Conditions: Locally Advanced or Metastatic Solid Tumors
Keywords: Ovarian cancer Triple negative breast cancer Small cell lung cancer Gastric cancer temozolomide BGB-290 antineoplastic agents alkylating, alkylating agents, Poly (ADP-ribose) polymerase inhibitors enzyme inhibitors Head and neck cancer Esophageal cancer Soft tissue sarcoma Non small cell lung cancer pamiparib
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 139
Healthy volunteers: no

Brief summary:
The primary objective of this study was to determine the safety and tolerability of pamiparib, the maximum tolerated dose (MTD) or maximum administered dose (MAD) for pamiparib combined with TMZ, to select the recommended Phase 2 dose (RP2D) and schedule of pamiparib in combination with TMZ, and to determine the antitumor activity of pamiparib in combination with TMZ.

Detailed description:

Arms:
arm 1: Pamiparib 60 mg twice daily on Days 1 to 28 in combination with pulse dosing of TMZ 40 mg once daily on Days 1 to 7 within a 28-day cycle arm 2: Pamiparib 60 mg twice daily on Days 1 to 28 in combination with pulse dosing of TMZ 60 mg once daily on Days 1 to 7 within a 28-day cycle arm 3: Pamiparib 60 mg twice daily on Days 1 to 28 in combination with pulse dosing of TMZ 80 mg once daily on Days 1 to 7 within a 28-day cycle arm 4: Pamiparib 60 mg twice daily on Days 1 to 28 in combination with pulse dosing of TMZ 100 mg once daily on Days 1 to 7 within a 28-day cycle arm 5: Pamiparib 60 mg twice daily on Days 1 to 28 in combination with pulse dosing of TMZ 120 mg once daily on Days 1 to 7 within a 28-day cycle arm 6: Pamiparib 60 mg twice daily on Days 1 to 28 in combination with pulse dosing of TMZ 40 mg once daily on Days 1 to 14 within a 28-day cycle arm 7: Pamiparib 60 mg twice daily in combination with TMZ 20 mg once daily administered continuously on Days 1 to 28 within a 28-day cycle arm 8: Pamiparib 60 mg twice daily in combination with TMZ 40 mg once daily administered continuously on Days 1 to 28 within a 28-day cycle arm 9: Participants with gastric or gastroesophageal junction cancer received TMZ 60 mg administered on Days 1 to 7 in combination with pamiparib 60 mg twice daily on Days 1 to 28 of each cycle arm 10: Participants with ovarian cancer, fallopian cancer, or primary peritoneal cancer received TMZ 60 mg administered on Days 1 to 7 in combination with pamiparib 60 mg twice daily on Days 1 to 28 of each cycle arm 11: Participants with Small Cell Lung Cancer (SCLC) received TMZ 60 mg administered on Days 1 to 7 in combination with pamiparib 60 mg twice daily on Days 1 to 28 of each cycle arm 12: Participants with triple negative breast cancer (TNBC) received TMZ 60 mg administered on Days 1 to 7 in combination with pamiparib 60 mg twice daily on Days 1 to 28 of each cycle arm 13: Participants with non-small cell lung cancer (NSCLC), esophageal cancer, squamous head and neck cancer, or soft tissue sarcomas whose tumors are homologous recombination deficiency (HRD)+ received TMZ 60 mg administered on Days 1 to 7 in combination with pamiparib 60 mg twice daily on Days 1 to 28 of each cycle

Interventions: intervention 1: Pamiparib intervention 2: Temozolomide
Intervention descriptions: intervention 1: Administered by mouth as a capsule twice daily intervention 2: TMZ at various doses administered by mouth as a capsule once daily.

Protocol document:
Prot_000.pdf: 
BGB-290-103 
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CLINICAL STUDY PROTOCOL
 
Protocol Title:  
A Phase 1b Study to Assess the Safety, Tolerability, and 
Clinical Activity of BGB-290 in Combination with 
Temozolomide (TMZ) in Subjects with Locally Advanced or 
Metastatic Solid Tumors 
 
Protocol Number: 
BGB-290-103 
 
Original Protocol: 
20 March 2017 
Version: 
1.0 
 
Protocol Amendment 2: 19 June 2020 
Version: 
3.0 
 
IND No.: 
128234 
EUDRACT No.: 
2017-001553-14 
 
Study Phase: 
1b 
 
Sponsor:  
BeiGene USA, Inc. 
2955 Campus Drive, Suite 200 
San Mateo, CA 94403 
USA 
 
Sponsor Medical Monitor: 
 
 
  
 
Confidentiality Statement 
This Document Is Not for Distribution – Do Not Copy 
This document contains confidential information and is the proprietary property of BeiGene, Ltd., and its 
subsidiaries. This document is for use by individuals and their designated representatives for their 
confidential review, consideration, and/or participation in investigational trial(s). This document may not 
be copied or distributed for review by any unauthorized individuals without the prior written authorization 
of BeiGene, Ltd., or one of its subsidiaries. Your acceptance of this document constitutes agreement that 
you will not disclose the information contained herein to others without prior written authorization from 
BeiGene, Ltd., or one of its subsidiaries.
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SIGNATURES 
 
PROTOCOL TITLE: 
A Phase 1b Study to Assess the Safety, Tolerability, and Clinical 
Activity of BGB-290 in Combination with Temozolomide (TMZ) 
in Subjects with Locally Advanced or Metastatic Solid Tumors 
 
PROTOCOL NO: 
BGB-290-103 
 
BeiGene USA, Inc., Approval: 
      ___ 19 June 2020__ 
 
 Date 
Sponsor Medical Monitor
 
 
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SYNOPSIS 
 
Name of 
Sponsor/Company: 
BeiGene USA, Inc. 
Name of Finished 
Product: 
Pamiparib 
Name of Active 
Ingredient: 
BGB-290 
Title of Study: 
A Phase 1b Study to Assess the Safety, Tolerability, and Clinical Activity 
of BGB-290 in Combination with Temozolomide (TMZ) in Subjects with 
Locally Advanced or Metastatic Solid Tumors 
Protocol No: 
BGB-290-103 
Study Centers: 
Approximately 35 sites in the United States (US), Europe, Asia, 
and the Pacific region 
Study Phase: 
Phase 1b 
Treatment 
Duration: 
Patients will receive daily treatment during the study until occurrence of 
progressive disease, unacceptable toxicity, death, withdrawal of consent, 
lost to follow-up, or study termination by sponsor. 
Objectives: 
Primary: 
• 
To determine the safety and tolerability of pamiparib (also known as BGB-290) when given 
orally in combination with temozolomide (TMZ) (pulsed and continuous)  
• 
To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) for 
pamiparib combined with TMZ (pulsed and continuous) 
• 
To select the recommended Phase 2 dose (RP2D) and schedule of pamiparib in combination 
with TMZ 
• 
To determine the preliminary antitumor activity of pamiparib in combination with TMZ 
Secondary:  
• 
To characterize the pharmacokinetics (PK) of pamiparib and TMZ 
Exploratory: 
• 
To evaluate candidate biomarkers in tumor tissue and in peripheral circulation as potential 
markers of response, resistance, or disease progression 
Test Product, Dose, 
and Mode of 
Administration: 
Pamiparib (BGB-290) administered orally (PO) twice a day (BID) in doses 
of 10 mg, 20 mg, 40 mg, or 60 mg capsules, depending on dose level and 
availability 
Temozolomide administered PO once a day (QD) in doses of 5 mg, 20 mg, 
100 mg, and 140 mg capsules, depending on dose level and availability 
Reference Therapy, 
Dose, and Mode of 
Administration: 
Not applicable 
Study Design: 
This is an open-label, multi-center Phase 1b study to evaluate the combined use of pamiparib, a 
poly (ADP -ribose) polymerase (PARP) inhibitor and TMZ, a DNA-alkylating agent in patients with 
locally advanced and metastatic solid tumors. This study consists of two phases: a dose escalation phase 
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and a dose expansion phase. The dose escalation phase of the study will evaluate the safety, tolerability, 
preliminary efficacy, and PK in addition to determining the MTD or MAD for the combination. In the 
dose expansion phase of this study, the safety, antitumor activity and PK profile of the combination will 
be evaluated further. Preliminary biomarkers for efficacy will also be explored through both phases of the 
study. The dose first phase of the study consists of a modified 3+3 dose escalation scheme utilizing a 
fixed dose of pamiparib in combination with escalating doses of TMZ. There will be two arms that will 
undergo dose escalation independently, starting with Dose Level 1. In Arm A, TMZ will be administered 
once a day during Days 1 to 7 of each 28-day cycle (pulsed). In Arm B, TMZ will be administered once a 
day continuously during each 28-day cycle. The second phase (dose expansion) of the study will further 
evaluate the safety and anti-tumor activity of pamiparib in combination with TMZ at the dose and 
schedule that will be chosen based on all data available from the dose escalation phase. The expansion 
phase will enroll patients in 6 different cohorts according to indication and/or homologous recombination 
deficiency (HRD) status as follows: Cohort 1: HRD positive (HRD+) ovarian cancer; Cohort 2: HRD+ 
triple-negative breast cancer (TNBC); Cohort 3: HRD+ metastatic castration-resistant prostate cancer 
(mCRPC); Cohort 4: ES-SCLC; Cohort 5: G/GEJ cancer; and Cohort 6: patients who have HRD+ non- 
squamous non-small cell lung cancer (NSCLC), squamous NSCLC, esophageal cancer, squamous head 
and neck cancer or soft-tissue sarcomas. Enrollment into these cohorts will occur simultaneously and 
independently. 
It is expected that approximately 250 patients will be enrolled in the entire study. Each expansion cohort 
will enroll approximately 20-25 patients; cohorts might enroll additional patients based on emerging data, 
but the total number of patients enrolled in the study will not exceed 250 patients. 
Enrollment will start at Dose Level 1 and follow the escalation scheme outlined below (interim dose 
levels may be tested based on available clinical and PK data).  
Dose Escalation 
 
Arm A  
(Pulse Dosing of TMZ) 
Arm B  
(Continuous Dosing of TMZ) 
Dose 
Level 
Pamiparib 
Continuous 
TMZ 
Days 1 to 7, every 
28 days 
Pamiparib 
Continuous 
TMZ 
Continuous 
-1 
60 mg BID 
20 mg QD 
60 mg BID 
20 mg QD* 
1 
60 mg BID 
40 mg QD* 
60 mg BID 
40 mg QD 
2 
60 mg BID 
80 mg QD 
60 mg BID 
80 mg QD 
3 
60 mg BID 
120 mg QD 
60 mg BID 
120 mg QD 
≥4 
60 mg BID 
Increase by ≤ 50% 
each time until MTD 
reached 
60 mg BID 
Increase by ≤ 50% each 
time until MTD 
reached 
*Starting dose; BID = twice daily; MTD = maximum tolerated dose; QD = once daily; TMZ = 
temozolomide 
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The dose and schedule of pamiparib + TMZ intended for the second phase of the study will be 
determined once the safety and tolerability profiles of each dose escalation and schedule arms has been 
evaluated. The protocol allows for additional dose adjustments of pamiparib to be explored based on 
available safety data and the recommendation of the safety team. Patients in the dose expansion phase 
will be enrolled into one of 6 different cohorts based on their disease characteristics and/or HRD status. 
Patients will be evaluated for adverse events (AEs), (all grades, according to National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.03 [NCI CTCAE v. 4.03 or higher]), 
serious AEs (SAEs), and any AEs requiring study drug interruption or discontinuation, from initial dose 
of study drug until 30 days following their last dose of study drug or until study 
discontinuation/termination, or until they receive another anticancer therapy, whichever comes first. 
Patients who, at the time of progression, have an ongoing AE that leads to treatment discontinuation will 
be followed until the event resolves, the investigator assesses the event as stable, the patient is lost to 
follow-up, or the patient starts a different antitumor therapy. If a patient discontinues study drug due to 
reasons other than disease progression or death, then tumor assessments should continue to be performed 
following the scheduled assessment plan until disease progression, death, lost to follow-up, or withdrawal 
of consent to efficacy follow-up. 
In the absence of unacceptable toxicities or disease progression, patients will be offered continued study 
treatment of BGB-290 plus TMZ. Regardless of discontinuation of one or both study drugs, patients 
should continue on study with regular follow-up. Patients who have discontinued all study drugs should 
return to the clinic for an end-of-treatment (EOT) visit within 7 days after the last study treatment. After 
the EOT visit, patients should have regular follow-up for safety, efficacy, and survival. 
Planned Number of 
Patients: 
Dose Escalation Phase: Approximately 50 patients may be enrolled. More 
patients may be enrolled if additional doses/schedules are to be evaluated 
based on emerging data. 
Dose Expansion Phase: Approximately 200 patients in total will be treated 
in 6 cohorts. Each cohort will enroll approximately 20-25 patients each and 
will be evaluated separately. Cohorts can be closed due to futility or clinical 
efficacy based on statistical evaluation or due to insufficient patient 
recruitment. Cohorts can be also further expanded based on emerging data. 
Inclusion Criteria 
Patients must meet all the following criteria to be eligible for the study: 
All Cohorts 
1. Patient has voluntarily agreed to participate by signing an informed consent. 
2. Male or female and ≥ 18 years of age on day of signing an informed consent 
 
3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 
4. Ability to swallow whole capsules 
5. Patients who have histologic or cytologic-confirmed malignancy that has progressed to the 
advanced or metastatic stage. 
6. Agree to provide tumor archival tissue 
a. Dose Escalation Phase: If available, agreement to provide archival tumor tissue for 
exploratory biomarker analyses 
Note: If archival tumor tissue is not available, an optional fresh biopsy is highly 
recommended. 
b. Dose Expansion Phase: Patients enrolled in the HRD+ cohorts must provide archival 
tissue or fresh biopsy (if archival tissue is not available) for prospective central 
assessment of HRD status. Other cohorts may provide tissue if available for retrospective 
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analysis 
7. Patients must have adequate organ function as indicated by the following screening laboratory 
values (obtained ≤ 2 weeks prior to Day 1): 
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
b. Platelets ≥ 100 x 109/L (Note: Criterion must be met without a transfusion within 2 
weeks prior to obtaining the sample)  
c. Hemoglobin ≥ 10 g/dL or ≥ 6.2 mmol/L (Note: Criterion must be met without a 
transfusion within 2 weeks prior to obtaining the sample) 
d. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated creatinine clearance 
 50 mL/min (calculated using the institutional standard method) 
e. Total serum bilirubin ≤ 1.5 x ULN (total bilirubin must be < 4 x ULN for patients with 
Gilbert’s syndrome or if indirect bilirubin concentrations are suggestive of extrahepatic 
source of elevation) 
f. Aspartate and alanine aminotransferase (AST and ALT, respectively)  3 x ULN  
OR ≤ 5 x ULN for patients with liver metastases 
8. Female patients of childbearing potential and female partners of male study patients must agree 
to practice highly effective methods of birth control (Appendix 2) for the duration of the study 
and for ≥ 6 months after the last dose of study drug. In addition, non-sterile male patients must 
agree to practice highly effective methods of birth control (Appendix 2) and avoid sperm 
donation for the duration of the study and for ≥ 6 months after the last dose of study drug. 
9. Willingness and ability to comply with all protocol-specified requirements  
Dose Escalation Phase only 
10. Patients must have disease that is either measurable or evaluable per Response Evaluation 
Criteria in Solid Tumors (RECIST) v1.1. 
Dose Expansion Phase only 
11. Patients must have measurable disease per RECIST v1.1 criteria (except where noted below). 
Note: Tumor lesions used for freshly acquired biopsies should not be included as target lesions 
unless there are no other suitable target lesions available. 
12. Ovarian Cancer (Expansion Cohort 1) 
a. 
Patients must have received at least one line of platinum-containing therapy in the 
advanced or metastatic setting. 
b. Patients must not have progressed or have recurrent disease within 6 months of the 
completion of the last platinum-containing regimen. 
• 
Note: Patients can receive additional therapy after the last platinum-containing 
regimen as long as the criteria for platinum-sensitivity is met. 
c. Patients with known or suspected deleterious mutations in BReast CAncer susceptibility 
gene (BRCA)1 or BRCA2 are classified as HRD+, regardless of the molecular signature 
result. 
• 
If HRD or BRCA1/2 mutation status is unknown or has not been previously 
evaluated, the patients must undergo tissue screening using the Myriad 
myChoice® HRD diagnostic test to determine eligibility. 
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13. Triple-Negative Breast Cancer (Expansion Cohort 2) 
a. Patients with known or suspected deleterious mutations in BRCA1 or BRCA2 are 
classified as HRD+, regardless of the molecular signature result. 
• 
If HRD or BRCA1/2 mutation status is unknown or has not been previously 
evaluated, the patient must undergo tissue screening using the Myriad 
myChoice® HRD diagnostic test to determine eligibility. 
b. 0-1 prior platinum-containing treatment in any treatment setting 
• Note: Patients could have received additional therapy after the last 
platinum-containing regimen as long as the other eligibility criteria are met. 
c. Received ≤ 3 prior lines of therapy in the advanced or metastatic setting 
 
14. Metastatic Castration-Resistant Prostate Cancer (Expansion Cohort 3) 
a. 
Patients with known or suspected deleterious mutations in BRCA1 or BRCA2 are 
classified as HRD+, regardless of the molecular signature result. 
• If HRD or BRCA1/2 mutation status is unknown or has not been previously 
evaluated, the patient must undergo tissue screening using the Myriad 
myChoice® HRD diagnostic test to determine eligibility. 
b. 
The patient may be either chemotherapy-naïve or have previously had no more than two 
taxane-based chemotherapy regimens including docetaxel and carbazitaxel. If docetaxel 
is used more than once, this will be considered as one regimen. 
c. 
The patient may be pre-or post-treatment with a novel androgen receptor targeted agent 
(e.g., abiraterone and/or enzalutamide). 
d. 
At least 2 weeks since the completion of prior flutamide, bicalutamide, and nilutamide, 
or enzalutamide and abiraterone treatment 
e. 
At least 2 weeks from any radiotherapy, with the exception of a single fraction of 
radiotherapy for the purposes of palliation (confined to one field) 
f. 
Documented prostate cancer progression as assessed by the investigator with one of the 
following: 
• 
Prostate-specific antigen (PSA) progression defined by a minimum of 3 rising 
PSA levels with an interval of ≥ 1 week between each determination. The PSA 
value at the screening visit should be ≥ 2 µg/L (2 ng/ml). 
• 
Radiographic progression of soft tissue disease by modified RECIST v1.1 
criteria 
• Surgically or medically castrated. The testosterone levels do not need to 
be checked as long as the patient has been on chemical castration or 
undergone surgical castration for > 4 months. In all cases, the luteinizing 
hormone-releasing hormone (LHRH) antagonist/agonist is to be 
continued in these patients. 
• 
Patients with only non-measurable bone lesions must have either progression 
with 2 or more new lesions or have PSA progression within the 6-week period 
before study drug administration. 
15. Extensive Stage Small Cell Lung Cancer (Expansion Cohort 4) 
a. Received ≤ 2 prior lines of therapy 
16. Gastric/Gastroesophageal Junction Cancer (Expansion Cohort 5) 
a. Received ≤ 2 prior lines of therapy 
17. HRD+ Solid Tumors, Multiple Indications (Expansion Cohort 6) 
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a. Patient has histologic or cytologic-confirmed advanced (metastatic and/or unresectable)  
• 
nonsquamous non-small cell lung cancer (NSCLC) 
• 
squamous NSCLC 
• 
esophageal cancer 
• 
squamous head and neck cancer 
• 
soft-tissue sarcomas (undifferentiated pleomorphic sarcoma, leiomyosarcoma, 
malignant peripheral nerve sheath tumor, dedifferentiated liposarcoma, 
myxofibrosarcoma) 
b. Patients must have tumors with homologous recombination deficiency (HRD+) as 
centrally determined by the Myriad myChoice® HRD Plus assay irrespective of any 
known molecular signature 
c. Patients with nonsquamous NSCLC, squamous NSCLC, esophageal cancer and 
squamous head and neck cancer must have received at least 1 but not more than 3 prior 
lines of therapy.  
d. Patients with soft tissue sarcoma must have received at least 1 but no more than 3 
prior lines of therapy. Treatment naïve patients may be allowed if, in the opinion 
of the investigator, available standard of care first line therapy is not appropriate. 
 
