Primary Endpoints ....................................................................................... 39 
3.2.2 Secondary Endpoints ................................................................................... 39 
3.2.3 Exploratory Endpoints ................................................................................. 40 
4 
INVESTIGATIONAL PLAN .......................................................................................... 41 
4.1 Overall Study Design ............................................................................................... 41 
4.1.1 Phase 1 Portion ............................................................................................ 41 
4.1.2 Phase 2 Portion ............................................................................................ 50 
4.1.3 Follow-up for Toxicities .............................................................................. 56 
4.1.4 End of Study ................................................................................................ 56 
4.2 Selection of Study Population .................................................................................. 57 
4.2.1 Inclusion Criteria ......................................................................................... 57 
4.2.2 Exclusion Criteria ........................................................................................ 58 
4.2.3 Other Eligibility Criteria Considerations ..................................................... 60 
4.2.4 Patient Discontinuation and Withdrawal ..................................................... 60 
5 
STUDY TREATMENTS ................................................................................................. 63 
5.1 Description of Pamiparib ......................................................................................... 63 
5.2 Dosage and Administration...................................................................................... 63 
5.2.1 Treatment interruption and treatment discontinuation ................................. 63 
5.3 Treatment Assignment ............................................................................................. 68 
5.4 Packaging and Labelling .......................................................................................... 68 
5.5 Handling and Storage ............................................................................................... 68 
5.6 Product Accountability ............................................................................................ 68 
5.7 Assessment of Treatment Compliance ..................................................................... 69 
5.8 Treatment of Pamiparib Overdose ........................................................................... 69 
5.9 Occupational Safety ................................................................................................. 69 
6 
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ......................... 70 
6.1 Permitted Medications ............................................................................................. 70 
6.2 Prohibited Medications ............................................................................................ 70 
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6.2.1 Medications to be used with Caution ........................................................... 70 
7 
STUDY ASSESSMENTS ............................................................................................... 72 
7.1 Pre-screening............................................................................................................ 72 
7.2 Screening.................................................................................................................. 72 
7.2.1 Demographic and Baseline Assessments ..................................................... 72 
7.3 Assessments During Treatment ............................................................................... 73 
7.3.1 Laboratory Evaluation ................................................................................. 73 
7.3.2 Physical Examination and Vital Signs ......................................................... 73 
7.3.3 Electrocardiogram ........................................................................................ 74 
7.3.4 Computed Tomography ............................................................................... 75 
7.3.5 Tumor Antigens ........................................................................................... 76 
7.4 Safety Assessment ................................................................................................... 76 
7.4.1 Safety Evaluation ......................................................................................... 76 
7.5 Efficacy Assessment ................................................................................................ 77 
7.5.1 Phase 1 Portion ............................................................................................ 77 
7.5.2 Phase 2 Portion ............................................................................................ 78 
7.6 Follow-up Assessments ........................................................................................... 78 
7.7 Pharmacokinetic Assessment ................................................................................... 79 
7.7.1 Blood Samples collection and handling ....................................................... 79 
7.8 
 ........................................................................................... 81 
7.9 Appropriateness of Measurements ........................................................................... 81 
8 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................... 82 
8.1 Monitoring ............................................................................................................... 82 
8.2 Data Management/Coding ....................................................................................... 83 
8.3 Quality Assurance Audit .......................................................................................... 84 
9 
SAFETY MONITORING AND REPORTING............................................................... 85 
9.1 Adverse Events ........................................................................................................ 85 
9.1.1 Definition and Reporting of an Adverse Event ............................................ 85 
9.1.2 Assessment of Severity ................................................................................ 85 
9.1.3 Assessment of Causality .............................................................................. 86 
9.1.4 Follow-Up of Adverse Events ..................................................................... 87 
9.1.5 Laboratory Test Abnormalities .................................................................... 87 
9.2 Definition of a Serious Adverse Event .................................................................... 88 
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9.3 Suspected Unexpected Serious Adverse Reaction ................................................... 88 
9.4 Timing, Frequency, and Method of Capturing Adverse Events and Serious Adverse 
Events ....................................................................................................................... 89 
9.4.1 Adverse Event Reporting Period ................................................................. 89 
9.4.2 Eliciting Adverse Events.............................................................................. 89 
9.5 Study Specific AEs/SAEs Reporting Instructions ................................................... 89 
9.5.1 Disease Progression ..................................................................................... 89 
9.5.2 Death ............................................................................................................ 89 
9.6 Prompt Reporting of Serious Adverse Events ......................................................... 90 
9.6.1 Timeframes for Submitting Serious Adverse Events................................... 90 
9.6.2 Completion and Transmission of the Serious Adverse Event Report .......... 90 
9.6.3 Regulatory Reporting Requirements for Serious Adverse Events ............... 90 
9.7 Pregnancy Reporting ................................................................................................ 91 
9.8 Expedited Reporting to Health Authorities, Ethics Committees and Investigators . 91 
10 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .................................. 92 
10.1 Sample Size Considerations ..................................................................................... 92 
10.2 General Considerations for Data Analysis ............................................................... 92 
10.2.1 Analysis Populations .................................................................................... 92 
10.2.2 Interim Analysis ........................................................................................... 93 
10.2.3 Patient Disposition ....................................................................................... 93 
10.2.4 Demographics and Other Baseline Characteristics ...................................... 93 
10.2.5 Prior and Concomitant Therapy ................................................................... 93 
10.3 Efficacy Analyses .................................................................................................... 94 
10.3.1 Primary Efficacy Analyses .......................................................................... 94 
10.3.2 Secondary Efficacy Analyses ...................................................................... 94 
10.3.3 Exploratory Efficacy Analyses .................................................................... 95 
10.4 Safety Analyses ........................................................................................................ 95 
10.4.1 Maximum Tolerated Dose ........................................................................... 95 
10.4.2 Adverse Event .............................................................................................. 95 
10.4.3 Laboratory Assessments .............................................................................. 96 
10.4.4 Extent of Exposure ....................................................................................... 96 
10.5 Pharmacokinetic Analyses ....................................................................................... 96 
10.6
 ................................................................................................. 97 
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11 ETHICS............................................................................................................................ 98 
11.1 Regulatory Authority Approval ............................................................................... 98 
11.2 Ethical Conduct of the Study and Ethics Approval ................................................. 98 
11.3 Informed Consent..................................................................................................... 98 
11.4 Investigator Reporting Requirements ...................................................................... 98 
12 STUDY ADMINISTRATION....................................................................................... 100 
12.1 Study and Study Center Closure ............................................................................ 100 
12.2 Records Retention .................................................................................................. 100 
12.3 Provision of Study Results and Information to Investigators ................................ 101 
12.4 Information Disclosure and Inventions .................................................................. 101 
12.4.1 Publication Policy ...................................................................................... 102 
13 REFERENCES .............................................................................................................. 103 
14 APPENDICES ............................................................................................................... 106 
APPENDIX 1: SIGNATURE OF INVESTIGATOR............................................................ 106 
APPENDIX 2: CLINICAL LABORATORY ASSESSMENTS ........................................... 107 
APPENDIX 3: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS .......................................................................................... 108 
APPENDIX 4: BLOOD REQUIREMENTS ......................................................................... 109 
APPENDIX 5: THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES .............................................................................................. 111 
APPENDIX 6: CHRONIC KIDNEY DISEASE EPIDEMIOLOGY COLLABORATION 
(CKD-EPI) EQUATION ............................................................................................... 121 
APPENDIX 7: EVALUATION OF RESPONSE ACCORDING TO CA-125..................... 122 
APPENDIX 8: PROHIBITED MEDICATIONS .................................................................. 126 
APPENDIX 9: MEDICATIONS TO BE USED WITH CAUTION ..................................... 127 
APPENDIX 10: MEDICATIONS TO BE USED WITH CAUTION ................................... 128 
APPENDIX 11: FEMALES OF CHILDBEARING POTENTIAL AND 
CONTRACEPTION ...................................................................................................... 129 
APPENDIX 12: NEW YORK HEART ASSOCIATION CLASSIFICATION .................... 130 
 
 
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LIST OF TABLES 
Table 1.  
Summary of Patient Response Rate with Olaparib .......................................... 28 
Table 2: 
PARP Enzyme Inhibition and DNA Trapping Activity of PARP 
Inhibitors .......................................................................................................... 30 
Table 3.  
Suggested Dose Escalation Scheme................................................................. 42 
Table 4.  
Dose-Limiting Toxicity Assessment Criteria .................................................. 43 
Table 5.  
Study Visit Schedule in Phase 1 Portion.......................................................... 45 
Table 6.  
Pharmacokinetic Sampling in Phase 1 Portion ................................................ 49 
Table 7.  
Study Visit Schedule in Phase 2 Portion.......................................................... 51 
Table 8.  
Pharmacokinetic Sampling in Phase 2 Portion ................................................ 55 
Table 9. 
Criteria for interruption and re-initiation of Pamiparib due to 
treatment associated adverse event .................................................................. 64 
Table 10. 
Time Frame for Reporting Serious Adverse Events to the Sponsor 
or Designee ...................................................................................................... 90 
Table 11. 
CA-125 response measurement ..................................................................... 123 
Table 12. 
Evaluation of best overall response in patients without initial 
measurable disease and who are evaluable by CA-125 ................................. 124 
Table 13. 
Best overall response in patients with measurable disease and who 
are also evaluable by CA-125 ........................................................................ 125 
 
 
LIST OF FIGURES 
Figure 1.  
Correlation of PAR Inhibition in Peripheral-blood Mononuclear 
Cells with Pamiparib Dose............................................................................... 33 
Figure 2. 
Schema of overall study design of Phase 1/2 study Pamiparib-102 ................ 41 
 
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List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
AE 
adverse event 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
AUC 
area under the plasma concentration-time curve 
AUC0-inf 
area under the plasma concentration time curve from zero 
extrapolated to infinity calculated using the linear up/log down 
trapezoidal method 
AUC0-12h 
area under the plasma concentration-time curve from zero to 
12 hours post-dose 
AUClast 
area under the plasma concentration-time curve from zero to 
the last measurable concentration 
BID 
twice daily 
BGB-290 
study drug code 
BOR 
best overall response 
BRCA 
breast cancer susceptibility gene 
BRCA1/2 
breast cancer susceptibility gene 1/ gene 2 
CA-125 
carcinoma antigen-125 
CBR 
clinical benefit rate 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CL/F 
apparent clearance 
Cmax 
maximum observed plasma concentration 
CR 
complete response 
CT 
computed tomography 
CYP 
cytochrome P450 
DCR 
disease control rate 
DDI 
drug-drug interaction  
DLT 
dose-limiting toxicity 
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 
EEP 
efficacy evaluable population 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
GCIG 
Gynecological Cancer Intergroup 
GCP 
Good Clinical Practice 
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Abbreviation 
Definition 
HGOC 
high grade ovarian cancer 
HIV 
Human immunodeficiency virus 
HR 
hazard ratio 
HRD 
homologous recombination defects 
IB 
Investigator’s Brochure 
IC50 
half inhibitory concentration 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRR 
independent radiology review 
MDS 
myelodysplastic syndrome  
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute Common Toxicity Criteria for 
Adverse Events 
NE 
not evaluated 
ORR 
objective response rate 
OS 
overall survival 
pamiparib 
BGB-290 
PAR 
poly(ADP-ribose) 
PARP 
poly(ADP-ribose) polymerase 
PBMCs 
peripheral blood mononuclear cells 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression free survival 
PK 
pharmacokinetic(s) 
PO 
Orally 
PROC 
platinum-resistant ovarian cancer 
PR 
partial response 
PT 
preferred term 
PSOC 
platinum-sensitive ovarian cancer 
QTc 
QT interval corrected for heart rate 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SD 
stable disease 
SMC 
Safety Monitoring Committee 
SOC 
system organ class 
SOP 
standard operating procedure 
SP 
safety population 
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Abbreviation 
Definition 
TEAE 
treatment emergent adverse event 
TNBC 
Triple negative breast cancer 
t1/2 
elimination half-life 
Tmax 
time of maximum observed plasma concentration 
ULN 
upper limit of normal 
Vz/F 
apparent volume of distribution during the terminal phase 
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1 INTRODUCTION 
1.1 
Background and Pharmacology 
Poly (ADP-ribose) polymerase (PARP) proteins are involved in DNA replication, 
transcriptional regulation, and DNA damage repair. Inhibition of PARP converts common 
single-strand DNA breaks into double-strand breaks during DNA replication. 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. 
Small molecule inhibitors of PARP1/2 represent a class of anticancer agents that exert their 
cytotoxic effect by modulating the PARylation activity of PARP1/2 and trap PARP proteins 
on damaged DNA. Since the discovery of synthetic lethality of PARP inhibitors in breast 
cancer susceptibility gene (BRCA)-deficient cells and, more broadly, cells with homologous 
recombination defects (HRD), accumulation of unrepaired single-strand DNA breaks 
resulting from catalytic PARP inhibition has been considered central to the mechanism of 
action of PARP inhibitors. More recently, it has been demonstrated that PARP inhibitors also 
trap PARP1- and PARP2-DNA complexes at DNA damage sites and that PARP-trapping can 
be more cytotoxic than unrepaired single-strand DNA breaks (Pommier et al 2016; O'Connor 
2015; Lord and Ashworth 2017). In the clinic, PARP inhibitors, including olaparib, 
rucaparib, niraparib, and talazolparib, have demonstrated sustained anti-tumor responses as a 
single agent in patients with BRCA1- or BRCA2-mutant tumors, while still achieving a 
favorable safety profile. Olaparib (FDA Summary Review for Regulatory Action: Olaparib) 
and rucaparib (NDA 209115 Rubraca) are two PARP inhibitors that are approved as a single 
agent for patients with advanced ovarian cancer who have a germline mutation in the BRCA 
gene. 
Pamiparib (also known as BGB-290) is a potent and selective inhibitor of PARP1 and PARP2 
(BGB-290 Investigator’s Brochure). It showed potent PARP-trapping activity and 
anti-proliferative activity against a number of cell lines harboring BRCA gene mutations or 
HRDs. In combination studies, pamiparib demonstrated strong synergism with temozolomide 
in a number of small cell lung cancer and glioblastoma cell lines. 
1.2 
PARP Inhibitors in the Treatment of Breast Cancer and Ovarian Cancer 
Breast Cancer 
Breast cancer is a clinically and biologically heterogenous disease characterized by diverse 
genomic signatures and protein expression patterns. Up to 10% of breast cancers can be 
linked to germline mutations in BRCA1 and/or BRCA2 genes (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 reconstitution or homology 
directed repair. (Yoshida and Miki 2004; O’Sullivan 2014) Many investigations have shown 
that HRD is critical in response to platinum and PARP inhibitor therapy.  
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Triple negative breast cancer (TNBC) is considered an aggressive disease, characterized by 
absence of the estrogen, progesterone and human epidermal growth factor 2 receptors, with 
frequent association with BRCA1 mutations.  
Clinical studies support the use of platinum compounds in BRCA1/2 mutated breast cancer in 
the neo-adjuvant and advanced disease treatment setting including metastatic 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 overall tumor response rates 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 objective response 
rate (ORR) and PFS in the subgroup of patients with germline BRCA1/2 mutated breast 
cancer. When added to either docetaxel (Fan et al 2013) or gemcitabine, (Hu et al 2015) 
Hu-13 clinical outcomes were superior in the combination treatment arms containing cisplatin 
over the comparator monotherapy arms.  
It has been hypothesized that inhibition of PARP, in combination with DNA-damaging 
chemotherapeutics, would be highly effective in tumors lacking BRCA function. (Tutt et al 
2010; Bryant et al 2005; Farmer et al 2005; O'Shaughnessy et al 2009)  
PARP inhibitors have been tested clinically in breast cancer patients with BRCA1/2. In a 
single-arm, open-label study, olaparib (400 mg or 100 mg orally twice daily [PO BID]) was 
administered to women with BRCA1- and/or BRCA2-mutant, advanced breast cancer (of 
which >50 percent 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 adverse events (AEs) were fatigue, nausea, and vomiting.  
Other Phase 3 studies investigating single-agent PARP inhibitors in patients with germline 
BRCA1/2 mutated breast cancer are ongoing (olaparib, niraparib, and talazoparib). 
Ovarian Cancer 
Currently two PARP inhibitors, olaparib and rucaparib, have been approved by the Food and 
Drug Administration (FDA) for women with advanced ovarian cancer with BRCA1/2 
mutation. In addition, olaparib and niraparib were approved by the FDA and European 
Medicines Agency for the maintenance treatment of patients with recurrent epithelial ovarian, 
fallopian tube, or primary peritoneal cancer, who achieved a CR or PR with platinum-based 
chemotherapy. 
Data from clinical studies support the use of PARP inhibitors as monotherapy in patients with 
BRCA mutation and treated with multiple lines of chemotherapy. The effectiveness of 
rucaparib was demonstrated in 106 patients with deleterious BRCA mutation associated 
advanced ovarian cancer who had been treated with two or more chemotherapies on two 
single-arm open-label trials. All 106 patients received rucaparib 600 mg PO BID as 
monotherapy until disease progression or unacceptable toxicity. Objective response rate 
(ORR) as assessed by the investigator was 54% (95% CI: 44, 64) with 9% complete 
responses (CRs) and 45% partial responses (PR). Median duration of response (DOR) was 
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9.2 months (95% CI 6.6, 11.6). Investigator-assessed ORR was 66% (52/79; 95% CI [54, 76]) 
in platinum-sensitive patients, 25% (5/20; 95% CI [9, 49]) in platinum-resistant patients, and 
0% (0/7; 95% CI [0, 41]) in platinum-refractory patients (NDA 209115 Rubraca).  
Olaparib (Study 42), was a single-arm, open-label, multi-center study assessing the response 
rate of olaparib in patients with advanced cancers who have a deleterious germline BRCA 
mutation (FDA Summary Review for Regulatory Action: Olaparib). Of the 193 patients with 
ovarian cancer on this trial, 137 patients with measurable, germline BRCA 
mutation-associated ovarian cancer treated with three or more prior lines of chemotherapy 
who were enrolled to this trial were assessed. The overall response and DOR in patients with 
germline BRCA mutation advanced ovarian cancer who received 3 or more prior lines of 
chemotherapy in Study 42 are summarized in below (Table 1).  
Table 1.  
Summary of Patient Response Rate with Olaparib 
Response 
N=137 
Objective Response Rate (95% CI) 
34% (26, 42) 
Complete Response 
2% 
Partial Response 
32% 
Median Duration of Response in months (95% CI) 
7.9 (5.6, 9.6) 
Adapted from: https://www.accessdata fda.gov/drugsatfda docs/nda/2014/206162Orig1s000SumR.pdf 
In a randomized study with approximately 300 women with platinum-sensitive high-grade 
recurrent epithelial ovarian cancer (EOC), patients were randomly assigned to maintenance 
treatment with the PARP inhibitor, olaparib, or placebo (Ledermann et al 2014). Results 
from this study showed a significant improvement in progression free survival (PFS) in 
patients treated with olaparib compared with placebo (8 versus 5 months, hazard ratio [HR] 
for progression or death 0.35, 95% CI 0.25-0.49), although interim analysis found no overall 
survival (OS) benefit (30 months in both, HR 0.94, 95% confidence interval [CI] 0.63-1.39). 
A subanalysis of data from this study showed a significant benefit in PFS with olaparib 
compared with placebo among patients with a known BRCA mutation (median, 11 versus 
4 months, HR 0.18, 95% CI 0.10-0.31), with a trend towards improved OS (HR 0.73, 95% CI 
0.45-1.17), which became more pronounced at a longer follow-up (>5 years) (Ledermann et 
al 2012; Ledermann, et al 2016). In a recent double-blind Phase 3 study (NOVA), 553 
patients with platinum-sensitive, recurrent ovarian cancer were randomized 2:1 to receive a 
PARP inhibitor, niraparib or placebo (Mirza et al 2016). Patients were stratified according to 
presence or absence of a germline BRCA mutation. The non-germline BRCA cohort was 
further classified by HRD status, and patients with somatic BRCA mutations were also 
included. Patients treated with niraparib had an increased PFS in all cohorts compared with 
placebo. In the germline BRCA group, PFS was 21.0 versus 5.5 months (HR 0.27, 95% CI 
0.17-0.41); in the overall non-germline BRCA cohort, PFS was 9.3 versus 3.9 months (HR 
0.45, 95% CI 0.34-0.61); and in the HRD-positive subgroup of the non-germline BRCA 
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cohort, PFS was 12.9 versus 3.8 months (HR 0.38, 95% CI 0.24-0.59). The most common 
Grade 3 or 4 toxicities associated with niraparib were thrombocytopenia (34%), anemia 
(25%), and neutropenia (20%). Myelodysplastic syndrome (MDS) occurred in 5 of 367 
patients (1.4%) who received niraparib. 
Another PARP inhibitor, veliparib, was evaluated in a Phase 2 study in 50 women with a 
known BRCA mutation. Veliparib treatment resulted in a 26% ORR and the median PFS and 
OS were 8 and 20 months, respectively (Coleman et al 2015).  
1.3 
Nonclinical Data on 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 harboring BRCA gene mutations or HRD, as well as in vivo models. 
1.3.1 
Nonclinical Safety Data for Pamiparib 
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-a-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. The maximum 
tolerated dose (MTD) was considered to be 6 mg/kg in rats and 3 mg/kg in dogs for both 
28-day and 91-day toxicity studies.  
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. 
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There was no apparent inhibition of pamiparib on human ether-a-go-go related gene channel 
as the half inhibitory concentration (IC50) was 12.4 μM; for comparison, the IC50 of the 
positive control amitriptyline was 1.9 μM. No effects on blood pressure, heart rate, or 
electrocardiograms (ECGs) were noted in telemetry-instrumented conscious dogs. No effects 
on central 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 (BGB-290 
Investigator’s Brochure).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
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Please refer to the BGB-290 Investigator’s Brochure for additional information. 
1.4 
Clinical Data for Pamiparib 
Pamiparib is currently being studied in two Phase 1a studies: BGB-290-AU-002 in Australia, 
n=56 (as of 27 January 2017) and BGB-290-102 in China, n=15 (as of 25 September 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. Preliminary results for BGB-290-102 Phase 1 study in China are also summarized 
below. 
1.4.1 
Pharmacokinetics of BGB-290-AU-002 and BGB-290-102 Phase 1 studies 
Pharmacokinetics for BGB-290-AU-002 study 
In the first-in-human (FIH) Phase 1 study, interim PK data of pamiparib showed that 
pamiparib is rapidly absorbed and eliminated after oral administration. The maximum 
observed serum concentration (Cmax) and the drug exposure (the area under the plasma 
concentration time curve [AUC]) increased in a nearly dose-proportional manner from 
2.5 mg twice daily (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. 
Further, in 6 patients that received 60 mg BID of pamiparib, the AUClast at high-fat fed status 
is 85% of it at fast status; the Cmax at high-fat fed status is 63% of it at fast status, while the 
Tmax was prolonged. With the inter- patient variability of 54%, coefficient of variation (CV) 
observed at 45 patients in Phase 1a, the food effect results suggest that AUC of pamiparib 
was not altered by food. Based on the overall consistent AUC with high fat meal, pamiparib 
may be administered with or without food. 
Pharmacokinetics for BGB-290-102 Phase 1 study 
In this Phase 1 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 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 
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(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) and approximately 50% between-subject variability in PK, 
these differences represent a very preliminary result and need to be interpreted with caution. 
Importantly, as described in Section 1.4.3, there were no dose limiting toxicities in this study 
at 60 mg BID  
 