Exclusion Criteria 
Patients will be excluded from the study for any of the following reasons: 
1. 
Known hypersensitivity to any temozolomide component or to dacarbazine (DTIC) 
2. 
Prior treatment with a PARP inhibitor  
3. 
Received chemotherapy, biologic therapy, immunotherapy, or investigational agent 
within 3 weeks prior to Day 1 (or ≤ 5 half-lives, whichever is shorter) (unless otherwise 
noted in the Inclusion Criteria) 
4. 
Patients who are considered to be refractory to platinum-based therapy (e.g., progressive 
disease at the first tumor assessment while receiving platinum treatment) (for patients in 
Dose Expansion Phase only) 
5. 
Have any unresolved acute effects of any prior therapy of Grade 2 or higher, except for 
AEs not constituting a safety risk by investigator judgment 
6. 
Had a major surgical procedure, open biopsy, or significant traumatic injury ≤ 4 weeks 
prior to Day 1, or anticipation of need for major surgical procedure during the course of 
the study  
• 
Placement of a vascular access device is not considered major surgery 
7. 
Have other diagnosis of malignancy 
• 
Except for surgically excised non-melanoma skin cancer, adequately treated 
carcinoma in situ of the cervix, localized prostate cancer treated with curative 
intent, adequately treated low-stage bladder cancer, ductal carcinoma in situ 
treated surgically with curative intent, or a malignancy diagnosed > 2 years ago, 
with no current evidence of disease and no therapy ≤ 2 years prior to Day 1. 
8. 
Patient who has received local radiotherapy of non-target lesions for local symptom 
control within the last 4 weeks must have recovered from any adverse effects of 
radiotherapy before recording baseline symptoms. 
9. 
Have untreated leptomeningeal or brain metastasis. Patient with previously treated brain 
metastases is eligible if the metastases have shown no progression on brain computed 
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tomography (CT) or magnetic resonance imaging (MRI) over at least 4 weeks, the patient 
has no symptoms due to the brain metastases, and the patient has been off corticosteroids 
for ≥ 2 weeks. 
10. 
Have active infection requiring systemic treatment 
11. 
Have known human immunodeficiency virus (HIV) infection or serologic status 
reflecting active viral hepatitis infection as follows: 
• 
Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) 
carriers whose HBV DNA is > 500 IU/mL should be excluded. Note: Inactive 
HBsAg carriers and patients with treated and stable hepatitis B 
(HBV DNA < 500 IU/mL) can be enrolled. Patients receiving antivirals at 
screening should have been treated for > 2 weeks before the first dose of study 
drug(s). 
12. 
Have any of the following cardiovascular criteria: 
• 
Current evidence of cardiac ischemia 
• 
Current symptomatic pulmonary embolism 
• 
Acute myocardial infarction ≤ 6 months prior to Day 1 
• 
Heart failure of New York Heart Association Classification III or IV 
(Appendix 3) ≤ 6 months prior to Day 1 
• 
Grade ≥2 ventricular arrhythmia ≤ 6 months prior to Day 1 
• 
Cerebral vascular accident (CVA) ≤ 6 months prior to Day 1 
13. 
Have an active inflammatory gastrointestinal disease, chronic diarrhea, or had previous 
complete gastric resection or lapband surgery 
Note: Gastroesophageal reflux disease under treatment with proton pump inhibitors is 
allowed (assuming no drug interaction potential). 
14. 
Use or have anticipated need for food or drugs known to be strong or moderate 
cytochrome P450 (CYP)3A inhibitors or strong CYP3A inducers ≤10 days (or ≤ 5 half-
lives, whichever is shorter) prior to Day 1 (Protocol Appendix 4) 
15. 
Are pregnant or nursing (females of childbearing potential require a negative serum 
pregnancy test ≤ 7 days before Day 1) 
16. 
Have hereditary problems of galactose intolerance, the Lapp lactase deficiency, or 
glucose-galactose malabsorption 
Study Endpoints: 
Primary Endpoints 
Escalation: Incidence and nature of DLTs  
Expansion: Incidence, nature, and severity of AEs, graded according to the NCI CTCAE v. 4.03 
                  Objective response rate (ORR), as assessed using RECIST v1.1 
Secondary Endpoints 
Pharmacokinetic parameters of pamiparib and TMZ, including but not limited to Ctrough 
Time-to event- endpoints: e.g., duration of response (DOR), disease control rate (DCR), progression-free 
survival (PFS), and overall survivals (OS) 
Exploratory Endpoints 
Candidate predictive biomarkers, including, but not limited to, expression and mutations of genes in the 
deoxyribonucleic acid (DNA) damage response pathway, and relationship to efficacy and resistance 
Statistical Methods: 
Approximately 50 patients will be enrolled in the dose escalation phase. A sample size of 20-25 patients 
in an expansion cohort will provide the half width of the 90% confidence interval of the ORR 
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approximately 13% to 20% when the observed ORR is approximately 40%. Hence, the low bound is 
above 20%. This is considered adequate in the preliminary assessment of anticancer activity of pamiparib 
and TMZ combination therapy. An expansion cohort can be further expanded to confirm efficacy. Up to 
200 patients will be enrolled in the expansion cohorts. 
Populations: 
Safety Population includes all patients who received any dose of pamiparib and/or TMZ. The Safety 
Population will be used for all safety analyses. 
Efficacy Evaluable Population includes patients in the Safety Population who had measurable disease at 
baseline (or prostate cancer patients as per inclusion criteria 14f) and had at least one post-baseline tumor 
assessment unless discontinued treatment due to clinical progression or death prior to tumor assessment. 
DLT Evaluable Population includes patients who received ≥ 70% of each study drug during the DLT 
assessment window and had sufficient safety evaluation. Additionally, patients who had a DLT event 
during the DLT assessment window despite receiving < 70% of the scheduled dose will also be 
considered evaluable. 
PK Population includes all patients for whom valid pamiparib PK parameters can be estimated. 
Safety Analysis: 
Safety will be assessed by monitoring and recording of all AEs graded by the NCI CTCAE v. 4.03. 
Laboratory values (CBC, clinical chemistry, coagulation, and urinalysis), vital, physical exams, and ECG 
findings will also be used in determining safety. Descriptive statistics will be used to analyze all safety 
data in the Safety Population. 
DLT Analysis: 
Dose-limiting toxicity in the DLT evaluation period will be used to determine the dose and schedule of 
pamiparib plus TMZ in the expansion cohorts. The DLT events will be summarized descriptively at each 
combination dosing level in the DLT Evaluable Population.  
Pharmacokinetic Analyses: 
Population PK analysis may be carried out for pamiparib to include plasma concentrations from this 
study in an existing model. PK parameters such as Cmin will be summarized and additional PK 
parameters, such as apparent clearance (CL/F) of the drug from plasma and area under the plasma 
concentration-time curve (AUC) may be derived from the population PK analysis if supported by data. 
Population PK analysis may be reported separately from the final clinical study report (CSR). 
Trough and/or peak plasma concentrations of TMZ will be summarized and compared with appropriate 
historical controls. 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by data. 
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TABLE OF CONTENTS 
SIGNATURES .................................................................................................................................2 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF TABLES .........................................................................................................................17 
LIST OF FIGURES .......................................................................................................................17 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................18 
1. 
INTRODUCTION ......................................................................................................22 
1.1. 
Poly (ADP-ribose) Polymerase Inhibitors and Pamiparib ..........................................22 
1.2. 
PARP Inhibitors in the Treatment of Solid Tumors ...................................................22 
1.3. 
PARP Inhibitors and Temozolomide (TMZ) ..............................................................26 
1.4. 
Nonclinical Data .........................................................................................................27 
1.4.1. 
Nonclinical Data on Pamiparib ...................................................................................27 
1.4.2. 
Nonclinical Data on Pamiparib in Combination with TMZ .......................................30 
1.5. 
Clinical Data for Pamiparib ........................................................................................31 
1.5.1. 
Pharmacokinetics of BGB-290-AU-002 .....................................................................31 
1.5.2. 
Exploratory Biomarker Data .......................................................................................32 
1.5.3. 
Clinical Safety and Preliminary Efficacy for BGB-290-AU-002 ...............................33 
1.6. 
Study Rationale ...........................................................................................................33 
1.6.1. 
Rationale for Dose Selection of Pamiparib ................................................................34 
1.6.2. 
Rationale for Dose Selection of Temozolomide (TMZ) .............................................34 
1.7. 
Risk-Benefit Assessment ............................................................................................34 
1.8. 
Study Conduct ............................................................................................................35 
2. 
STUDY OBJECTIVES ..............................................................................................36 
2.1. 
Primary Objectives .....................................................................................................36 
2.2. 
Secondary Objectives .................................................................................................36 
2.3. 
Exploratory Objectives ...............................................................................................36 
3. 
STUDY ENDPOINTS ................................................................................................37 
3.1. 
Primary Endpoints ......................................................................................................37 
3.2. 
Secondary Endpoints ..................................................................................................37 
3.3. 
Exploratory Endpoints ................................................................................................37 
4. 
STUDY DESIGN .......................................................................................................38 
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4.1. 
Summary of Study Design ..........................................................................................38 
4.2. 
Details of Dose Escalation ..........................................................................................39 
4.2.1. 
Starting Dose and Dose Escalation Approach ............................................................39 
4.2.2. 
Rules for Dose Escalation ...........................................................................................40 
4.2.3. 
Assessment of Dose-Limiting Toxicity ......................................................................41 
4.2.4. 
Definition of Dose-Limiting Toxicity ........................................................................41 
4.3. 
Expansion Cohorts ......................................................................................................42 
5. 
STUDY POPULATION .............................................................................................44 
5.1. 
Inclusion Criteria ........................................................................................................44 
5.2. 
Exclusion Criteria .......................................................................................................47 
6. 
STUDY TREATMENT ..............................................................................................49 
6.1. 
Study Drugs ................................................................................................................49 
6.1.1. 
Pamiparib (BGB-290) .................................................................................................49 
6.1.2. 
Temozolomide ............................................................................................................49 
6.1.3. 
Modifications of Study Drugs ....................................................................................51 
6.1.4. 
Product Accountability ...............................................................................................54 
6.1.5. 
Assessment of Treatment Compliance .......................................................................54 
6.1.6. 
Treatment of Overdose from Study Drugs .................................................................55 
6.1.7. 
Occupational Safety ....................................................................................................55 
6.2. 
Concomitant Medications and Non-Drug Therapies ..................................................55 
6.2.1. 
Permitted Medications ................................................................................................55 
6.2.2. 
Prohibited Medications ...............................................................................................55 
6.2.3. 
Medications to Be Used with Caution ........................................................................56 
7. 
STUDY PROCEDURES ............................................................................................57 
7.1. 
Informed Consent .......................................................................................................57 
7.2. 
Patient Demographics and Other Baseline Characteristics ........................................57 
7.2.1. 
Demography ...............................................................................................................57 
7.2.2. 
Medical History ..........................................................................................................57 
7.2.3. 
Cancer Characteristics ................................................................................................57 
7.2.4. 
Other Baseline Parameters ..........................................................................................58 
7.3. 
Physical Examination, Vital Signs, ECOG Performance Status, Weight, and 
Height .........................................................................................................................58 
7.4. 
Adverse Events ...........................................................................................................58 
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7.5. 
Electrocardiogram .......................................................................................................58 
7.6. 
Laboratory Studies ......................................................................................................59 
7.6.1. 
Hematology Studies ....................................................................................................59 
7.6.2. 
Clinical Chemistry ......................................................................................................59 
7.6.3. 
Coagulation .................................................................................................................59 
7.6.4. 
Hepatitis B and C Testing ...........................................................................................60 
7.6.5. 
Urinalysis with Dipstick .............................................................................................60 
7.6.6. 
Pregnancy Test ............................................................................................................60 
7.6.7. 
CA-125 Measurements ...............................................................................................60 
7.6.8. 
PSA Measurements .....................................................................................................60 
7.7. 
Tumor Assessment ......................................................................................................61 
7.8. 
Pharmacokinetics of Pamiparib and Temozolomide ..................................................62 
7.8.1. 
PK of Pamiparib .........................................................................................................62 
7.8.2. 
PK of TMZ .................................................................................................................62 
7.9. 
Biomarker Assessments ..............................................................................................62 
7.9.1. 
Blood for biomarker analysis......................................................................................63 
7.9.2. 
Tumor tissues for biomarker analysis .........................................................................63 
7.9.3. 
Optional tumor biopsy for pharmacodynamics analysis (Dose Escalation and 
Dose Expansion Cohorts 1-5) .....................................................................................64 
7.10. 
Appropriateness of Measurements .............................................................................64 
8. 
STUDY VISITS AND FOLLOW-UP ........................................................................65 
8.1. 
Prescreening (Dose Expansion Only, Days -84 to -29 prior to Screening) ................65 
8.2. 
Screening Period (Day -28 to Day -1) ........................................................................65 
8.3. 
Assessments during Treatment Period ........................................................................65 
8.3.1. 
PK Intensive Visit (Day -2 to Day 1) (Dose Escalation Cohort ONLY) ....................65 
8.3.2. 
Cycle 1 (28 days) ........................................................................................................66 
8.3.3. 
Subsequent Cycles ......................................................................................................66 
8.3.4. 
Unscheduled Visits .....................................................................................................66 
8.4. 
End-of-Treatment Visit ...............................................................................................66 
8.5. 
Follow-up Assessments ..............................................................................................67 
8.5.1. 
Safety Follow-Up ........................................................................................................67 
8.5.2. 
Efficacy Follow-Up ....................................................................................................67 
8.5.3. 
Survival Follow-Up ....................................................................................................68 
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8.5.4. 
Lost to Follow-Up.......................................................................................................68 
8.6. 
End of Study for Individual Patients ..........................................................................68 
8.7. 
End of Study ...............................................................................................................68 
9. 
DATA HANDLING AND QUALITY ASSURANCE ..............................................70 
9.1. 
Data Collection ...........................................................................................................70 
9.2. 
Data Management/Coding ..........................................................................................70 
9.3. 
Quality Assurance .......................................................................................................71 
10. 
SAFETY MONITORING AND REPORTING .........................................................72 
10.1. 
Adverse Events ...........................................................................................................72 
10.1.1. 
Definition and Reporting of an Adverse Event ..........................................................72 
10.2. 
Definition of a Serious Adverse Event .......................................................................75 
10.3. 
Definition of a Suspected Unexpected Serious Adverse Reaction .............................76 
10.4. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious 
Adverse Events ...........................................................................................................76 
10.4.1. 
Adverse Event Reporting Period ................................................................................76 
10.4.2. 
Eliciting Adverse Events ............................................................................................76 
10.5. 
Specific Instructions for Recording Adverse Events and Serious Adverse 
Events .........................................................................................................................76 
10.5.1. 
Diagnosis versus Signs and Symptoms ......................................................................76 
10.5.2. 
Adverse Events Occurring Secondary to Other Events ..............................................77 
10.5.3. 
Persistent or Recurring Adverse Events .....................................................................77 
10.5.4. 
Disease Progression ....................................................................................................77 
10.5.5. 
Death ...........................................................................................................................77 
10.6. 
Prompt Reporting of Serious Adverse Events ............................................................78 
10.6.1. 
Timeframes for Submitting Serious Adverse Events .................................................78 
10.6.2. 
Completion and Transmission of the Serious Adverse Event Report ........................78 
10.6.3. 
Regulatory Reporting Requirements for Serious Adverse Events .............................78 
10.7. 
Pregnancy Reporting ..................................................................................................79 
10.8. 
Expedited Reporting to Health Authorities, Ethics Committees, and 
Investigators ................................................................................................................79 
11. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .......................80 
11.1. 
Primary, Secondary, and Exploratory Study Endpoints .............................................80 
11.2. 
Statistical Analysis ......................................................................................................80 
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11.2.1. 
Analysis Populations ..................................................................................................80 
11.2.2. 
Patient Disposition ......................................................................................................80 
11.2.3. 
Demographics and Other Baseline Characteristics .....................................................80 
11.2.4. 
Prior and Concomitant Therapy ..................................................................................81 
11.2.5. 
Efficacy Analyses .......................................................................................................81 
11.2.6. 
Pharmacokinetic Analyses ..........................................................................................82 
11.2.7. 
Exploratory Analyses ..................................................................................................82 
11.3. 
Safety Analyses ..........................................................................................................83 
11.3.1. 
Extent of Exposure .....................................................................................................83 
11.3.2. 
Dose-limiting Toxicity ................................................................................................83 
11.3.3. 
Adverse Events ...........................................................................................................83 
11.3.4. 
Laboratory Analyses ...................................................................................................84 
11.3.5. 
Vital Signs ..................................................................................................................84 
11.3.6. 
Electrocardiogram .......................................................................................................84 
11.4. 
Sample Size Consideration .........................................................................................84 
11.5. 
Interim Analysis ..........................................................................................................85 
11.6. 
Other Statistical Issues ................................................................................................85 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS ...............86 
12.1. 
Regulatory Authority Approval ..................................................................................86 
12.2. 
Investigator Responsibilities .......................................................................................86 
12.2.1. 
Good Clinical Practice ................................................................................................86 
12.2.2. 
Ethical Conduct of the Study and Ethics Approval ....................................................86 
12.2.3. 
Informed Consent .......................................................................................................87 
12.2.4. 
Investigator Reporting Requirements .........................................................................87 
12.2.5. 
Confidentiality ............................................................................................................87 
12.2.6. 
Electronic Case Report Forms ....................................................................................88 
12.2.7. 
Drug Accountability ...................................................................................................88 
12.2.8. 
Site Inspections ...........................................................................................................89 
12.2.9. 
Protocol Adherence ....................................................................................................89 
12.2.10. 
Financial Disclosure ...................................................................................................89 
12.3. 
Sponsor Responsibilities .............................................................................................90 
12.3.1. 
Protocol Modifications ...............................................................................................90 
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12.3.2. 
Use of Information and Publication ............................................................................90 
12.4. 
Study and Study Center Closure .................................................................................91 
12.5. 
Records Retention and Study Files .............................................................................91 
12.5.1. 
Study Files and Retention of Records ........................................................................91 
12.5.2. 
Provision of Study Results and Information to Investigators .....................................92 
12.6. 
Information Disclosure and Inventions ......................................................................93 
12.7. 
Joint Investigator/Sponsor Responsibilities ................................................................93 
12.7.1. 
Access to Information for Monitoring ........................................................................93 
12.7.2. 
Access to Information for Auditing or Inspections ....................................................94 
13. 
REFERENCES ...........................................................................................................95 
14. 
APPENDICES ..........................................................................................................101 
APPENDIX 1. SCHEDULE OF ASSESSMENTS ..................................................................102 
APPENDIX 2. CONTRACEPTION GUIDELINES AND DEFINITION OF 
CHILDBEARING POTENTIAL .............................................................................109 
APPENDIX 3. NEW YORK HEART ASSOCIATION CLASSIFICATION .........................110 
APPENDIX 4. PROHIBITED MEDICATIONS ........................................................................111 
APPENDIX 5. THE RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
(RECIST) GUIDELINES .........................................................................................112 
APPENDIX 6. DRUGS THAT PROLONG THE QT INTERVAL AND/OR INDUCE 
TORSADES DE POINTES PROHIBITED MEDICATIONS ...................................121 
APPENDIX 7. MEDICATIONS TO BE USED WITH CAUTION ............................................122 
APPENDIX 8. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS .....................................................................................123 
APPENDIX 9. EVALUATION OF RESPONSE ACCORDING TO CA-125 ........................124 
APPENDIX 10. PROSTATE CANCER CLINICAL STUDIES WORKING GROUP 2 
(PCWG2) CRITERIA TO GUIDE ASCRIBING DISEASE RESPONSE ..............127 
APPENDIX 11. SIGNATURE OF INVESTIGATOR .............................................................129 
 
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LIST OF TABLES 
Table 1: 
Dose Escalation Scheme for Pamiparib plus TMZ .....................................................40 
Table 2: 
Comparison of Temozolomide Dosing: Flat fixed versus BSA-based .......................50 
Table 3: 
Criteria for Interruption and Modification of Pamiparib and Temozolomide 
Dosing .........................................................................................................................52 
Table 4: 
Time Frame for Reporting Serious Adverse Events to the Sponsor or 
Designee .....................................................................................................................78 
Table 5: 
Estimated Objective Response Rate and 90% Confidence Interval for 
20-25 Patients .............................................................................................................85 
 
LIST OF FIGURES 
Figure 1: 
DNA-trapping Activity of Pamiparib and Other PARP Inhibitors .............................29 
Figure 2: 
Combination Activity of Pamiparib and Temozolomide in H209 Small Cell 
Lung Cancer Xenograft Model ...................................................................................30 
Figure 3: 
Combination Activity of Pamiparib and Temozolomide in H209-T 
Intracranial Model ......................................................................................................31 
Figure 4: 
PAR inhibition was plotted against BGB-290 dose at the time of PBMC 
collection .....................................................................................................................32 
Figure 5: 
PAR inhibition was plotted against BGB-290 drug level in the plasma at the 
time of PBMC collection ............................................................................................32 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ADL 
activities of daily living 
AIC 
5-amino-imidazole-4-carboxamide 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukemia 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
ATM 
ataxia-telangiectasia mutated 
AUC 
area under the plasma concentration-time curve 
BER 
base excision repair 
BID 
twice daily 
BGB-290 
study drug code 
BOR 
best overall response 
BRCA 
BReast CAncer susceptibility gene 
gBRCAm 
germline BReast CAncer susceptibility gene mutation 
BSA 
body surface area 
BUN 
blood urea nitrogen 
CA-125 
carcinoma antigen-125 
CBC 
complete blood count 
CHO 
Chinese hamster ovary 
CI 
confidence interval 
CL/F 
apparent clearance 
Cmin 
minimum observed plasma concentration 
Cmax 
maximum observed plasma concentration 
Ctrough 
lowest concentration reached before the next dose administered 
CNA 
circulating nucleic acids 
CNS 
central nervous system 
CNA 
circulating nucleic acids 
CR 
complete response 
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Abbreviation 
Definition 
CSR 
clinical study report 
CT 
computed tomography 
CTFG 
Clinical Trial Facilitation Group 
CVA 
cerebral vascular accident 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DSB 
double strand break 
DTIC 
dacarbazine 
EC50 
half maximal effective concentration 
eCCGs 
eCRF Completion Guidelines 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EOC 
epithelial ovarian cancer 
EOT 
end-of-treatment 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose-positron emission tomography 
FP 
fluorescence polarization 
GCIG 
Gynecologic Cancer Intergroup 
GCP 
Good Clinical Practice 
G/GEJ 
gastric/gastroesophageal junction 
GLP 
Good Laboratory Practices 
gBRCA 
germline BRCA 
HCT 
hematocrit 
hERG  
human ether-a-go-go related gene  
HRD 
homologous recombination deficiency 
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Abbreviation 
Definition 
HR 
hazard ratio 
HRR 
homologous recombination repair 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
IC50 
half inhibitory concentration 
IEC 
Independent Ethics Committee 
IND 
investigational new drug 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
KM 
Kaplan-Meier 
LDH 
lactic acid dehydrogenase 
LHRH 
luteinizing hormone-releasing hormone  
MAD 
maximum administered dose 
mCRPC 
metastatic castration-resistant prostate cancer 
MDS 
myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPG 
N-methylpurine glycosylase 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MTIC 
5-(3-methyltriazen-1-yl)imidazole-4-carboxamide 
NAD 
nicotinamide adenine dinucleotide 
NCI CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse Events 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
OTC 
over-the-counter 
Pamiparib 
BGB-290 
PAR 
poly(ADP-ribose) 
PARP 
poly(ADP-ribose) polymerase 
PBMCs 
peripheral blood mononuclear cells 
PCWG2 
Prostate Cancer Clinical Trials Working Group 2 
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Abbreviation 
Definition 
PD 
pharmacodynamic 
PET 
positron emission tomography 
PFS 
progression-free survival 
PK 
pharmacokinetic(s) 
PLT 
platelet 
PO 
orally 
PR 
partial response 
PSA 
prostate-specific antigen  
PT 
preferred term 
QD 
once daily 
QTc 
QT interval corrected for heart rate 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SCLC 
small cell lung cancer 
SD 
stable disease 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
SOC 
system organ class 
SSB 
single strand DNA breaks 
t1/2 
elimination half-life 
Tmax 
time to reach maximum (peak) plasma concentration 
TEAE 
treatment-emergent adverse event 
TMZ 
temozolomide 
TNBC 
triple-negative breast cancer 
ULN 
upper limit of normal 
US 
United States 
Vz/F 
apparent volume of distribution 
WBC 
white blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
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1. 
INTRODUCTION 
1.1. 
Poly (ADP-ribose) Polymerase Inhibitors and Pamiparib 
Poly (ADP-ribose) polymerase (PARP) proteins are involved in deoxyribonucleic acid (DNA) 
replication, transcriptional regulation, and DNA damage repair. Inhibition of PARP converts 
common single-strand DNA breaks (SSBs) into double strand- breaks (DSBs) during DNA 
replication. DNA-bound PARP1/2 catalyzes the synthesis of poly (ADP-ribose) (PAR) into 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. [1] 
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. In normal cells, PARP trapping is overcome by homologous recombination 
repair (HRR) factors such as BReast CAncer susceptibility gene (BRCA)1/2, ataxia-
telangiectasia mutated (ATM), and other HRR proteins. Thus, cancer cells with homologous 
recombination deficiencies (HRDs) are more susceptible to PARP inhibitors in a mechanism 
known as synthetic lethality, which is when two conditions in combination are lethal but 
independently would not cause cell death. [2] 
In the clinic, PARP inhibitors, including olaparib, rucaparib, niraparib, and talazoparib, have 
demonstrated sustained anti-tumor responses as a single agent in patients with BRCA1- or 
BRCA2-mutant tumors, while achieving a favorable safety profile. Olaparib and rucaparib are 
approved as single agent for patients with advanced ovarian cancer who have germline mutations 
in the BRCA gene. (Approved product package inserts are available online). 
Pamiparib (also known as BGB-290) is a potent and selective inhibitor of PARP1 and PARP2. 
Pamiparib showed potent ability to trap PARP proteins on damaged DNA (DNA-trapping 
activity) and anti-proliferative activity against a number of cell lines harboring BRCA gene 
mutations or homologous recombination defects.  
1.2. 
PARP Inhibitors in the Treatment of Solid Tumors 
As discussed above PARP inhibitors induce synthetic lethality in cancers with HRD. This study 
will enroll patients with tumors likely to harbor DNA damage repair deficiencies susceptible to 
treatment with PARP inhibitors as described below.  
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. [3] Both BRCA1 and 4 are tumor suppressor 
genes; and when mutated, can lead to a higher risk of cancer by disabling DNA repair processes 
called homologous recombination or homology directed repair. [4, 5]. Many investigations have 
shown that HRD is critical for the response to both platinum and PARP inhibitor therapy.  
Triple-negative breast cancer (TNBC) is considered an aggressive disease, characterized by high 
tumor grade, absence of both hormone receptors (estrogen and progesterone) and the HER2 
receptor and frequent association with BRCA1 mutations.  
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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. [6, 7, 8, 9] The 
TNT study [9] 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 [10] or gemcitabine, [11] 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. [12, 13, 14, 15] 
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 [BID]) was administered to 
women with BRCA1- and/or BRCA2-mutant, advanced breast cancer (of which > 50% were 
triple negative). [16] 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 Food and Drug 
Administration (FDA) approved for women with advanced ovarian cancer with BRCA1/2 
mutation. In addition, olaparib was approved by the European Medicines Agency (EMA) as 
maintenance therapy for ovarian cancer patients with BRCA1/2 mutation. 
Data from clinical studies support the use of PARP inhibitors for women with platinum-sensitive 
epithelial ovarian cancer (EOC). [17, 18, 19] In a randomized study with ~300 women with 
platinum-sensitive high-grade recurrent EOC, patients were randomly assigned to treatment with 
the PARP inhibitor olaparib or placebo. [20] Results from this study showed a significant 
improvement in PFS in patients treated with olaparib compared with placebo (8 versus 5 months; 
hazard ratio [HR] for progression or death 0.35, 95% confidence interval (CI) 0.25˗0.49), 
although interim analysis found no overall survival (OS) benefit (30 months in both; HR 0.94; 
95% 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). [17, 18] 
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. [19] 
Patients were stratified according to presence or absence of a germline BRCA mutation (gBRCA). 
The non-gBRCA cohort was further classified by HRD status and also included patients with 
somatic BRCA mutations. Patients treated with niraparib had an increased PFS in all cohorts 
compared with placebo. In the gBRCA group, PFS was 21.0 versus 5.5 months (HR 0.27; 95% 
CI; 0.17-0.41). In the overall non-gBRCA cohort, PFS was 9.3 versus 3.9 months (HR 0.45; 95% 
CI; 0.34-0.61). In the HRD positive (HRD+) subgroup of the non-gBRCA 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 
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associated with niraparib were thrombocytopenia (34%), anemia (25%), and neutropenia (20%). 
Myelodyspastic 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. [21] 
Prostate Cancer 
Prostate cancer is the second most common cancer in men worldwide. [22] Recent sequencing 
data indicates that more than 20% of metastatic castration-resistant prostate cancer (mCRPC) 
have HRD due to germline and/or somatic loss-of-function in key homologous recombinant 
genes including BRCA2, ATM, CHEK2, NSBP1, FANCJ, that could potentially confer a 
‘BRCAness’ phenotype and susceptibility to PARP inhibition via synthetic lethality. [23, 24, 25, 
26] Recently, it has been shown that prostate cancer patients with germline BRCA1/2 mutations 
have a higher risk of nodal or distant metastases and poorer overall survival than patients without 
mutations. [27] Data from clinical studies has demonstrated that these patients respond to 
treatment with PARP inhibitors. [28] 
 
In a Phase 2 study, 49 patients with mCRPC who had received at least two prior regimens and 
had received prior docetaxel chemotherapy were treated with the PARP inhibitor olaparib 
(400 mg BID). [24] In this study, 16 patients (33%), had DNA repair mutations. The primary 
endpoint of the study was a composite response rate that included ORR, a ≥ 50% decrease in 
serum prostate-specific antigen (PSA), and/or a decrease in circulating tumor cells. Fourteen of 
the 16 (88%) patients with DNA repair mutations had a response based upon these criteria 
compared to only 1 of 33 (3%) patients without an identified DNA-repair gene abnormality.  
 
In another Phase 2 study, 153 patients with mCRPC were treated with abiraterone plus 
prednisone or abiraterone, prednisone, and veliparib. [29] There was a trend toward 
improvement in the PSA response rate (71 versus 64%) and in PFS (11.0 versus 8.8 months) 
with the addition of veliparib, but neither were statistically significant. However, there were 
statistically significant differences in the PSA response rate (89 versus 57%) and measurable 
disease response rate (80 versus 38%) in patients with an identifiable defect in a DNA repair 
gene. 
Gastric Cancer  
Genetic abnormalities in gastric cancer include alterations in the DNA damage response gene 
ATM. The loss of ATM has been demonstrated to be synthetically lethal with inhibition of PARP, 
supporting the use of platinum-based treatment as well as PARP inhibitors.  
Studies showed that gastric cancer cell lines, particularly those with a low expression level of 
ATM protein, are sensitive to olaparib. [30, 31] A randomized, double-blind placebo-controlled 
Phase 2 study was conducted in 124 patients with recurrent or metastatic gastric cancer treated 
with olaparib (100 mg BID daily) in combination with paclitaxel (80 mg/m2 on days 1, 8, and 15 
of every 28-day cycle ) or placebo. [32] Results from this study showed the combination therapy 
significantly improved OS in both the overall population (median 13.1 versus 8.3 months) and in 
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those whose tumors contained low levels of ATM protein. However, there was no difference in 
PFS in either the overall population or in those patients with ATM-low tumors. 
A Phase 3 clinical study with paclitaxel with or without olaparib as a second line treatment 
recently reported results. [33] Asian patients with advanced, previously treated gastric cancer 
were treated with either paclitaxel or paclitaxel in combination with the PARP inhibitor olaparib; 
18% of 535 randomized patients were ATM-deficient. Results of the study in the overall 
population demonstrated numerically higher overall survival for patients treated with olaparib 
plus paclitaxel (6.9 versus 8.8 months; HR 0.79; p =0.0262). However due to a statistical 
correction made due to inclusion of a co-primary endpoint of the ATM-deficient subgroup, this 
did not reach statistical significance (which would have required a p value of < 0.025). In the 
ATM-deficient subgroup, radiological response rates were significantly higher for patients 
treated with olaparib (37% versus 16%; p=0.03), and a non-statistically significant trend towards 
improvement in overall survival was also noted (10 versus 12 months; HR 0.73; p = 0.25). [34] 
Small Cell Lung Cancer 
Small cell lung cancer (SCLC) constitutes about 15% of newly diagnosed lung cancer cases and 
occurs predominantly in cigarette smokers. [35] Approximately 50% of SCLC patients have 
brain metastases at the time of postmortem examination.  
Preliminary data from Phase 1 studies has demonstrated some efficacy of PARP inhibitors in 
SCLC patients. In a Phase 1 study, talazoparib was administered as a single agent in patients 
with previously treated, advanced SCLC with germline mutations in BRCA1 and BRCA2. [36] In 
this study, 10% of patients treated with talazoparib had a partial response and 25% had a clinical 
benefit (complete response [CR], partial response [PR], or stable disease [SD] lasting ≥ 16 
weeks) with a median duration or response of 13.7 weeks (95% CI; 12.0-15.3 weeks). The most 
common adverse events in this study were myelosuppression, fatigue, nausea, and alopecia. 
A Phase 1 study of veliparib administered in combination with standard doses of cisplatin and 
etoposide was conducted in treatment naïve- patients with extensive stage SCLC (n = 9). [37] 
The recommended Phase 2 dose of veliparib was 100 mg. The preliminary efficacy in 7 
evaluable patients were: 1 CR (14.3%), 4 PR (57.1%), and 2 SD (28.6%). Grade 3-5 hematologic 
AEs included neutropenia, leukopenia, lymphopenia, and thrombocytopenia. 
PARP inhibitor Monotherapy Treatment in Indications with Homologous Recombination 
Deficiency 
High frequency of HRD has been identified in subsets of ovarian cancer, and in uterine, lung 
squamous, esophageal, sarcoma, bladder, lung adenocarcinoma, head and neck and gastric 
cancer samples. [38, 39] 
A limited number of studies have evaluated the efficacy of niraparib, rucaparib, talazoparib and 
olaparib in different indications with HRD, as assessed by a variety of methods and 
demonstrated antitumor activity in HRD+ patients even in the absence of BRCA 1/2 mutations. 
Niraparib treatment of advance stage ovarian cancer patients (QUADRA study) elicited an ORR 
of 17.5% (N=126) in HRD+/ BRCA wild type patients as determined by the Myriad myChoice® 
assay, irrespective of platinum sensitivity. [40] 
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Second and 3rd line, platinum sensitive ovarian cancer patients determined to have loss of 
heterozygosity (LOH) high/BRCA wild type disease by the Foundation Medicine NGS test and 
treated with rucaparib (ARIEL 2 trial) also showed an ORR= 29.3% (n=82). [41] Rucaparib 
treatment of HER2 negative metastatic breast cancer patients with LOH high or somatic BRCA 
mutant tumors as assessed by Foundation medicine NGS resulted in an ORR of 10.8% (N=37). 
[42] 
Olaparib treatment of metastatic pancreatic cancer patients without genomic BRCA 1/2 
mutations, but with mutations in DNA damage response genes (based on historical data) elicited 
an ORR of 21.8% (N=31). [61] Patients with biliary tract, bladder, colorectum, lung, esophageal 
and uterine cancer with genomic BRCA1/2 mutations treated with olaparib showed an ORR of 
8.3% (N=12).  [62]  
Finally, talazoparib treatment of patients with solid tumors harboring mutations in a selected 
panel of genes (PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, RAD50, RAD51C, RAD51D, 
MRE11, ATR, PTEN, FANCA, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL) resulted 
in an ORR of 15% (N=20). [43]  
1.3. 
PARP Inhibitors and Temozolomide (TMZ) 
Temozolomide (TMZ) induces apoptosis and cell death by methylating guanine at 
the O6 position, initiating a double-strand break in the DNA and cell cycle arrest. PARP1 and 
PARP2 have a key role in the base excision repair (BER) of N-methylpurines 
(N7-methylguanine and N3-methyladenine) that are generated by TMZ. In the presence of a 
functional BER system, these damaged bases are promptly repaired and do not contribute to 
TMZ cytotoxicity. The first step of the BER process is the excision of the modified base by N-
methylpurine glycosylase (MPG). The subsequent removal of the basic residues by 
apurinic/apyrimidinic endonuclease results in the generation of DNA damage that is finally 
repaired by the coordinate intervention of PARP1, DNA polymerase, XRCC1, and ligase III. 
Inhibition of PARP activity hampers PARylation of PARP1 and PARP2, interrupting the 
completion of the repair process mediated by BER. [44]  
Therefore, increased anti-tumor activity due to the combination of PARP inhibition and TMZ is 
the consequence of increased DNA damage that eventually results in apoptosis and/or growth 
arrest. Repeated treatments with TMZ and PARP inhibitors also downregulate transcription and 
delay recovery of BER components in tumor cells. [45, 46] This might further contribute to 
sensitizing cancer cells to the TMZ and PARP inhibitor combination. 
Several clinical studies have been conducted with PARP inhibitors (olaparib, rucaparib, 
veliparib, and talazoparib) in combination with TMZ. [47, 48, 49, 50, 51, 52, 53, 54] To 
determine the maximum tolerated dose (MTD) in these studies, TMZ was administered at 
standard doses (135 to 150 mg/m2/day or up to 1000 mg/m2/month) with increasing doses of the 
PARP inhibitor. All studies experienced the challenge of significant myelosuppression as dose-
limiting toxicities (DLT) and observed anti-tumor activity was only modest. 
In a single-arm Phase 2 study, veliparib was tested in combination with TMZ in 41 women with 
advanced TNBC (8 with BRCA germline mutation) and the overall response rate was 7% across 
the entire study population. However, patients with BRCA mutations had a 37.5% overall 
response rate. [47] 
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Veliparib (40 mg BID) in combination with TMZ was also studied in patients with mCRPC. The 
primary endpoint was a ≥ 30% decrease in PSA level. [48] Modest activity was seen in the 
25 evaluable patients; 2 (8%) had a confirmed PSA response, 13 (52%) had stable PSA levels, 
the median PFS was 9 weeks (95% CI: 7.9-17) and the median overall survival was 39.6 weeks 
(95% CI: 26.6-not estimable). The most common Grade 3/4 adverse events occurring in >10% of 
patients were thrombocytopenia and anemia. 
In a recent study talazoparib, a PARP inhibitor with very good DNA-trapping activity, was used 
in combination with TMZ in patients with advanced malignancies. In contrast to previous 
studies, mentioned above, standard doses of talazoparib (0.5 to 1 mg) were administered with 
low doses of TMZ in patients with non-BRCA1/2-mutated cancers. [54] The starting dose of 
TMZ was 25 mg/m2, approximately 12.5% of the therapeutic dose, and the MTD was identified 
as 1 mg talazoparib plus 37 mg/m2 of TMZ. This regimen was better tolerated than reported for 
prior studies, with less thrombocytopenia and neutropenia. Furthermore, promising efficacy was 
observed, with 11 patients (61%) experiencing either a PR or SD. These preliminary clinical 
results are in support of the hypothesis that PARP inhibitors with strong DNA-trapping activity 
may only require relatively low TMZ dose levels to exert their anti-tumor activity. 
Continuous dosing of TMZ is thought to enhance the antitumor activity through sustained 
depletion of the DNA repair protein O6-alyklyguanine DNA alkyltransferase. [55] Several 
studies have used continuous dosing of TMZ in patients with solid tumors, lymphoma, 
melanoma, and glioblastoma. [55, 56, 57, 58] In these studies, the dose of TMZ ranged from a 
daily dose of 150 mg/m2 for 5 days during each 28-day cycle to 75 mg/m2 daily for 6 to 7 weeks 
and 50 mg/m2 daily up to 1 year. In a study of continuous TMZ (75 mg/m2 daily for 6 weeks), 
the most common AEs were lymphopenia (60%). Of note, 2 (2%) patients had opportunistic 
disease (pneumocystis pneumonia and aspergillus pneumonia). [57] In a study of continuous 
TMZ (50 mg/m2 daily for up to 1 year), the most common Grade 3/4 AEs were nausea and 
vomiting; the most common hematological adverse event was Grade 3 lymphocytopenia, and 
Grade 1/2 opportunistic infections (thrush) but no pneumocystis pneumonia. [58]  
1.4. 
Nonclinical Data 
1.4.1. 
Nonclinical Data on Pamiparib 
Pamiparib is a highly potent and selective inhibitor of PARP1 and PARP2 that sets itself apart 
from other PARP inhibitors by combining potent DNA-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 homologous recombination defects as well as in vivo models. 
1.4.1.1. 
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 (hERG) channel activity assays and in vivo studies of cardiovascular function 
in dogs, as well as central nervous system (CNS) and respiratory system function tests in rats. 
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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 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 
(CHO) 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 SSBs. 
In the general toxicity studies in rats and dogs, no gross lesions or histopathological changes 
were noted in male and female reproductive organs. No embryo-fetal toxicity studies were 
conducted or are planned as they were not considered essential because of its genotoxicity and 
bone marrow inhibition. 
There was no apparent inhibition of pamiparib on hERG 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 CNS or respiratory functions were 
noted in Sprague-Dawley rats. No abnormal changes in the cardiovascular, CNS, 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. [59] 
1.4.1.2. 
PARP Trapping Data for Pamiparib 
A subset of PARP inhibitors are able to trap PARP enzymes at damaged DNA sites, and these 
trapped PARP-DNA complexes appear to be more cytotoxic than unrepaired DNA breaks caused 
by PARP inactivation. [60] The DNA-trapping activity of pamiparib was measured by a 
fluorescence polarization (FP) binding assay similar to the method described in the literature. 
[60] Fluorescence-labeled nicked DNA was pre-incubated with PARP1and PARP inhibitors 
(pamiparib, olaparib, and veliparib). Nicotinamide adenine dinucleotide (NAD) was added to 
initiate PARylation reaction. PARylation reduced the FP signal by freeing the DNA from PARP1. 
The potency of PARP inhibitors to trap PARP1-DNA complexes was derived from measuring the FP 
signal as a function of compound concentration. Pamiparib showed potent DNA-trapping activity 
(with IC50 of 13 nM), similar to olaparib and 30-fold more potent than veliparib (Figure 1).  
 
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1.4.2. 
Nonclinical Data on Pamiparib in Combination with TMZ 
The anti-proliferative effect of pamiparib in combination with TMZ was evaluated in 8 human 
GB cell lines resistant to single-agent TMZ (EC50 of 32 M or greater). In 7 of 8 cell lines, 
pamiparib demonstrated synergism with TMZ with a shift in half maximal effective 
concentration (EC50) for TMZ of 5-fold or greater. This synergism was also demonstrated in vivo 
in an H209 small cell lung cancer xenograft model (Figure 2). Pamiparib (2.73 mg/kg BID x 21 
days) as single-agent treatment had no significant effect on tumor growth. TMZ (50 mg/kg QD, 
Days 1-5 of each 28-day cycle) as single-agent treatment was quite effective in this model 
resulting in objective responses in all animals (1 PR and 7 CRs in 8 animals) after the first cycle 
of treatment. However, 6 of these 8 animals developed TMZ resistance after three cycles of 
treatment, and the mean tumor volume reached 505 mm3 on Day 66. Addition of pamiparib 
(0.68 mg/kg BID, Days 1-5 of each 28-day cycle) resulted in objective responses in all animals 
(2 PRs and 6 CRs in 8 animals) after the first cycle of treatment. After completion of 3 cycles of 
treatment (on Day 66), most animals were still tumor-free (6/8), and the mean tumor volume was 
12 mm3. Thus, the combination of pamiparib and TMZ significantly enhanced TMZ anti-tumor 
activity and delayed resistance. 
Figure 2: 
Combination Activity of Pamiparib and Temozolomide in H209 Small Cell 
Lung Cancer Xenograft Model 
 
Diamonds = vehicle; squares = Pamiparib 2.73 mg/kg twice per day on Days 1 to 21; circles = temozolomide 
50 mg/kg once per day on Days 1 to 5, Days 29 to 33, and Days 57 to 61; triangles = temozolomide 50 mg/kg once 
per day and pamiparib 0.68 mg/kg twice per day on Days 1 to 5, Days 29 to 33, and Days 57 to 61; SEM = standard 
error of the mean. 
 
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Given the significant brain penetrance of pamiparib, its activity was further explored in an 
intracranial tumor model in nude mice for H209-T DCLC xenografts (Figure 3). H209-T is a 
TMZ-resistant cell line generated by treating H209-xenografted tumors with multiple cycles of 
TMZ in vivo. In this model, pamiparib (2.73 mg/kg BID) as single-agent treatment had no 
significant effect on tumor growth, with a median survival of 24 days compared to median 
survival of 22.5 days in the vehicle-treated group. H209-T intracranial xenografts showed 
resistance to the TMZ treatment alone (50 mg/kg), with median survival of 26.5 days. However, 
the combination of pamiparib and TMZ significantly prolonged animal survival compared to 
TMZ alone (p < 0.01), with a median survival of 54 days. The result suggests pamiparib in 
combination with TMZ can overcome TMZ resistance in this intracranial model. 
Figure 3: 
Combination Activity of Pamiparib and Temozolomide in H209-T 
Intracranial Model 
Dashed black line = vehicle; solid black line = pamiparib 2.73 mg/kg twice daily; dashed gray line = temozolomide      
50 mg/kg once per day for 5 days; solid gray line = temozolomide 50 mg/kg once per day and pamiparib 0.68 mg/kg 
twice per day on Days 1 to 5, Days 15 to 19, and Days 29 to 33 
1.5. 
Clinical Data for Pamiparib 
1.5.1. 
Pharmacokinetics of BGB-290-AU-002 
In the first-in-human Phase 1 study, interim PK data of pamiparib showed that pamiparib is 
rapidly absorbed and eliminated after oral administration. The maximum serum concentration 
(Cmax) and the drug exposure (the area under the concentration-time curve [AUC]) increased in a 
nearly dose proportional manner from 2.5 mg BID to 120 mg BID both after the single dose 
administration and at the steady state. The terminal half-life was determined to be approximately 
13 hours, with a range of 5.4 to 34 hours. At the steady state, from 2.5 mg BID to 120 mg BID, 
drug exposure was increased in a dose-dependent manner, with an approximately 2-fold 
accumulation.  
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1.5.2. 
Exploratory Biomarker Data 
The PAR formation from peripheral-blood mononuclear cells (PBMCs) was detected by ELISA 
to explore the dose-responsive PD activity in the Pamiparib Phase 1 monotherapy study. Blood 
samples for PK and isolation of PBMCs were obtained at baseline, on day 1 (pre-dose), and 
days 1 and 17 (4 hours post-dose) of Cycle 1 (Figure 4). 
Figure 4: 
PAR inhibition was plotted against BGB-290 dose at the time of PBMC 
collection 
PBMC = peripheral blood mononuclear cell 
 
The PD activity at 4h post-dose on D1 and D17 were reported as percentage PAR inhibition from 
pre-dose. PD/PK correlation analyses were conducted from 30 patients who received doses of 
2.5, 5, 10, 20, 40, 60, 80, and 120 mg BID. Robust PAR inhibition in PBMCs was observed even 
at the first dose level of 2.5mg BID, consistent with the clinical activity observed, and appeared 
to be maximal at doses ≥ 10mg BID. The PD activity also increased in an exposure-dependent 
manner with sustained PAR inhibition in PBMCs being observed at steady state exposures 
expected in patients treated with 10 mg BID, or higher, doses (Figure 5, arrow). 
Figure 5: 
PAR inhibition was plotted against BGB-290 drug level in the plasma at the 
time of PBMC collection 
PBMC = peripheral blood mononuclear cell 
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1.5.3. 
Clinical Safety and Preliminary Efficacy for BGB-290-AU-002 
BGB-290-AU-002 is a first-in-human study evaluating pamiparib to characterize the safety, 
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 was conducted in 5 Australian study centers and preliminary data for 45 patients are 
available (cut-off date of 30 September 2016).  
The preliminary safety data indicate the most frequent related AEs ( 10% of patients) assessed 
as related were nausea (58%, n = 26), vomiting (51%, n = 23), fatigue (29%, n = 13), diarrhea 
(18%, n=8), dry mouth (16%, n=7), and decreased appetite (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 percent of the patients experienced a 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 
BGB-290: anemia (n=5), neutropenia (n=3), hypophosphatemia (n=1), nausea (n=1), and fatigue 
(n=1). Serious AEs reported as related to BGB-290 included anemia (n=2) and nausea (n=1).  
The DLT of BGB-290 was persistent Grade 2 nausea despite optimal standard medical therapy 
observed in the 120 mg BID cohort (n=2) and in one patient each in the 40 mg and 80 mg BID 
cohorts. The MTD of BGB-290 was 80 mg PO BID. 
Ten patients achieved either complete (n=2) or partial (n=8) responses; all responses were 
observed in patients with gynecological cancers, and responses were observed in the lowest dose 
cohorts (2.5 mg BID). 
Based upon the overall safety, efficacy, and PK profile of pamiparib, the dose for further 
investigation was determined to be 60 mg PO BID. 
1.6. 
Study Rationale 
Alkylating agents such as TMZ cause SSBs in DNA, which leads to the recruitment of PARP1 
and 2 to bind to the site of damage to repair the SSBs. PARP inhibitors are a class of drugs 
designed to compete at the PARP enzyme binding site and act as catalytic inhibitors, leading to 
accumulation of unrepaired SSBs. [60] Thus PARP inhibition enhances the cytotoxicity of the 
BER pathway, and therefore, enhances TMZ cytotoxicity. 6261, 62] 
The study populations proposed for the expansion phase of this study are patients with tumors 
likely to harbor DNA damage repair deficiencies susceptible to treatment with PARP inhibitors. 
It is hypothesized that increased DNA damage by TMZ and PARP inhibition will provide 
synergism resulting in an increased anti-tumor activity in advanced solid tumors. Furthermore, 
the clinical data for the use of PARP inhibitors in patients with TNBC, ovarian cancer, mCRPC, 
gastric cancer, and SCLC discussed in Section 1.2, along with the data describing the use of 
PARP inhibitors plus TMZ in Section 1.3, supports evaluating pamiparib in combination with 
TMZ in this patient population.  
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1.6.1. 
Rationale for Dose Selection of Pamiparib 
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 below the 
regimen for this study (10 mg versus 60 mg BID). The dose of pamiparib chosen for this study is 
based on the recommended Phase 2 dose (RP2D) determined in the Phase 1 monotherapy study, 
BGB-290-AU-002, discussed in Section 1.5.  
1.6.2. 
Rationale for Dose Selection of Temozolomide (TMZ) 
As discussed in Section 1.3, previous combination studies using standard doses of TMZ and 
increasing low doses of PARP inhibitors had only modest anti-tumor effects and increased 
cytopenia. A recent study that used sub-therapeutic doses of TMZ with standard doses of 
talazoparib showed more promising anti-tumor effects and a better safety profile [36]. Similarly, 
this study is designed to use the RP2D of pamiparib (60 mg BID) with low doses of TMZ, 
starting from 40 mg/day up to 120 mg/day (23 mg/m2/day to 69 mg/m2/day) or higher which 
corresponds to 15%-46% of its recommended dose (150mg/m2/day) when administered daily for 
5 days every 28 days (see Section 6.1 , Table 2). In addition, continuous dosing of TMZ will start 
at 40 mg/day and would potentially increase up to 120 mg/day of TMZ, which translates to 30% 
and 92%, respectively, of a daily dose of 75 mg/m2. [56, 59] 
In summary, pamiparib is a promising selective inhibitor of PARP1 and PARP2 that exhibits 
excellent DNA-trapping activity making it an excellent candidate to determine the effects of 
combining PARP inhibition with TMZ in these patient populations. 
1.7. 
Risk-Benefit Assessment 
Pamiparib has been studied in nonclinical toxicity and Phase 1 clinical studies. Pamiparib 
toxicities are largely consistent with the safety profile shared by other PARP inhibitors with the 
important exception that pamiparib may cause less myelosuppression. PARP inhibitors, 
including pamiparib, show a partial overlap with the safety profile of TMZ. Therefore, patients of this 
study may experience AEs typical for these study drugs at a higher frequency and/or severity. In 
addition, patients may encounter AEs that are uniquely caused by the novel combination(s). 
However, with the lower doses of TMZ being used in this study, it is possible there could be 
fewer myelosuppressive-related AEs than previously seen in other studies using TMZ in 
combination with PARP inhibitors. 
Myelodysplastic syndrome and acute myeloid leukemia (AML) have been reported in a small 
number (< 1%) of patients treated with PARP inhibitors, especially in patients harboring a 
germline BRCA mutation. [63] Typically, patients who develop MDS and AML while on PARPi 
therapy had a history of extensive previous chemotherapy and some had a history of previous 
cancer or bone marrow abnormalities. To date, there have been no reports of MDS or AML in 
patients treated with pamiparib and no fatal drug reactions. Patients in this study will be 
monitored monthly for hematological toxicities and events of MDS and AML will be reported as 
serious AEs (SAEs). 
Preliminary data show that pamiparib appears to be generally well tolerated in patients with 
advanced solid tumors. The safety profile for single-agent pamiparib is similar to that of other 
PARP inhibitors. Given the dire prognosis of the patients that will be enrolled in this study and 
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the limited treatment options, the risk of combining pamiparib with TMZ appears acceptable in 
the context of a Phase 1 study with close monitoring through AE reporting, recording of vital 
signs and ECGs, clinical laboratory testing, and tumor assessments. As outlined in Section 1.1 
and Section 1.6, scientific rationale and supportive data are strong for combining PARP 
inhibitors with TMZ in TNBC, ovarian cancer, mCRPC, and other solid tumors with 
homologous recombination deficiency as well as in SCLC and gastric cancer.  
1.8. 
Study Conduct 
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC), and in accordance with Good 
Clinical Practice (GCP) standards. 
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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
• To determine the safety and tolerability of pamiparib when given orally in 
combination with temozolomide (TMZ; pulsed and continuous)  
• To determine the maximum tolerated dose (MTD) or maximum administered dose 
(MAD) for pamiparib combined with TMZ (pulsed and continuous) 
• To select the recommended Phase 2 dose and schedule of pamiparib in combination 
with TMZ  
• To determine the antitumor activity of pamiparib in combination with TMZ 
2.2. 
Secondary Objectives 
• To characterize the pharmacokinetics (PK) of pamiparib and TMZ 
2.3. 
Exploratory Objectives 
• To evaluate candidate biomarkers in tumor tissue and in peripheral circulation as 
potential markers of response, resistance, or disease progression 
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3. 
STUDY ENDPOINTS 
3.1. 
Primary Endpoints 
• Dose Escalation Phase: Incidence and nature of DLTs  
• Incidence, nature, and severity of AEs, graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), v4.03 
• Objective response rate (ORR), as assessed using RECIST v1.1 
3.2. 
Secondary Endpoints 
• Pharmacokinetic parameters of pamiparib and TMZ, including but not limited to 
Ctrough 
• Time-to-event endpoints, e.g., duration of response (DOR), disease control rate 
(DCR), progression free survival (PFS), and overall survivals (OS) 
3.3. 
Exploratory Endpoints 
• Candidate predictive biomarkers, including, but not limited to expression and 
mutations of genes in the DNA damage response pathway and relationship to efficacy 
and resistance 
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4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is an open-label, multi-center Phase 1b study to evaluate the combined use of pamiparib, a 
PARP inhibitor, with a DNA-alkylating agent, TMZ, in patients with locally advanced and 
metastatic solid tumors. The study consists of a dose escalation phase and a dose expansion 
phase. The dose escalation phase of the study will evaluate the safety, tolerability, preliminary 
efficacy, and PK, in addition to determining the MTD and/or MAD for the combination. In the 
dose expansion phase of this study, the safety, preliminary efficacy, and PK profile of the 
combination will be further evaluated in specific patient populations. Preliminary biomarkers for 
efficacy will also be explored during both phases of the study. 
Dose Escalation: 
The dose escalation phase of the study consists of a modified 3+3 dose escalation scheme 
utilizing a fixed dose of pamiparib in combination with escalating doses of TMZ. There will be 
two arms that will undergo dose escalation independently. In Arm A, TMZ will be administered 
once a day during Days 1 to 7 of each 28-day cycle (pulsed). In Arm B, TMZ will be 
administered once a day continuously during each 28-day cycle. 
Dose Expansion: 
The dose expansion phase of the study will further evaluate the safety and anti-tumor activity of 
pamiparib in combination with TMZ at the dose and schedule that will be chosen based on all 
data available from the dose escalation phase.  
It is expected that approximately 250 patients will be enrolled in the entire study. Patients will be 
enrolled in 6 different cohorts based on their disease characteristics and/ or HRD status as 
described in Section 4.3; Enrollment into these cohorts will occur simultaneously and 
independently of each other. Each expansion cohort will enroll up to 20-25 patients each and 
may enroll additional patients based on emerging data, but the total patients enrolled in the study 
will not exceed 250 patients.  
Adverse events (AEs) that occur during and after the treatment period with study drug(s) will be 
followed and documented as outlined in Section 7.4 and Section 10. AEs will be graded 
according to NCI CTCAE v4.03. 
Pharmacokinetic analysis will be performed for both pamiparib and TMZ during Cycle 1. 
Biomarker analysis will include but is not limited to germline BRCA1/2 mutations, DNA HRD 
status, and somatic mutation analysis. 
Anti-tumor activity will be evaluated by the treating investigator using standard RECIST v1.1 
criteria (Appendix 5). Tumor response will also be evaluated according to the Gynecologic 
Cancer Intergroup (GCIG) criteria for patients with ovarian cancer. In addition, the Prostate 
Cancer Clinical Trials Working Group 2 (PCWG2) criteria will be used for patients with prostate 
cancer. 
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Patients who, at the time of progression, have an ongoing AE that leads to treatment 
discontinuation, will be followed until the event resolves, the investigator assesses the event as 
stable, the patient is lost to follow-up, or the patient starts a different anti-tumor therapy. If a 
patient discontinues study drug due to reasons other than disease progression or death, then 
tumor assessments should continue to be performed following the scheduled assessment plan 
until the start of new anticancer therapy, disease progression, death, lost to follow-up, or 
withdrawal of consent to efficacy follow-up. 
In the absence of unacceptable toxicities or disease progression, patients will be offered 
continued study treatment of BGB-290 plus TMZ. Regardless of discontinuation of one or more 
study drugs, patients should continue on study with regular follow-up (Section 8.5). Patients who 
have discontinued all study drugs should return to the clinic for an end-of-treatment (EOT) visit 
within 7 days after the last study treatment (Section 8.4). After the EOT visit, patients should 
have regular follow-up for safety, efficacy, and survival as outlined in Section 8.5. 
Study procedures and assessments are further detailed in Section 7 and Section 8, and a Schedule 
of Assessments can be found in Appendix 1 Table 1. 
4.2. 
Details of Dose Escalation  
4.2.1. 
Starting Dose and Dose Escalation Approach 
The dose escalation phase consists of two arms as follows: 
Arm A (pulse TMZ dosing): continuous pamiparib (60 mg BID) in combination with 
increasing doses of TMZ (flat doses of 40, 80, 120 mg QD and higher, if tolerated) 
administered on Days 1 to 7 of each 28-day cycle 
Arm B (continuous TMZ dosing): pamiparib (60 mg BID) in combination with 
increasing doses of TMZ (flat doses of 20, 40, 80, 120 mg QD and higher, if tolerated) 
administered continuously. 
A minimum of three patients will be enrolled in Arm A, Dose Level 1, before patients are 
enrolled into Arm B, Dose Level 1. Subsequently, enrollment and dose escalation decisions for 
the two arms will occur independently of each other. 
The dose for pamiparib will be the RP2D of 60 mg PO BID (‘full-dose’ pamiparib) based on the 
rationale outlined in Section 1.6. Since TMZ is given as a DNA-damaging sensitizer for 
pamiparib and to simplify TMZ dosing, flat-dosing will be used for TMZ. The first dose level of 
40 mg QD corresponds to 23 mg/m2 assuming an average body surface area of 1.73 m2. 
Subsequent dose levels of 80 mg and 120 mg correspond 46 mg/m2 and 69 mg/m2, respectively. 
Additional higher dose levels may be explored, and the TMZ dose will not be increased by more 
than 50% each time nor will it exceed the approved daily dose at the corresponding schedule. 
Once the MTD has been determined in Arm A (pulse dosing) and taking into consideration all 
data available for Arm B at that time, further dose escalation may be pursued for Arm A by 
extending the time window of TMZ administration by no more than one additional week per 
dose escalation step. For example, TMZ administration at the MTD dose level may be extended 
to Days 1 to 14 and then to Days 1 to 21 following dose escalation rules outlined in 
Section 4.2.2. 
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If the MTD is exceeded with the starting dose of TMZ, then a dose level of 20 mg QD TMZ 
(Dose Level -1) may be explored. (Table 1). 
Table 1: 
Dose Escalation Scheme for Pamiparib plus TMZ 
 