 
 
 
 
 
 
 
 
 
1.4.2 
 
 
 
 
 
 
 
 
 
 
 
  
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Figure 1.  
Correlation of PAR Inhibition in Peripheral-blood Mononuclear Cells 
with Pamiparib Dose  
Abbreviations: BID, twice daily; C1D1, Cycle 1 Day 1; C1D17, Cycle 1 Day 17; PBMC, peripheral blood mononuclear cell; 
PD, pharmacodynamics 
1.4.3 
Clinical Safety and Preliminary Efficacy for BGB-290-AU-002 and BGB-290-
102 Phase 1 study 
Clinical Safety and Preliminary Efficacy for BGB-290-AU-002 study 
BGB-290-AU-002 is a FIH study evaluating pamiparib to characterize the safety, the MTD, 
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 orally 
(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 adverse events (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 adverse events (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 MTD 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. 
Clinical Safety and Preliminary Efficacy for BGB-290-102 Phase 1 study 
The Phase 1 portion of study BGB-290-102 evaluated the safety, tolerability, PK, and 
preliminary efficacy of pamiparib in Chinese patients with advanced high-grade, 
non-mucinous, epithelial ovarian cancer, 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). Treatment-related 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 8 HGOC patients (all platinum-resistant/refractory) 
showed 2 patients with partial response (on treatment: n=2; BRCA1/2 mutation: n=1) and 4 
with stable disease (on treatment: n=4; BRCA1/2 mutation: n=2). Median duration of 
treatment for 9 HGOC patients was 133 days (range: 8–260). Available preliminary efficacy 
data for 5 TNBC patients showed progressive disease (PD) for all 5 (BRCA1/2 mutation: 
n=1).  
1.5 
Study Rationale 
The study will be conducted in compliance with the protocol, good clinical practice (GCP), 
The Declaration of Helsinki and the applicable regulatory requirement(s). 
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This is a two-phase study. Phase 1 (dose escalation) of this study will evaluate the safety and 
tolerability, as well as determine the recommended Phase 2 Dose (RP2D) of pamiparib. The 
PK profile, and the preliminary anti-tumor activity of the pamiparib will also be studied. 
Phase 2 of this study will further evaluate the anti-tumor activity of the pamiparib, its safety 
and PK profile
 
 
The study population used for Phase 2 consists of patients with advanced high grade, 
non-mucinous, epithelial ovarian cancer of either known deleterious or suspected deleterious 
germline BRCA1/2 mutations susceptible to treatment with PARP inhibitor. 
Pamiparib is a potent and selective inhibitor of PARP1 and PARP2. It showed potent 
PARP-trapping activity and anti-proliferative activity against a number of cell lines harboring 
BRCA gene mutations or HRD. Mutations of BRCA1 and BRCA2 predispose cells to 
increased risk of malignancies, particularly breast and ovarian cancer.  
The reported prevalence of BRCA1/2 mutations in patients with ovarian cancer varies in 
different studies, ranging from 10% to 20%. To date, there have been two major 
epidemiological researches about BRCA1/2 mutations in China. One study included 
916 patients with unselected consecutive EOC from Eastern China, with an overall mutation 
incidence of 16.7%, which is consistent with pervious global data (Shi et al 2017). The other 
study included 826 patients from 3 top cancer hospitals and 2 major tertiary hospitals in 
China; the prevalence rate or gBRCAm was determined to be 28.5% (Wu et al 2017). 
Rationale for Dose Selection in Phase 1 
Pamiparib has demonstrated a favorable toxicology and safety pharmacology profile in 
clinical and non-clinical experiments. 
The starting dose for pamiparib will be 20 mg BID in this study, which is 1/3 of RP2D 
(60 mg BID) and 1/4 of MTD (80 mg BID) determined from the on-going FIH Phase 1 study 
of pamiparib in Australia. 
Three dose levels of 20, 40 and 60 mg BID are planned for this dose escalation portion 
(Phase 1). An intermediate, not pre-defined, and not previously-evaluated dose or a less 
frequent dosing schedule could be evaluated in the dose escalation portion if necessary. 
Rationale for Phase 2 
Pamiparib is a particularly promising PARP inhibitor to study in solid tumors as it has a 
unique combination of attributes. It 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 RP2D (10 mg versus 60 mg BID). PK 
modeling predicts that the RP2D of pamiparib can achieve brain concentrations required for 
anti-tumor activity.  
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Rationale for Selection of pamiparib Dose in Phase 2 
Based upon the overall safety, efficacy, and PK profile of pamiparib, the dose of pamiparib 
60 mg PO BID was confirmed as RP2D using available clinical data from study 
BGB-290-AU-002 and the Phase 1 portion of this study. 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 BGB-290 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 
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: 
 
AE profile observed from 15 female Chinese patients in BGB-290-102 study was 
generally consistent with that from 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 
 
Average steady-state pamiparib plasma exposure (Cmax, AUC) at 60 mg BID in 
Chinese patients was approximately 35% higher than for Australian patients 
(AU-002). In summary, pamiparib is an excellent candidate to determine the effects of 
PARP inhibition in advanced cancers. 
1.6 
Benefit-Risk Assessment 
Pamiparib is the investigational product with safety data gathered from non-clinical and 
Phase 1 clinical studies. Preliminary safety results of pamiparib from the ongoing Phase 1a 
clinical trial were summarized above. Patients enrolled in this clinical study using pamiparib 
must be closely monitored by means of reporting AEs, recording vital signs and ECGs, and 
conducting clinical laboratory safety tests on blood and urine, with particular attention paid to 
the safety profile of what is currently known. Pamiparib and other PARP inhibitors (eg, 
olaparib) in clinical trials have shown some side effects including fatigue, somnolence, 
nausea, loss of appetite, anemia and thrombocytopenia (NDA 209115 Rubraca; FDA 
Summary Review for Regulatory Action: Olaparib; Weil and Chen 2011). MDS and AML 
have been reported in a small number (<1%) of patients treated with PARP inhibitors, 
especially in patients harboring a germline BRCA mutation (FDA Summary Review for 
Regulatory Action: Olaparib). Patients who develop MDS and AML while on PARP 
inhibition therapy typically had a history of extensive previous chemotherapy and some had a 
history of previous cancer or bone marrow abnormalities. Patients in this study will be 
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monitored monthly for hematological toxicities and reports of MDS and AML will be 
reported as SAEs.  
In Phase 1 (dose escalation), high grade non-mucinous ovarian cancer (including fallopian 
cancer, or primary peritoneal cancer), or TNBC, will be recruited. Even though BRCA1 and 
BRCA2 mutations are not required, enrichment of this patient population is encouraged. In 
Phase 2, HGOC (including fallopian cancer, or primary peritoneal cancer) patients with 
germline BRCA1/2 mutation will be recruited. The PARP inhibitors, including pamiparib in 
clinical development, have shown clinical benefit in these patient populations.  
1.7 
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 GCP 
standards.  
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2 STUDY OBJECTIVES 
2.1 
Phase 1 Portion 
2.1.1 
Primary Objectives 
 To evaluate the safety and tolerability of pamiparib for advanced cancer in Chinese 
patients 
 To determine the recommended Phase 2 dose of pamiparib 
2.1.2 
Secondary Objectives 
 To characterize the pharmacokinetics of pamiparib in Chinese patients  
 To evaluate the clinical anti-tumor activity of pamiparib in Chinese patients with TNBC 
or high-grade epithelial, non-mucinous ovarian cancer (including fallopian cancer, or 
primary peritoneal cancer) 
 To evaluate the relationship between pamiparib PK and clinical endpoints 
2.1.3 
Exploratory Objectives 
 
 
2.2 
Phase 2 Portion 
2.2.1 
Primary Objectives 
 To evaluate the efficacy of pamiparib as measured by objective response rate according to 
Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (RECIST V 1.1), by 
independent radiology review (IRR) in patients with advanced platinum-sensitive or 
platinum-resistant high grade, non-mucinous, epithelial ovarian cancer (including 
fallopian or primary peritoneal cancer), harboring germline BRCA1/2 mutations 
2.2.2 
Secondary Objectives 
 To evaluate the efficacy of pamiparib as measured by progression free survival, duration 
of response by both IRR and investigator review, and overall survival by investigator 
review 
 To evaluate the efficacy of pamiparib as measured by the ORR by investigator review 
 To evaluate the safety and tolerability of pamiparib 
 To evaluate the efficacy of pamiparib as measured by disease control rate (DCR), best 
overall response (BOR) and clinical benefit rate (CBR) by both IRR and investigator 
review 
 To evaluate the carcinoma antigen-125 (CA-125) response rate per Gynecological Cancer 
Intergroup (GCIG) for CA-125 changes 
 To further characterize the PK of pamiparib 
2.2.3 
Exploratory Objectives 
 
 
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3 STUDY ENDPOINTS 
3.1 
Phase 1 Portion 
3.1.1 
Primary Endpoint 
 Incidence of adverse events, overall and by severity, and incidence of SAEs according to 
National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.03 
(NCI-CTCAE); laboratory abnormalities; changes in laboratory assessments, ECGs, and 
assessment of physical examinations. 
3.1.2 
Secondary Endpoints 
 PK parameters of pamiparib and possibly its major metabolite(s) at selected time points: 
area under the plasma concentration-time curve from 0 to the last measurable 
concentration (AUClast), maximum observed plasma concentration (Cmax), and time to 
reach Cmax (Tmax); elimination half-life (t1/2), apparent clearance (CL/F), and apparent 
volume of distribution during terminal phase (Vz/F) and other applicable parameters. 
 Efficacy assessment by the investigator based on the RECIST, version 1.1: 
o ORR is defined as the proportion of patients who had confirmed CR or PR  
o DOR is defined as the time from the first determination of a confirmed overall 
response until the first documentation of progression or death, whichever comes 
first 
o DCR is defined as a BOR of CR, PR and stable disease (SD) 
o CBR is defined as a BOR of CR, PR and SD lasting ≥24 weeks 
o PFS is defined as the time from first dose of study medication to the first 
documented disease progression or death due to any cause, whichever occurs first 
3.1.3 
Exploratory Endpoint 
 
 
 
3.2 
Phase 2 Portion 
3.2.1 
Primary Endpoints 
 ORR as defined above in advanced HGOC patients by IRR 
3.2.2 
Secondary Endpoints 
 DOR and PFS as defined above 
 OS is defined as time from the first dose of study medication to the date of death due to 
any cause 
 ORR as defined above in advanced HGOC patients by investigator review  
 CA-125 response rate per GCIG criteria for CA-125 changes 
 Incidence of AEs, overall and by severity, and incidence of SAEs; laboratory 
abnormalities; changes in laboratory assessments, ECGs, and assessment of physical 
examinations such as vital signs 
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 PK parameters of pamiparib and possibly its major metabolite(s) at selected time points: 
AUClast, Cmax, and Tmax 
 For patients participating in intensive PK sample collection: AUC0-12h, Cmax, Cmin, and 
Tmax 
 DCR and CBR as defined above 
3.2.3 
Exploratory Endpoints 
 