Arm A  
(Pulse Dosing of TMZ) 
Arm B  
(Continuous Dosing of TMZ) 
Dose Level 
Pamiparib 
Continuous 
TMZ 
Days 1 to 7, every 28 
days 
Pamiparib 
Continuous 
TMZ 
Continuous 
-1 
60 mg BID 
20 mg QD 
60 mg BID 
20 mg QD* 
1 
60 mg BID 
40 mg QD* 
60 mg BID 
40 mg QD 
2 
60 mg BID 
80 mg QD 
60 mg BID 
80 mg QD 
3 
60 mg BID 
120 mg QD 
60 mg BID 
120 mg QD 
≥4 
60 mg BID 
Increase by ≤ 50% 
each time until MTD 
reached 
60 mg BID 
Increase by ≤50% 
each time until MTD 
reached 
*Starting dose; BID = twice daily; MTD = maximum tolerated dose; QD = once daily; TMZ = temozolomide 
If the MTD is exceeded for a combination regimen that is considered inadequate for further 
exploration based on all data available at that time, alternative regimens may be explored after 
discussions with all investigators. For example, alternative regimens for pamiparib dosing may 
be explored such as lower doses of pamiparib continuously or full-dose pamiparib for Days 1 to 
21 of each 28-day cycle. 
Depending on emerging safety data from this and other pamiparib Phase 1 studies, the pamiparib 
regimen may be switched to QD (≤ 120 mg QD) for one or both of the arms at any time during 
or after dose escalation. The first QD regimen of pamiparib will be at a dose level already 
cleared for the BID regimen. 
4.2.2. 
Rules for Dose Escalation 
Dose escalation will occur in accordance with the following modified 3 + 3 dose escalation rules: 
A minimum of three patients will be initially enrolled per cohort. 
• If none of the first three evaluable patients enrolled in a given cohort experience a 
DLT, dose escalation may proceed. 
• If one of the first three evaluable patients enrolled in a given cohort experiences a 
DLT, additional patients (for a minimum of six evaluable patients) will be enrolled in 
that cohort.  
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− If less than one third- of evaluable patients in a given cohort experiences a DLT 
(e.g., DLTs in fewer than two of six patients), escalation will proceed to the next 
higher dose level. 
If a DLT is observed in at least one-third or more of patients (e.g., two or more of up to six 
patients), the MTD will have been exceeded, and dose escalation will be stopped. 
• Additional patients (for a minimum of six evaluable patients) will be assessed for 
DLTs at the preceding dose level (if a minimum of six evaluable patients had not 
already been assessed at that dose level). 
• If the MTD is exceeded at a given dose level, a lower or intermediate dose level may 
be assessed for toxicity in the same manner as described above. 
If the MTD is exceeded at a given dose level, the next highest dose level at which less than one 
third of evaluable patients in a given cohort experiences a DLT (e.g., DLTs in fewer than two of 
six patients) will be declared the MTD. 
If less than one third- of evaluable patients (e.g., DLTs in fewer than two of six patients) at the 
highest dose level experience a DLT, this dose level will be declared the MAD. 
Available data relevant for dose escalation decisions for TMZ, including AEs, laboratory 
assessments, and PK analyses, will be reviewed by the Medical Monitor, investigators, 
PK scientist, and clinical trial manager. On the basis of a review of these data and in consultation 
with the investigators, a determination will be made as to the next appropriate dose escalation 
step. 
4.2.3. 
Assessment of Dose-Limiting Toxicity 
Dose-limiting toxicities will be assessed during the DLT assessment window starting with the 
first day of study drug administration for each arm and all dose levels.  
The DLT assessment window will encompass the first cycle of 28 days.  
Patients who withdraw or are withdrawn from the study prior to completing the DLT assessment 
window for reasons other than a DLT will not be considered evaluable for DLT and will be 
replaced, if needed, to meet patient number requirement for dose escalation. Patients who do not 
receive ≥70% of scheduled pamiparib and TMZ dosing during the DLT assessment window will 
not be considered evaluable for DLTs and will be replaced, if needed, to meet patient number 
requirement for dose escalation. 
4.2.4. 
Definition of Dose-Limiting Toxicity 
A DLT is defined as one of the following toxicities occurring during the DLT assessment 
window and considered by the investigator to be related to pamiparib:  
• Grade  3 non-hematologic, non-hepatic major organ AE, with the following 
exceptions:  
− Grade 3 nausea, vomiting, or diarrhea that resolves to Grade  1 with optimal 
medical management within 3 days 
− Grade 3 electrolyte disturbances that respond to correction within 3 days  
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• Grade  4 neutropenia lasting >7 days  
• Grade  3 febrile neutropenia 
• Grade  3 thrombocytopenia with clinically significant bleeding 
• Grade  4 thrombocytopenia lasting  7 days 
• Grade 4 anemia 
• Grade  3 total bilirubin or hepatic transaminases (alanine aminotransferase [ALT or 
SGPT] or aspartate aminotransferase [AST or SGOT]) with the following exceptions: 
− For patients with Grade 1 hepatic transaminase levels at baseline, a hepatic 
transaminase level of  7.5 x upper limit of normal (ULN) will be considered a 
DLT. 
− For patients with Grade 2 hepatic transaminase levels at baseline, a hepatic 
transaminase level  10 x ULN will be considered a DLT. 
4.3. 
Expansion Cohorts 
The dose expansion phase of the study will begin once the safety and tolerability have been 
reviewed for the dose escalation cohorts and the preferred dose and schedule of pamiparib plus 
TMZ has been determined. Approximately 200 patients will be enrolled in the dose expansion 
phase with approximately 20-25 patients enrolled into each cohort. Enrollment into each cohort 
will occur in parallel. 
Expansion Cohort 1: Patients with platinum-sensitive high-grade epithelial, non-mucinous, 
ovarian cancer, fallopian cancer, or primary peritoneal cancer with either known deleterious or 
suspected deleterious germline or somatic BRCA1/2 mutation or with DNA HRD. 
Expansion Cohort 2: Patients with TNBC with either known deleterious or suspected deleterious 
germline or somatic BRCA1/2 mutation or with DNA HRD who have received 0-1 prior 
platinum-containing treatment in any treatment setting and treated with ≤ 3 prior regimens. 
Expansion Cohort 3: Patients with mCRPC with either known deleterious or suspected 
deleterious germline or somatic BRCA1/2 mutation or with documented HRD. 
Expansion Cohort 4: Patients with extensive-stage SCLC who have been treated with ≤ 2 prior 
regimens. 
Expansion Cohort 5: Patients with gastric or gastroesophageal junction cancer who have been 
treated with ≤ 2 prior regimens. 
Expansion Cohort 6: Patients with non-squamous and squamous NSCLC, esophageal cancer, 
squamous head and neck cancer, or soft tissue sarcomas (specific subtypes: undifferentiated 
pleomorphic sarcoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, 
dedifferentiated liposarcoma, myxofibrosarcoma) whose tumors are HRD+ as determined 
centrally by the Myriad myChoice® HRD Plus assay. Patients with NSCLC, esophageal and 
head and neck cancer may have received at least 1 but no more than 3 prior lines of therapy. 
Patients with soft tissue sarcoma may have received at least 1 but no more than 3 prior lines of 
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therapy OR no therapy if, in the opinion of the investigator, standard of care first line therapy is 
not appropriate.  
The safety and PK assessments, as well as the rules for continued dosing in the cohort-expansion 
phase, will be identical to those in the dose escalation phase.  
Each cohort will be evaluated independently for study endpoints and can be closed due to lack of 
enrollment, anti-tumor activity or other reasons. Cohorts may be also further expanded based on 
clinical emerging data. 
If the frequency of Grade ≥ 3 toxicities or other unacceptable chronic toxicities in the 
cohort-expansion phase suggests that the MTD has been exceeded at that dose level, any 
remaining accrual at that dose level will be halted. Consideration will then be given to enrolling 
additional patients (up to 20 patients) into an expansion cohort at a lower dose level. 
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5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
Patients must meet all the following criteria to be eligible for the study: 
All Cohorts  
1. Patient has voluntarily agreed to participate by signing an informed consent 
2. Male or female and ≥ 18 years of age at the time of informed consent 
3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 
4. Ability to swallow whole capsules 
5. Patients who have histologic or cytologic-confirmed malignancy that has progressed to 
the advanced or metastatic stage 
6. Agree to provide archival tumor tissue 
a. Dose Escalation Phase: If available, agreement to provide archival tumor tissue for 
exploratory biomarker analyses 
Note: If archival tumor tissue is not available, an optional fresh biopsy is highly 
recommended. 
b. Dose Expansion Phase: patients enrolled in the HRD+ cohorts must provide archival 
tissue or fresh biopsy (if archival tissue is not available) for prospective central 
assessment of HRD status. Other cohorts may provide tissue, if available, for 
retrospective analysis. 
7. Patients must have adequate organ function as indicated by the following screening 
laboratory values (obtained ≤ 2 weeks prior to Day 1): 
a. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L 
b. Platelets ≥ 100 x 109/L (Note: Criterion must be met without a transfusion within the 
2 weeks prior to obtaining the sample) 
c. Hemoglobin ≥ 10 g/dL or ≥ 6.1 mmol/L (Note: Criterion must be met without a 
transfusion within the 2 weeks prior to obtaining the sample) 
d. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated creatinine 
clearance  50 mL/min (calculated using the institutional standard method) 
e. Total serum bilirubin ≤ 1.5 x ULN (total bilirubin must be < 4 x ULN for patients 
with Gilbert’s syndrome or if indirect bilirubin concentrations are suggestive of 
extrahepatic source of elevation) 
f. Aspartate and alanine aminotransferase (AST and ALT, respectively)  3 x ULN OR 
≤ 5 x ULN for patients with liver metastases 
8. Female patients of childbearing potential and female partners of male study patients must 
agree to practice highly effective methods of birth control (Appendix 2) for the duration 
of the study and for ≥ 6 months after the last dose of study drug. In addition, non-sterile 
male patients must agree to practice highly effective methods of birth control 
(Appendix 2) and avoid sperm donation for the duration of the study and for ≥ 6 months 
after the last dose of study drug. 
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9. Willingness and ability to comply with all protocol-specified requirements  
Dose Escalation Phase only 
10. Patient must have disease that is either measurable or evaluable per RECIST v1.1 criteria. 
Dose Expansion Phase only 
11. Patient must have measurable disease per RECIST v1.1 criteria (except where noted 
below). 
Note: tumor lesions used for freshly acquired biopsies should not be included as target 
lesions unless there are no other suitable target lesions available 
12. Ovarian Cancer (Expansion Cohort 1) 
a. Patients must have received at least one line of platinum-containing therapy in the 
advanced or metastatic setting. 
b. Patients must not have progressed or have recurrent disease within 6 months of the 
completion of the last platinum-containing regimen. 
• Note: Patients can receive additional therapy after the last platinum-containing 
regimen as long as the criteria for platinum-sensitivity is met. 
c. Patients with known or suspected deleterious mutations in BRCA1 or BRCA2 HRD+, 
regardless of the molecular signature result. 
• If HRD or BRCA1/2 mutation status is unknown or has not been previously 
evaluated, the patient must undergo tissue screening using the Myriad 
myChoice® HRD diagnostic test to determine eligibility. 
13. Triple-Negative Breast Cancer (Expansion Cohort 2) 
a. Patients with known or suspected deleterious mutations in BRCA1 or BRCA2 are 
classified as HRD+, regardless of the molecular signature result.  
• If HRD or BRCA 1/2 mutation status is unknown or has not been previously 
evaluated, the patient must undergo tissue screening using the Myriad 
myChoice® HRD diagnostic test to determine eligibility. 
b. 0-1 prior platinum-containing treatment in any treatment setting 
• Note: Patients could have received additional therapy after the last 
platinum-containing regimen as long as the other eligibility criteria are met. 
c. Received ≤ 3 prior lines of therapy in the advanced or metastatic setting 
14. Metastatic Castration-Resistant Prostate Cancer (Expansion Cohort 3) 
a. Patients with known or suspected deleterious mutations in BRCA1 or BRCA2 are 
classified as HRD+, regardless of the molecular signature result.  
• If HRD or BRCA1/2 mutation status is unknown or has not been previously 
evaluated, the patient must undergo tissue screening using the Myriad 
myChoice® diagnostic test to determine eligibility. 
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b. The patient may be either chemotherapy-naïve or have previously had no more than 
two taxane-based chemotherapy regimens including docetaxel and carbazitaxel. If 
docetaxel is used more than once, this will be considered as one regimen. 
c. The patient may be pre- or post-treatment with a novel androgen receptor targeted 
agent (e.g., abiraterone and/or enzalutamide). 
d. At least 2 weeks since the completion of prior flutamide, bicalutamide, and 
nilutamide, or enzalutamide and abiraterone treatment 
e. At least 2 weeks from any radiotherapy, with the exception of a single fraction of 
radiotherapy for the purposes of palliation (confined to one field) 
f. Documented prostate cancer progression as assessed by the investigator with one of 
the following: 
• Prostate-specific antigen (PSA) progression defined by a minimum of 3 rising 
PSA levels with an interval of ≥ 1 week between each determination. The 
PSA value at the screening visit should be ≥ 2 µg/L (2 ng/ml). 
• Radiographic progression of soft tissue disease by modified RECIST v1.1 
criteria 
• Surgically or medically castrated. The testosterone levels do not need to be 
checked as long as the patient has been on chemical castration or undergone 
surgical castration for > 4 months. In all cases, the luteinizing 
hormone-releasing hormone (LHRH) antagonist/agonist is to be continued in 
these patients. 
• Patients with only non-measurable bone lesions must have either progression 
with 2 or more new lesions or have PSA progression within the 6-week period 
before study drug administration. 
15. Extensive Stage Small Cell Lung Cancer (Expansion Cohort 4) 
a. Received ≤ 2 prior lines of therapy 
16. Gastric/Gastroesophageal Junction Cancer (Expansion Cohort 5) 
a. Received ≤ 2 prior lines of therapy 
17. HRD+ Solid Tumors, Multiple Indications (Expansion Cohort 6) 
a. Patient has histologic or cytologic-confirmed advanced (metastatic and/or 
unresectable)  
• non-squamous non-small cell lung cancer (NSCLC) 
• squamous NSCLC 
• esophageal cancer 
• squamous head and neck cancer 
• soft-tissue sarcomas (undifferentiated pleomorphic sarcoma, leiomyosarcoma, 
malignant peripheral nerve sheath tumor, dedifferentiated liposarcoma, 
myxofibrosarcoma) 
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b. Patients must have tumors with homologous recombination deficiency (HRD+) as 
centrally determined by the Myriad myChoice® HRD Plus assay irrespective of their 
known molecular signature 
c. Patients with nonsquamous NSCLC, squamous NSCLC, esophageal cancer, 
squamous head and neck cancer must have received at least 1 but not more than 3 
prior lines of therapy.  
d. Patients with soft tissue sarcoma must have received at least 1 but no more than 3 
prior lines of therapy. Treatment naïve patients may be allowed if, in the opinion of 
the investigator, available standard of care first line therapy is not appropriate 
5.2. 
Exclusion Criteria 
Patients will be excluded from the study for any of the following reasons: 
1. Known hypersensitivity to any temozolomide (TMZ) component or to dacarbazine 
(DTIC) 
2. Prior treatment with a PARP inhibitor  
3. Received chemotherapy, biologic therapy, immunotherapy, or investigational agent 
within 3 weeks prior to Day 1 (or ≤ 5 half-lives, whichever is shorter) (unless otherwise 
noted in the Inclusion Criteria)  
4. Patients who are considered to be refractory to platinum-based therapy (e.g., progressive 
disease at the first tumor assessment while receiving platinum treatment) (for patients in 
dose expansion phase only) 
5. Have any unresolved acute effects of any prior therapy of Grade 2 or higher, except for 
AEs not constituting a safety risk by investigator judgment 
6. Had a major surgical procedure, open biopsy, or significant traumatic injury ≤ 4 weeks 
prior to Day 1, or anticipation of need for major surgical procedure during the course of 
the study  
• Placement of vascular access device is not considered major surgery 
7. Have other diagnosis of malignancy 
• Except for surgically excised non-melanoma skin cancer, adequately treated 
carcinoma in situ of the cervix, localized prostate cancer treated with curative 
intent, adequately treated low-stage bladder cancer, ductal carcinoma in situ 
treated surgically with curative intent, or a malignancy diagnosed > 2 years 
ago, with no current evidence of disease and no therapy ≤ 2 years prior to 
Day 1. 
8. Patient who has received local radiotherapy of non-target lesions for local symptom 
control within the last 4 weeks must have recovered from any adverse effects of 
radiotherapy before recording baseline symptoms. 
9. Have untreated leptomeningeal or brain metastasis. Patients with previously treated brain 
metastases are eligible if the metastases have shown no progression on brain computed 
tomography (CT) or magnetic resonance imaging (MRI) over at least 4 weeks, the 
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patients have no symptoms due to the brain metastases, and the patients have been off 
corticosteroids for ≥ 2 weeks. 
10. Have active infection requiring systemic treatment 
11. Have known human immunodeficiency virus (HIV) infection or serologic status 
reflecting active viral hepatitis infection as follows: 
• Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) 
carriers whose HBV DNA is > 500 IU/mL should be excluded. Note: Inactive 
HBsAg carriers and patients with treated and stable hepatitis B (HBV DNA 
< 500 IU/mL) can be enrolled. Patients receiving antivirals at screening 
should have been treated for > 2 weeks before the first dose of study drug(s). 
12. Have any of the following cardiovascular criteria: 
• Current evidence of cardiac ischemia 
• Current symptomatic pulmonary embolism 
• Acute myocardial infarction ≤ 6 months prior to Day 1 
• Heart failure of New York Heart Association Classification III or IV 
(Appendix 3) ≤ 6 months prior to Day 1 
• Grade ≥ 2 ventricular arrhythmia ≤ 6 months prior to Day 1 
• Cerebral vascular accident (CVA) ≤ 6 months prior to Day 1 
13. Have an active inflammatory gastrointestinal disease, chronic diarrhea, or had previous 
complete gastric resection or lapband surgery 
Note: Gastroesophageal reflux disease under treatment with proton pump inhibitors is 
allowed (assuming no drug interaction potential). 
14. Use or have anticipated need for food or drugs known to be strong or moderate 
cytochrome P450 (CYP)3A inhibitors or strong CYP3A inducers ≤ 10 days (or ≤ 5 half-
lives, whichever is shorter) prior to Day 1(Appendix 4) 
15. Are pregnant or nursing (females of childbearing potential require a negative serum 
pregnancy test ≤ 7 days before Day 1) 
16. Have hereditary problems of galactose intolerance, the Lapp lactase deficiency, or 
glucose-galactose malabsorption 
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6. 
STUDY TREATMENT  
6.1. 
Study Drugs 
6.1.1. 
Pamiparib (BGB-290) 
Patients will receive pamiparib as 10 mg, 20 mg, 40 mg, or 60 mg capsules, depending on dose 
level and capsule availability. 
6.1.1.1. 
Packaging and Labelling 
Pamiparib capsules are provided in a container with a child-resistant closure and labelled in 
accordance with all applicable local regulatory requirements. 
6.1.1.2. 
Handling and Storage 
The instructions for drug ordering are in the Pharmacy Binder. Pamiparib must be kept at 
15-30°C. An accurate study drug accountability log must be maintained and kept up-to-date at all 
times. 
6.1.1.3. 
Dosage and Administration 
Pamiparib 60 mg will be administered PO BID, once in the morning and once in the evening, 
approximately 12 hours apart, each day for the protocol-prescribed dosing period. Pamiparib can 
be dosed with TMZ. 
A lower dose of pamiparib or a QD regimen for pamiparib may be explored (see Section 4.2.1). 
Patients will be instructed to swallow the capsules whole, in rapid succession, with water. 
Patients will be required to fast for at least 2 hours before and 1 hour after each pamiparib 
administration. Water is allowed during the fasting period. 
A dose of pamiparib should be skipped if it is not taken within 2 hours of the scheduled time. An 
extra dose of pamiparib should not be taken to make up for a missed dose. If vomiting occurs 
during the course of treatment, no re-dosing of the patient is allowed before the next scheduled 
dose. 
On days with PK assessments, pamiparib (first dose) and TMZ should be administered in the 
clinic. 
6.1.2. 
Temozolomide 
6.1.2.1. 
Packaging and Labelling 
Capsules of TMZ are available in 5 mg, 20 mg, 100 mg, and 140 mg, depending on dose level and 
capsule availability. Please refer to the package insert for detailed information. 
6.1.2.2. 
Handling and Storage 
Please refer to the package insert for detailed information. 
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6.1.2.3. 
Dosage and Administration 
Temozolomide will be administered PO QD, preferably in the morning (see dosing schedule 
below Table 2). TMZ can be administered with pamiparib. The daily dose and schedule will be 
determined as outlined in Section 4.2.1. 
Patients will be instructed to swallow the capsules whole, in rapid succession, with water. 
Patients will be required to fast for at least 2 hours before and one hour after each TMZ 
administration. Water is allowed during the fasting period. 
A dose of TMZ should be skipped if it is not taken within 2 hours of the scheduled time. An extra 
dose of TMZ 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. 
In this study, TMZ will be administered as a flat dose rather than based on body surface area 
(BSA). The conversion of dose levels for TMZ for this study into BSA-based doses are as 
follows in Table 2.  
Table 2: 
Comparison of Temozolomide Dosing: Flat fixed versus BSA-based 
Flat Dose QD 
BSA Equivalent1 
20 mg 
11.5 mg/m2 
40 mg 
23.0 mg/m2 
60 mg 
34.7 mg/m2 
80 mg 
46.0 mg/m2 
120 mg 
69.0 mg/m2 
BSA = body surface area; QD = once daily 
1  Dose equivalent information is provided for reference only and assumes an average body surface area of 1.73 m2 
On days with PK assessments, pamiparib and TMZ should be administered in the clinic. 
6.1.2.4. 
Temozolomide and Pamiparib Drug-drug Interaction Potential 
Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species, 
5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) and to TMZ acid metabolite. MTIC 
is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC), which is known to be an 
intermediate in purine and nucleic acid biosynthesis, and to methylhydrazine, which is believed 
to be the active alkylating species. Cytochrome P450 enzymes play only a minor role in the 
metabolism of TMZ and MTIC (USPI). 
A CYP phenotyping study using human liver microsomes with selective CYP inhibitors and 
recombinant CYP enzymes suggests that CYP3A is the major CYP isoform responsible for 
pamiparib metabolism while CYP2C8 contributes to pamiparib metabolism to a lesser extent. 
Pamiparib is a moderate inhibitor for CYP2C9 (IC50 = 6.48 M) while its IC50 for other CYP 
isozymes are all greater than 10 M. Pamiparib is not a time-dependent CYP inhibitor of the 
7 major CYP isozymes tested (please refer to the IB for additional information [59]. 
Consequently, the drug-drug interaction potential between pamiparib and TMZ is believed to be 
low when co-administered. 
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6.1.3. 
Modifications of Study Drugs 
6.1.3.1. 
General Considerations for Modifications of Study Drugs 
AEs should be assessed as best as possible regarding their relatedness to one or both study 
drug(s). Investigators should discuss potential dose modifications with the Medical Monitor prior 
to implementation, if feasible. Regardless of discontinuation of one or both study drugs, patients 
should continue on study, with regular follow-up as outlined in Section 8.5. 
Patients who experience a DLT during the DLT assessment window, or a clinically significant 
Grade 2 toxicity or Grade 3 or 4 toxicity considered related to study drug(s) after the DLT 
assessment window, may temporarily suspend study drug. Depending on the toxicity, study drug 
may resume within 28 days after discussion with the Medical Monitor. 
Dosing of pamiparib and TMZ can be interrupted for approximately 28 days for medical events 
that are not associated with toxicity related to these study drugs or disease progression without 
discontinuing the patient from the study. If study drug is planned to be held > 28 days, the 
medical monitor must be contacted before permanent patient discontinuation. 
Criteria for dose modifications and suggested guidelines for the management of toxicities related 
to pamiparib and/or TMZ are summarized below. These general guidelines may be modified at 
the discretion of the investigator based on best clinical judgement at that time. Any toxicities 
related to pamiparib and/or TMZ should be managed according to standard medical practice.  
6.1.3.2. 
Dose Interruption and Modification of Pamiparib and Temozolomide 
As discussed in Section 1.3 and Section 1.6, PARP inhibitors show at least partial overlap with 
the safety profile of TMZ, thus making it likely that patients in this study may experience 
pamiparib and TMZ-related AEs at a higher frequency and/or severity. In addition, patients may 
encounter AEs that are uniquely caused by the novel combination of pamiparib and TMZ.  
In the context of this study, the role of TMZ is to sensitize tumor cells to pamiparib through 
DNA damage that can be caused by relatively low doses of TMZ. Given the favorable safety 
profile of pamiparib (Section 1.5), it is reasonable to assume that a Grade 3 or 4 AE is more 
likely to be due to the addition of TMZ to pamiparib rather than pamiparib on its own. Following 
this rationale, the decision of a dose reduction will affect TMZ first, and a maximum of 
two TMZ dose reductions are allowed.  
Patients enrolled in the pulsed schedule (Arm A) who undergo AEs may re-start TMZ after the 
AE has recovered at the same dose or at a reduced dose as specified in Table 3, provided 3 weeks 
have passed from the last full TMZ dosing. For alternate scenarios, please contact the medical 
monitor for instructions. Pamiparib should be resumed and administered continuously at 60 mg 
BID, unless a dose reduction is specified.  
Should TMZ dose reduction in itself be insufficient to ensure tolerability of the combination 
regimen, dose reductions of pamiparib in 20 mg increments may be discussed with the Medical 
Monitor, and a maximum of two pamiparib dose reductions is allowed. Depending on the 
toxicity that is triggering a second TMZ dose reduction, the possibility of a concurrent pamiparib 
dose reduction may be discussed with the Medical Monitor. If the blood count levels have not 
recovered to NCI-CTCAE Grade 1 or less after 4 weeks, further investigations should be 
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considered, including bone marrow analysis and blood sample for cytogenetics. If MDS or AML 
is confirmed, discontinue pamiparib. The criteria for dose modifications and reductions for 
pamiparib and TMZ are outlined in Table 3. 
Table 3: 
Criteria for Interruption and Modification of Pamiparib and Temozolomide 
Dosing 
Worst toxicity 
CTCAE 4.03 Grade (value) 
Recommended dose modification any time during a cycle of therapy 
Hematologic 
Anemia (hemoglobin, Hgb) 
Grade 2 (Hb < 10 - 8 g/dL) 
First occurrence: continue dosing at current dose level 
Second and subsequent occurrences: hold pamiparib and TMZ until 
resolved to ≤ Grade 1 or baseline 
• 
If resolved ≤ 14 days, then maintain dose levels 
• 
If resolved > 14 days, then  TMZ by 1 dose level and continue 
pamiparib at same dose 
Grade 3 (Hb < 8 g/dL) 
 