 
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4 INVESTIGATIONAL PLAN 
4.1 
Overall Study Design 
This is a Phase 1/2, open-label, multi-center study of pamiparib administered PO BID to adult 
Chinese patients with advanced solid tumors which have progressed despite standard therapy 
or for which no standard therapy exists. 
The study will continue until the last patient has died, becomes lost to follow up, or 
withdraws from study, or until sponsor decides to terminate the study. 
Figure 2. 
Schema of overall study design of Phase 1/2 study Pamiparib-102 
Abbreviations: HGOC, high grade ovarian cancer; BID, twice daily 
4.1.1 
Phase 1 Portion 
The Phase 1 portion of this study is designed to evaluate the safety, tolerability and PK 
profile of pamiparib in Chinese advanced cancer patients and to determine RP2D of 
pamiparib for Chinese patients. In the FIH study of pamiparib in Australia, the RP2D and 
MTD were determined to be 60 mg BID and 80 mg BID, respectively. In this study, three 
dose levels, 20 mg, 40 mg, and 60 mg BID, will be evaluated. The purpose of this study is to 
determine the RP2D and MTD, if any, of pamiparib in Chinese cancer patients. Dose 
escalation will follow a modified 3+3 dose escalation design. 
Patients will be screened for eligibility up to 21 days prior to the first dose of pamiparib. The 
starting dose will be 40 mg/day (20 mg BID; see Section 1.5 for the justification of the 
starting dose level). The 23-day initial treatment cycle (Cycle 1) of each dose level will 
consist of a single administration of pamiparib (20 mg) on the morning of Day 1, followed by 
one day treatment-free period (Day 2) and a 21-day period of repeated drug administration 
(BID, once in the morning and once in the evening 12 hours ± 2 hour apart, Days 3 to 23). 
Safety evaluation of at least 3 patients completing one cycle of treatment at that dose level is 
required prior to determining the next dose level and dose regimen for the next cohort. 
If a patient wishes to continue study treatment upon completion of Cycle 1, the patient can 
continue study treatment in 21-day Cycle 2 (with no treatment-free or rest period) and 
subsequent cycles, at the discretion of the investigator. 
After the first patient in the first dose level receives the Cycle 1, Day 1 dose, subsequent 
patients in that cohort will not be dosed until the first patient has been observed for at least 
24 hours to exclude unexpected acute toxicity. The continuous safety evaluation will be 
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performed by the sponsor, the coordinating investigator, and investigators. A Safety 
Monitoring Committee (SMC) will be established to determine the dose levels to be 
administered and dose regimen during dose escalation, and their decision will depend on the 
data available from the previous dose levels. The suggested dose escalation scheme is 
presented in Table 3. 
Table 3.  
Suggested Dose Escalation Scheme 
Step 
Daily dose (mg)1 
1 
20 BID 
2 
40 BID 
3 
60 BID 
1. 
The actual dose levels and dose regimens administered in each step will depend on the data available from 
the previous step, as determined by the Safety Monitoring Committee. 
4.1.1.1 
Dose Escalation 
Safety evaluation of at least 3 patients completing one cycle of treatment at that dose level 
and dose regimen is required prior to determining the next dose level and dose regimen for 
the next cohort. 
The study will follow a modified 3+3 dose escalation scheme. At least 3 patients will be 
enrolled into each cohort, up to a maximum of 6 patients in total. The DLT assessment and 
dose escalation scheme will follow the same principles as stipulated for a standard 3+3 dose 
escalation design. For example, 3 additional patients will be enrolled if a DLT is observed in 
1 of 3 patients; an additional 2 patients will be enrolled if a DLT is observed in 1 of 4 
patients; and an additional 1 patient will be enrolled if a DLT is observed in 1 of 5 patients. 
No additional patients are required if a DLT is observed in 1 of 6 patients. In this case, it will 
move to the next cohort. 
If none of the patients in the cohort experience DLT by the end of Cycle 1, the dose to be 
administered in the next cohort will be increased by up to 100%, as determined by the SMC. 
If 1 out of 6 patients experience a DLT by the end of Cycle 1, the dose to be administered in 
the next cohort will be increased by up to 50%, as determined by the SMC. However, due to 
the capsule sizes available (10 mg and 40 mg), if a 50% dose increase is not possible, the 
SMC will select the most appropriate dose level that utilizes whole capsules. 
No additional patients will be treated at a given dose level if 2 or more of the patients in a 
cohort develop a DLT in Cycle 1. In this instance, the MTD is considered to have been 
exceeded. If the MTD is exceeded, the lower dose level previously evaluated will be deemed 
as MTD or the next lower intermediate dose level will be explored, as determined by the 
SMC. 
The SMC will also determine the dose level and dose regimen for each cohort. The dose 
regimen chosen will be dependent on the available PK data and various dose regimens may 
be explored (eg, daily dosing, etc.). The dose level and dose regimen selected will be 
communicated to IRB/ IEC. 
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MTD is the dose level at which 0 or 1 out of 6 patients experience DLT, provided that ≥ 33% 
of patients experienced DLT (eg, 2 or 3 out of 6 patients) at the next higher dose level. RP2D 
is smaller or equal to MTD. Even though an MTD may have been reached, a RP2D may still 
be selected which will take into account the MTD as well as available information on lower 
dose level of AEs, AEs occurring in later cycles, PK, pharmacodynamics and efficacy data. 
This decision will be made at a SMC meeting where the dose for the dose expansion phase is 
decided. At least 6, and up to 10 patients could be accrued at RP2D to further assess safety.  
Dose escalation will continue until RP2D or MTD, if any, is reached.  
4.1.1.2 
Dose-Limiting Toxicity 
All AEs will be evaluated according to the NCI-CTCAE Version 4.03. A DLT is defined as 
an AE, or abnormal laboratory value that occurs during the DLT assessment window, is 
assessed as unrelated to disease progression, intercurrent illness, or concomitant medications 
and meets one of the following criteria (Table 4):  
Table 4.  
Dose-Limiting Toxicity Assessment Criteria 
Hematologic: 
 
 
Grade 4 neutropenia lasting >7 days 
 
Febrile neutropenia  
 
Grade 3 neutropenic infection 
 
Grade 3 thrombocytopenia with bleeding 
 
Grade 4 thrombocytopenia 
 
Grade 4 anemia 
Non-hematologic: 
 
 
≥ Grade 3 nausea, vomiting and diarrhea despite optimal supportive care 
 
Any other clinically relevant ≥ Grade 3 non-hematologic toxicity 
(excluding asymptomatic biochemical abnormalities that are not clinically 
significant and resolve to ≤ Grade 2 in <7 days) 
 
Any toxicity grade which in the judgment of the investigator or sponsor is 
dose limiting. 
The evaluable patient population for the determination of RP2D will consist of patients who 
have met the minimum safety evaluation requirements of the study. The minimum safety 
evaluation requirements will have been met if, in Cycle 1, the patient has been treated with at 
least 75% of the expected dose of pamiparib, (ie, completed at least 18 days of treatment), 
and observed for ≥ 23 days following the first dose, and has completed all required safety 
evaluations or the patient experiences DLT during Cycle 1. Patients who do not meet these 
minimum safety evaluation requirements will be regarded as ineligible for the 
RP2D-determining population and will be replaced. 
4.1.1.3 
Dose Continuation, Intra-patient Dose Escalation and Dose De-escalation 
In the absence of unacceptable toxicity, disease progression, or patient withdrawal, patients 
may continue with BID administrations of pamiparib at the discretion of the investigator. The 
sponsor may consider to roll over those patients who are still on treatment and derive clinical 
benefit to a new study to continue receiving pamiparib treatment and follow for safety and 
other clinical relevant information if this study has been ended. 
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Intra-patient dose escalation is not allowed in this study. 
In the event of a DLT, treatment will be stopped and supportive therapy administered as 
required. If the toxicity resolves or subsides to Grade 0, Grade 1 or Grade 2 (Grade 2 is only 
applicable to neutropenia) within 14 days and interruption or delay of treatment for no more 
than 21 days of the onset of the DLT and the patient is showing clinical benefit in the 
investigator’s opinion, resumption of treatment after resolution of a DLT will be at the next 
lower dose level tested (or 50% lower if the DLT occurs with the first dose level). If the 
toxicity does not resolve to Grade 0, Grade 1 or Grade 2 (Grade 2 is only applicable to 
neutropenia) within 14 days of onset, the patient must be withdrawn from the study. Any 
exception to this must be agreed upon by the investigator and the medical monitor.  
The visit schedule for Phase 1 portion is presented in Table 5. 
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Table 5.  
Study Visit Schedule in Phase 1 Portion 
Assessments6 
Screening1 
Cycle 1 
(23 days) 
Cycle 2 
(21 days) 
Cycle 3 
(21 days) 
Cycle 4 and 
Subsequent Cycles 
(every 21 days for 
1 cycle in Year 1, 
every 12 weeks 
± 7 days thereafter) 
EOT Visit2 
Safety 
Follow-up3 
Day of Study 
D -21 to -1 
D1 
D2 
D3 
D10 
D17 
D24 
D45 
D66~ 
Within 5 
days after 
last dose 
30 ± 5 days 
after last 
dose 
Allowed time window 
 
 
 
 
 
 
±2 days 
±2 days 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Baseline demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history/treatment4 
X 
 
 
 
 
 
 
 
 
 
 
Concurrent medications 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Physical examination5 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
X 
X 
 
 
 
 
X 
X 
X 
X 
 
Hematology7 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Clinical chemistry7 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
CA-1258 
X 
EVERY 6 WEEKS ± 7 DAYS in the First Year 
EVERY 12 WEEKS ± 7 DAYS starting with the Second Year 
 
 
Coagulation 
 
X 
 
 
X 
X 
X 
X 
X 
X 
 
Urinalysis9 
X 
 
 
 
 
 
X 
X 
X 
X 
 
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Assessments6 
Screening1 
Cycle 1 
(23 days) 
Cycle 2 
(21 days) 
Cycle 3 
(21 days) 
Cycle 4 and 
Subsequent Cycles 
(every 21 days for 
1 cycle in Year 1, 
every 12 weeks 
± 7 days thereafter) 
EOT Visit2 
Safety 
Follow-up3 
Day of Study 
D -21 to -1 
D1 
D2 
D3 
D10 
D17 
D24 
D45 
D66~ 
Within 5 
days after 
last dose 
30 ± 5 days 
after last 
dose 
Allowed time window 
 
 
 
 
 
 
±2 days 
±2 days 
 
12-lead 
electrocardiogram10 
X 
X 
 
 
X 
 
X 
X 
X 
X 
 
Disease assessment11 
-28 to -1 
X 
EVERY 6 WEEKS ± 7 DAYS in the First Year 
EVERY 12 WEEKS ± 7 DAYS starting with the Second Year 
 
 
Adverse events (including 
serious) 12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CT or MRI13 
X 
EVERY 6 WEEKS ± 7 DAYS in the First Year 
EVERY 12 WEEKS ± 7 DAYS starting with the Second Year  
 
 
Pregnancy test14 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
Blood sample collection for 
BRCA1/2 mutation testing15 
X 
 
 
 
 
 
 
 
 
 
 
Archival tissue15 
(additional consent 
required) 
X 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetic blood 
sampling17 
 
X 
X 
X 
X 
 
X 
X 
 
 
 
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Assessments6 
Screening1 
Cycle 1 
(23 days) 
Cycle 2 
(21 days) 
Cycle 3 
(21 days) 
Cycle 4 and 
Subsequent Cycles 
(every 21 days for 
1 cycle in Year 1, 
every 12 weeks 
± 7 days thereafter) 
EOT Visit2 
Safety 
Follow-up3 
Day of Study 
D -21 to -1 
D1 
D2 
D3 
D10 
D17 
D24 
D45 
D66~ 
Within 5 
days after 
last dose 
30 ± 5 days 
after last 
dose 
Allowed time window 
 
 
 
 
 
 
±2 days 
±2 days 
 
Investigational product 
administration18 
 
CONTINUOUS 
 
 
Bone ECT Scan19 
-28 to -1 
X 
 
 
 
 
 
 
 
 
 
 
Abbreviations: CA-125, carcinoma antigen -125; CT: computed tomography; D, Day; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; MRI, 
magnetic resonance imaging; PK, pharmacokinetic; X, to be performed; EOT, end of treatment; ECT, emission computed tomography 
1. 
Screening assessments will be completed within 21 days prior to the first dose of pamiparib, with the exception of disease assessment (see footnote 11 and 18). 
2. 
EOT visit will be conducted at the earliest day possible within 5 days of the last dose of pamiparib if possible 
3. 
Safety follow-up visit should occur 30 ± 5 days after the last dose of pamiparib 
4. 
Date of and response to last platinum treatment must be documented unless no platinum treatment has been received before. Patients are defined as platinum-sensitive if 
disease progression by RECIST or CA-125 criteria had occurred ≥ 6 months after their last platinum treatment while platinum-resistant is defined as disease progression that 
occurred < 6 months after the last platinum treatment  
5. 
Full physical exam includes the following items: 1) general appearance; 2) head, eyes, ears, nose and throat; 3) neck; 4) heart; 5) chest (including lungs); 6) abdomen; 7) 
extremities; 8) skin; 9) lymph nodes; 10) cardio-vascular; and 11) neurological status. Only at baseline and EOT visit is the full physical examination required. In other visits 
(or as clinically indicated), limited symptom-directed physical examinations will be performed 
6. 
All assessments, unless stated otherwise, must be performed before investigational product administration in each cycle 
7. 
In the event of neutropenia (absolute neutrophil count <1000/mm3), thrombocytopenia (platelets of less than 50,000/mm3), or ≥ Grade 3 clinical chemistry toxicity, these 
assessments will be conducted as frequently as the physician feels needed until toxicity resolves to ≤ Grade 2 
8. 
Patients with high grade epithelial tumor, non-mucinous ovarian cancer, fallopian cancer, or primary peritoneal cancer will have CA-125 tested in local laboratory within 
2  weeks before the dose of pamiparib, every 6 weeks ± 7 days after the first dose of the study drug in the first year, then every 12 weeks ± 7 days thereafter. The CA-125 
responses must be confirmed and maintained for at least 28 days. Patients can be evaluated according to CA-125 only if they have a pretreatment sample that is at least twice 
the upper limit of reference range and within 2 weeks before starting the treatment 
9. 
If urine protein is ≥ 2+, a 24-hour urine sample for total protein will be obtained and evaluated 
10. Three electrocardiograms (12-lead ECGs) will be performed at screening after at least a 10-minute rest. If there is any clinically meaningful abnormality observed based on 
the investigators judgment for the first ECG test, the other 2 additional ECG tests will be requested at least 5 minutes apart and all 3 test results should be recorded. If the 
clinically meaningful abnormality was observed in 2 of 3 ECG tests, the patient is not eligible for this study. It is not required to conduct 3 ECG tests for all patients at 
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screening. The ECG time points for pharmacokinetic sampling in conjunction with PK will be obtained as per Table 6. Patients should be in the semi-recumbent or supine 
position. If prolongation of QT or QT interval corrected for heart rate (QTc) is noted during the first 15 days, 12-lead ECGs will be performed weekly during Week 3 to Week 
6, and then once every 3 weeks, on Day 1 of every cycle from Cycle 3 onwards, for the remaining duration of treatment 
11. Disease assessment during the screening may be completed up to 28 days prior to the first dose of pamiparib. Afterwards, disease assessments will be performed once every 
6 weeks ± 7 days after the first dose of pamiparib in the first year, then every 12 weeks ± 7 days thereafter to assess all known disease. For patients with treatment terminated 
prior to documentation of disease progression, they shall be subjected to CT/MRI radiographic assessment according to the previous visit assessment scheme, until 1) 
commencement of new treatment, 2) disease progression, 3) death or 4) termination of the study 
12. After informed consent has been signed, but prior to study treatment, only SAEs should be reported 
13. A CT scan or MRI scan of the chest, abdomen, and pelvis will be performed once every 6 weeks ± 7 days in the first year, then every 12 weeks ± 7 days thereafter to assess all 
known disease 
14. For women of childbearing potential including those who have had a tubal ligation, 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 prior to dosing. A serum pregnancy test must be performed if urine pregnancy test is 
positive or equivocal  
15. Baseline blood samples for all patients should be collected for retrospective germline BRCA1/2 mutation testing. Blood sample will be taken from each patient. 
16. Archival tumor tissues will be collected, if available 
17. The pharmacokinetic blood samples will be collected at the time points specified in Table 6 
18. A single dose of pamiparib will be administered on the morning of Day 1 of Cycle 1. Multiple administrations will start on Day 3 (Cycle 1 only) or on Day 1 (Cycle 2 and 
onwards) and continue throughout for each cycle 
19. Bone ECT scan at baseline is required if the patient has known bone metastases or has symptoms that could be due to bone metastases. The bone ECT test window duration 
could be expanded to -28 days from -21 days at baseline. In the subsequent visits, whether to conduct bone ECT scan depends on the clinical indication and investigator’s 
decision. Only bone lesion confirmed by CT/MRI or X ray could be recorded as non-target lesion and should be followed with the same method of examination 
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Table 6.  
Pharmacokinetic Sampling in Phase 1 Portion 
Procedure 
Cycle 1 
Cycle 2 
Cycle 3 
 
Day 1 
Day 
2 
Day 3 
Day 10 
Day 1±2 
Day 1±2 
Hours 
Pre-dose4 
0.5 
1 
2 
4 
6 
9 
123 
24 
481 
Pre-dose4 
0.5 
1 
2 
4 
6 
9 
123 
Pre-
dose4 
2 
Pre-
dose4 
2 
12-lead ECG 
for PK 
sampling 
X 
 
 
X2 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
X 
X 
X 
X 
Vital signs 
X 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X 
X1 
X 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X 
X2 
X 
X2 
PK sampling 
X 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X 
X1 
X 
X2 
X2 
X2 
X2 
X2 
X2 
X2 
X 
X2 
X 
X2 
Abbreviations: ECG, electrocardiogram; PK, pharmacokinetics 
General note: It is important that pharmacokinetic (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) scheduled ECG; 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. 
1. 
On Day 3, within 1h before the morning dose 
2. 
For all procedures, a window period of ±10 minutes exists within 0.5-1h, ±20 min within 2-4h, ±30 min within 6-24h after the study drug is taken 
3. 
It should be pre-evening dose 
4. 
The window period is within 1h before morning dose 
 
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4.1.2 
Phase 2 Portion 
Approximately 100 evaluable patients (80 previously treated platinum-sensitive and 20 previously 
treated platinum-resistant) with advanced high grade (Grade 2 or Grade 3 endometriod epithelial 
cancer is acceptable too), non-mucinous, epithelial ovarian cancer (including fallopian cancer, or 
primary peritoneal cancer) of either known deleterious or suspected deleterious BRCA1/2 mutations 
who have received at least two lines of prior therapies will be enrolled. 
Patients are defined as platinum-sensitive if disease progression by RECIST, version 1.1, had 
occurred ≥ 6 months after their last dose of platinum treatment, while platinum-resistant is defined as 
disease progression that occurred < 6 months after the last dose of platinum. 
Patients will be screened for eligibility up to 21 days prior to the first dose of pamiparib and will 
take pamiparib at 60 mg BID on Day 1 of Cycle 1 (21-day cycle) and continuously in all subsequent 
cycles. Patients will be instructed to swallow the capsules whole, in rapid succession, with water. 
Pamiparib can be administered with or without food. 
The visit schedule for Phase 2 portion is presented in Table 7. 
Rescreening under limited condition 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. 
4.1.2.1 
Safety, Tolerability and Efficacy 
Phase 2 portion will investigate efficacy in patients with selected tumor types and further evaluate 
safety and tolerability of pamiparib at 60 mg BID. 
Patients will be monitored for safety, tolerability, and efficacy throughout the study. Radiological 
assessment of tumor response status should be performed approximately once every 6 weeks 
± 7 days for the first 18 weeks, thereafter once every 9 weeks ± 7 days for the remaining period in 
the first year, and then once every 12 weeks ± 7 days starting with the second year. For patients with 
first a response as complete response (CR) or partial response (PR), a response confirmation will 
need to be performed during the following 4-6 weeks, then patients will keep original tumor 
assessments schedule per protocol. 
Tumor response will be assessed by IRR and investigators separately based on RECIST, version 1.1.  
Patients will continue treatment until occurrence of unacceptable toxicities, disease progression, 
withdrawal of consent, investigator discretion, or delay of treatment due to unresolved toxicities for 
more than 21 days. Dose interruption due to investigational drug-related anemia could be on hold for 
up to 56 days consecutively. 
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Table 7.  
Study Visit Schedule in Phase 2 Portion 
Assessments7 
Pre- 
screening1 
Screening1 
Cycle 1 
(21 days) 
Cycle 2 
(21 days) 
Cycle 3 and 
subsequent 
Cycles 
(every 21 days for 
one cycle) 
Unscheduled 
Visit2 
EOT Visit3 
Safety 
Follow-up4 
Survival 
Follow-
up5 
Day of Study 
 Before 
screening 
D -21 to -1 
D1 
D22 
D43~ 
Varies 
Within 
5 days after 
last dose 
30 ± 5 days 
after last 
dose 
Every 
12 weeks 
± 7 days 
Allowed time window 
 
 
 
±3 days 
±3 days 
Informed consent 
X 
X 
 
 
 
 
 
 
 
Baseline demographics 
 
X 
 
 
 
 
 
 
 
Medical history/treatment 
history6 
 
X 
 
 
 
 
 
 
 
Concurrent medications 
 
X 
X 
X 
X 
X 
X 
X 
 
Physical examination8 
 
X 
X 
X 
X 
X 
X 
 
 
Vital signs 
 
X 
X 
X 
X 
X 
X 
 
 
Height 
 
X 
 
 
 
 
 
 
 
Weight 
 
X 
 
 
 
X 
X 
 
 
ECOG performance status 
 
X 
X 
X 
X 
X 
X 
 
 
Hematology9 
 
-7 to -1 
X 
X 
X 
X 
X 
X 
 
 
Clinical chemistry9 
 
-7 to -1 
X 
X 
X 
X 
X 
X 
 
 
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Assessments7 
Pre- 
screening1 
Screening1 
Cycle 1 
(21 days) 
Cycle 2 
(21 days) 
Cycle 3 and 
subsequent 
Cycles 
(every 21 days for 
one cycle) 
Unscheduled 
Visit2 
EOT Visit3 
Safety 
Follow-up4 
Survival 
Follow-
up5 
Day of Study 
 Before 
screening 
D -21 to -1 
D1 
D22 
D43~ 
Varies 
Within 
5 days after 
last dose 
30 ± 5 days 
after last 
dose 
Every 
12 weeks 
± 7 days 
Allowed time window 
 
 
 
±3 days 
±3 days 
CA-12510 
 
-14 to -1 
X 
EVERY 6 WEEKS ± 7 DAYS for the first 18 
weeks, thereafter EVERY 9 WEEKS ± 7 DAYS 
for the remaining period in first year EVERY 12 
WEEKS ± 7 DAYS starting with the second 
year 
 
 
 
 
Urinalysis11 
 
-14 to -1 
X 
X 
 
 
X 
X 
X 
 
12-lead electrocardiogram12 
 
-14 to -1 
X 
 
 
 
X 
X 
X 
 
Disease assessment13 
 
X 
EVERY 6 WEEKS ± 7 DAYS for the first 18 
weeks, thereafter EVERY 9 WEEKS± 7 DAYS 
for the remaining period in first year  
EVERY 12 WEEKS ± 7 DAYS starting with 
the second year13 
 
 
 
 
Adverse events (including 
serious)14 
 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test15 
 
-7 to -1 
X 
 
X 
X 
X 
X 
X 
 
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Assessments7 
Pre- 
screening1 
Screening1 
Cycle 1 
(21 days) 
Cycle 2 
(21 days) 
Cycle 3 and 
subsequent 
Cycles 
(every 21 days for 
one cycle) 
Unscheduled 
Visit2 
EOT Visit3 
Safety 
Follow-up4 
Survival 
Follow-
up5 
Day of Study 
 Before 
screening 
D -21 to -1 
D1 
D22 
D43~ 
Varies 
Within 
5 days after 
last dose 
30 ± 5 days 
after last 
dose 
Every 
12 weeks 
± 7 days 
Allowed time window 
 
 
 
±3 days 
±3 days 
Blood sample collection for 
BRCA1/2 mutation testing16 
X 
 
 
 
 
 
 
 
 
Pharmacokinetic blood 
sampling17 
 
 
X 
X 
 
 
 
 
 
Tumor Tissues18 
 
X 
 
 
 
 
 
 
 
Investigational product 
administration 19 
 
 
CONTINUOUS 
X 
 
 
 
Bone ECT Scan20 
 
-28 to -1 
X 
 
 
 
X 
 
 
 
Survival follow-up visit 
 
 
 
 
 
 
 
 
X 
Abbreviations: CA-125, carcinoma antigen-125; CT, computed tomography; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EOT, End 
of Treatment; MRI, magnetic resonance imaging; PBMCs, peripheral blood mononuclear cells; PD, progression disease; PK, pharmacokinetic; X, to be performed. 
1. 
Screening assessments will be completed within 21 days prior to the first dose of pamiparib, with the exception of disease assessment. Pre-screening for germline BRCA 
mutation test (blood sample) can be completed prior to the study eligibility 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 PD is suspected, imaging studies should be performed and
 
 
3. 
EOT visit should be conducted at the earliest day as possible within 5 days of the last dose of pamiparib, if possible. If discontinuation is due to unresolved toxicities for more 
than 21 days (56 days for anemia), EOT visit should be conducted at the earliest day as possible within 5 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. CA-125 and ECG do not have to be repeated if it was 
performed within 14 days of the EOT visit, For the other required assessment, 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. 
Approximately 30 days after the last day of pamiparib, a safety follow-up visit will occur with the outlined safety assessments. If a new anti-cancer therapy is initiated before 
this safety follow-up, a safety follow-up should be scheduled as soon as possible ideally before other anti-cancer treatment starts. 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. If discontinuation is due to unresolved toxicities for more than 
21 days, safety follow-up could be scheduled 30 ± 5 days after the last dose of treatment. 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 5 days after permanent discontinuation is determined 
5. 
Patients will be followed for survival via phone contact approximately every 12 weeks ± 7 days or as otherwise directed by the sponsor 
6. 
Date of and response to last platinum treatment must be documented (unless no platinum treatment has been received). Patients are defined as platinum-sensitive if disease 
progression by RECIST or CA-125 criteria had occurred ≥ 6 months after their last dose of platinum treatment while platinum-resistant is defined as disease progression that 
occurred < 6 months after the last dose of platinum 
7. 
All assessments, unless stated otherwise, must be performed before investigational product administration in each cycle 
8. 
Full physical examination includes the following items: 1) general appearance; 2) head, eyes, ears, nose and throat; 3) neck; 4) heart; 5) chest (including lungs); 6) abdomen; 
7) extremities; 8) skin; 9) lymph nodes; 10) cardio-vascular; and 11) neurological status. Only at baseline and EOT visit is full physical examination required. In other visits 
(or as clinically indicated), limited symptom-directed physical examinations will be performed 
9. 
If the assessments were performed within 4 days of Cycle 1 Day 1, they do not need to be repeated on Cycle 1 Day 1. Weekly hematology test should be done for the first 
3 cycles during the study. In the event of neutropenia (absolute neutrophil count < 1000/mm3), thrombocytopenia (platelets of < 50,000/mm3), or Grade ≥ 3 clinical chemistry 
toxicity (per NCI-CTCAE, version 4.03), these assessments will be conducted as frequently as needed until toxicity resolves to Grade ≤ 2 
10. Patients will have CA-125 tested in local laboratory within 2 weeks before the dose of pamiparib, once every 6 weeks ± 7 days after the first dose of pamiparib for the first 
18 weeks, thereafter once every 9 weeks± 7 days for the remaining period in the first year, and then every 12 weeks ± 7 days starting with the second year. The CA-125 
responses must be confirmed and maintained for at least 28 days. Patients can be evaluated according to CA-125 only if they have a pretreatment sample that is at least twice 
the upper limit of the reference range and within 2 weeks before starting the treatment 
11. 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 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 
12. 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 8 
13. Disease assessment during the screening may be completed up to 28 days prior to pamiparib administration. Afterwards, disease assessments will be performed once every 
6 weeks ± 7 days after the first dose of pamiparib for the first 18 weeks and thereafter every 9 weeks± 7 days for the remaining period in the first year, then every 12 weeks 
± 7 days afterwards. For patients with first response as complete response or partial response, a response confirmation will be needed to be performed at following 4-6 weeks, 
then patients will keep original disease assessments schedule per protocol. A CT scan or MRI scan of the chest, abdomen, and pelvis will be performed. Patients with 
treatment terminated prior to documentation of PD, shall be subjected to CT/MRI radiographic assessment according to the previous visit assessment scheme, until 1) 
commencement of new treatment, 2) disease progression, 3) death or 4) termination of the study 
14. After informed consent has been signed, but prior to study treatment, only SAEs should be reported 
15. For women of childbearing potential including those who have had a tubal ligation, 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 prior to dosing. A serum pregnancy test must be performed if urine pregnancy test is 
positive or equivocal  
16. 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 being eligible for the study. Blood sample will be taken from each patient 
17. The PK blood samples will be collected at the time points specified in Table 8 
18. Archival tumor tissues will be collected, if available 
19. BID dosing of pamiparib starts from Cycle 1 Day 1 
20. Bone ECT scan at baseline is required if the patient has known bone metastases or has symptoms that could be due to bone metastases. The bone emission computed 
tomography (ECT) test window duration could be expanded to -28 days from -21 days at baseline. 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, bone ECT scans should 
be repeated when a complete response is identified in target lesion or when progression in bone is suspected 
 
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Table 8.  
Pharmacokinetic Sampling in Phase 2 Portion 
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 for serial PK group is: 1) vital sign measurements; 2) scheduled triplicate ECGs; 3) PK 
blood samples (to be performed at the precise protocol scheduled time, and to be completed within 30 minutes after completion of vital sign measurements, and 
within 5 minutes after completion of ECG); and 4) any other scheduled or unscheduled measurements at that time point. For sparse PK sampling, the sequence of 
collection at a particular time point 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 volume will be taken for each sample 
2. 
Triplicate ECGs will be collected from at least 15 patients who contribute to serial PK, with the option to be collected from more patients from sparse PK group, if applicable. 
Triplicate ECGs for each patient should be obtained from a calibrated machine provided for the study and the same machine must be used for all ECG assessments. The 
triplicate ECGs results will also be sent to a central reader so that a concentration-QTc analysis can be attempted12-lead ECGs will be performed on the rest of patients who 
contribute to sparse PK without triplicate ECGs. Triplicate or 12-lead ECGs will be performed on Cycle 1 Day 1 and Cycle 2 Day 1 prior to pamiparib PK assessments. 
3. 
Serial PK sampling will be collected on approximately 15 patients on Cycle 1 Day 1 and Cycle 2 Day 1 at time points of pre-dose, 0.5, 1, 2, 4, 6, 9, and 12 hours after study 
drug is taken. A window period of ± 10 min exists within 0.5-1 hour, ± 20 min within 2-4 hours, ±30 min within 6-12 hours. Serial PK sampling will be collected in this study 
and only in patients from sites that area able to adequately perform PK sampling, handling, and processing procedures as outlined in the laboratory manual 
4. 
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 
Procedure 
Cycle 1 
Cycle 2 
Days 
Day 1 
Day 1±3 
Hours 
Pre- dose 
0.5 
1 
2  
4 
6 
9 
12 
Pre-
dose 
0.5 
1 
2 
4 
6 
9 
12 
ECGs2 
X1 
 
 
X1 
 
 
 
 
X1 
 
 
X1 
 
 
 
 
Vital signs 
X1 
 
 
X1 
 
 
 
 
X1 
 
 
X1 
 
 
 
 
Serial PK sampling3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sparse PK sampling4 
X1 
 
 
X1 
 
 
 
 
X1 
 
 
X1 
 
 
 
 
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4.1.3 
Follow-up for Toxicities 
When treatment is interrupted or permanently discontinued due to an AE or abnormal laboratory 
value, the patient must be followed at a frequency as medically indicated until resolution or 
stabilization of the event, whichever comes first. All patients will be followed for AEs and SAEs for 
at least 30 days following the last dose of pamiparib. 
For prolonged hematological toxicities, treatment should be interrupted and blood counts should be 
monitored weekly until recovery. If the levels have not recovered to NCI-CTCAE ≤ Grade 1 or 
baseline after 8 weeks, the patient should be referred to a hematologist for further investigations, 
including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is diagnosed, 
treatment of pamiparib must be permanently discontinued, and the event should be reported as an SAE 
regardless of causality. 
4.1.4 
End of Study 
The study termination is defined as the time point when data collection for the patient will stop.  The 
study will continue until the last patient has died, becomes lost to follow up, or withdraws from 
study, or until sponsor decides to terminate the study.  
The sponsor has the right to terminate this study at any time.  Reasons for terminating the study early 
may include, but are not limited to, the following:  
 The incidence or severity of adverse events in this or other studies indicates a potential 
health hazard to patients  
 Overall patient enrollment is unsatisfactory 
The sponsor will notify each investigator if a decision is made to terminate the study.  Should this be 
necessary, prematurely discontinued patients should be seen as soon as possible for an EOT visit and 
Safety Follow-up visit. 
The investigators may be informed of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the patient’s interests.  The investigator will be 
responsible for informing IRBs/Independent Ethics Committees (IECs) of the early termination of 
the trial. 
The sponsor has the right to close a site at any time.  The decision will be notified to the site in 
advance. Reasons for closing a site may include but are not limited to the following:  
 Excessively slow recruitment  
 Poor protocol adherence  
 Inaccurate or incomplete data recording  
 Good Clinical Practice (GCP) noncompliance 
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 Study activity is completed (ie, all patients have completed and all obligations have been 
fulfilled)]  
4.2 
Selection of Study Population 
4.2.1 
Inclusion Criteria 
Patients may be enrolled in the study only if they meet all of the following criteria: 
1. Patients have voluntarily agreed to participate by giving written informed consent 
2. Age 18 years (including 18 years) on the day of signing informed consent 
3. Patients meet the following eligibility criteria for the corresponding part of the study: 
1) Phase 1 Portion: 
a) The patients must have a histologically or cytologically confirmed locally advanced or 
metastatic TNBC, or high-grade, non-mucinous, epithelial ovarian cancer (including 
fallopian or primary peritoneal cancer) for which no effective standard therapy is 
available 
b) BRCA1 and BRCA2 mutations are not required but enrichment of this patient population 
is preferred 
c) Patients must agree to retrospective germline BRCA testing using blood samples 
d) Archival tumor tissues will be collected, if available 
2)  Phase 2 Portion: 
a) Patients who have histologically or cytologically confirmed high-grade (Grade 2 or 
Grade 3 endometrioid epithelial cancer is acceptable too), non-mucinous, epithelial 
ovarian cancer (including fallopian, or primary peritoneal cancer), harboring germline 
BRCA1/2 mutation and must meet the following criteria: 
i. 
Patients must have received at least 2 lines of standard chemotherapy, currently 
with relapsed/progressive disease or have withdrawn due to unacceptable toxicity 
from most recent standard treatment 
ii. 
Platinum-sensitive or platinum-resistant patients 
(Patients are defined as platinum sensitive if disease progression by RECIST, 
version 1.1, had occurred ≥ 6 months after their last platinum treatment, while 
platinum-resistant is defined if disease progression occurred < 6 months after the 
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last platinum treatment 
iii. 
If mixed histology, >50% of the primary tumor had to be confirmed to be 
high-grade (Grade 2 or Grade 3 endometrioid epithelial cancer is acceptable too), 
non-mucinous, epithelial ovarian cancer 
b) All patients will be required to undergo germline BRCA1/2 mutation testing using blood 
samples prior to enrolment 
c) Archival tumor tissues will be collected, from all patients, if available 
4. Patients must have measurable disease as defined per the RECIST, version 1.1 
5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 (Appendix 3) 
6. Life expectancy ≥ 12 weeks 
7. Patients must have adequate organ function as indicated by the following laboratory values: 
 Absolute neutrophil count (ANC) ≥ 1,500/mm3 or 1.5 x 109/L 
 Platelets ≥ 75,000/mm3 or 75 x 109/L 
 Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L 
(If transfusion is used, at least 14 days should pass before re-test for hematology is performed 
at the screening visit) 
 Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m2 by Chronic Kidney 
Disease Epidemiology Collaboration Equation (CKD-EPI EQ; Appendix 6)  
 Serum total bilirubin ≤ 1.5 x upper limit of normal (ULN)  
 Aspartate aminotransferase and alanine aminotransferase ≤ 3 × ULN  
8. Females of childbearing potential and nonsterile males (only for Phase 1), must practice 
highly effective method of birth control (Appendix 11) for the duration of the study and for at 
least 6 months after the last study drug administration  
4.2.2 
Exclusion Criteria 
Patients will not be entered in the study for any of the following reasons: 
1. Patients who have been treated with chemotherapy, biologic therapy, immunotherapy, 
investigational agent, anti-cancer Chinese medicine, or anti-cancer herbal remedies ≤ 14 days 
(or ≤5 half-lives, whichever is shorter) prior to starting study drug, or who have not 
adequately recovered from the side effects of such therapy 
2. Patients who have undergone major surgery for any cause ≤ 4 weeks prior to starting study 
drug. Patients must have adequately recovered from the previous treatment and have a stable 
clinical condition before entering this study 
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3. Patients who have undergone radiotherapy for any cause ≤ 14 days prior to starting study 
drug. Patients must have adequately recovered from the previous treatment and have a stable 
clinical condition before entering this study 
4. Untreated and/or active brain metastases 
 A scan to confirm the absence of brain metastases is not required. 
 Patients with treated brain metastases must be off corticosteroids for ≥ 14 days and have no 
signs or symptoms of progressive brain metastases 
5. Prior therapies targeting PARP 
6. Inability to swallow oral medications (capsules and tablets) without chewing, breaking, 
crushing, opening or otherwise altering the product formulation.  
7. Patients with any of the following cardiovascular criteria:  
 Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily 
living, ≤ 28 days prior to Day 1   
 Evidence of symptomatic pulmonary embolism within 28 days prior to Day 1 
 Acute myocardial infarction ≤ 6 months prior to Day 1  
 Heart failure of the New York Heart Association Classification III or IV (see Appendix 12) 
≤ 6 months prior to Day 1 
 ≥ Grade 2 ventricular arrhythmia ≤ 6 months prior to Day 1  
 Cerebrovascular accident ≤ 6 months prior to Day 1 
8. Patients with other malignant cancer: 
 Except for surgically excised non-melanoma skin cancer, adequately treated carcinoma in 
situ of the cervix, 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 
9. Diagnosis of myelodysplastic syndrome (MDS) 
10. Known human immunodeficiency virus (HIV) infection, active viral hepatitis, or active 
tuberculosis 
11. Use ≤ 10 days (or ≤ 5 half-lives, whichever is shorter), prior to Day 1, or anticipated need for 
food or drugs known to be strong or moderate CYP3A inhibitors or strong CYP3A inducers 
(Appendix 8) 
12. Pregnancy or nursing: 
 Females of childbearing potential require a negative urine or serum pregnancy test ≤ 7 days 
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before Day 1 
13. Significant intercurrent illness that may result in the patient’s death prior to death from 
HGOC, or TNBC (only for Phase 1 portion) 
14. Known history of intolerance to the excipient of the pamiparib capsule 
15. 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 
16. Active bleeding disorder, including gastrointestinal bleeding, as evidenced by hematemesis, 
significant hemoptysis, or melena ≤ 6 months before Day 1 
17. Any illness that investigator thinks makes the patient unsuitable for entry into the study 
18. Unsolved acute effects of prior therapy of ≥ Grade 2 
 Except for AEs not considered a likely safety risk (eg, alopecia, neuropathy, and specific 
laboratory abnormalities) 
4.2.3 
Other Eligibility Criteria Considerations 
To assess any potential impact on patient eligibility with regard to safety, the investigator must refer 
to the IB for detailed information regarding warnings, precautions, contraindications, AEs, and other 
significant data pertaining to pamiparib being used in this study (BGB-290 Investigator’s Brochure).   
4.2.3.1 
Patient Restrictions 
The following restrictions may affect patient participation in this study: 
 The investigator must be informed as soon as possible about any medications taken from the 
time of screening until the patient is discharged from the study 
 In Phase 1 portion, patients will be required to fast for 2 hours before and 1 hour after pamiparib 
administration on all days throughout the study, water will be allowed freely. Grapefruit juice is 
not allowed throughout the study. No other dietary restrictions will apply 
 In Phase 2 portion, patients will be instructed to swallow the capsules whole, in rapid succession, 
with water. Pamiparib can be administered with or without food based on the pamiparib food 
effect evaluation result 
4.2.4 
Patient Discontinuation and Withdrawal 
Patients may withdraw at any time or be discontinued from the study at the discretion of the 
investigator should any untoward AEs occur. In addition, a patient may be withdrawn by the 
investigator or the sponsor if he/she violates the study plan or for administrative and/or other safety 
reasons. The investigator or study coordinator must notify the sponsor immediately when a patient 
has been discontinued/withdrawn due to an AE. Any AE which is present at the time of 
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discontinuation/withdrawal should be followed in accordance with the safety requirements outlined 
in Section 7.4. In the event that a patient is prematurely discontinued from the study at any time due 
to an AE (as defined in Section 9.1) the procedures stated in Section 9 must be followed. 
If a patient is prematurely discontinued from participation in the study for any reason, the 
investigator must make every effort to perform end of treatment (EOT) visit at the earliest day 
possible within 5 days of the last dose of pamiparib: physical examination, vital signs,12-lead ECG, 
hematology, biochemistry, and AE assessment. If the discontinuation is due to unresolved toxicities 
for more than 21 days (56 days for anemia), EOT visit should be conducted at the earliest day as 
possible within 5 days after permanent discontinuation is determined. 
In the Phase 1 portion, in addition to the post-study assessments, if a DLT occurs, the investigator 
will obtain, when possible, a 4 mL blood sample for analysis of plasma pamiparib concentration. 
Patients who discontinue or are withdrawn for any reason other than DLT during Cycle 1 will be 
considered for replacement after due consideration by the sponsor and/or SMC if the minimum 
number of patients needed for the evaluation of RP2D is not met. 
 