• 
Subsequent occurrence following dose reduction for anemia:  
• 
Continue pamiparib and TMZ without interruption with 
appropriate supportive care based on clinical assessment OR 
• 
Hold pamiparib and TMZ and treat as medically indicated to get 
Hgb to ≥ 9 g/dL, then restart at reduced dose level OR 
• 
Hold pamiparib andTMZ and treat as medically indicated to get 
Hgb to ≥ 9 g/dL, then  TMZ by 1 additional dose level 
Grade 4 (life threatening 
consequences; urgent intervention 
indicated) 
• 
Second occurrence following dose reduction for anemia:  
• 
Hold pamiparib and TMZ and treat as medically indicated to get 
Hgb to ≥ 9 g/dL, then  TMZ by 1 additional dose level  
• 
Third occurrence following 2 dose reductions for anemia:  
• 
Discontinue pamiparib and TMZ if anemia is not caused by any 
other confounding event, e.g., gastrointestinal hemorrhage 
• 
Hold pamiparib and TMZ and treat as medically indicated to get 
Hgb to ≥ 9 g/dL, then restart at reduced dose level 
Neutropenia (ANC) 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
Hold pamiparib and TMZ until resolved to Grade ≤ 1 or baseline 
• If resolved ≤ 7 days, then maintain dose levels 
• If resolved > 7 days, then  TMZ by 1 dose level 
Grade 4 (ANC < 0.5 x 109/L) 
Hold pamiparib and TMZ until resolved to Grade ≤ 1 or baseline and 
 TMZ by 1 dose level 
Febrile neutropenia (ANC < 1.0 x 
109/L with single temperature of > 
38.3°C or sustained temperature of 
≥ 38°C for > 1 hour) 
Hold pamiparib and TMZ until resolved and 
 TMZ by 1 dose level 
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Table 3: 
Criteria for Interruption and Modification of Pamiparib and Temozolomide 
Dosing (Continued) 
Worst toxicity 
CTCAE 4.03 Grade (value) 
Recommended dose modification any time during a cycle of therapy 
Thrombocytopenia 
Grade 3 (PLT < 50- 25 x 109/L) 
Hold pamiparib and TMZ until resolved to Grade ≤1 or baseline  
• If resolved ≤ 7 days, then maintain dose levels 
• If resolved > 7 days, then  TMZ by 1 dose level 
Grade 4 (PLT < 25 x 109/L) 
Hold pamiparib and TMZ until resolved to Grade ≤ 1 or baseline and 
 TMZ by 1 dose level 
Renal 
Serum Creatinine 
2-3 x ULN 
Hold BGB-290 and TMZ until resolved to Grade ≤1 or baseline  
• If resolved ≤7 days, then maintain dose levels 
• If resolved >7 days, then  TMZ by 1 dose level 
Grade 3 (>3.0 - 6.0 x ULN) and 
Grade 4 (>6.0 x ULN) 
Permanently discontinue pamiparib and TMZ 
Hepatic 
Bilirubin 
 
Grade 2 (> 1.5 - 3.0 x ULN) and 
Grade 3 (> 3.0- 10.0 x ULN) 
Hold pamiparib and TMZ until resolved to Grade ≤ 1 or baseline  
• If resolved ≤ 7 days, then maintain dose levels 
• If resolved > 7 days, then  pamiparib and TMZ by 1 dose level 
Grade 4 (> 10.0 x ULN) 
Permanently discontinue pamiparib and TMZ 
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 (e.g. review of peripheral blood 
smear and haptoglobin determination), then  pamiparib and TMZ by 
1 dose level and continue study drug administration at the discretion of the 
investigator. 
AST or ALT 
Grade 3 (> 5 and ≤ 20 x ULN) 
Hold pamiparib and TMZ until AST and/or ALT resolved to ≤ 5 x ULN or 
baseline 
• If ≤ 5 x ULN within 14 days, then  pamiparib and TMZ by 1 dose 
level 
• If second episode, discontinue pamiparib and TMZ 
• If persistent for > 14 days, discontinue pamiparib and TMZ 
Grade 4 (> 20 x ULN) 
Permanently discontinue pamiparib and TMZ 
Pancreatic 
Pancreatitis 
Grade 3 or 4 
Permanently discontinue pamiparib and TMZ 
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Table 3: 
Criteria for Interruption and Modification of Pamiparib and Temozolomide 
Dosing (Continued) 
Worst toxicity 
CTCAE 4.03 Grade (value) 
Recommended dose modification any time during a cycle of therapy 
Cardiac 
Cardiac - prolonged QTc interval 
QTcF > 500 ms 
or 
> 60 ms from the highest value 
at baseline or predose 
• Obtain triplicate ECGs (5 minutes apart) ~1 hour after initial ECG  
• If mean QTcF > 500 ms, hold pamiparib and TMZ until evaluation of 
ECGs by cardiologist  
a. Cardiology evaluation as soon as practical but within 7 days of 
initial abnormal ECG  
• If mean QTcF > 500 ms confirmed by cardiologist, discontinue 
pamiparib and TMZ 
Cardiac general 
Grade 3 
Hold pamiparib and TMZ until resolved to Grade ≤ 1 or baseline and 
 TMZ 1 dose level 
 
Grade 4 
Permanently discontinue pamiparib and TMZ 
Other adverse events 
Grade 3 
Hold pamiparib and TMZ until resolved to Grade ≤ 1 or baseline and 
 TMZ by 1 dose level 
No dose reduction required for asymptomatic laboratory abnormalities 
Grade 4 
Permanently discontinue pamiparib and TMZ 
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
ECG = electrocardiogram; Hgb = hemoglobin; ms = milliseconds; PLT = platelet; QTc = QT interval corrected 
for heart rate; QTcF = QT interval corrected for heart rate using Fridericia’s formula; TMZ = temozolomide; 
ULN = upper limit normal  
 
6.1.4. 
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. 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. The inventoried supplies will be returned to the sponsor or destroyed on site, after 
receiving written sponsor approval. 
All unused TMZ will be destroyed on site according to regulations and local guidelines.  
6.1.5. 
Assessment of Treatment Compliance 
On all visits to the study center, patients will be questioned in regard to compliance with study 
instructions. 
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6.1.6. 
Treatment of Overdose from Study Drugs 
Overdose is defined as a patient having taken (accidentally or intentionally) a dose of pamiparib 
or TMZ that exceeded the dose assigned per protocol by ≥ 20%. Patients with a suspected 
overdose should be managed with appropriate supportive therapy as determined by the 
investigator in consultation with the Medical Monitor. Any AEs occurring as a result of an 
overdose should be reported to the Medical Monitor as well as being included in standard AE 
reporting. 
6.1.7. 
Occupational Safety 
Pamiparib is not expected to pose significant occupational safety risks 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. 
6.2. 
Concomitant Medications and Non-Drug Therapies 
6.2.1. 
Permitted Medications 
All treatments and supportive care, including antiemetic therapy, hematopoietic growth factors 
and/or red blood cell/platelet transfusions, that the investigator considers necessary for a 
patient’s welfare may be administered at the discretion of the investigator in keeping with the 
local standards of medical care. All concomitant medications taken during the study will be 
recorded on the electronic case report form (eCRF) including all prescription and over-the-
counter (OTC) drugs, herbal supplements, and intravenous (IV) medications and fluids. If 
changes occur during the study period, documentation of changes in drug dosage, frequency, 
route, and date will also be included on the eCRF. 
All concomitant medications taken by or administered to the patient within 28 days before Day 1 
and 30 days after the last day of study drug 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 medications. 
6.2.2. 
Prohibited Medications 
Patients are not allowed to receive other anticancer therapy, including surgery, radiation therapy 
(RT), and cytotoxic, biologic, investigational agent, anticancer Chinese medicine, or hormone 
therapy. Bisphosphonate and denosumab use are permitted if the patient had already been 
receiving it at a stable dose ≥ 28 days prior to Day 1. Palliative treatment of isolated lesions 
(except target lesions) with local radiation therapy is allowed. 
The primary metabolic pathway for pamiparib involves the CYP3A isoform, thus co-
administration of strong/moderate inhibitors of CYP3A with pamiparib should be avoided. Also 
avoid strong CYP3A inducers with pamiparib. Please refer to the drugs/substances presented in 
Appendix 4 and to http://medicine.iupui.edu/clinpharm/ddis/main-table/ for a more complete list 
of medications that should be avoided. 
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Avoid the use of drugs that are known to cause prolongation in QT/QTc interval and/or induce 
Torsades des Pointes. Please refer to Appendix 6 for a list of these drugs. If the use of any of 
these drugs is necessary, the Medical Monitor should be contacted. 
Avoid valproic acid as it decreases oral clearance of temozolomide (see package insert for 
temozolomide). 
Grapefruit juice is not allowed throughout the study. No other dietary restrictions will apply. 
6.2.3. 
Medications to Be Used with Caution 
Based on preliminary in vitro screening assays, pamiparib is not a strong inhibitor of other 
human CYP isoenzymes tested. It is a moderate inhibitor of CYP2C9 (IC50 = 6.48 M). 
Investigators need to be aware that pamiparib has the potential to interfere with the appropriate 
metabolism of medications that rely on CYP2C9 and follow the prescribing information 
recommendations for use with CYP2C9 inhibitors. Therefore, careful monitoring should be used 
when co-prescribing CYP2C9 substrates with a narrow therapeutic index, such as phenytoin and 
warfarin. 
Examples of these medications are listed in Appendix 7, and these should be used cautiously 
with drug concentration monitoring where appropriate. 
In addition to CYP3A, pamiparib can also be metabolized by CYP2C8 in human liver 
microsomes, but to a lesser extent. See Appendix 7 for medications that should be used with 
caution for that reason. 
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7. 
STUDY PROCEDURES 
7.1. 
Informed Consent 
All patients will provide their written informed consent before the performance of any study 
related procedures. 
A separate informed consent (Section 8.1) must be signed by patients who undergo collection of 
blood and/or biopsy to provide fresh tumor tissue sample for HRD/BRCA mutation central 
laboratory testing during prescreening.  
During the informed consent process, male patients should be advised to seek advice on 
cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility 
due to therapy with temozolomide. 
7.2. 
Patient Demographics and Other Baseline Characteristics 
7.2.1. 
Demography 
Demographic data will include gender, age or date of birth, race, and ethnicity. 
7.2.2. 
Medical History 
The medical history and prior medications assessments are the same for both the dose escalation 
and dose expansion phases of the study. 
Clinically significant medical history findings (e.g., previous diagnoses, diseases, or surgeries) 
not pertaining to the study indication, which started before the patient signed the informed 
consent, and were 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 of 
signs or symptoms that require medical intervention. Concurrent medical signs and symptoms 
must be documented to establish baseline severities. 
7.2.3. 
Cancer Characteristics 
The following information will be collected: the date and stage of initial cancer diagnosis, 
anatomic site of metastases, all prior anticancer therapies including surgery, radiation therapy, 
and systemic treatments with dates administered. Start dates, stop dates, best response, and 
reasons for treatment discontinuation will be collected. 
Patients with ovarian cancer are defined as platinum-sensitive if disease progression by 
RECIST v1.1 or GCIG CA-125 criteria had occurred more than 6 months after their last 
platinum chemotherapy. Ovarian cancer patients are defined as platinum-resistant if disease 
progression occurred less than 6 months after their last platinum chemotherapy but after their 
post-treatment evaluation, and as platinum-refractory if they experienced disease progression 
while receiving platinum chemotherapy, up to the date of their post-treatment evaluation. 
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7.2.4. 
Other Baseline Parameters  
Information will also be collected regarding prior medications/significant non-drug therapies, 
smoking history, childbearing potential (Appendix 2) and any other assessments that are done for 
the purpose of eligibility for inclusion into the study (physical examination, vital signs, complete 
blood count [CBC] and blood chemistry, urinalysis, pregnancy test, and ECG). For further 
details on eligibility assessments, please see Section 5 and Appendix 1. 
7.3. 
Physical Examination, Vital Signs, ECOG Performance Status, 
Weight, and Height 
A complete or limited physical examination, vital signs (systolic and diastolic blood pressure 
[SBP and DBP, respectively], pulse rate, oral, temporal, or tympanic temperature, and respiratory 
rate), weight, height (Screening only) and ECOG performance status will be performed at 
timepoints specified in Appendix 1. 
A complete physical examination should include an evaluation of general appearance as well as 
head, eyes, ears, nose and throat, neck, heart, chest (including lungs), abdomen, extremities, skin, 
lymph nodes, cardiovascular status and neurological status. A limited physical examination should 
be directed at the evaluation of symptoms or specific safety issues. New or worsening 
abnormalities should be recorded as AEs if appropriate. 
ECOG performance status will be determined as outlined in Appendix 8. 
7.4. 
Adverse Events 
Safety assessments should be performed at all site visits throughout the study. See 
Appendix 1 Table 1 for the schedule of assessments and windows for assessments. 
SAEs, regardless of the relationship to the study drug, will be collected from the time of patient 
informed consent. After initiation of study drug, all AEs and SAEs, regardless of relationship to 
study drug, will be reported until 30 days after the last study treatment or initiation of new 
anticancer therapy. All treatment-related AEs and SAEs will be followed until resolution or 
stabilization. The accepted regulatory definition of AEs and important additional requirements 
for SAE reporting are outlined in Section 10. 
7.5. 
Electrocardiogram 
During screening, a single 12-lead ECG with assessment of PR interval, QRS duration, and QTc 
interval will be obtained within 14 days of Cycle 1 Day1. The screening ECG will be read 
locally to determine eligibility. 
Dose Escalation and Expansion Cohorts 1-5 ONLY 
During Cycle 1 and the pamiparib PK intensive period (Day -2), ECGs will be performed in 
triplicate on a machine provided by the sponsor within a 5-minute window prior to pamiparib 
PK assessments (see below and Section 7.8) at the timepoints indicated below: 
• Pre-dose (within 30 min prior to dose)  
• Post-dose: 
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− 1 hour (± 15 min) 
− 2 hours (± 30 min) 
− 4 hours (± 30 min) 
− 6 hours (±30 min) 
ECGs for each patient should be obtained from the same machine whenever possible. Central 
read of ECGs obtained during the PK assessments will be performed for dose escalation and 
dose expansion cohorts 1-5. 
Locally obtained ECGs should be performed if clinically indicated for all patients enrolled in the 
study. 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.  
7.6. 
Laboratory Studies 
Samples for a complete blood count (CBC), chemistry, and coagulation profiles will be drawn 
and analyzed locally. All other required blood samples will be sent to central laboratory for 
analysis throughout the study. 
A detailed description of the procedures for sample collection, handling, storage, and shipment 
of the laboratory samples and all materials, such as test tubes and labels, is provided in the Study 
Manual. 
Laboratory studies will be performed at the timepoints specified in Appendix 1 (including 
allowed windows of assessment) and may also be performed as medically necessary. Laboratory 
assessments should be done before study drug administration.  
Screening blood and urine tests must be performed within 14 days of Day 1. If they were 
performed within 4 days of Day 1, they do not need to be repeated on Cycle 1 Day 1. 
7.6.1. 
Hematology Studies 
A CBC includes hemoglobin, hematocrit, platelet count, red blood cell (RBC) count and white 
blood cell (WBC) count with differential. 
7.6.2. 
Clinical Chemistry 
Chemistry includes albumin, alkaline phosphatase (ALP), AST, ALT, bicarbonate, blood urea 
nitrogen (BUN), calcium, chloride, creatinine, glucose, lactic acid dehydrogenase (LDH), 
phosphate, potassium, sodium, total bilirubin, and total protein.  
7.6.3. 
Coagulation 
The coagulation profile includes international normalized ratio (INR) and activated partial 
thromboplastin time (aPTT), to be performed only at screening and as clinically indicated. 
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7.6.4. 
Hepatitis B and C Testing 
Hepatitis B and C testing will be performed by a local laboratory at screening and as clinically 
indicated and will include HBV/hepatitis C virus (HCV) serology (hepatitis B surface antigen, 
hepatitis B surface antibody, hepatitis B core antibody, and HCV antibody) and viral load 
assessment (HBV DNA and HCV RNA). 
7.6.5. 
Urinalysis with Dipstick 
Urinalysis will be assessed using urine dipstick. Urine microscopy will be performed if urine 
dipstick is abnormal. Urinalysis includes pH, glucose, protein, ketones, bilirubin, blood, and 
specific gravity. If urine protein is ≥ 2+ by dipstick, a 24-hour urine for total protein and a 
random urine for total protein and creatinine will be performed at screening only or as clinically 
indicated. All tests will be performed in local laboratories. 
7.6.6. 
Pregnancy Test 
Clinical Trial Facilitation Group (CTFG) recommendations related to contraception and 
pregnancy testing in clinical studies include for females with childbearing potential the use of 
highly effective forms of birth control (Appendix 2) and testing for pregnancy every 28 days. 
During screening, a serum pregnancy test must be obtained ≤ 7 days prior to Day 1. For 
subsequent pregnancy testing on study and at EOT, urine pregnancy tests are allowed. If a urine 
pregnancy test is positive, a confirmatory serum pregnancy test is required. 
7.6.7. 
CA-125 Measurements 
CA-125 levels will be collected for ovarian cancer patients and tested in a certified local 
laboratory during screening and every 8 weeks (± 7 days) following the first administration of 
the investigational medical product (Appendix 1). 
Increases and decreases in CA-125 levels will be tracked in order to assess CA-125 responses by 
the GCIG criteria described in Appendix 9. 
7.6.8. 
PSA Measurements 
PSA levels will be collected for prostate cancer patients and tested in a certified local laboratory 
during screening and every 8 weeks (±7 days) following the first administration of the 
investigational medical product (Appendix 1). In addition, the three most recent PSA levels prior 
to screening will need to be provided to determine a baseline doubling time. 
Increases and decreases in PSA will be tracked in order to assess PSA responses by the PCWG2 
criteria described in Appendix 10. PSA changes from baseline (either increment or decline) and 
maximal change in PSA will be recorded and responses assigned by PCWG2 criteria. PSA 
responses and progression must be confirmed 28 days later.  
Although serial PSA will be measured in this study and PSA progression documented by the 
PCWG2 criteria, the PSA value on its own is not considered a reliable measure of clinical benefit 
and does not correlate tightly with survival. PSA flares may occur early in the study drug 
administration and may therefore confound response assessment. Additionally, there is emerging 
data that PARP-1 is implicated in multiple other essential cellular functions separate from DNA 
repair including ETS gene-mediated transcription regulation which may have a bearing on the 
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response assessments by PSA. PSA reading should not be applied as the sole criteria to consider 
discontinuation of study drugs. In absence of evidence of radiological or clinical evidence of 
disease progression, patients with mCRPC should continue in the study despite an increment in 
PSA. Therefore, patients will not be taken off study purely for rising PSA levels in the absence 
of worsening scans and symptoms since PARP inhibitors may impact tumor growth without 
impacting PSA secretion. PSA response and PSA progression will be defined according to the 
consensus guidelines of the PCWG2 criteria (Appendix 10). 
7.7. 
Tumor Assessment 
Tumor imaging (CT or MRI, with preference for CT) will be performed at screening and every 
8 weeks (±7 days) from Cycle 1 Day 1 until disease progression. Any evaluable disease must be 
documented at screening and reassessed at each subsequent tumor evaluation. At the 
investigator’s discretion, CT scans may be repeated at any time if progressive disease is 
suspected. An objective response is considered confirmed once repeat assessments  4 weeks 
after initial documentation are available.  
A CT scan or MRI of the thorax, 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 at baseline as target or non-target 
lesions using RECIST v1.1. The CT scan will be used for the evaluation criteria RECIST v1.1 by 
the investigator at each study center. Routine use of positron emission tomography (PET) scans 
should not be used to assess radiologic response to treatment for this study. 
Unless contraindicated, intravenous contrast product must be used to maximize visualization of 
all lesions. Patients who are at increased risk of allergic reaction to iodinated contrast media 
should not have enhanced CT, but should instead be provided magnetic resonance imaging 
(MRI) with gadolinium enhancement patient per 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. Patients with bone pain or biochemical 
changes suggestive of bony disease without other clear explanation should have a bone scan at 
baseline and if bone metastases are documented should then have bone scans or other appropriate 
imaging examinations as clinically indicated.  
The same imaging technique should be used on the same patient throughout the study.  
After first documentation of response (CR or PR), imaging performed at the next regularly 
scheduled timepoint may be used for response confirmation.  
Patients who permanently discontinue study drugs prior to progressive disease will continue with 
regular tumor assessments as per protocol every 8 weeks (±7 days) until disease progression, 
administrative issues, start of other anticancer therapy or any other reason listed in Section 8.4, 
whichever occurs first. This imaging schedule will be maintained regardless of any intermediate 
unscheduled scans. Patients who withdraw from the study for clinical or symptomatic 
deterioration before objective documentation of progressive disease will be requested to undergo 
appropriate imaging to confirm progressive disease. Every effort will be made to confirm a 
clinical diagnosis of progressive disease by imaging. 
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All efforts will be made to ensure that the imaging equipment, contrast agent, and person 
(investigator or radiologist) performing the evaluation is kept constant throughout a patient’s 
course on study. 
7.8. 
Pharmacokinetics of Pamiparib and Temozolomide 
Blood will be collected to characterize the PK of both pamiparib and temozolomide. 
Additionally, blood may also be used to explore the presence of metabolites in a qualitative or 
semi-quantitative manner. 
Blood sampling for PK will be collected at the timepoints specified in Schedule of Assessments 
(Appendix 1 Table 1).  
Details concerning handling of the PK plasma samples, including labeling and shipping 
instructions will be provided in the Study Manual.  
Samples will be shipped to the central laboratory where they will be stored and batch shipped to 
the designated bioanalytical laboratory for quantification of plasma pamparib and TMZ 
concentrations using a validated method. 
7.8.1. 
PK of Pamiparib 
To better characterize the pamiparib PK profile prior to TMZ administration, the first 15 patients 
enrolled into the study in dose escalation will undergo intensive PK sampling starting on Day -2 
at the following timepoints: pre-dose (within 30 min prior to dose), 30 minutes (± 5 min), 1 hour 
(± 15 min), 2 hours (± 30 min), 4 hours (± 30 min), 6 hours (± 30 min); 24 hours (± 2 hours) 
post-dose on Day -1; and 48 hours (± 2 hours) post-dose on Day 1 as detailed in Table 2 of 
Appendix 1. 
After 15 patients have completed intensive PK sampling, all other patients enrolled in dose 
escalation and expansion will have PK samples collected at the following timepoints: pre-dose 
(within 30 min prior to dose), 1 hour (± 15 min), 2 hours (± 30 min), and 4 hours (± 30 min) post 
dose on both Cycle 1 Day 1 and Cycle 1 Day 15. The time of study drug administration on the 
day prior to Cycle 1 Day 15 must be recorded on the eCRF. Details concerning collection and 
handling of the PK plasma samples will be provided in the Study Manual. 
7.8.2. 
PK of TMZ 
Pharmacokinetic samples will be collected from patients in all cohorts at the following 
timepoints: pre-dose (within 30 min prior to dose) and 1 hour (± 15 min) post dose on Cycle 1 
Day 1 and Cycle 1 Day 7. The time of study drug administration on the day prior to Cycle 1 Day 
7 must be recorded on the eCRF. 
 