4.2.4.1 
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: 
 PD 
 AE 
 Pregnancy 
 Protocol violation 
 Patient withdrew consent for study treatment 
o Patients may voluntarily withdraw consent from study treatment at any time 
o Patients should continue to participate in the follow-up phase, if a patient withdraws 
consent from the treatment phase only 
 Investigator’s discretion 
 Start of other anti-cancer therapy 
4.2.4.2 
End of Treatment Visit 
The end of treatment (EOT) visit should occur within 5 days after pamiparib has been 
permanently discontinued. Required assessments are listed in Table 5 for Phase 1 and Table 7 for 
Phase 2. The visit at which tumor assessments showed PD 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 PD. For the other required 
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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. 
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5 STUDY TREATMENTS 
5.1 
Description of Pamiparib 
Patients will receive pamiparib as 10 mg 
 capsules, or 40 mg 
 capsules, 
depending on the dose level for Phase 1. 
Patients will receive pamiparib as 20 mg rich 
 capsules for Phase 2. 
5.2 
Dosage and Administration 
Phase 1 Portion 
The pamiparib will be taken once on Day 1 of Cycle 1 (morning only), followed by a 1-day 
treatment-free period (Day 2). Regular daily administration of pamiparib will commence on the 
morning of Day 3 of Cycle 1, as a 21-day period of repeated drug administration (Days 3 to 23). 
During subsequent cycles, the patients will take pamiparib BID from Day 1 to Day 21 (with no 
treatment-free or rest period). 
Patients will be required to fast for at least 2 hours before and 1 hour after each administration of 
pamiparib throughout the study. 
Phase 2 Portion 
The patients will take pamiparib at 60 mg BID daily 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 parmiparib may cause, patients are encouraged to take parmiparib 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.  
The toxicity-related treatment delay must be agreed upon by the investigator and the sponsor 
Medical Monitor.  
5.2.1 
Treatment interruption and treatment discontinuation 
All dose modifications should be based on the worst preceding toxicity. Generally, all dose 
interruptions or treatment discontinuation will be based on investigational drug-related AEs. For 
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reasons other than drug-related AEs, eg, safety concerns due to the poor health condition, if deemed 
necessary by the investigators, dose modifications could be applied after discussion with medical 
monitor. 
Each patient is only allowed up to 2 dose reductions. In addition, a patient must discontinue 
treatment with pamiparib if, after treatment is resumed at a lower dose, the toxicity recurs with the 
same or worse severity.  
Table 9. 
Criteria for interruption and re-initiation of Pamiparib due to treatment 
associated adverse event 
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 
(8 ≤ Hgb <10 
g/dL) 
9 ≤ Hgb < 10 
g/dL 
 
Continue dosing at current dose level and treat with appropriate 
supportive care as medically indicated 
8 ≤ Hgb < 9 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 GI 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 test should be done weekly thereafter until adequate recovery. 
2) For any patients showing Hgb dropping > 2 g/dL especially within a short time without alternative 
explanation such as gastrointestinal bleeding,  pamiparib by 1 dose level should be considered 
3) Dose increase can be considered in certain cases, depending on approval from the medical monitor, 
provided Hgb has been maintained above 9 g/dL for at least 3 months 
Neutropenia (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 
Thrombocytopenia (platelet count, PLT) 
Grade 3 (PLT <50 - 25  109/L) 
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 (PLT <25  109/L) 
Hold pamiparib until resolved to Grade ≤1 or baseline and 
 pamiparib by 1 dose level 
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Toxicity 
Recommended Dose Modificationa 
Renal 
Estimated glomerular filtration rate (CKD-EPI EQ; Appendix 6) 
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 
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 ≤5  ULN within 14 days, then  pamiparib by 1 dose level 
 
If second episode, permanently discontinue pamiparib 
 
If persistent for >14 days, permanently discontinue pamiparib 
Grade 4 (>20  ULN) 
Permanently discontinue pamiparib 
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Toxicity 
Recommended Dose Modificationa 
Pancreatic 
Pancreatitis 
Grade 3 or 4 
Permanently discontinue pamiparib 
Cardiac 
Cardiac - Prolonged QTc interval 
QTcF >500 msec 
A change in QTc interval >60 
msec from baseline or pre-dose 
value of whichever is the 
highest 
 
Obtain triplicate ECGs (2 to 3 minutes apart) ~1 hour after initial 
ECG  
 
If mean QTcF >500 msec, or a change in QTc interval >60 msec 
from baseline, 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 msec, or a change in QTc interval >60 msec 
from baseline 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 
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 
Grade 4 (>20  ULN) 
Permanently discontinue pamiparib 
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, aspartate 
aminotransferase; CKD-EPI EQ: 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. 
For Phase 2 portion, the dose level of pamiparib is 60 mg BID (level 1), 40mg BID (level -1) and 
20mg BID (level -2). Reescalation using intermediate doses may be possible providing tolerability is 
good, please contact sponsor medical monitor for discussion. 
In the event of a DLT (see Table 4), treatment will be stopped and supportive therapy administered 
as required. If the toxicity resolves or subsides to Grade 0, Grade 1 or Grade 2 (Grade 2 is only 
applicable to neutropenia) within 14 days and interruption or delay of treatment for no more than 
21 days of the onset of the DLT and the patient is showing clinical benefit in the investigator’s 
opinion, resumption of treatment after resolution of a DLT will be at the next lower dose level tested 
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(or 50% lower if the DLT occurs with the first dose level). If the toxicity does not resolve to 
Grade 0, Grade 1 or Grade 2 (Grade 2 is only applicable to neutropenia) within 14 days of onset, the 
patient must be withdrawn from the study. Any exception to this must be agreed upon by the 
investigator and the medical monitor. 
For management and follow-up of toxicity also refer to Section 4.1.3. 
5.3 
Treatment Assignment 
Each patient enrolled in this study will receive a unique patient number which will be assigned when 
the patient is enrolled in the study. Patient will be assigned in chronological order starting with the 
lowest number. Once a patient number have been assigned to a patient, it cannot be reassigned to 
any other patient. 
If a patient is replaced in Phase 1 portion, the replacement patient will be assigned the next available 
patient number. 
5.4 
Packaging and Labelling 
Pamiparib capsules will be provided in a child-resistant high-density polyethylene 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 and name of investigator. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
5.5 
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 patient 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. Pamiparib must be kept at 15-30oC and protected 
from light. 
5.6 
Product Accountability 
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 drug accountability records throughout the course of the study. 
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This person(s) will document the amount of pamiparib received from the sponsor, the amount 
supplied and/or administered to and returned by patients, if applicable. 
After completion of the study, all unused pamiparib will be inventoried and packaged for return 
shipment by the hospital unit pharmacist. The inventoried supplies will be returned to the sponsor or 
destroyed on site, after receiving written sponsor approval. 
5.7 
Assessment of Treatment Compliance 
On all visits to the study center, patients will be questioned in regard to compliance with study 
instructions. 
5.8 
Treatment of Pamiparib Overdose 
Overdose is defined as: the patient has taken (accidentally or intentionally) a dose exceeding 120 mg 
BID or higher. Patients with a suspected overdose should be managed with appropriate supportive 
therapy as determined by the investigator in consultation with the medical monitor. Any adverse 
effects occurring as a result of an overdose should be reported to the medical monitor as well as 
being included in standard AE reporting. 
5.9 
Occupational Safety 
Pamiparib is not expected to pose significant occupational safety risk to the study center personnel 
under normal conditions of use and administration. A material safety data sheet describing 
occupational hazards and recommended handling precautions will be provided to the investigator, 
where this is required by local laws, or is available upon request from the sponsor. 
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6 CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES 
6.1 
Permitted Medications 
All treatments 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 taken during the study will be recorded on the eCRF including all 
prescription, over-the-counter (OTC) drugs, herbal supplements, and intravenous (IV) medications 
and fluids. If changes occur during the study period, documentation of drug dosage, frequency, 
route, and date will also be included on the eCRF. 
All concomitant medications received within 30 days before the first dose of study medication and 
30 days after the last dose of study medication should be recorded. 
The eCRF entry must include the dose, regimen, route, indication, and start and stop dates of use of 
the prior and concomitant medication. 
6.2 
Prohibited Medications 
Patients are not allowed to receive other anti-cancer therapy, including surgery, radiation therapy, 
immunotherapy, investigational agents, cytotoxic, biologic or hormone therapy, anti-cancer Chinese 
medicine or anti-cancer herbal remedies. Hormone replacement therapy is allowed. Bisphosphonate 
and denosumab use is permitted if the patient has already been receiving it at a stable dose for >28 
days prior to Day 1.  
The primary metabolic pathway for pamiparib involves the CYP3A isoform. Co-administration of 
strong/moderate inhibitors of CYP3A or strong CYP3A inducers with pamiparib is not permitted 
(FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers). 
Please refer to the drugs/substances listed in Appendix 8 and to 
http://medicine.iupui.edu/clinpharm/ddis/main-table/ for a more complete list of medications that are 
not permitted. 
Grapefruit juice is not allowed at any time during the study.  No other dietary restrictions will apply. 
6.2.1 
Medications to be used with Caution 
Based on preliminary in vitro screening assays, pamiparib is not a strong inhibitor of other human 
CYP isoenzymes tested. It is a moderate inhibitor of CYP2C9 (IC50 = 6.48 µM). Investigators 
should be aware that pamiparib has the potential to interfere with the appropriate metabolism of 
medications that rely on CYP2C9. Investigators should follow the prescribing information 
recommendations for use with CYP2C9 inhibitors. Examples of these medications include, but are 
not limited to medications presented in Appendix 9 and these should be used cautiously with the 
monitoring of drug concentrations where appropriate. 
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In addition to CYP3A, pamiparib can also be metabolized by CYP2C8 in human liver microsomes, 
but to a lesser extent. The compounds/substances presented in Appendix 10 are associated with 
possible interactions with pamiparib through the CYP2C8 metabolic pathway and should also be 
used cautiously. 
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7 STUDY ASSESSMENTS 
7.1 
Pre-screening 
In Phase 2, all patients including those with known germline BRCA1/2 mutation should undergo 
blood sampling for examination or confirmation of germline BRCA1/2 mutation prior to screening. 
The mutation test will be performed in the qualified central laboratory. 
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 being eligible for the study. 
The following will be performed during pre-screening blood sample collection: 
 Obtain written pre-screening informed consent form (ICF) from the patient or the patient’s legal 
representative 
 Prepare blood sample and ship to the qualified central lab for mutation analysis as specified in 
the laboratory manual 
7.2 
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 5 for the Phase 1 portion, and Table 7 for the Phase 2 portion. The PK sampling time points 
are presented in Table 6 for the Phase 1 portion, and Table 8 for the Phase 2 portion. 
Rescreening under limited condition 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. 
7.2.1 
Demographic and Baseline Assessments 
7.2.1.1 
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 and database. 
7.2.1.2 
Medical History/ Prior medications 
Clinically significant medical history findings (eg, previous diagnoses, diseases, or surgeries) which 
started prior to signing the ICF, and are considered relevant for the patient’s study eligibility, 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 
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of signs or symptoms that require medical intervention. Concurrent medical signs and symptoms 
must be documented to establish baseline severities. 
The details regarding prior therapies administered for the disease under investigation which include: 
start/stop dates, reason for stopping, best response, and date of best response, will be collected. 
7.2.1.3 
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 4.1.4. Except for 
disease assessment, screening assessments will be completed within 21 days prior to the first dose of 
the pamiparib. Disease assessments may be completed up to 28 days prior to pamiparib 
administration. In the Phase 1 portion, baseline blood samples should be collected from all patients 
at screening for retrospective germline BRCA mutation testing. In the Phase 2 portion, a blood 
sample at baseline for germline BRCA mutation testing will not be collected because all patients will 
have undergone this collection during the pre-screening phase. Screening assessments completed 
within 96 hours of administration can be used as Day 1 assessments as indicated in Table 5 for 
Phase 1, and Table 7 for Phase 2.  
All the baseline data will be captured in the source documents and in the eCRF. Any results falling 
outside the normal range will be repeated at the discretion of the investigator. 
7.3 
Assessments During Treatment 
Safety, PK, and efficacy assessments will be performed throughout the study. The list of events and 
the time when they will be performed are presented in Table 5 for Phase 1 and Table 7 for Phase 2.  
7.3.1 
Laboratory Evaluation 
Laboratory assessments should be performed at a local certified laboratory on Day 1 before 
pamiparib administration. Laboratory assessments need not be repeated on Day 1 if these 
assessments were completed for screening within 96 hours 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 
Table 5 for Phase 1, and Table 7 for Phase 2. 
7.3.2 
Physical Examination and Vital Signs 
A complete physical examination, vital signs (systolic blood pressure, diastolic blood pressure, pulse 
rate, temperature), and weight will be performed at the time points specified in Table 5 for Phase1 
and Table 7 for Phase 2. 
Full physical examination includes: 1) examination of general appearance; 2) head, eyes, ears, nose 
and throat; 3) neck; 4) heart; 5) chest (including lungs); 6) abdomen; 7) extremities; 8) skin; 9) 
lymph nodes; 10) cardio-vascular; and 11) neurological status. Only at baseline and EOT visit is the 
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full physical examination required. In other visits (or as clinically indicated), limited symptom-
directed physical examinations will be performed. 
ECOG performance status will be evaluated at screening, on Day 1 of Cycle 1 and additional Cycles, 
and at mandatory EOT Visit. 
Vital signs will include body temperature, pulse rate, and blood pressure. To the extent feasible, 
blood pressure will be taken on the same arm throughout the study. A large cuff should be used for 
obese patients. Patients should be resting in a sitting position for 10 minutes prior to obtaining vital 
signs. If blood pressure is >150/100 in a patient without a history of hypertension, or increased 
>20 mmHg (diastolic) from baseline measurement in a patient with a previous history of 
hypertension, the assessment should be repeated in 10 minutes for confirmation. 
7.3.3 
Electrocardiogram 
7.3.3.1 
For Phase 1 Portion 
Three 12-lead ECGs will be performed at screening, at least 5 minutes apart and after at least a 
10-minute rest. Patients should be in the semi-recumbent or supine position. To minimize postural 
variability, it is important that patients are resting and in a supine position for 5 minutes prior to each 
ECG collection. Blood draws and other procedures should be avoided during the period immediately 
before ECG measurement, and activity should be controlled as much as possible to minimize 
variability because of the effects of physiologic stress.  
Electrocardiograms will be obtained at the time points specified in Table 6. If prolongation of QT or 
QT interval corrected for heart rate (QTc) is noted during the first 15 days, 12-lead ECGs will be 
performed weekly during Week 3 to Week 6, and then once every 3 weeks, on Day 1 of every cycle 
from Cycle 3 onwards, for the remaining duration of treatment. 
Significant QTcF prolongation will be defined as an interval ≥ 500 msec or an interval which 
increases by ≥ 60 msec over baseline. Either of these conditions should be documented on two or 
more ECG tracings separated by at least 5 minutes. Where two or more ECG tracings are carried out, 
confirm that the PK blood sample has been collected within the specified time window; the time 
points for PK blood collection shall not be deferred due to repeated ECG tracings. The ECG tracing 
should be examined and a manual measurement by a trained physician should be performed to assess 
the accuracy of the equipment being used. 
If a patient has significant QTc prolongation： 
 He/she will be withdrawn from the investigational product administration if the investigator 
and/or the medical monitor determine the patient is at risk. 
 The patient will be monitored, treated appropriately, and closely followed (ECGs at least 3 times 
per week) until the QT and QTc interval return to within 30 msec of baseline. 
 The medical monitor will be consulted prior to administering further doses or re-challenging. 
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 The medical monitor will be consulted prior to administering higher doses. 
7.3.3.2 
For Phase 2 Portion 
A single 12-lead ECG with assessment of PR interval, QRS duration, and QTc interval will be 
obtained as outlined in Table 6. Additional ECGs will be performed if clinically indicated. To 
minimize postural variability, follow procedures as outlined in the Phase 1 portion. Screening ECG 
must be performed within 14 days of first dose. 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.  
During the PK sample collection (Table 8), ECGs will be performed in triplicate on Day 1 of Cycles 
1 and 2 prior to pamiparib PK assessments. ECGs for each patient should be obtained from a 
calibrated machine provided for the study and the same machine must be used for all ECG 
assessments on Day 1. Triplicate ECGs results will be sent to a central reader. 
7.3.4 
Computed Tomography 
A CT scan of the chest, abdomen, and pelvis plus other relevant evaluations as appropriate, 
including bone scan for patients with bone metastasis, will be performed to assess all known disease. 
All known disease must be documented as target or non-target lesions using RECIST, version 1.1. 
The CT scan will be used for disease assessment by the investigator at each study center. 
Unless contraindicated, intravenous contrast product must be used to maximize visualization of all 
lesions. Five-millimeter contiguous scans at baseline and subsequent scanning once every 6 weeks ± 
7 days (as calculated by the date of the first administration of pamiparib) for the first 18 weeks, 
thereafter once every 9 weeks± 7 days for the remaining period in the first year, and then once every 
12 weeks ±7 days starting with the second year until progression, with mandatory imaging coverage 
from thoracic inlet to symphysis pubis should be performed. For patients with a first response as CR 
or PR, a response confirmation will need to be performed during the following 4-6 weeks, then 
patient will keep original tumor assessments schedule per protocol. Patients who are at increased risk 
of allergic reaction to iodinated contrast media should not have enhanced CT, but should instead be 
provided MRI with gadolinium enhancement according to local protocol, with mandatory imaging 
coverage from thoracic inlet to symphysis pubis plus unenhanced CT scanning with coverage from 
the thoracic inlet to the inferior costophrenic recess. 
If a CT scan for tumor assessment is performed in a positron emission tomography (PET)/CT 
scanner, the CT acquisition must be consistent with the standards for a full-contrast diagnostic CT 
scan.  
If clinically indicated, bone ECT scans (Technetium-99m [TC-99m]) or sodium fluoride PET (NaF-
PET) should be performed at screening for patients with ovarian cancer, fallopian cancer, and 
primary peritoneal cancer. If bone metastases are present at screening and cannot be seen on CT or 
MRI scans, or if clinically indicated, ECT or NaF-PET bone scans should be repeated when CR is 
identified in target disease, or when progression in bone is suspected. 
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The same imaging technique should be used in a patient throughout the study.  
Patients with treatment terminated prior to documentation of PD shall be subjected to CT/MRI 
radiographic assessment according to the previous visit assessment scheme, until 1) commencement 
of new treatment, 2) disease progression, 3) death or 4) termination of the study. (eg, once every 
6 weeks ± 7 days in the first year, then every 12 weeks ±7 days afterwards). 
Lesions that are expected to require palliative radiotherapy while in the study should not be included 
as target lesions, but should be listed as non-target lesions. 
For Phase 2 section, all CT/MRI etc, imaging materials will be required to be sent for IRR. 
7.3.5 
Tumor Antigens 
For Phase 1, blood tumor antigen such as CA-125 will be tested in a certified local laboratory during 
screening (within 14 days prior to administration), every 6 weeks ± 7 days in the first year after the 
initiation of the study, then approximately every 12 weeks ± 7 days thereafter as specified Table 5. 
For Phase 2, CA-125 will be tested in a certified local laboratory during screening (within 14 days 
prior to administration), once every 6 weeks ± 7 days for the first 18 weeks, thereafter once every 9 
weeks ± 7 days for the remaining period in the first year, and then once every 12 weeks ± 7 days 
starting with the second year as specified in Table 7. 
7.4 
Safety Assessment 
Vital signs, weight, physical examinations, ECOG performance status, ECGs and laboratory safety 
tests (eg, prothrombin time/activated partial thromboplastin time, urinalysis, complete blood count, 
serum chemistries) will be obtained and assessed at designated intervals throughout the study (see 
Table 5 for Phase 1, and Table 7 for Phase 2). 
For the Phase 2 portion, 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 AEs. Study activities of 
an unscheduled visit should be performed based on the reason for the unscheduled visit and are 
outlined in Table 7. If PD is suspected, imaging studies should be performed and 
 