7.9. 
Biomarker Assessments 
The biomarker analysis includes but it is not limited to germline BRCA1/2 mutation, HRD status, 
and somatic mutation analysis. Blood and biopsies for biomarker analysis will be collected at the 
timepoints specified in Schedule of Assessments (Appendix 1 Table 1). 
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7.9.1. 
Blood for biomarker analysis 
All patients will provide blood samples for analysis of baseline germline BRCA and/or other 
mutations.   
All patients will also provide blood samples to be processed into serum, plasma, and cell 
fractions for the analysis of germline mutations, and circulating markers, such as, but not limited 
to, circulating nucleic acids (CNA). 
7.9.2. 
Tumor tissues for biomarker analysis 
Patients from Dose Escalation, patients from Dose Expansion Cohorts 1-3 with known HRD 
or BRCA mutation status and patients from Dose Expansion Cohorts 4 and 5 
An archived, formalin-fixed, paraffin-embedded tumor sample will be collected from all patients, 
if available, for retrospective analysis of HRD mutational status. Archival tumor tissue shall be 
sent to the central laboratory for biomarker testing (either a formalin-fixed, paraffin-embedded 
block with tumor tissue [preferred] or approximately 10 unstained slides). The most recent tumor 
block is preferred.  
In the absence of archival tumor tissues, a fresh baseline biopsy of a tumor lesion is highly 
recommended. Written patient consent is required for fresh tumor biopsies. 
An optional biopsy will also be taken at the EOT visit for the patients who have confirmed 
disease progression from accessible tumor sites. These samples will be used to explore resistance 
mechanism(s). If feasible, any follow up biopsy should be from the same tumor lesion as the 
baseline biopsy. Written patient consent is required for fresh tumor biopsies.  
Fresh biopsies should be limited to readily accessible tumor lesions (e.g., skin, peripheral lymph 
nodes, lung, liver, or internal lymph node metastases which can be readily accessed using 
CT guidance). If performed, a tissue cylinder should be obtained that has proper size for 
histological examination and biomarker analysis.  
Patients from Dose Expansion Cohorts 1-3 with unknown BRCA 1/2 mutation or HRD status 
and Cohort 6 
All patients who are potential candidates for enrollment on these cohorts must provide a 
mandatory archival tumor tissue sample (either a formalin-fixed, paraffin-embedded block with 
tumor tissue [preferred] or approximately 10 unstained slides) for central prospective testing of 
HRD status in order to determine their eligibility. The most recent tumor block is preferred. If no 
archival tumor tissue is available, a mandatory fresh tumor biopsy should be performed. Written 
patient informed consent is required for archival tissue or biopsy collection (prescreening 
informed consent). 
Any tissues taken during pre-screening period will not be re-collected at screening or Cycle 1 
Day 1. 
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7.9.3. 
Optional tumor biopsy for pharmacodynamics analysis (Dose Escalation and 
Dose Expansion Cohorts 1-5) 
An optional biopsy for pharmacodynamics at Cycle 1 Day 1 and Cycle 1 Day 15 is highly 
recommended. If feasible, any follow up biopsy should be ideally taken from the same tumor 
lesion as the baseline biopsy.  
Instructions for the processing, storage, and shipping of samples will be provided in the Study 
Manual. 
7.10. 
Appropriateness of Measurements 
All safety, PK, and tumor assessments used in this study are standard, i.e., widely used and 
generally recognized as reliable, accurate, and relevant. PK and PD assays will be performed 
using validated GLP methods. 
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8. 
STUDY VISITS AND FOLLOW-UP 
8.1. 
Prescreening (Dose Expansion Only, Days -84 to -29 prior to 
Screening) 
During the dose expansion phase of the study, patients in the Expansion Cohorts 1 to 3 (ovarian, 
TNBC, and mCRPC, respectively; see Section 5.1) who have unknown biomarker status will 
undergo pre-screening for evaluation of HRD status. All patients in the Dose Expansion Cohort 6 
will undergo prescreening for central evaluation of HRD status. A separate pre-screening 
informed consent must be obtained. 
An archival tumor sample is acceptable; however, if not available, a fresh tumor biopsy must be 
obtained for HRD testing. 
The following will be performed during the pre-screening visit: 
• Obtain written informed consent from the patient to perform a tumor biopsy if it is 
required for the purpose of meeting the eligibility of the study 
• Prepare tumor samples and ship to the qualified central lab for mutation analysis as 
specified in the Study Manual 
8.2. 
Screening Period (Day -28 to Day -1) 
A signed, written informed consent must be obtained prior to screening assessments and before 
any study-specific assessments are initiated. Results of standard-of-care tests or examinations 
performed prior to obtaining informed consent and within the screening windows may be used 
and do not need to be repeated as long as they meet protocol specifications. The study-specific 
assessments and procedures are shown in the Schedule of Assessments in Appendix 1 Table 1. 
Screening Period assessments are the same for the dose escalation and dose expansion phases of 
the study and will be completed within 28 days prior to the first dose of the investigational 
product. Some assessments have a narrower screening window as shown in the Schedule of 
Assessments in Appendix 1 Table 1. Screening assessments obtained within 4 days of Day 1 do 
not have to be repeated on Day 1. 
8.3. 
Assessments during Treatment Period 
Safety assessments should be performed at all visits to the study center and throughout the study. 
8.3.1. 
PK Intensive Visit (Day -2 to Day 1) (Dose Escalation Cohort ONLY) 
To better characterize the pamiparib PK profile prior to TMZ administration, the first 
approximately 20 patients enrolled into the study will undergo intensive PK sampling starting on 
Day -2 as detailed in Appendix 1 Table 2. 
Once 20 patients have completed the pamiparib PK intensive sampling, the remainder of patients 
will undergo limited PK sampling as detailed in Appendix 1 Table 1. Any modifications to 
assignment of PK sampling schedule may be implemented following discussion with the Medical 
Monitor.  
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Patients who participate in the PK intensive sampling will have baseline assessments performed 
on Day -2 before pamiparib dosing rather than on Day 1 as detailed in Appendix 1 Table 2. 
Note: The collection of blood for the pamiparib PK 48-hour post-dose timepoint must occur 
prior to the administration of pamiparib and TMZ on Day 1. 
8.3.2. 
Cycle 1 (28 days) 
During Cycle 1, all assessments (except for PK post-dose blood collection) performed during the 
clinic visit must be done prior to study drug administration. On days with PK assessments, 
pamiparib (first dose) and TMZ should be administered in the clinic. 
For the Dose Expansion Cohorts, a 2-day window is allowed during Cycle 1 visits. 
A list of all of the activities during Cycle 1 is found in the Schedule of Assessments Table 
(Appendix 1 Table 1). 
8.3.3. 
Subsequent Cycles  
A list of all of the activities during subsequent cycles in the first year are listed in the Schedule of 
Assessments Table (Appendix 1 Table 1). 
All assessments performed during the clinic visits and subsequent cycles must be done prior to 
study drug administration (unless otherwise noted).  
8.3.4. 
Unscheduled Visits 
Unscheduled visits may be performed at any time at the patient’s or the investigator’s request 
and may include vital signs/physical examination; ECOG Performance Status; AE review; 
concomitant medications and procedures review; radiographic assessments; physical 
examination of liver, spleen, and lymph nodes; disease-related constitutional symptoms; and 
hematology and clinical chemistry laboratory assessments. The date and reason for the 
unscheduled visit must be recorded in the source documentation. 
If an unscheduled visit is necessary to assess toxicity or for suspected PD, then diagnostic tests 
may be performed based on the investigator assessment as appropriate, and the results of these 
tests should be entered on the unscheduled visit eCRF. 
8.4. 
End-of-Treatment Visit 
Patients who discontinue from study drug for any of the reasons listed below will undergo an 
EOT visit within 7 days of discontinuation of all study drugs. If routine laboratory tests 
(e.g., hematology, clinical chemistry) were completed ≤ 7 days before the EOT Visit, these tests 
do not need to be repeated.  
However, the EOT visit may occur later than 7 days after discussion with the Medical Monitor 
for specific circumstances, such as prolonged hospitalization. If the EOT Visit did not occur until 
30 days (± 7 days) or later after the last dose of pamiparib and TMZ, the EOT Visit may also be 
used as the Safety Follow-up Visit. 
Patients with a required EOT visit may discontinue study drug for any of the following reasons: 
• Disease progression 
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• Investigator decision 
• Adverse event(s) 
• Pregnancy 
• Patient withdrew consent for study drug 
− Patients may voluntarily withdraw consent from study drug at any time 
− Patients may continue to participate in the Follow-up Phase, if the patient 
withdraws consent from the Treatment Phase 
• Start of other anticancer therapy 
• Patient noncompliance 
Study site staff should first counsel patients who are significantly noncompliant 
(e.g., missing 2 treatment cycles) on the importance of study drug compliance and 
drug accountability. The investigator may, in consultation with the medical monitor, 
discontinue patients from treatment who are consistently noncompliant 
The reason for discontinuation from study drug will be recorded on the eCRF. 
All the assessments performed for the EOT visit are listed in the Schedule of Assessments 
(Appendix 1 Table 1). 
The visit at which the assessment showed progressive disease may be used as the EOT visit 
provided that all required assessments were performed. A CT does not have to be repeated at the 
EOT visit if it was performed within 14 days of the visit or at a prior response evaluation that 
documented progressive disease. ECG does not have to be repeated if it was performed within 
14 days of the EOT visit. 
8.5. 
Follow-up Assessments 
8.5.1. 
Safety Follow-Up  
All patients who discontinue study drugs will have a safety follow-up approximately 30 days 
after the last day of study drugs to collect AEs and SAEs that may have occurred after the patient 
discontinued from the study drugs as well as concomitant medications. The investigator or 
his/her designee will also contact the patient to collect AE and SAE information as well as any 
new anticancer therapy given after the last day of study drugs. A laboratory assessment is only 
required if the patient had an ongoing laboratory abnormality at the previous visit that the 
investigator considered to be related to study drugs.  
8.5.2. 
Efficacy Follow-Up  
Patients who were not discontinued from study drugs due to disease progression and meet 
criteria otherwise (e.g., discontinued for AE and no new anticancer therapy) will be followed 
every 8 weeks (± 7 days) until disease progression, administrative issues, start of other anticancer 
therapy or any other reason listed in Section 8.4, whichever occurs first.  
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If the patient refuses to return for these visits or is unable to do so, every effort should be made 
to contact the patient or patient’s guardian by telephone to determine the patient’s disease status 
and survival. 
8.5.3. 
Survival Follow-Up  
Patients enrolled during the dose expansion phase of the study will be followed for survival and 
further anticancer therapy information post progression via phone contact (with the patient’s 
guardian, if applicable) or other means (e.g., clinic visit or review of medical records) 
approximately every 3 months (Appendix 1 Table 1). 
8.5.4. 
Lost to Follow-Up  
If attempts to contact the patient by telephone are unsuccessful, additional attempts should be 
made to obtain protocol-required follow-up information. It may be possible to obtain the 
information from other contacts, such as referring physicians or relatives. Attempts of contact 
should be documented in the patient’s source documents. If a patient cannot be contacted despite 
all attempts, the patient will be considered lost to follow-up, and death information should be 
obtained through a public record search if local agencies permit. 
8.6. 
End of Study for Individual Patients 
Patients who end participation in the study do not contribute additional data at any subsequent 
visits (including the EOT and all follow-up visits). Patients who end participation in the study 
may do so under the following circumstances: 
• Patient withdrew consent for study participation 
− Patients may voluntarily withdraw consent from the study at any time. 
• Lost to follow-up 
• Death 
• Study termination by sponsor 
• Other, as per the discretion of the sponsor or health authority 
The reason for discontinuation from study participation will be recorded on the eCRF.  
8.7. 
End of Study  
The end of study is defined as the timepoint when the final data point is collected from the last 
patient in the study. This is when the last patient dies, withdraws consent, or is lost to follow up. 
Alternatively, the end of study is when the sponsor decides to terminate the study. 
The sponsor has the right to terminate this study at any time. Reasons for terminating the study 
early include but are not limited to the following:  
• The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients 
• Overall patient enrollment is unsatisfactory 
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The sponsor will notify each investigator if a decision is made to terminate the study. Should this 
be necessary, prematurely discontinued patients must be seen for an EOT Visit and Safety 
Follow-up Visit as described in Section 8.4 and Section 8.5.1. 
The investigators may be informed of additional procedures to be followed to ensure that 
adequate consideration is given to the protection of the patients’ interests. The investigator will 
be responsible for informing IRBs/IECs of the early termination of the study. 
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9. 
DATA HANDLING AND QUALITY ASSURANCE 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures (SOPs), working practice documents, and applicable regulations and 
guidelines. Site audits may be made periodically by the sponsor’s or the contract research 
organization’s (CRO’s) qualified compliance auditing team, which is an independent function 
from the study team responsible for conduct of the study. 
9.1. 
Data Collection 
Data required by the protocol will be entered into the eCRFs in an electronic data capture (EDC) 
system that is compliant with all regulatory requirements or transmitted to BeiGene by third 
party vendors, as applicable.  
Data collection in the eCRF must follow the instructions described in the eCRF Completion 
Guidelines (eCCGs). The investigator has ultimate responsibility for the collection and reporting 
of all clinical data entered in the eCRF. The investigator or designee as identified on Form FDA 
1572 must sign the completed casebooks to attest to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of BeiGene and should not be made available 
in any form to third parties without written permission from BeiGene, except for authorized 
representatives of BeiGene or appropriate regulatory authorities. 
9.2. 
Data Management/Coding 
All final patient data, both eCRF and external data (e.g., laboratory data), collected according to 
the protocol, will be stored at BeiGene at the end of the study.  
Standard procedures (including following data review guidelines, computerized validation to 
produce queries, and maintenance of an audit file which includes all database modifications) will 
be followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
During the course of the study, a study monitor will make site visits to review protocol 
compliance, compare eCRFs against individual patient’s medical records, and ensure that the 
study is being conducted according to pertinent regulatory requirements. 
eCRF entries will be verified with source documentation. The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. Checking the eCRFs 
for completeness, clarity, and cross checking with source documents is required to monitor the 
progress of the study. Direct access to source data is also required for inspections and audits and 
will be carried out giving due consideration to data protection and medical confidentiality. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®). Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Concomitant diseases/medical history will be coded using the 
MedDRA®. 
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9.3. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct quality assurance audits. Regulatory agencies may also conduct a regulatory inspection 
of this study. Such audits/inspections can occur at any time during or after completion of the 
study. If an audit or inspection occurs, the investigator and institution agree to allow the 
auditor/inspector direct access to all relevant documents and to allocate his/her time and the time 
of his/her personnel to the auditor/inspector to discuss findings and any relevant issues. 
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10. 
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. 
10.1. 
Adverse Events 
10.1.1. 
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 (e.g., 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.  
10.1.1.1. 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 v4.03. 
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 (ADL)  
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated, disabling, limiting self-
care ADL  
• Grade 4: Life-threatening consequences; urgent intervention indicated  
• Grade 5: Death related to AE  
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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 10.2. 
10.1.1.2. Assessment of Causality 
The investigator is obligated to assess the relationship between the study drugs 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, 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 Pamiparib Investigator’s 
Brochure [59] 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.  
The causality of each AE should be assessed and classified by the investigator as “related” or 
“not related”. An AE is considered related if there is “a reasonable possibility” that the AE may 
have been caused by the study drug (i.e., there are facts, evidence, or arguments to suggest 
possible causation). A number of factors should be considered in making this assessment, 
including: 
• Temporal relationship of the AE to the administration of study drug(s)/study 
procedure 
• Whether an alternative etiology has been identified  
• Mechanism of action of the study drugs 
• Biological plausibility 
An AE should be considered ‘related’ to study drug if any of the following are met: 
• There is clear evidence to suggest a causal relationship and other possible 
contributing factors can be ruled out. 
• There is evidence to suggest a causal relationship and the influence of other factors is 
unlikely. 
• There is some evidence to suggest a causal relationship (e.g., 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 (e.g., the patient’s clinical condition or 
other concomitant AEs). 
An AE should be considered ‘unrelated’ to study drug if any of the following are met: 
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• An unreasonable temporal relationship between administration of the study drug and 
the onset of the AE (e.g., the AE occurred either before or too long after 
administration of the product for it to be considered product-related) 
• A causal relationship between the study drug and the AE is biologically implausible 
(e.g., death as a passenger in an automobile accident) 
• A clearly more likely alternative explanation for the AE is present (e.g., typical 
adverse reaction to a concomitant drug and/or typical disease-related AE) 
 
10.1.1.3. Follow-Up of Adverse Events 
After the initial AE or SAE report, the investigator is required to proactively follow each patient 
and provide further information to the sponsor on the patient’s condition. 
All AEs and SAEs documented at a previous visit/contact and designated as ongoing will be 
reviewed at subsequent visits/contacts. 
All AEs and SAEs will be followed until resolution, the condition stabilizes or is considered 
chronic, the AE or SAE is otherwise explained, the patient is lost to follow-up or the patient 
withdraws consent. Once resolved, the appropriate AE or SAE eCRF page(s) will be updated. 
The investigator will ensure that follow-up includes any supplemental investigations as may be 
indicated to elucidate the nature and/or causality of the AE or SAE. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of 
the AE or SAE. The investigator is obligated to assist. If a patient dies during participation in the 
study or during a recognized follow-up period, the sponsor will be provided with a copy of any 
post-mortem findings, including histopathology. 
New or updated information will be recorded on the originally completed SAE report/eCRF, 
with all changes signed and dated by the investigator. The updated SAE report/eCRF should be 
re-sent to the sponsor within the time frames outlined in Section 10.5.1.  
10.1.1.4. Laboratory Test Abnormalities 
Abnormal laboratory findings (e.g., clinical chemistry, CBC, coagulation, or urinalysis) or other 
abnormal assessments (e.g., ECGs, X-rays, or vital signs) that are judged by the investigator as 
clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE (as 
defined in Section 10.1.1) or an SAE (as defined in Section 10.2).  
Clinically significant abnormal laboratory findings or other abnormal assessments that are 
detected during the study or are present at baseline and significantly worsen following the start 
of the study will be reported as AEs or SAEs. However, clinically significant abnormal 
laboratory findings or other abnormal assessments that are associated with the disease being 
studied, unless judged by the investigator as more severe than expected for the subject’s 
condition, or that are present or detected at the start of the study and do not worsen, will not be 
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reported as AEs or SAEs. They should only be reported as AEs or SAEs if they induce clinical 
signs or symptoms, need active intervention, require dose interruption or discontinuation or are 
clinically significant in the opinion of the investigator. 
The investigator will exercise his/her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. 
10.2. 
Definition of a Serious Adverse Event 
An SAE is any untoward medical occurrence that, at any dose:  
• Results in death  
• Is life-threatening  
Note: The term “life-threatening” in the definition of “serious” refers to an AE in 
which the patient was at risk of death at the time of the AE. It does not refer to an AE 
which hypothetically might have caused death if it were more severe.  
• Requires hospitalization or prolongation of existing hospitalization  
Note: In general, hospitalization signifies that the patient was admitted (usually 
involving at least an overnight stay) to the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the AE 
is serious. When in doubt as to whether “hospitalization” occurred or was necessary, 
the AE should be considered serious.  
− Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an SAE. 
− Hospitalization for social/convenience considerations is not considered an SAE.  
− Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience, is not considered an SAE.  
• 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 (e.g., 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 (e.g., may jeopardize the patient or may require medical/surgical 
intervention to prevent one of the outcomes listed above).  
The following are NOT considered SAEs:  
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• Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline  
• Hospitalization for social/convenience considerations  
• Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience 
10.3. 
Definition of a Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction is a serious adverse reaction that is both 
unexpected (i.e., not present in the study drug’s reference safety information) and meets the 
definition of a serious adverse drug reaction, the specificity or severity of which is not consistent 
with those noted in the Pamiparib Investigator’s Brochure. [59] 
10.4. 
Timing, Frequency, and Method of Capturing Adverse Events and 
Serious Adverse Events 
10.4.1. 
Adverse Event Reporting Period 
After informed consent has been signed but prior to the administration of the study drug, only 
SAEs should be reported. 
After initiation of study drug, all AEs and SAEs, regardless of relationship to study drug, will be 
reported until 30 days after the last study treatment or initiation of new anticancer therapy.  
After a patient is discontinued from the study, investigators are not obligated to actively seek 
AEs or SAEs from the former patients. After this period, the investigator should report any SAEs 
that are believed to be related to prior study drug treatment. 
10.4.2. 
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?  
10.5. 
Specific Instructions for Recording Adverse Events and Serious 
Adverse Events 
10.5.1. 
Diagnosis versus Signs and Symptoms 
If a diagnosis is known at the time of reporting, this should be recorded in the eCRF (and SAE 
report, as applicable), rather than the individual signs and symptoms (e.g., record only hepatitis 
rather than elevated transaminases, bilirubin, or jaundice). However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome at the time 
of reporting, each individual AE should be recorded as an SAE or AE on the eCRF (and SAE 
report, if applicable). If a diagnosis is subsequently established, it should replace the individual 
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signs and/or symptoms as the AE term on the eCRF (and SAE report, if applicable), unless the 
signs/symptoms are clinically significant. 
10.5.2. 
Adverse Events Occurring Secondary to Other Events 
In general, AEs occurring secondary to other AEs (e.g., clinical sequelae or a cascade of AEs) 
should be identified by their primary cause. For example, if severe vomiting is known to result in 
dehydration, it is sufficient to record only vomiting as the SAE or AE on the eCRF (and SAE 
report, if applicable). However, if a patient initially has a non-serious AE, and it subsequently 
becomes an SAE, both AEs should be reported separately on the eCRF. The onset date of the 
non-serious AE should be recorded as the start date of the non-serious AE. The onset date of the 
SAE should be recorded as the start date when the non-serious AE becomes an SAE.  
10.5.3. 
Persistent or Recurring Adverse Events 
A persistent AE is one that extends continuously, without resolution, between patient evaluation 
timepoints. Such AEs should only be recorded once on the AE eCRF (and SAE report, if 
applicable). If a persistent AE worsens in grade, it should be recorded as a new AE on the eCRF 
(and a stop date should be recorded in the previous AE).  
A recurrent AE is one that occurs and resolves between patient evaluation timepoints, and 
subsequently recurs. All recurrent AEs should be recorded separately on the eCRF (and SAE 
report, if applicable).  
10.5.4. 
Disease Progression 
Disease progression is measured as an efficacy endpoint and is not considered to be an AE. 
However, if there are separate identifiable clinical sequelae that result from disease progression, 
those sequelae are reportable as AEs. For instance, a patient with pleural effusion presents with 
shortness of breath. The cause of the shortness of breath is a pleural effusion resulting from 
disease progression. The AE term should be reported as “pleural effusion” instead of disease 
progression or metastasis to lungs. If a patient has a seizure that is determined to be associated 
with a brain metastasis, the term “seizure” should be recorded as the AE instead of disease 
progression or brain metastasis. If a patient experienced multi-organ failure due to disease 
progression, the term “multi-organ failure” should be reported as the AE instead of disease 
progression. Deaths that are assessed by the investigator as solely due to disease progression 
should be recorded on Study Completion or Early Discontinuation eCRF as efficacy data. They 
should not be reported as an SAE. If deaths are assessed by the investigator as not solely due to 
disease progression, whether they are assessed as related or not related to the study drug, they 
should be reported as SAE immediately.  
If there is any uncertainty regarding whether an AE is due to disease progression, it should be 
reported as an AE. 
10.5.5. 
Death 
Death is an outcome, not an event. If an AE/SAE results in death, then the term of the AE that 
caused or contributed to fatal outcome should be recorded as the single medical concept. If the 
cause of death is unknown and cannot be ascertained at the time of reporting, record 
“unexplained death”. 
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10.6. 
Prompt Reporting of Serious Adverse Events 
10.6.1. 
Timeframes for Submitting Serious Adverse Events 
Serious adverse events will be reported promptly (within 24 hours) to the sponsor or designee as 
described in Table 4 and the Study Manual once the investigator determines that the AE meets 
the protocol definition of an SAE. 
Table 4: 
Time Frame for Reporting Serious Adverse Events to the Sponsor or 
Designee 
Type of SAE 
Initial SAE 
Report 
Documentation 
Timeframe for 
sending 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 report form 
SAE, serious adverse event. 
10.6.2. 
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 10.5.1. The SAE Report will 
always be completed as thoroughly as possible with all available details of the event and 
forwarded to the sponsor or designee within the designated timeframes.   
If the investigator does not have all information regarding an SAE, he/she is not to wait to 
receive additional information before notifying the sponsor or designee of the SAE and 
completing the form. The form will be updated when additional information is received. The 
investigator will always provide an assessment of causality at the time of the initial report as 
described in Section 10.1.1.2.The sponsor will provide contact information for SAE receipt.  
10.6.3. 
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 10.5.2. The sponsor has a legal responsibility to notify, as appropriate, both 
the local regulatory authority and other regulatory agencies about the safety of a product under 
clinical investigation. The investigator, or responsible person according to local requirements, 
will comply with the applicable local regulatory requirements related to the reporting of SAEs to 
regulatory authorities and the IRB/IEC. 
All suspected unexpected serious adverse reactions will be submitted to all applicable regulatory 
authorities and investigators for pamiparib studies. 
When a study center receives an initial or follow-up safety report or other safety information 
(e.g., revised Investigator’s Brochure) from the sponsor, the investigator or designated 
responsible person is required to promptly notify his/her IRB or IEC. The investigator should 
place copies of Safety Reports from the sponsor in the Investigator Site File. 
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10.7. 
Pregnancy Reporting 
If a female patient or the partner of a male patient becomes pregnant while receiving 
investigational therapy or within 6 months after the completion of the last dose of study drug, a 
pregnancy report form should be completed and expeditiously submitted to the sponsor to 
facilitate outcome follow-up. Information on the status of the mother and child will be forwarded 
to the sponsor. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any premature termination of the pregnancy will be reported. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous should always be reported as an 
SAE. Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the 
study drug should be recorded and reported as an SAE.  
10.8. 
Expedited Reporting to Health Authorities, Ethics Committees, and 
Investigators 
The sponsor will promptly assess all SAEs against cumulative study drug experience to identify 
and expeditiously communicate new safety findings to regulatory authorities, investigators, IRBs 
and IECs based on applicable legislation.  
To determine the reporting requirements for individual SAEs, the sponsor will assess the 
expectedness of the SAEs using the following reference documents: 
• Pamiparib (BGB-290) Investigator’s Brochure [59] 
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11. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
All statistical analyses will be performed by the sponsor or designee after the study is completed 
and the database is locked and released. Details of the statistical analyses will be included in a 
separate statistical analysis plan (SAP). 
11.1. 
Primary, Secondary, and Exploratory Study Endpoints 
Please refer to Section 3 for a full listing of study endpoints. 
11.2. 
Statistical Analysis 
For the dose escalation phase, data will be summarized by dose level. For the dose expansion 
phase, data will be summarized by cohort.  
Descriptive statistics will be mainly used in describing the anticancer activities and tolerability of 
the pamiparib and TMZ combination regimens. Confidence intervals will be constructed to 
describe the precision of the point estimates of interest (e.g. objective response rate and disease 
control rate).  
11.2.1. 
Analysis Populations 
Safety Population includes all patients who received any dose of pamiparib and/or TMZ. The 
Safety Population will be used for all safety analyses. 
Efficacy Evaluable Population includes patients in the Safety Population who had measurable 
disease (or evaluable disease for patients enrolled into the dose escalation phase) at baseline (or 
prostate cancer patients as per inclusion criterion 14f) and had at least one post-baseline tumor 
assessment unless discontinued treatment due to clinical progression or death prior to tumor 
assessment. 
DLT Evaluable Population includes patients who received ≥ 70% of each study drug during the 
DLT assessment window and had sufficient safety evaluation. Additionally, patients who had a 
DLT event during the DLT assessment window despite receiving < 70% of the scheduled dose 
will also be considered evaluable.  
PK Population includes all patients for whom valid pamiparib PK parameters can be estimated. 
11.2.2. 
Patient Disposition 
The number of patients enrolled, treated, discontinued from study drug, and those with major 
protocol deviations will be counted by cohort. The primary reason for study drug discontinuation 
will be summarized according to the categories in the eCRF. The end of study status (alive, dead, 
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. 
11.2.3. 
Demographics and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized by cohort in the Safety 
Population using descriptive statistics. Continuous variables include age, weight, vital signs, time 
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since initial tumor diagnosis, time since metastatic disease; categorical variables include sex, age 
group (< 65 versus ≥ 65 years), race, disease stage, ECOG-PS, prior line of therapy in the 
metastatic setting, and geographic region. 
11.2.4. 
Prior and Concomitant Therapy 
Concomitant medications will be assigned an 11-digit code using the WHO-DD 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 (CSR) for this 
protocol. Prior medications will be defined as medications 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 CSR of this protocol. 
11.2.5. 
Efficacy Analyses 
No formal hypothesis testing is planned in this Phase 1b study.  
For solid tumors other than prostate cancer, tumor assessment based on investigator assessment 
according to RECIST v1.1 will be used to calculate ORR, DCR, PFS, and DOR, as well as 
timepoint estimate PFS-6m. Overall survival (OS) and OS-6m will be summarized as well. For 
patients with ovarian cancer, tumor response may also be assessed by investigators based on 
GCIG criteria which use carcinoma antigen-125 (CA-125) in combination with 
RECIST v1.1 (Appendix 9).  
For patients with prostate cancer, PSA and tumor lesions will be evaluated together to determine 
the tumor response according to PCWG2 criteria (Appendix 10). 
ORR is defined as the proportion of patients who have a best overall response (BOR) of CR or 
PR, where BOR is defined as the best response recorded from the first dose of study drugs until 
data cut, disease progression, or start of new anti-neoplastic treatment. Binomial exact 90% and 
95% confidence intervals will be calculated for ORR in each cohort. 
DCR is defined as the proportion of patients with BOR of CR, PR, and SD. It will be 
summarized similarly as ORR. 
PFS is defined as the time from the date of the first dose of study drugs to disease progression or 
death, whichever occurs first.  
PFS censoring rule will follow FDA Guidance for Industry, Clinical Trial Endpoints for 
Approval of Cancer drugs and Biologics (2007). Patients who have a clinical determination of 
progression should undergo imaging and laboratory assessments, if possible, to correlate 
radiographic findings with the clinical findings. Data for patients without disease progression or 
death by the time of analysis will be censored at the time of the last tumor assessment. Data from 
patients who are lost to follow-up prior to documented disease progression will be censored at 
the last tumor assessment date when the patient is known to be progression-free. More details 
will be given in the SAP.  
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DOR is defined as the time from the date of the earliest documented response to disease 
progression or death for any cause, whichever occurs earlier. Only responders will be included in 
the DOR calculation.  
OS is defined as the time from the date of the first dose of study drugs to death. 
Time to event variables PFS, DOR, and OS will be estimated using the Kaplan-Meier (KM) 
method. KM estimates of PFS, DOR, and OS will be plotted over time. Median PFS, DOR, and 
OS, if estimable, in each cohort will be presented, along with their 2-sided 95% confidence 
intervals using a generalized Brookmeyer and Crowley method. The PFS-6m and OS-6m, 
defined as the percentages of patients in the analysis population who remain alive and 
progression free at 6 months (or alive at 6 months for OS-6m), will be estimated using the KM 
method along with the corresponding 95% confidence interval constructed using Greenwood’s 
formula. 
Maximum tumor shrinkage per patient will be presented in waterfall plots.  
Primary analysis of efficacy endpoints will be carried out based on the maturity of the efficacy 
and safety data in the study, which will be determined by the sponsor. 
ORR and DCR will be summarized in the specified subgroups: sex, age group (< 65 versus ≥ 
65), race, disease stage, ECOG-PS (0 versus 1), number of prior lines of therapy, and geographic 
region. 
11.2.6. 
Pharmacokinetic Analyses 
For patients who contributed full PK profiles up to 48 hours on Cycle 1 Day 1, and up to 6 hours 
on Cycle 1 Day 15 (Section 8.3.1), the following PK parameters will be derived: Cmax, Tmax, t1/2, 
apparent clearance of the drug from plasma (CL/F), and Vz/F. 
For the remaining patients, population PK analysis may be carried out for pamiparib to include 
plasma concentrations from this study in an existing model. PK parameters such as Cmin will be 
summarized, and additional PK parameters such as CL/F and AUC may be derived from the 
population PK analysis if supported by data. Population PK analysis may be reported separately 
from the final CSR. 
Trough and/or peak plasma concentrations of TMZ will be summarized and compared with 
appropriate historical control. 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by 
data. 
11.2.7. 
Exploratory Analyses 
Exploratory endpoints include blood and tumor biomarkers and will be analyzed using the Safety 
Population. The correlation of predictive biomarkers with efficacy endpoints for study treatment 
will be explored. 
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11.3. 
Safety Analyses 
Safety will be assessed by monitoring and recording of all AEs graded by NCI CTCAE v4.03. 
Laboratory values (CBC, clinical chemistry, coagulation, and urinalysis), vital, physical exams, 
and ECGs findings will also be used in determining the safety. 
11.3.1. 
Extent of Exposure 
Extent of exposure to each study drug will be summarized in each cohort descriptively as the 
number of cycles received (number and percentage of patients), duration of exposure (days), 
cumulative total dose received per patient (mg), dose intensity, and relative dose intensity. 
The number (percentage) of patients requiring dose reductions, dose delay, and drug 
discontinuation due to AEs will be summarized by dose level. Frequency of dose reduction and 
dose delay will be summarized by categories. 
Patient data listings will be provided for all dosing records and for calculated summary statistics. 
11.3.2. 
Dose-limiting Toxicity 
Dose-limiting toxicity in the DLT evaluation period will be used to determine the dose and 
schedule of pamiparib plus TMZ in the expansion cohorts. The DLT events will be summarized 
descriptively at each combination dosing level in the DLT evaluable Population.  
11.3.3. 
Adverse Events 
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using MedDRA®. Adverse events will be coded to 
MedDRA® (Version 19.0 or higher) lower level term closest to the verbatim term. The linked 
MedDRA® preferred term (PT) and primary system organ class (SOC) are also captured in the 
database. 
A treatment emergent adverse event (TEAE) is defined as an AE that had an onset date on or 
after the first dose of study drugs up to 30 days following study drug discontinuation or was 
worsening in severity from baseline (pretreatment). Only those AEs that were treatment 
emergent will be included in summary tables. All AEs, treatment emergent or otherwise, will be 
presented in patient data listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
SOC and PT. A patient will be counted only once by the highest grade according to 
NCI CTCAE v.4.03 within an SOC and PT, even if the patient experienced more than one TEAE 
within a specific SOC and PT. The number (percentage) of patients with TEAEs will also be 
summarized by relationship to the study drug. Treatment-related AEs include those events 
considered by the investigator to be possibly or probably related to study drug or with missing 
assessment of the causal relationship. Serious adverse events, deaths, TEAE with Grade 3 or 
above, related TEAE and TEAEs that led to treatment discontinuation, dose reduction or dose 
delay will be summarized. 
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11.3.4. 
Laboratory Analyses 
Clinical laboratory (i.e., CBC, serum chemistry, and qualitative urinalysis) values will be 
evaluated for each laboratory parameter by cohort. Abnormal laboratory values will be flagged 
and identified as those outside (above or below) the normal range. Reference (normal) ranges for 
laboratory parameters will be included in the CSR for this protocol. Descriptive summary 
statistics (e.g., n, mean, standard deviation, median, minimum, maximum for continuous 
variables; n [%] for categorical variables) for laboratory parameters and their changes from 
baseline will be calculated. Laboratory values will be summarized by visit and by worst post-
baseline visit. 
Laboratory parameters that are graded in NCI CTCAE v.4.03 will be summarized by CTCAE 
grade. In the summary of laboratory parameters by CTCAE grade, parameters with CTCAE 
grading in both high and low directions (e.g., calcium, glucose, magnesium, potassium, sodium) 
will be summarized separately. 
11.3.5. 
Vital Signs 
Descriptive statistics for vital sign parameters (SBP and DBP, heart rate, respiratory rate, 
temperature, weight) and changes from baseline will be presented by visit and cohort. Vital signs 
will be listed by patient and visit. 
11.3.6. 
Electrocardiogram 
Electrocardiogram assessments will be performed at Screening and during BGB-290 PK 
collection timepoints (Dose Escalation and Dose Expansion Cohorts 1-5) or at Screening, EOT 
and as clinically indicated (Cohort 6) as specified in the Schedule of Assessments 
(Appendix 1 Table 1). Change from baseline to each post-baseline visit in ECG findings will be 
summarized by visit and/or timepoint. Descriptive statistics for ECG parameters and changes 
from baseline will be presented. 
11.4. 
Sample Size Consideration 
Approximately 250 patients (50 in the dose escalation phase and 200 in the dose expansion 
phase) will be enrolled. A sample size of 20-25 patients in an expansion cohort will provide the 
half width of the 90% confidence interval of the ORR approximately 13% to 20% when the 
observed ORR is approximately 40%. Hence, the low bound is above 20%. This is considered 
adequate in the preliminary assessment of anticancer activity of pamiparib and TMZ 
combination therapy. An expansion cohort can be further expanded to confirm efficacy. 
 
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Table 5: 
Estimated Objective Response Rate and 90% Confidence Interval for 
20-25 Patients 
Sample Size 
No. of 
Responders 
Response Rate 
Confidence Interval 
Lower Limit 
Upper Limit 
20 
8 
40% 
22% 
61% 
21 
8 
38% 
21% 
58% 
 
9 
43% 
24% 
63% 
22 
8 
36% 
20% 
56% 
 
9 
41% 
23% 
60% 
23 
9 
39% 
22% 
58% 
 
10 
43% 
26% 
62% 
24 
9 
38% 
21% 
56% 
 
10 
42% 
25% 
60% 
25 
10 
40% 
24% 
58% 
11.5. 
Interim Analysis 
No interim analysis is planned. 
11.6. 
Other Statistical Issues 
A final analysis prior to study termination will be performed. The time and scope of the final 
analysis will be included in the SAP. 
Any other statistical/analytical issues will be discussed in the SAP. 
 
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12. 
STUDY ADMINISTRATION AND INVESTIGATOR 
OBLIGATIONS 
12.1. 
Regulatory Authority Approval 
The sponsor will obtain approval to conduct the study from the appropriate regulatory agency in 
accordance with any applicable country-specific regulatory requirements or file the protocol to 
appropriate regulatory agency before the study is initiated at a study center in that country. 
12.2. 
Investigator Responsibilities 
12.2.1. 
Good Clinical Practice 
This study will be conducted by the principal investigator and the study center in full 
conformance with the International Council for Harmonisation E6 guideline for GCP and the 
principles of the Declaration of Helsinki or the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the individual. The study will 
also comply with the requirements of the International Council for Harmonisation E2A guideline 
(Clinical Safety Data Management: Definitions and Standards for Expedited Reporting). 
12.2.2. 
Ethical Conduct of the Study and Ethics Approval 
This study will be conducted in accordance with GCP and all applicable regulatory requirements, 
including, where applicable, the current version of the Declaration of Helsinki. 
The investigator (or sponsor, where applicable) is responsible for ensuring that this protocol, the 
study center’s informed consent form, and any other information that will be presented to 
potential patients (e.g., advertisements or information that supports or supplements the informed 
consent) are reviewed and approved by the appropriate IEC/IRB. 
The IEC/IRB must be constituted in accordance with all applicable regulatory requirements. The 
sponsor will provide the investigator with relevant document(s)/data that are needed for IEC/IRB 
review and approval of the study. 
Before the study drug(s) can be shipped to the study center, the sponsor or its authorized 
representative must receive copies of the IEC/IRB approval, the approved informed consent 
form, and any other information that the IEC/IRB has approved for presentation to potential 
patients. 
If the protocol, the informed consent form, 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 informed consent form 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 IEC/IRB approval of the amended informed consent form/other information and the 
approved amended informed consent form/other information must be forwarded to the sponsor 
promptly. 
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12.2.3. 
Informed Consent 
The investigator is responsible for obtaining written informed consent from each individual 
participating in this study after adequate explanation of the aims, methods, objectives, and 
potential hazards of the study and before undertaking any study-related procedures. The 
investigator must utilize an IRB/IEC-approved consent form for documenting written informed 
consent. Each informed consent will be appropriately signed and dated by the patient or the 
patient’s legally authorized representative and the person obtaining consent. 
Informed consent will be obtained before the patient can participate in the study. The case 
history or clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained before participation in the study. 
The ICFs will be revised whenever there are changes to study procedures or when new 
information becomes available that may affect the willingness of the patient to participate. The 
final revised IRB/IEC-approved consent forms must be provided to the sponsor for health 
authority submission purposes. 
Patients must be re-consented to the most current version of the ICFs (or to a significant new 
information/findings addendum in accordance with applicable laws and IRB/IEC policy) during 
their participation in the study. For any updated or revised ICFs, the case history or clinical 
records for each patient shall document the informed consent process and that written informed 
consent was obtained using the updated/revised ICFs for continued participation in the study. 
A copy of each signed ICF must be provided to the patient or the patient’s legally authorized 
representative. All signed and dated ICFs must remain in each patient’s study file or in the site 
file and must be available for verification by study monitors at any time. 
12.2.4. 
Investigator Reporting Requirements 
As indicated in Section 10.1, the investigator (or sponsor, where applicable) is responsible for 
reporting SAEs to the IEC/IRB, in accordance with all applicable regulations. Furthermore, the 
investigator may be required to provide periodic safety updates on the conduct of the study at 
his/her study center and notification of study closure to the IEC/IRB. Such periodic safety 
updates and notifications are the responsibility of the investigator and not of the sponsor. 
12.2.5. 
Confidentiality 
The principal investigator shall code the medical information obtained during the study with a 
unique patient identification number assigned to each patient enrolled in the study. This approach 
ensures that patients’ names are not included in any data set transmitted to any sponsor location. 
Patient medical information obtained during this study is confidential and may only be disclosed 
to third parties as permitted by the signed ICF (or a separate authorization for the use and 
disclosure of personal health information that has been signed by the patient), unless permitted or 
required by law. 
In the event of a breach of the confidentiality of a patient’s personal and medical information, the 
principal investigator and sponsor, as appropriate, shall fulfill all mediation steps and reporting 
obligations under applicable data privacy laws. 
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Medical information may be given to a patient’s personal physician or other appropriate medical 
personnel responsible for the patient’s welfare for treatment purposes. 
Data generated during this study must be available for inspection upon request by representatives 
of the United States Food and Drug Administration and all other national and local health 
authorities; by sponsor monitors, representatives, and collaborators; and by the IRBs/IECs for 
each study site, as appropriate. 
The investigator must ensure that patients’ anonymity will be strictly maintained and that their 
identities are protected from unauthorized parties. The investigator agrees that all information 
received from the sponsor, including but not limited to the IB, this protocol, eCRFs, the 
investigational new drug application, and any other study information, remain the sole and 
exclusive property of the sponsor during the conduct of the study and thereafter. This 
information is not to be disclosed to any third party (except employees or agents directly 
involved in the conduct of the study or as required by law) without prior written consent from the 
sponsor. The investigator further agrees to take all reasonable precautions to prevent the 
disclosure by any employee or agent of the study site to any third party or otherwise into the 
public domain. 
If a written contract for the conduct of the study is executed and includes confidentiality 
provisions inconsistent with this section, that contract’s provisions shall apply to the extent they 
are inconsistent with this section. 
12.2.6. 
Electronic Case Report Forms 
For each patient enrolled, an eCRF must be completed and signed by the principal investigator or 
subinvestigator within a reasonable time-period after data collection. This also applies to records 
for those patients who discontinue the study early. If a patient withdraws from the study, the 
reason must be noted in the appropriate eCRF. If a patient is withdrawn from the study because 
of a treatment-limiting AE, thorough efforts should be made to clearly document the outcome. 
The eCRFs exist within an EDC system with controlled access managed by BeiGene or its 
authorized representative for this study. Study staff will be appropriately trained in the use of 
eCRFs and applications of electronic signatures before being given access to the EDC system. 
Original data and any changes of data will be recorded using the EDC system, with all changes 
tracked by the system and recorded in an electronic audit trail. The investigator attests that the 
information contained in the eCRFs is true by providing an electronic signature within the EDC 
system. After final database lock, the investigator will receive a copy of the patient data at their 
specific study site on CD-ROMs for archiving the data at the study site. 
12.2.7. 
Drug Accountability 
The investigator or designee (i.e., pharmacist) is responsible for ensuring adequate accountability 
of all used and unused study drug. This includes acknowledgment of receipt of each shipment of 
study product (quantity and condition), patient dispensing records, and returned or destroyed 
study product. Dispensing records will document quantities received from the sponsor and 
quantities dispensed to patients, including lot number, date dispensed, patient identifier number, 
patient initials, and the initials of the person dispensing the medication. 
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At study initiation, the monitor will evaluate the site’s standard operating procedure for study 
drug disposal/destruction to ensure that it complies with BeiGene’s requirements specified in the 
Pharmacy Manual. At appropriate times during the conduct of the study or at the end of the 
study, following final drug inventory reconciliation by the monitor, the study site will dispose of 
and/or destroy all unused study drug supplies, including empty containers, according to these 
procedures. If the site cannot meet the sponsor’s requirements for disposal, arrangements will be 
made between the site and the sponsor or its representative for destruction or return of unused 
study drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 
12.2.8. 
Site Inspections 
This study will be organized, performed, and reported in compliance with the protocol, standard 
operating procedures, working practice documents, and applicable regulations and guidelines. 
Site audits may be performed periodically by the sponsor’s or the contract research 
organization’s qualified compliance auditing team, which is an independent function from the 
study team responsible for conduct of the study. 
Site visits will be conducted by the sponsor or an authorized representative to inspect study data, 
patients’ medical records, and eCRFs. The investigator is to permit national and local health 
authorities; sponsor study monitors, representatives, and collaborators; and IRB/IEC members to 
inspect all facilities and records relevant to this study. 
12.2.9. 
Protocol Adherence 
The investigator is responsible for ensuring the study is conducted in accordance with the 
procedures and evaluations described in this protocol. Investigators ascertain they will apply due 
diligence to avoid protocol deviations. 
The investigator is to document and explain any deviations from the approved protocol. The 
investigator must promptly report any major deviations that might impact patient safety and/or 
data integrity to the sponsor and to the IRB/IEC, in accordance with established IRB/IEC 
policies and procedures. 
12.2.10. 
Financial Disclosure 
Investigators are required to provide the sponsor with sufficient accurate financial information in 
accordance with regulations to allow the sponsor to submit complete disclosure or certification to 
the absence of certain financial interest of the clinical investigators and/or disclose those 
financial interests, as required, to the appropriate health authorities. This is intended to ensure 
financial interests and arrangements of the clinical investigators with BeiGene that could affect 
reliability of data submitted to health authorities are identified and disclosed by the sponsor. 
Investigators are responsible for providing information about their financial interests before 
participation in the study and to update this information if any relevant changes occur during the 
study and for 1 year after completion of the study (i.e., last patient, last visit). 
 