.  
AEs will be graded and recorded throughout the study according to NCI-CTCAE, version 4.03. 
Characterization of toxicities will include severity, duration, and time to onset. Safety endpoints will 
include all types of AEs, in addition to laboratory safety assessments, ECOG performance scale 
status, ECGs, and vital signs. 
7.4.1 
Safety Evaluation 
The continuous safety evaluation will be performed by the sponsor, the coordinating investigator, 
and investigators. For Phase 1 portion, a SMC will be established for the determination of dose 
levels to be administered during dose escalation and dose regimens in this study. Details of the 
safety monitoring process will be specified in a dedicated SMC charter. 
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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 or non-laboratory toxicities. 
Patients with treatment terminated prior to documentation of PD shall be subjected to 
CT/MRI/CA-125 disease assessment according to the previous visit assessment scheme, until 1) 
commencement of new treatment, 2) disease progression, 3) death or 4) termination of the study. 
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 (only for Phase 2). Patients 
will have their survival status assessed approximately every 3 months 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. 
7.7 
Pharmacokinetic Assessment 
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 frozen. 
Samples must remain frozen in a freezer set 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. 
7.7.1 
Blood Samples collection and handling 
Time points of PK sampling are specified in Table 6 for Phase 1 and Table 8 for Phase 2. PK 
sampling will be conducted according to the laboratory manual. The actual time each sample was 
collected 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 detailed collection and handling opinion of PK blood sample and sample for BRCA1/2 mutation 
test, please refer to laboratory manual. If there is any inconsistency in blood sample collection and 
handling between protocol and lab manual, lab manual will take priority.  
Phase 1 Portion: 
For patients participating in Phase 1 of the study, a total of 22 blood samples will be collected for 
determination of pamiparib concentration. These samples will be collected at the time points 
presented in Table 6. Details concerning handling of the PK plasma samples, including labeling and 
shipping instructions will be provided in the study manual. 
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Cycle 1 Days 1, 2 and 3 Blood Samples 
Ten blood samples (2 mL each) will be collected on Days 1, 2 and 3 at the following time points: 
pre-dose (within 1 hour before pamiparib administration) and 0.5, 1, 2, 4, 6, 9, 12, 24 and 48 hours 
post-dose (the 48-hour PK sample will be collected on Day 3 before morning dose). 
Cycle 1 Day 10 Blood Samples 
Eight blood samples (2 mL each) will be collected on Cycle 1 Day 10 at the following time points: 
pre-dose (within 1 hour before pamiparib administration) and 0.5, 1, 2, 4, 6, 9 and 12 hours 
post-dose. 
Cycle 2 Day 1 and Cycle 3 Day 1 Blood Samples 
Two blood samples (2 mL each) will be collected on Cycle 2 Day 1 and Cycle 3 Day 1 pre-dose 
(within 1 hour before pamiparib administration) and 2 hours post-dose. 
Other Blood Samples 
Blood samples (2 mL) should be obtained, when possible, for analysis of plasma pamiparib in the 
event of a DLT. the investigator must record the time the blood samples obtained and the time of the 
previous administration in the eCRF. 
Should a drug-drug interaction (DDI) between pamiparib and a concomitant medication be 
suspected, further blood samples for PK analyses may be taken to characterize the extent of the 
interaction. 
Phase 2 Portion: 
Sparse PK samples will be collected for all patients at sites with the capacity to collect PK samples 
for determination of pamiparib and possibly its major metabolite(s). Serial PK samples will be 
collected in approximately 15 patients at selected sites with the capacity to collect serial PK samples 
on Cycle 1 Day 1 and Cycle 2 Day 1 at the following time points: pre-dose, 0.5, 1, 2, 4, 6, 9 and 12 
hours post dose. These samples will be collected at the time points presented in Table 8. The 
triplicate ECGs will also be collected from at least 15 patients from those who could contribute to 
PK collection in this Phase 2 trial, with the option to collect from more patients. The triplicate ECGs 
results will also be sent to a central reader so that a concentration-QTc analysis can be attempted. 
Cycle 1 Day 1 and Cycle 2 Day 1 Blood Samples  
Four blood samples (2 mL each) will be collected on Cycle 1 Day 1 and Cycle 2 Day 1 at the 
following time points: pre-dose (within 1 hour before pamiparib administration) and 2 hours 
post-dose for sparse PK sample collection. 
Except for sparse PK sample collection, on Cycle 1 Day 1 and Cycle 2 Day 1, sixteen additional 
blood samples (2 mL each) will be collected at the following time points: 0.5, 1, 4, 6, 9 and 12 hours 
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post-dose for serial PK sample collection (only 15 patients will participate in serial PK test in 
selected sites, which have the capability to conduct intensive PK sample collection). 
If DDI between pamiparib and concomitant drug is suspected, additional blood samples can be 
collected for PK analysis to characterize the extent of interaction. 
7.8 
 
7.9 
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 QUALITY CONTROL AND QUALITY ASSURANCE 
According to the GCP guidelines, the sponsor is responsible for implementing and maintaining 
quality assurance and quality control systems with written standard operating procedures (SOPs). 
Quality control will be applied to each stage of data handling. 
The following steps will be taken to ensure the accuracy, consistency, completeness, and reliability 
of the data: 
 Investigator meeting(s) 
 Certified local laboratories for laboratory measurements and 12-lead ECGs 
 Study center initiation visit 
 Early study center visits post-enrollment 
 Routine study center monitoring 
 Ongoing study center communication and training 
 Data management quality control checks 
 Continuous data acquisition and cleaning 
 Internal review of data 
 Quality control check of the final clinical study report 
 Certified independent radiology review (Phase 2 Section) 
 Certified ECT result central reading (for patients who contribute to PK sample collection in 
Phase 2 portion) 
In addition, the sponsor and/or the contract research organization clinical quality assurance 
department may conduct periodic audits of the study processes, including, but not limited to the 
study center, central laboratories, vendors, clinical database, and the final clinical study report. When 
audits are conducted, access must be authorized for all study-related documents including medical 
history and concomitant medication documentation to authorized Sponsor’s representatives and 
regulatory authorities. 
8.1 
Monitoring 
In accordance with applicable regulations, GCP, and sponsor procedures, the sponsor and/or contract 
research organization monitors will contact the study center prior to the patient enrollment to review 
the protocol and data collection procedures with the study center personnel. In addition, the medical 
monitor will periodically contact the study center, including conducting on-site visits. The extent, 
nature and frequency of on-site visits will be based on such considerations as the study objective 
and/or endpoints, the purpose of the study, study design complexity, and enrollment rate. 
During these contacts, the medical monitor will: 
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 Check the progress of the study 
 Review study data collected 
 Conduct source document verification 
 Identify any issues and address their resolution 
This will be done in order to verify that: 
 Data are authentic, accurate, and complete 
 Safety and rights of patients are being protected 
 Study is conducted in accordance with the currently approved protocol (and any amendments), 
GCP, and all applicable regulatory requirements 
The investigator agrees to allow the monitor direct access to all relevant documents and to allocate 
his/her time and the time of his/her personnel to the medical monitor to discuss findings and any 
relevant issues. 
At study closure, monitors will also conduct all activities described in Section 12.1. 
8.2 
Data Management/Coding 
Data generated within this clinical study will be handled according to the relevant SOPs of the data 
management and biostatistics departments. 
An electronic data capture (EDC) system will be used for this study, meaning that all eCRF data will 
be entered in electronic forms at the study center. Data collection will be completed by authorized 
study center personnel designated by the investigator. Appropriate training and security measures 
will be completed with the investigator and all authorized study center personnel prior to the study 
being initiated and any data being entered into the system for any patients. 
The eCRFs should always reflect the latest observations on the patients participating in the study. 
Therefore, the eCRFs are to be completed as soon as possible during or after the patient’s visit. To 
avoid inter-observer variability, every effort should be made to ensure that the same individual who 
made the initial baseline determinations completes all safety evaluations. The investigator must 
verify that all data entries in the eCRFs are accurate and correct. If some assessments are not done, 
or if certain information is not available or not applicable or unknown, the investigator should 
indicate this in the eCRF. The investigator will be required to electronically sign off on the clinical 
data. 
The monitor will review the eCRFs and evaluate them for completeness and consistency. The eCRF 
will be compared with the source documents to ensure that there are no discrepancies between 
critical data. All entries, corrections, and alterations are to be made by the responsible investigator or 
his/her designee. The monitor cannot enter data in the eCRFs. Once clinical data of the eCRF have 
been submitted to the central server, corrections to the data fields will be audit trailed, meaning that 
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the reason for change, the name of the person who performed the change, together with time and 
date will be logged. Roles and rights of the study center personnel responsible for entering the 
clinical data into the eCRF will be determined in advance. If additional corrections are needed, the 
responsible monitor or data manager will raise a query in the EDC application. The appropriate 
study center personnel will answer queries sent to the investigator. 
The eCRF is essentially considered a data entry form and should not constitute the original (or 
source) medical records unless otherwise specified. Source documents are all documents used by the 
investigator or hospital that relate to the patient’s medical history, that verify the existence of the 
patient, the inclusion and exclusion criteria and all records covering the patient’s participation in the 
study. They include laboratory notes, ECG results, memoranda, pharmacy dispensing records, 
patient files, etc. 
The investigator is responsible for maintaining source documents. These will be made available for 
inspection by the study monitor at each monitoring visit. The investigator must submit a completed 
eCRF for each patient who receives pamiparib, regardless of the duration. All supportive 
documentation submitted with the eCRF, such as laboratory or hospital records, should be clearly 
identified with the study and patient number. Any personal information, including patient name, 
should be removed or rendered illegible to preserve individual confidentiality. 
Electronic CRF records will be automatically appended with the identification of the user, by means 
of their unique user ID. Specified records will be electronically signed by the investigator to 
document his/her review of the data and acknowledgement that the data are accurate. This will be 
facilitated by means of the investigator’s unique user ID and password; date and time stamps will be 
added automatically at the time of the electronic signature. If an entry on an eCRF requires change, 
the correction should be made in accordance with the relevant software procedures. All changes will 
be fully recorded in a protected audit trail, and a reason for the change will be required. 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 18.1 
or higher, and graded using the current version of NCI-CTCAE. Concomitant medications will be 
coded using the World Health Organization Drug Dictionary. Concomitant diseases/medical history 
will be coded using the MedDRA, version 18.1 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 any relevant issues found. 
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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 pre-existing condition including an increase in severity, 
frequency, duration, and/or has an association with a significantly worse outcome  
 New conditions detected or diagnosed after study drug administration even though it may have 
been present before the start of the study 
 Signs, symptoms, or the clinical sequelae of a suspected interaction 
 Signs, symptoms, or the clinical sequelae of a suspected overdose of either study drug or a 
concurrent medication (overdose per se should not be reported as an AE or SAE) 
When an AE or SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory results and diagnostics reports) relative to the AE or SAE. 
The investigator will then record all relevant information regarding an AE or SAE in the eCRF. 
However, there may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this instance, all patient identifiers will be blinded on the copies of the medical 
records prior to submission to the sponsor.  
9.1.2 
Assessment of Severity 
The investigator will make an assessment of 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. 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living  
 Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living  
 Grade 4: Life-threatening consequences; urgent intervention indicated  
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 Grade 5: Death related to AE  
NOTE: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity (for 
example, grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or 
life-threatening [Grade 4]), whereas seriousness is classified by the criteria based on the regulatory 
definitions. Seriousness serves as the guide for defining regulatory reporting obligations from the 
Sponsor to applicable regulatory authorities as described in Section 9.2. 
9.1.3 
Assessment of Causality 
The investigator is obligated to assess the relationship between 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. 
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 
makes assessment of causality for every SAE prior to 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 in light of 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 to the study drug, and 
there is reasonable temporal relationship; the occurrence of AE is definitely attributed to the 
pharmacological effect of study treatment. 
 Probably related: There is a reasonable temporal relationship to suggest a causal relationship to 
the study drug; the occurrence of AE could not be explained by the patient’s medical history, 
concurrent medical condition, or other the patient’s signs or symptoms. 
 Possibly related: There is some evidence to suggest a causal relationship to the study drug (eg, 
the AE occurred within a reasonable time after administration of the study drug). However, the 
influence of other factors may have contributed to the AE (such as the patient’s clinical 
condition, other concomitant AEs). 
 Unlikely related: There is little evidence to suggest there is a causal relationship to the study 
drug. There is another reasonable explanation for the AE such as disease or other drugs. 
 Unrelated: An AE will be considered “not related” to the use of study drug if any of the 
following criteria are met:  
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o An unreasonable temporal relationship between administration of the drug and the onset on 
the AE (eg, the AE occurred either before, or too long after administration of the 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. 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 
post-mortem findings, including histopathology. 
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 9.6.1. 
9.1.5 
Laboratory Test Abnormalities 
Abnormal laboratory findings (e.g., chemistry, hematology, coagulation [only for Phase 1 portion]) 
or other abnormal assessments (ECGs, X-rays, vital signs) that are judged by the investigator as 
clinically significant will be recorded as adverse events or serious adverse events. 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 left to 
the judgment of the investigator; in general, these are the abnormalities that are associated with 
clinical signs or symptoms, require active medical intervention, or lead to dose interruption or 
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discontinuation, or require close observation, or 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.  
 Results in disability/incapacity 
NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle), which may interfere 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 judgement (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 pre-existing 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 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction that is both 
unexpected (ie, not present in the product’s Reference Safety Information [RSI] in the IB) and meets 
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the definition of a serious adverse drug reaction (SADR), the specificity or severity of which is not 
consistent with those noted in the IB. 
9.4 
Timing, Frequency, and Method of Capturing Adverse Events and Serious Adverse 
Events 
9.4.1 
Adverse Event Reporting Period 
After main informed consent has been signed at screening but prior to study treatment, only SAEs 
should be reported. 
After initiation of study treatment, all AEs and SAEs, regardless of relationship to study treatment, 
will be reported until 30 days after last study treatment or initiation of new anti-cancer therapy, 
whichever occurs first. After this period, the investigator should report any SAEs including death 
that are believed to be related to prior study treatment.  
9.4.2 
Eliciting Adverse Events 
The investigator or designee will ask about AEs by asking the following standard questions: 
 How are you feeling?  
 Have you had any medical problems since your last visit?  
 Have you taken any new medicines since your last visit?  
9.5 
Study Specific AEs/SAEs Reporting Instructions 
9.5.1 
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 adverse event term. 
Instead, the symptoms, signs or clinical sequelae that result from disease progression should be 
reported as the adverse events.  
For instance, 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 multi-organ failure due to disease progression, the term “multi-organ 
failure” should be reported as the SAE with death as outcome instead of reporting “fatal disease 
progression” or “death due to disease progression”.  
9.5.2 
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, e.g. “death”, “death of 
unknow cause”, or “death unexplained”. 
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9.6 
Prompt Reporting of Serious Adverse Events 
9.6.1 
Timeframes for Submitting Serious Adverse Events 
SAEs will be reported promptly (within 24 hours) to the sponsor or designee as described in Table 
10 once the investigator determines that the AE meets the protocol definition of an SAE. 
Table 10. 
Time Frame for Reporting Serious Adverse Events to the Sponsor or Designee 
 
Timeframe for 
Making Initial 
Report 
Documentation 
Method 
Timeframe for 
Making Follow-
up Report 
Documentation 
Method 
Reporting 
Method 
All SAEs  
Within 24 hours of 
first knowledge of 
the SAE 
SAE Report 
As expeditiously 
as possible 
SAE Report 
Email or fax 
SAE form or 
Pregnancy 
form 
Abbreviations: AE, adverse event; SAE, serious adverse event 
9.6.2 
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 9.6.1. The SAE Report will always 
be completed as thoroughly as possible with all available details of the SAE, signed by the 
investigator, 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. 
9.6.3 
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 9.6.2. 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 SUSARs (as defined in Section 9.3), will be submitted to applicable regulatory authorities and 
investigators. 
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 
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10 DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
10.1 
Sample Size Considerations 
Approximately 14-18 evaluable patients will be enrolled in Phase 1 portion of the trial. In the Phase 
2 portion of the trial, approximately 100 evaluable patients will be enrolled.  
In recurrent HGOC patients, it is assumed that ORR is 52% with pamiparib in previously treated 
platinum-sensitive patients with BRCA mutation. A total of 80 evaluable patients will give 98% 
power to demonstrate a statistical difference versus a historical response rate of 30% using a 
binomial exact test at an alpha of 0.025. The 2-sided exact 95% CI is (40.5%, 63.3%) when the 
observed ORR is 52%. Approximately 20 patients will be enrolled to the platinum-resistant HGOC 
patients.  
Hence, approximately 118 patients will be enrolled to obtain 14-18 evaluable patients in Phase 1 and 
100 evaluable patients in Phase 2.  
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 (CV%) as appropriate, median, minimum, and maximum 
 Categorical variables: frequencies and percentages 
 Time to event variables: number of non-missing observations (N), 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 phase, then by dose. The analysis methods described in this section are 
directed to Phase 2 portion of the trial. However, they will be applied to the Phase 1 portion of data 
analyses whenever appropriate.  
Further description of the statistical methods and analyses will be provided in the statistical analysis 
plan. 
10.2.1 
Analysis Populations 
The Safety Population (SP) includes all patients who received at least one dose of pamiparib. 
The Efficacy Evaluable Population (EEP) includes all patients in the SP who had measurable disease 
at baseline per RECIST, version 1.1 and had at least one post baseline tumor assessment unless 
discontinued treatment due to clinical progression or death prior to tumor assessment. 
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The DLT Population includes all patients who received at least 75% of pamiparib or who 
experienced a DLT event during the DLT observation period (Cycle 1). 
The PK Population includes all patients for whom valid pamiparib PK parameters can be estimated.  
The Evaluable for CA-125 Response Population is defined as the subset of subjects in the SP with 
baseline CA-125 ≥ 2 x ULN (Rustin et al 2004). This will be the primary analysis set for the analysis 
of CA-125 response rate. 
10.2.2 
Interim Analysis 
No formal interim analysis is planned. A brief data summary will be performed once the Phase 1 
dose escalation portion of the trial is completed. 
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 SP 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 
Phase 2 
Hypothesis testing of ORR will only be performed in the patients with high grade platinum-sensitive 
ovarian cancer (PSOC). The primary analysis will be carried out using IRR data in EEP. Efficacy 
endpoints based on investigator assessed tumor response will be presented as the sensitivity analysis. 
ORR of pamiparib per IRR is assumed as 52% in patients with recurrent PSOC. The historical rate in 
a similar population is estimated as 30%. The null and alternative hypotheses are set as follows: 
 H0:  ORR=30% 
 Ha:  ORR >30% 
A binomial exact test will be performed for hypothesis testing in recurrent PSOC EEP. 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 SP.  
ORR in evaluable recurrent high-grade platinum-resistant ovarian cancer (PROC), as well as in all 
evaluable recurrent HGOC will be summarized descriptively. 
10.3.2 
Secondary Efficacy Analyses 
Phase 2  
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 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 analyzed in the SP 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 point (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. 
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BOR is defined as the best response recorded from the start of pamiparib until data cut off or start of 
new anti-neoplastic treatment. BOR and their 95% CIs will be summarized in the EEP. Sensitivity 
analysis of BOR will be carried out in the SP. The proportion of each response category (CR, PR, 
SD, PD and NE) will be presented in the EEP and SP. 
Data will be summarized by platinum status and overall. Data assessed by IRR and investigator will 
be summarized. 
DCR and CBR and their 95% CIs will be summarized in the EEP and SP.  
The analysis of CA-125 response rate will be conducted on the evaluable for CA-125 analysis set 
and will be same as the analysis of objective response rate. The analysis of change in CA-125 (the 
maximum percent change from baseline) will be conducted in the SP. Summary statistics, 2-sided 
95% confidence intervals, and graphical summaries will be generated for the percent change from 
baseline in CA-125. 
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 ECGs findings will also be 
used in determining the safety. Descriptive statistics will be used to analyze all safety data in the SP. 
10.4.1 
Maximum Tolerated Dose 
The MTD is defined as the dose that produces an “acceptable” level of toxicity or that, if exceeded, 
would put patients at “unacceptable” risk for toxicity. The MTD for this study is defined as the dose 
level at which 0/6 or 1/6 patients experiences DLT, provided that ≥33% of patients experienced DLT 
at the next higher dose level in Cycle 1. 
10.4.2 
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 or was worsening in severity from 
baseline (pretreatment). 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. 
DLT events will be summarized by dose level in Phase 1 dose escalation portion. 
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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. Select laboratory 
data will be summarized by grade. Vital signs and physical examination will also be summarized by 
visit. 
10.4.3 
Laboratory Assessments 
Hematology, clinical chemistry, and urinalysis values will be listed for each patient and flagged as 
high or low relative to the normal range, where applicable. Pre-dose values will be used to assess 
laboratory shifts occurring at post-dose. A comparison of pre-study and post-study values may be 
performed to identify any parameters that have not returned to pre-study levels. 
10.4.4 
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. Dose interruption, reduction and 
discontinuation will be summarized by frequency. 
10.5 
Pharmacokinetic Analyses 
PK parameters will be derived using standard non-compartmental methods with WinNonlin 
Professional, version 5.2 or higher (Pharsight Corp., Mountain View, California) or SAS®, version 
9.4 or higher (SAS Institute, Inc., Cary, North Carolina). Nominal sampling times will be used for 
interim PK parameter calculations, while actual sampling times will be used in the final PK 
parameter calculations. 
Where possible, the following PK parameters will be determined for pamiparib and possibly its 
major metabolite(s) on Cycle 1 Days 1, 2, 3: 
AUC0-inf 
Area under the plasma concentration-time curve from zero extrapolated to 
infinity calculated using the linear up/log down trapezoidal method 
AUC0-12h 
Area under the plasma concentration-time curve from zero to 12 hours post 
dose 
AUClast  
Area under the plasma concentration-time curve from zero to last time point of 
administration 
Cmax and Cmax,ss 
Maximum observed plasma concentration 
Tmax and Tmax,ss 
Time of maximum observed plasma concentration 
t1/2 
Elimination half-life 
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CL/F 
Apparent clearance 
Vz/F 
Apparent volume of distribution during the terminal phase 
RAUC 
AUC accumulation ratio 
RCmax Cmax 
 
accumulation ratio (Phase IA: Cmax Cycle 1 Day 10/Cmax Cycle 1 Day 1) 
For patients in Phase 2, Tmax, Cmax, Cmin, and AUC0-12h (PK intensive patients only). 
Additional PK parameters may be calculated if deemed appropriate. 
Plasma pamiparib concentration-time data will be summarized and displayed in both tabular and 
graphical form. Concentration-time data will be analyzed with standard non-compartmental and/or 
compartmental PK methods. The PK parameters for a single dose profile (AUC0-12h, AUC0-inf, 
AUClast, Cmax, Tmax, t1/2, CL/F, and Vz/F) and after steady-state (AUClast,ss, Cmax,ss, Tmax,ss), will be 
calculated, if there are sufficient data. Individual patient parameter values, as well as a descriptive 
summary (mean, standard deviation, median, minimum, maximum, and the standard deviation and 
geometric mean of log-transformed parameters) by treatment group will be reported. Individual 
patient parameter values will be plotted against dose. 
Dose proportionality of AUC0-inf, AUCss, Cmax, and Cmax,ss for pamiparib may be assessed using the 
power model as described below and evaluated visually in graphical form. 
A linear regression model with the logarithm of the PK parameter (AUC, Cmax, and AUClast) as the 
dependent variable and the logarithm of the dose as the independent variable 
(log[PK]=α+β*log[Dose]) will be fitted. The model parameters (slope [β] and intercept [α]) will be 
estimated using least square regression. A minimum of 3 values per dose must be available for a 
given PK parameter to estimate dose proportionality with the power model. Point estimates and 
corresponding 2-sided 95% CIs for the slope parameter and the intercept parameter will be provided. 
10.6 
Biomarker Analyses 
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11 ETHICS 
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 before the study is initiated 
at a study center in China. 
11.2 
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, 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 informed consent) are reviewed and 
approved by the appropriate IEC/IRB. The investigator agrees to allow the IEC/IRB direct access to 
all relevant documents. The IEC/IRB must be constituted in accordance with all applicable 
regulatory requirements. The sponsor will provide the investigator with relevant document(s)/data 
that are needed for IEC/IRB review and approval of the study. Before pamiparib and CRFs can be 
shipped to the study center, the sponsor must receive copies of the IEC/IRB approved study, the 
approved ICF, and any other information that the IEC/IRB has approved for presentation to potential 
patients. 
If the protocol, the ICF, or any other information that the IEC/IRB has approved for presentation to 
potential patients is amended during the study, the investigator is responsible for ensuring the 
IEC/IRB reviews and approves, where applicable, these amended documents. The investigator must 
follow all applicable regulatory requirements pertaining to the use of an amended ICF including 
obtaining IEC/IRB approval of the amended form before new patients consent to take part in the 
study using this version of the form. Copies of the approved amended ICF/other information must be 
forwarded to the sponsor promptly. 
11.3 
Informed 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. 
11.4 
Investigator Reporting Requirements 
As indicated in Section 9.6, 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 
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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. 
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12 STUDY ADMINISTRATION 
12.1 
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 
 Resolution of data queries 
 Accountability, reconciliation, and disposal for unused pamiparib 
 Review of study records for completeness 
 Return of treatment codes to the sponsor 
 Shipment of PK and pharmacodynamic 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 non-compliance. 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, 
disposal will be made for all unused pamiparib in accordance with the applicable sponsor procedures 
for the study. 
Financial compensation to investigators and/or institutions will be in accordance with the agreement 
established between the investigator and the sponsor. 
12.2 
Records Retention 
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, electronic); however, caution needs to be exercised 
before such action is taken. The investigator must assure that all reproductions are legible, are a true 
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and accurate copy of the original, and meet accessibility and retrieval standards, including 
re-generating 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 or transfer of ownership of the records 
in the event the investigator leaves the study center. 
12.3 
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 of the test results, because the 
information generated from this study will be preliminary in nature, and the significance and 
scientific validity of the results will be undetermined at such an early stage of research. 
12.4 
Information Disclosure and Inventions 
All information provided by the sponsor and all data and information generated by the study center 
as part of the study (other than a patient’s medical records) are the sole property of the sponsor. 
All rights, title, and interests in any inventions, know-how or other intellectual or industrial property 
rights which 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 which 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 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. 
These restrictions do not apply to: 
 Information which becomes publicly available through no fault of the investigator or study 
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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 which may be published as described Section 12.4.1 
 If a written contract for the conduct of the study which includes provisions inconsistent with this 
statement is executed, that contract’s provisions shall apply rather than this statement. 
12.4.1 
Publication Policy 
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 trial will be described in the Clinical Study Agreement. 
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13 REFERENCES 
Arun B, Bayraktar S. Liu DD, et al. Response to neoadjuvant systemic therapy for breast cancer in 
BRCA mutation carriers and non-carriers: a single-institution experience. J Clin Oncol. 2011: 
29(28):3739-3746. 
Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with 
inhibitors of poly(ADP-ribose) polymerase. Nature 2005; 434: 913-917. 
Center for Drug Evaluation and Research: NDA/BLA Multi-disciplinary Review and Evaluation 
NDA 209115 Rubraca (rucaparib). 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/209115Orig1s000AdminCorres.pdf  
Coleman RL, Sill MW, Bell-McGuinn K, et al. A phase II evaluation of the potent, highly 
selective PARP inhibitor veliparib in the treatment of persistent or recurrent epithelial ovarian, 
fallopian tube, or primary peritoneal cancer in patients who carry a germline BRCA1 or BRCA2 
mutation - An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 
2015;137(3):386.  
Common Toxicity Criteria Version 4.03. Cancer Therapy Evaluation Program. 14 June 2010. 
Fan Y, Xu BH, Yuan P, et al. Docetaxel-cisplatin might be superior to docetaxel-capecitabine in 
the first-line treatment of metastatic triple-negative breast cancer. Ann Oncol. 2013 
May;24(5):1219-25. 
Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a 
therapeutic strategy. Nature. 2005;434(7035):917.  
FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeli
ng/ucm093664.htm 
FDA Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics (2007). https://www.fda.gov/downloads/Drugs/Guidances/ucm071590.pdf  
FDA Summary Review for Regulatory Action: Olaparib. 
https://www.accessdata.fda.gov/drugsatfda docs/nda/2014/206162Orig1s000SumR.pdf 
Gronwald J, Byrski T, Huzarski R, et al. Neoadjuvant therapy with cisplatin in BRCA-1 positive 
breast cancer patients. J Clin Oncol. 2009; 27:15s (suppl abst 502). 
Hu XC, Zhang J, Xu BH, et al. Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as 
first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-
label, multicentre, phase 3 trial. Lancet Oncol. 2015 Apr;16(4):436-46. 
Investigator’s Brochure, BGB-290. Edition 2.2, document number BGB-290-022016:2.2, Feb 2016. 
Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in platinum-sensitive 
relapsed ovarian cancer. N Engl J Med. 2012;366(15):1382.  
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Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-
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BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014 Jul;15(8):852-61. 
Ledermann JA, Harter P, Gourley C, et al. Overall survival in patients with platinum-sensitive 
recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis 
from a randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Oncol 
2016;17(11):1579.  
Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science. 2017; Mar 
17;355(6330):1152-1158. 
Mirza MR, Monk BJ, Herrstedt J, et al. ENGOT-OV16/NOVA Investigators. Niraparib 
Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med. 
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Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. 
Cancer Res. 2012; 72(21): 5588-99. 
O'Connor MJ. Targeting the DNA Damage Response in Cancer. Mol Cell. 2015; Nov 19;60(4):547-
60.  
Oken MM, Creech RH, Tormey DC, et al. Toxicity in response of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5(6):649-655. 
O'Shaughnessy J, Osborne C, Pippen J, et al. Efficacy of BSI-201, a poly (ADP-ribose) 
polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients 
with triple-negative breast cancer (TNBC): Results of a randomized phase II trial. J Clin Oncol. 
2009 27:18s, (suppl; abstr 3). 
O’Sullivan CC. Beyond breast and ovarian cancers: PARP inhibitors for BRCA mutation-
associated and BRCA-like solid tumors. Frontiers in Oncology. 2014 Feb 28;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.  
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Ricks TK, Chiu HJ, Ison G, et al. Successes and Challenges of PARP Inhibitors in Cancer Therapy. 
Front Oncol. 2015; Oct 14;5: 222. 
Rustin GJ, Quinn M, Thigpen T, et al. Re: new guidelines to evaluate the response to treatment in 
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Telli M, Optimizing chemotherapy in triple-negative breast cancer: the role of platinum. 2014 
ASCO education book. Asco.org/edbook. 
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. 
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, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in 
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Lancet. 2010;376(9737):235.  
Weil MK, Chen A. PARP Inhibitor Treatment in Ovarian and Breast Cancer. Curr Probl Cancer. 
2011 Jan–Feb; 35(1): 7–50. 
Welsch PL, Schubert EL, King MC. Inherited breast cancer: an emerging picture. Clin Genet. 
1998;54(6):447-58. 
Wu X, Wu L, Kong B et al. The First Nationwide Multicenter Prevalence Study of Germline 
BRCA1 and BRCA2 Mutations in Chinese Ovarian Cancer Patients. Int J Gynecol Cancer. 
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14 APPENDICES 
APPENDIX 1: SIGNATURE OF INVESTIGATOR 
PROTOCOL TITLE: 
An Open Label, Multi-Center Phase I/II Study to Evaluate Efficacy 
and Safety of BGB-290 in Chinese Subjects with Advanced Ovarian 
Cancer, Fallopian Cancer, and Primary Peritoneal Cancer or Advanced 
Triple Negative Breast Cancer 
Protocol Identifier: 
 
BGB-290-102 
 
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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APPENDIX 2: CLINICAL LABORATORY ASSESSMENTS 
Clinical Chemistry 
Hematology 
Coagulation (only 
for Phase 1) 
Urinalysis 
Alanine aminotransferase 
 
Hemoglobin (Hgb)  
International 
normalized ratio 
Blood 
Alkaline phosphatase 
Platelet count 
Partial thromboplastin 
time  
Glucose  
Aspartate aminotransferase 
White blood cell count  
Prothrombin time 
Ketones  
Albumin 
Lymphocyte count 
 
pH 
Bilirubin (total) 
Neutrophil count  
 
Protein1 
Blood urea nitrogen or urea 
 
 
Red blood cell 
Calcium 
 
 
Specific gravity 
Chloride 
 
 
White blood cell 
Creatinine 
 
 
 
Glucose 
 
 
 
Lactate dehydrogenase 
 
 
 
Magnesium 
 
 
 
Phosphate 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Total protein 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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, then obtain a 24-hour urine sample for the analysis of 
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 M.D., Group Chair. 
 
 
 
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EOT 
Clinical chemistry 
5 
Hematology 
2.5 
Coagulation 
3 
Total 
10.5 
Other blood samples3 4,5 
1 
Unscheduled blood samples for pharmacokinetic analysis may also be collected whenever any notable safety is seen, to 
evaluate if the observation is exposure related. 
2 
Cannulation for blood sampling for pharmacokinetics will be performed. Blood will be collected via the intravenous cannula 
pre-dose and at the time points specified in Table 6 for Phase 1 Portion, Table 8 for Phase 2 Portion. 
3 
Blood samples (4 mL) should be obtained, when possible, for analysis of plasma pamiparib in the event of a DLT. 
4 
Should a drug-drug interaction between pamiparib and a concomitant medication be suspected, further blood samples for PK 
analyses may be taken to characterize the extent of the interaction.  
5 
Additional blood PK samples will be taken to determine the plasma concentration of BGB-290 if there is an intra-patient 
dose escalation. The Investigator must record the time points for PK sampling and the time of dose administration before PK 
sampling in eCRFs. 
6 
For patients with ovarian cancer, fallopian tube cancer or primary peritoneal carcinoma, plasma CA-125 should be 
monitored every 6 week ± 7 days in the first year and every 12 weeks ± 7 days thereafter in the local laboratory in Phase 1 
study.  
 
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APPENDIX 5: THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) 
GUIDELINES 
The text below was obtained from the following reference: Eisenhauer EA, Therasse P, Bogaerts J, 
Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumors: revised 
RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228-247. 
DEFINITIONS 
Response and progression will be evaluated in this trial using the international criteria proposed by 
the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (Version 1.1). Changes in 
only the largest diameter (uni-dimensional measurement) of the tumor lesions are used in the 
RECIST criteria. Note: Lesions are either measurable or non-measurable using the criteria provided 
below. The term “evaluable” in reference to measurability will not be used because it does not 
provide additional meaning or accuracy. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the plane of 
measurement is to be recorded) with a minimum size of: 
 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice 
thickness and a minimum of 10 mm). 
 10 mm caliper measurement by clinical exam (when superficial). 
 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung). 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥ 15 mm in short axis when assessed by 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. 
Non-measurable 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 non-measurable 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 
non-measurable. 
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Bone lesions: 
 Bone scan, PET scan, or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance of 
bone lesions 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
 Blastic bone lesions are non-measurable. 
Cystic lesions: 
 Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) 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 non-cystic 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 which may be 
visible by imaging even if not involved by tumor. Pathological nodes which 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 
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coronal). The smaller of these measures is the short axis. For example, an abdominal node which is 
reported as being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, 
measurable node. In this example, 20 mm should be recorded as the node measurement. All other 
pathological nodes (those with short axis ≥10 mm but <15 mm) should be considered non-target 
lesions. Nodes that have a short axis <10 mm are considered non-pathological and should not be 
recorded or followed. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
Non-target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target 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 non-target lesions involving the same 
organ as a single item on the case record form (eg, “multiple enlarged pelvic lymph nodes” 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, 
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lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected for 
response assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (eg, for body scans). 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next. If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is 
concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
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 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, however, they must normalize for a patient to be 
considered in complete response. 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 which 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 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 in order to 
differentiate between response (or stable disease) and progressive disease. 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
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Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). 
Stable Disease (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 complete response 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 non-reproducible, 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. 
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Lesions that split or coalesce on treatment. When non-nodal lesions “fragment”, the longest 
diameters of the fragmented portions should be added together to calculate the target lesion sum. 
Similarly, as lesions coalesce, a plane between them may be maintained that would aid in obtaining 
maximal diameter measurements of each individual lesion. If the lesions have truly coalesced such 
that they are no longer separable, the vector of the longest diameter in this instance should be the 
maximal longest diameter for the “coalesced lesion”. 
Evaluation of Non-target Lesions 
While some non-target 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. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression (see comments below) of existing non-target 
lesions. (Note: the appearance of one or more new lesions is also considered progression). 
When the patient also has measurable disease. In this setting, to achieve “unequivocal progression” 
on the basis of the non-target disease, there must be an overall level of substantial worsening in 
non-target 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 non-target lesions is usually not sufficient to qualify for unequivocal progression 
status. The designation of overall progression solely on the basis of change in non-target disease in 
the face of SD or PR of target disease will therefore be extremely rare. 
When the patient has only non-measurable 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 applies 
here as noted above, however, in this instance there is no measurable disease assessment to factor 
into the interpretation of an increase in non-measurable disease burden. Because worsening in 
non-target disease cannot be easily quantified (by definition: if all lesions are truly non-measurable) 
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 non-measurable 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 
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would be ideal to have objective criteria to apply to non-measurable disease, the very nature of that 
disease makes it impossible to do so, therefore the increase must be substantial. 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments on 
detection of new lesions are important. There are no specific criteria for the identification of new 
radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not attributable 
to differences in scanning technique, change in imaging modality or findings thought to represent 
something other than tumor (for example, some “new” bone lesions may be simply healing or flare 
of pre-existing lesions). This is particularly important when the patient’s baseline lesions show 
partial or complete response. 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 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 pre-existing site of disease on CT that is not progressing on the basis 
of the anatomic images, this is not PD. 
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Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the trial until the end of the 
trial 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. The patient’s best overall response 
will depend on the findings of both target and non-target disease and will also take into consideration 
the appearance of new lesions. Furthermore, it also depends on the nature of the trial, the protocol 
requirements, and result measurements. Specifically, in non-randomized 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 overall response determination in trials where confirmation of complete or partial response 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 in Cycle 1, PR in Cycle 2, and PD in the last cycle has a best overall 
response of PR). When SD is believed to be best overall 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 overall response, the patient’s best overall response depends on the subsequent assessments. For 
example, a patient who has SD in Cycle 1, PD in Cycle 2 and does not meet minimum duration for 
SD, will have a best overall response of PD. The same patient lost to follow-up after SD in Cycle 1 
would be considered inevaluable. 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not completely 
evaluated 
No 
PR 
SD 
Non-PD or not completely 
evaluated 
No 
SD 
Not completely 
evaluated  
Non-PD 
No 
NE  
PD  
Any 
Yes or No  
PD  
Any 
PD  
Yes or No  
PD  
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Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Any 
Any  
Yes  
PD  
CR= complete 
response  
PR= partial response  
SD= stable disease  
PD= progressive disease 
NE=not evaluated  
CR, complete response; NE, not evaluated; PR, partial response; SD, stable disease; and PD, progressive 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 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 clearly explained in determination of response. 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 cycle). 
In some circumstances it may be difficult to distinguish local lesion from normal tissue. When the 
evaluation of complete response depends upon this determination, it is recommended that biopsy be 
conducted before the local lesion is assigned a status of complete response. FDG-PET may be used 
to confirm a response to a CR in a manner similar to a biopsy in cases where a local 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 case. However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy (including 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. 
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CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
In non-randomized 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 been 
confirmed in such trials. However, in all other circumstances, ie, in randomized trials (Phase 2 or 3) 
or trials where stable disease or progressive disease 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 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 to 8 weeks). 
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 progressive disease is 
objectively documented (taking as reference for progressive disease the smallest measurements 
recorded on study). The duration of overall complete response is measured from the time 
measurement criteria are first met for CR until the first date that recurrent or progressive disease is 
objectively documented. 
The duration of 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 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 cycle, 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: CHRONIC KIDNEY DISEASE EPIDEMIOLOGY COLLABORATION 
(CKD-EPI) EQUATION 
In adults, the most widely-used equations for estimating glomerular filtration rate (eGFR) from 
serum creatinine are the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Equation 
and the Modification of Diet in Renal Disease (MDRD) Study equation. The National Kidney 
Disease Education Program (NKDEP) calculators rely on creatinine determinations which are 
isotope dilution mass spectrometry (IDMS) traceable.  All laboratories should be using creatinine 
methods calibrated to be IDMS traceable.  Read more about creatinine standardization. 
This CKD-EPI equation calculator should be used when Scr reported in mg/dL.  This equation is 
recommended when eGFR values above 60 mL/min/1.73 m2 are desired. 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if 
black] 
where: 
Scr is serum creatinine in mg/dL, 
κ is 0.7 for females and 0.9 for males, 
α is -0.329 for females and -0.411 for males, 
min indicates the minimum of Scr /κ or 1, and 
max indicates the maximum of Scr /κ or 1. 
The equation does not require weight because the results are reported normalized to 1.73 m2 body 
surface area, which is an accepted average adult surface area. 
 
The online calculator for CKD-EPI can be found here: https://www.niddk.nih.gov/health-
information/health-communication-programs/nkdep/lab-evaluation/gfr-calculators/Pages/gfr-
calculators.aspx 
 
 
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APPENDIX 7: EVALUATION OF RESPONSE ACCORDING TO CA-125 
The text below was obtained from the following reference: Gordon John Sampson Rustin, etc. 
Definitions for Response and Progression in Ovarian Cancer Clinical Trials Incorporating RECIST 
1.1 and CA-125 Agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer. 
2011;21: 419-423. 
Definition of Response: 
A CA-125 response is defined as at least a 50% reduction in CA-125 levels from a pretreatment 
sample. The response must be confirmed and maintained by using the next scheduled CA-125 data 
(at least 28 days). Patients can be evaluated according to CA-125 only if they have a pretreatment 
sample that is at least twice the upper limit of the reference range and within 2 weeks before starting 
the treatment. 
To calculate CA-125 responses accurately, the following rules apply: 
 Intervening samples and the 28-day confirmatory sample must be less than or equal to (within an 
assay variability of 10%) the previous sample. 
 Variations within the reference range of CA-125 levels will not interfere with the response 
definition. 
 For each patient, the same assay method must be used, and the assay must be tested in a quality 
control scheme. 
 Patients are not evaluable by CA-125 if they have received mouse antibodies (unless the assay 
used has been shown not to be influenced by human antimouse antibody4, 5) or if there has been 
medical and/or surgical interference with their peritoneum or pleura during the previous 28 days 
(eg, paracentesis). If assessing therapy that includes 2 treatment modalities for relapse (eg, 
surgery and chemotherapy), any CA-125 response results from both treatment modalities. CA-
125 cannot distinguish between the effects of the 2 treatments. 
The date when the CA-125 level is first reduced by 50% is the date of the CA-125 response. To 
calculate response, an intent-to-treat analysis should be used that includes all patients with an initial 
CA-125 level of at least twice the upper limit of the reference range as eligible and evaluable. In 
addition, as a separate analysis, those patients who have a CA-125 response and whose CA-125 level 
falls to within the reference range can be classified as CA-125 complete responder see Table 5 for 
Phase 1, and Table 7 for Phase 2 where CA-125 is stated as normalized or normal, means within the 
reference range. Patients who have a fall of CA-125 to within the reference range but whose initial 
CA-125 was less than twice the upper limit of the reference range cannot therefore be classified as a 
CA-125 complete responder. 
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APPENDIX 8: PROHIBITED MEDICATIONS  
Strong and Moderate CYP3A Inhibitors and Strong CYP3A Inducers 
Strong CYP3A Inhibitors 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals: boceprevir, telaprevir 
Other: cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone,  
Protease Inhibitors: indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir 
 
Strong CYP3A Inducers 
Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. 
John’s wort (hypericum perforatum) 
 
Moderate CYP3A Inhibitors 
 
Antibiotics: ciprofloxacin, erythromycin 
Antifungals: fluconazole 
Protease inhibitors: amprenavir, atazanavir, darunavir, fosamprenavir 
Calcium channel blockers: diltiazem, verapamil 
Tyrosine kinase inhibitors (anti-cancer): imatinib 
Food products: grapefruit and juice (Citrus paradisi), Seville orange and juice (Citrus aurantium) 
Herbal medications: Schisandra sphenanthera 
Others: aprepitant, casopitant, cimetidine, cyclosporine, dronedarone, tofisopam  
 
 
 
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APPENDIX 9: MEDICATIONS TO BE USED WITH CAUTION 
 
Sensitive CYP2C9 Substrates or CYP2C9 Substrates with Narrow Therapeutic Index 
Celecoxib1 
Phenytoin2 
Warfarin2 
1. Sensitive substrates: Drugs that exhibit an AUC ratio (AUCi/AUC) of 5-fold or more when co-administered with a 
known potent inhibitor. 
2. Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (eg, Torsade de 
Pointes). 
 
 
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APPENDIX 10: MEDICATIONS TO BE USED WITH CAUTION 
 
Strong CYP2C8 Inhibitors 
Gemfibrozil 
 
 
 
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APPENDIX 11: FEMALES OF CHILDBEARING POTENTIAL AND CONTRACEPTION 
Contraception guidelines 
The Clinical Trials Facilitation Group (CTFG) recommendations related to contraception and 
pregnancy testing in clinical trials include the use of highly effective forms of birth control. These 
methods include the following: 
 
Combined (estrogen and progestogen containing) hormonal contraception associated with the 
inhibition of ovulation  
o Oral, intravaginal, or transdermal 
 
Progestogen-only hormonal contraception associated with the inhibition of ovulation 
o Oral, injectable, implantable 
 
An intrauterine device (IUD) 
 
Intrauterine hormone-releasing system (IUS) 
 
Bilateral tubal occlusion 
 
Vasectomized partner 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatment). Total sexual abstinence should only be 
used as a contraceptive method if it is in line with the patients’ usual and preferred lifestyle. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 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 used in 
combination with another acceptable method listed above. 
Definition of childbearing potential 
Childbearing potential is defined as being physiologically capable of becoming pregnant. No 
childbearing potential is defined as one or both of the following criteria: 
 
Surgically sterile (bilateral salpingectomy, bilateral oophorectomy, or hysterectomy) 
 
Post-menopausal, defined as 
- 
≥ 55 years of age with no spontaneous menses for ≥12 months OR 
- 
< 55 years of age with no spontaneous menses for ≥12 months AND with a 
post-menopausal follicle-stimulating (FSH) concentration >30 IU/mL 
 
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APPENDIX 12: NEW YORK HEART ASSOCIATION CLASSIFICATION 
 
NYHA 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, e.g. walking 
short distances (20-100 m). Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. 
 
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