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12.3. 
Sponsor Responsibilities 
12.3.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
initiated only by the sponsor. All protocol modifications must be submitted to the IRB/IEC 
together with, if applicable, a revised model informed consent in accordance with local 
requirements. Written documentation of IRB/IEC and required site approval must be obtained by 
the sponsor before changes can be implemented, except for changes necessary to eliminate an 
immediate hazard to patients or changes that involve logistical or administrative aspects only 
(e.g., change in medical monitor or contact information). 
Information on any change in risk and /or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand, and sign each revised 
informed consent form confirming willingness to remain in the study. 
12.3.2. 
Use of Information and Publication 
A clinical study report will be prepared and provided to the regulatory agency(ies) of 
participating countries. The sponsor will ensure that the report meets the standards set out in the 
ICH Guideline for Structure and Content of Clinical Study Reports (ICH E3). Note that an 
abbreviated report may be prepared in certain cases. 
The results of this study will be published or presented at scientific meetings in a timely, 
objective, and clinically meaningful manner that is consistent with good science, industry and 
regulatory guidance, and the need to protect the intellectual property of the sponsor, regardless of 
the outcome of the study. The data generated in this clinical study are the exclusive property of 
the sponsor and are confidential. For a multicenter study, the first publication or disclosure of 
study results shall be a complete, joint multicenter publication, or disclosure coordinated by the 
sponsor. Thereafter, any secondary publications will reference the original publication(s). 
Authorship will be determined by mutual agreement and all authors must meet the criteria for 
authorship established by the International Committee of Medical Journal Editors Uniform 
Requirements for Manuscripts or stricter local criteria (International Committee of Medical 
Journal Editors 2016).  
Each investigator agrees to submit all manuscripts, abstracts, posters, publications, and 
presentations (both oral and written) to the sponsor for review before submission or presentation 
in accordance with the clinical study agreement. This allows the sponsor to protect proprietary 
information, provide comments based on information from other studies that may not yet be 
available to the investigator, and ensure scientific and clinical accuracy. The details of the 
processes of producing and reviewing reports, manuscripts, and presentations based on the data 
from this study will be presented in the investigator’s clinical study agreement. Each investigator 
agrees that, in accordance with the terms of clinical study agreement, a further delay of the 
publication/presentation may be requested by the sponsor to allow for patent filings and/or 
protection in advance of the publication/presentation. 
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12.4. 
Study and Study Center Closure 
Upon completion of the study, the monitor will conduct the following activities in conjunction 
with the investigator or study center personnel, as appropriate: 
• Return of all study data to the sponsor 
• Data queries 
• Accountability, reconciliation, and arrangements for unused study drug(s) 
• Review of study records for completeness 
• Return of treatment codes to the sponsor 
• Shipment of samples (e.g., PK, biomarker, etc.) 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 significant 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, arrangements will be made for all unused study drug(s) in accordance with the 
applicable sponsor procedures for the study. 
Financial compensation to investigators and/or institutions will be in accordance with the 
agreement established between the investigator and the sponsor. 
12.5. 
Records Retention and Study Files 
12.5.1. 
Study Files and Retention of Records 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into at least the following 2 categories: (1) investigator’s study file and (2) patient 
clinical source documents. 
The investigator’s study file will contain the protocol/amendments, eCRF and query forms, 
IRB/IEC, and governmental approval with correspondence, informed consent, drug records, staff 
curriculum vitae and authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include (although not be limited to) 
the following: patient hospital/clinic records, physician’s and nurse’s notes, appointment book, 
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original laboratory reports, ECG, electroencephalogram, X-ray, pathology and special 
assessment reports, consultant letters, screening and enrollment log, etc. 
Following closure of the study, the investigator must maintain all study records in a safe and 
secure location. The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., 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 (e.g., 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 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: archival at an off-site facility or transfer of ownership of the 
records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and the sponsor to 
store these in sealed containers outside of the site so that they can be returned sealed to the 
investigator in case of a regulatory audit. When source documents are required for the continued 
care of the patient, appropriate copies should be made for storage outside of the site. 
Biological samples at the conclusion of this study may be retained as outlined in the agreement 
with the CRO managing the biological samples, a period of up to 10 years or as allowed by your 
IRB/IEC, whichever is shorter. 
12.5.2. 
Provision of Study Results and Information to Investigators 
When the clinical study report is completed, the sponsor will provide the major findings of the 
study to the investigator. 
In addition, details of the study drug assignment will be provided to the investigator to enable 
him/her to review the data to determine the outcome of the study for his/her patient(s). 
The sponsor will not routinely inform the investigator or patient the test results, because the 
information generated from this study will be preliminary in nature, and the significance and 
scientific validity of the results will be undetermined at such an early stage of research. 
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12.6. 
Information Disclosure and Inventions 
All information provided by the sponsor and all data and information generated by the study 
center as part of the study (other than a patient’s medical records) is the sole property of the 
sponsor. 
All rights, title, and interests in any inventions, know-how, or other intellectual or industrial 
property rights 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 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 in Section 12.2.3 
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. 
12.7. 
Joint Investigator/Sponsor Responsibilities 
12.7.1. 
Access to Information for Monitoring 
In accordance with ICH GCP guidelines, the study monitor must have direct access to the 
investigator’s source documentation in order to verify the data recorded in the eCRFs for 
consistency. 
The monitor is responsible for routine review of the eCRFs at regular intervals throughout the 
study to verify adherence to the protocol and the completeness, consistency, and accuracy of the 
data being entered on them. The monitor should have access to any patient records needed to 
verify the entries on the eCRFs. The investigator agrees to cooperate with the monitor to ensure 
that any problems detected in the course of these monitoring visits are resolved. 
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12.7.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of the sponsor may conduct inspections or audits any 
time during or after completion of this clinical study. If the investigator is notified of an 
inspection by a regulatory authority, the investigator agrees to notify the sponsor or its designee 
immediately. The investigator agrees to provide to representatives of a regulatory agency or the 
sponsor access to records, facilities, and personnel for the effective conduct of any inspection or 
audit. 
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13. 
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increases base excision repair gene transcripts in leukemic cells resistant to triazene 
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46. Tentori L, Portarena I, Vernole P, De Fabritiis P, Madaio R, Balduzzi A, et al. Effects of 
single or split exposure of leukemic cells to temozolomide, combined with 
poly(ADP-ribose) polymerase inhibitors on cell growth, chromosomal aberrations and 
base excision repair components. Cancer Chemother Pharmacol. 2001;47:361-9. 
47. Isakoff SJ, Overmoyer B, Tung NM, et al. A phase II trial of the PARP inhibitor veliparib 
(ABT888) and temozolomide for metastatic breast cancer. J Clin Oncol. 2010 28:15s, 
(suppl; abstr 1019). 
48. Hussain M, Carducci MA, Slovin S, Cetnar J, Qian J, McKeegan EM, et al. Targeting 
DNA repair with combination veliparib (ABT-888) and temozolomide in patients with 
metastatic castration-resistant prostate cancer. Invest New Drugs. 2014;32(5):904-12. 
49. Plummer R, Jones C, Middleton M, Wilson R, Evans J, Olsen A, et al. Phase I Study Of 
The Poly(ADP-Ribose) Polymerase Inhibitor, AG014699, In Combination With 
Temozolomide in Patients with Advanced Solid Tumors. Clin Cancer Res. 
2008;14(23):7917-23. 
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50. Plummer R, Lorigan P, Steven N, Scott L, Middleton MR, Wilson RH, et al. A phase II 
study of the potent PARP inhibitor, Rucaparib (PF-01367338, AG014699), with 
temozolomide in patients with metastatic melanoma demonstrating evidence of 
chemopotentiation. Cancer Chemother Pharmacol. 2013;71(5):1191-9.  
51. Bedikian AY, Papadopoulos NE, Kim KB, et al. A Phase IB Trial of Intravenous INO-
1001 plus oral temozolomide in subjects with unrecetable Stage-III or IV melanoma. 
Cancer Invest. 2009;27:756-63.  
52. Gabrielson A, Tesfaye AA, Marshall JL, Pishvaian MJ, Smaglo B, Jha R, et al. Phase II 
study of temozolomide and veliparib combination therapy for sorafenib-refractory 
advanced hepatocellular carcinoma. Cancer Chemother Pharmacol. 2015;76(5):1073-9.  
53. Gojo I, Beumer JH, Pratz KW, McDevitt MA, Baer MR, Blackford AL, et al. A Phase 1 
Study of the PARP Inhibitor Veliparib in Combination with Temozolomide in Acute 
Myeloid Leukemia. Clin Cancer Res. 2017;23(3):697-706.  
54. Wainberg ZA, Hecht JR, Konecny GE, Goldman JW, Sadeghi S, Chmielowski B, et al. 
Safety and efficacy results from a phase I dose-escalation trial of the PARP inhibitor 
talazoparib in combination with either temozolomide or irinotecan in patients with 
advanced malignancies. Abstract CT011; AACR Annual Meeting 2016. 
55. Rudek MA, Donehower RC, Statkevich P, Batra VK, Cutler DL, Baker SD. 
Temozolomide in patients with advanced cancer: phase I and pharmacokinetic study. 
Pharmacotherapy. 2004;24(1):16-25. 
56. Brock CS, Newlands ES, Wedge SR, Bower M, Evans H, Colquhoun I, et al. Phase I trial 
of temozolomide using an extended continuous oral schedule. Cancer Res. 
1998;58(19):4363-7. 
57. Su YB, Sohn S, Krown SE, Livingston PO, Wolchok JD, Quinn C, et al. Selective CD4+ 
lymphopenia in melanoma patients treated with temozolomide: a toxicity with therapeutic 
implications. J Clin Oncol. 2004;22(4):610-6.  
58. Perry JR, Bélanger K, Mason WP, Fulton D, Kavan P, Easaw J, et al. Phase II trial of 
continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J 
Clin Oncol. 2010;28(12):2051-7. 
59. Investigator’s Brochure, Pamiparib (BGB-290). Edition 5.1, Nov 2019. 
60. Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, et al. Trapping of 
PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res. 2012;72:5588–99. 
61. Curtin N J, Wang L Z, Yiakouvaki A, et al., Novel poly(ADP-ribose) polymerase-1 
inhibitor, AG14361, restores sensitivity to temozolomide in mismatch repair-deficient 
cells. Clin Cancer Res. 2004;10(3):881-9. 
62. Ratnam K and Low J A, Current development of clinical inhibitors of poly(ADP-ribose) 
polymerase in oncology. Clin Cancer Res. 2007;13(5):1383-8. 
63. Ricks TK, Chiu HJ, Ison G, Kim G, McKee AE, Kluetz P, et al. Successes and 
Challenges of PARP Inhibitors in Cancer Therapy. Front Oncol. 2015;14;5:222. 
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64. Golan T, Varadhachary, GR, Sela T, Fogelman DR, et al. Phase II study of olaparib for 
BRCAness phenotype in pancreatic cancer. J Clin Oncol. 2018;36(4):297. 
65. Kauffman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in 
patients with advanced cancer and germline BRCA1/2 mutation. J Clin Oncol. 
2015;33:244-51. 
 
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14. 
APPENDICES 
 
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APPENDIX 1. SCHEDULE OF ASSESSMENTS 
Appendix 1 Table 1: 
Schedule of Assessments and Procedures Schedule for Dose Escalation and Dose Expansion Phases 
Assessments 
Pre-
Screening 
(Dose 
Expansion 
only)1 
Screening2 
Cycle 1  
(28 days) 
Cycles 2- 5 
(28 days) 
Cycle 6 and 
Subsequent 
Cycles in 1st 
year 
(Every 28 
days) 
Subsequent 
Cycles in the 
2nd year and 
beyond 
(Every 28 
days) 
EOT3 
Safety 
Follow-up4 
Efficacy 
Follow-
Up 
Survival 
Follow-
Up5 
Day of Phase 
-84 to -29 
-28 to -1 
1 
7 
15 
22 
1 
15 
1  
1 
~7 days 
after 
last 
dose 
~30 ± 7 
days after 
last dose 
Every 
 8 
weeks  
Every  
~3 
months 
Allowed time  
window 
 
 
 
-2 
days6 
± 2 
days 
± 2 
days 
± 2 
days6 
± 2 
days 
± 3 
days 
± 3  
days 
 
 
±7  
days 
 
Pre-screening 
informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and 
cancer history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
Physical 
examination7 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Limited physical 
examination8 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Vital signs 
(including weight) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
performance 
status 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
 
 
12-lead ECG9 
 
-14 to -1 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Triplicate ECGs10 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Hematology11 
 
-14 to -1 
days 
X12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Clinical 
chemistry11 
 
-14 to -1 
X12 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
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Assessments 
Pre-
Screening 
(Dose 
Expansion 
only)1 
Screening2 
Cycle 1  
(28 days) 
Cycles 2- 5 
(28 days) 
Cycle 6 and 
Subsequent 
Cycles in 1st 
year 
(Every 28 
days) 
Subsequent 
Cycles in the 
2nd year and 
beyond 
(Every 28 
days) 
EOT3 
Safety 
Follow-up4 
Efficacy 
Follow-
Up 
Survival 
Follow-
Up5 
Day of Phase 
-84 to -29 
-28 to -1 
1 
7 
15 
22 
1 
15 
1  
1 
~7 days 
after 
last 
dose 
~30 ± 7 
days after 
last dose 
Every 
 8 
weeks  
Every  
~3 
months 
Allowed time  
window 
 
 
 
-2 
days6 
± 2 
days 
± 2 
days 
± 2 
days6 
± 2 
days 
± 3 
days 
± 3  
days 
 
 
±7  
days 
 
Coagulation 
 
-14 to -1 
X12 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis11,13 
 
-14 to -1 
X12 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy 
test14 
 
-7 to -1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
test15 
 
 
 
 
 
 
X 
 
X 
X 
X 
 
 
 
CT or MRI16 
 
X 
EVERY 8 WEEKS ± 7 DAYS 
X 
 
X 
 
Tumor antigens 17 
 
X 
EVERY 8 WEEKS ± 7 DAYS 
X 
 
X 
 
HBV/HCV tests 18   
 
X 
As clinically indicated 
 
 
 
 
TMZ Dosing  
Dose escalation 
 
 
Pulsed Dosing (Arm A): Once daily on Days 1 to 7 or Days 1-14 of each 28 day cycle 
Continuous Dosing (Arm B): Once daily continuously 
 
 
 
 
TMZ Dosing  
Dose Expansion 
 
 
RP2D= 60 mg QD 60 mg QD Days 1-7 of each cycle 
 
 
 
 
Pamiparib Dosing 
 
 
60 mg twice daily continuously 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concurrent 
medications19 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PK assessments20 
 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
Blood sample 
collection for 
biomarkers21 
 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
Archival Tumor 
Tissue or fresh 
tumor tissue22 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Fresh Tumor 
Tissues23 (Dose 
Escalation and 
Dose Expansion 
Cohorts 1-5; 
X 
 
X 
 
X 
 
 
 
 
 
X 
 
 
 
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Assessments 
Pre-
Screening 
(Dose 
Expansion 
only)1 
Screening2 
Cycle 1  
(28 days) 
Cycles 2- 5 
(28 days) 
Cycle 6 and 
Subsequent 
Cycles in 1st 
year 
(Every 28 
days) 
Subsequent 
Cycles in the 
2nd year and 
beyond 
(Every 28 
days) 
EOT3 
Safety 
Follow-up4 
Efficacy 
Follow-
Up 
Survival 
Follow-
Up5 
Day of Phase 
-84 to -29 
-28 to -1 
1 
7 
15 
22 
1 
15 
1  
1 
~7 days 
after 
last 
dose 
~30 ± 7 
days after 
last dose 
Every 
 8 
weeks  
Every  
~3 
months 
Allowed time  
window 
 
 
 
-2 
days6 
± 2 
days 
± 2 
days 
± 2 
days6 
± 2 
days 
± 3 
days 
± 3  
days 
 
 
±7  
days 
 
additional consent 
required) 
Survival Status  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOT: end-of-treatment; MRI: magnetic resonance imaging; PK: pharmacokinetic; TMZ: 
Temozolomide; 
X: to be performed. 
Notes: All assessments must be performed before investigational product administration in each cycle (except as otherwise noted).  
1. 
For Dose Expansion Only: Patients with an unknown germline or somatic BRCA mutation or unknown HRD for Expansion Cohorts 1 (ovarian cancer), 
2 (TNBC), 3 (mCRPC) and Cohort 6 (multiple indications) will undergo pre-screening for HRD testing for a period of up to 8 weeks prior to eligibility 
screening (Section 8.1). A separate pre-screening informed consent must be obtained. Any tissues taken during pre-screening period will not be re-
collected during the screening period.  
For Dose Escalation Only: Cycle 1 encompasses the DLT assessment window, and assessments of Day 1 of Cycle 2 at the end of the DLT assessment 
window are required for a patient to be DLT-evaluable. Assessments shown for Cycle 3 apply to all subsequent cycles except for MRI that occurs every 
second cycle (every 8 weeks). 
2. 
Screening must occur within 28 days of Day 1. Assessments obtained within 4 days of Day 1 do not have to be repeated on Day 1. Some assessments have 
a narrower screening window as shown in the table. Patient registration may occur as late as Day 1 prior to any study treatment. 
3. 
The EOT visit will occur within 7 days after a patient permanently discontinued study drugs for any of the reasons outlined in Section 8.4. A visit should 
be scheduled as soon as possible, but the EOT visit may occur later after discussion with the Medical Monitor for specific circumstances, such as 
prolonged hospitalization. The visit at which CT or MRI showed progressive disease may be used as the EOT visit provided that all required assessments 
were performed. If routine laboratory tests (e.g., hematology, clinical chemistry) were completed ≤ 7 days before the EOT Visit, these tests do not need to 
be repeated. The CT/MRI does not have to be repeated if it was performed within 14 days of the EOT visit or at a prior response evaluation that 
documented progressive disease. ECG does not have to be repeated if it was performed within 14 days of the EOT visit. If the EOT Visit did not occur 
until 30 days (± 7 days) or later after the last dose of pamiparib and TMZ, the EOT Visit may also be used as the Safety Follow-up Visit. 
4. 
All patients who permanently discontinue study drugs will have a safety follow-up approximately 30 days after the last day of study drugs to collect AEs 
and SAEs that may have occurred after the patient discontinued from the study drugs. If the patient does not require any laboratory assessments, the 
investigator or his/her designee will contact the patient to collect this information. (Protocol Section 8.5.1). 
5. 
Following permanent discontinuation of study drugs and/or Safety Follow-up parts of the study, every effort should be made to follow up with all patients 
by phone every 3 months for their survival status until patient death (Protocol Section 8.5.3). 
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6. 
A window of ±2 days on Cycle 1 Day 7 and Cycle 2 Day 1 is allowed during Dose Expansion Only.  
7. 
Complete 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; 11) neurological status.  
8. 
A limited physical examination should be directed at the evaluation of symptoms or specific safety issues. Changes from baseline abnormalities should be 
recorded at each subsequent physical examination. New or worsening abnormalities should be recorded as AEs if appropriate. 
9. 
A single 12-lead ECG will be performed during Screening within 14 days of Cycle 1 Day1 and at the EOT visit.  
10. For Dose Escalation and Dose Expansion Cohorts 1-5 Only: ECGs will be performed in triplicate within a 5-minute window prior to Pamiparib PK 
assessments on Day -2 or Days 1 and 15. ECGs collected on the days of PK assessment will be performed on a machine provided by the sponsor and will 
be sent to a central reader. The same machine should be used for each patient whenever possible. 
11. Hematology includes hemoglobin, platelet count, white blood cell count, neutrophil count, and lymphocyte count. 
Chemistry includes albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, blood urea nitrogen, chloride, creatinine, glucose, 
lactate dehydrogenase, phosphate, potassium, sodium, total bilirubin, and total protein. 
Urinalysis includes blood, glucose, ketones, protein, red blood cells, and white blood cells. 
In the event of clinically significant laboratory results, such as neutropenia (absolute neutrophil count < 1000/mm3), thrombocytopenia (platelets 
<50,000/mm3), or Grade ≥ 3 clinical chemistry toxicity (per NCI CTCAE v4.03), these assessments will be conducted as frequently as the investigator 
feels is necessary until toxicity resolves to Grade  
≤ 2. 
12. Screening blood and urine tests must be performed within 14 days of Day 1. If they were performed within 4 days of Day 1 they do not need to be repeated 
on Cycle 1 Day 1. 
13. If urine protein is ≥ 2+ by dipstick, a 24-hour urine for total protein and a random urine for total protein and creatinine will be obtained and evaluated 
(Section 7.6.3). 
14. Only in women of childbearing potential; a serum pregnancy test must be taken ≤ 7 days from Cycle 1, Day 1.  
15. For subsequent pregnancy testing on study and at EOT, urine pregnancy tests are allowed. If a urine pregnancy test is positive, a confirmatory serum 
pregnancy test is required. 
16. A computed tomography (CT) or MRI scan of the thorax, abdomen, and pelvis plus other relevant evaluations as appropriate will be performed once every 
8 weeks ± 7 days to assess all known disease. A CT/MRI taken within 28 days (Screening Period) of Cycle 1 Day 1 does not need to be re-taken. Patients 
without PD at the EOT Visit should be followed with tumor assessments every 12 weeks (± 7 days).  
17. Blood tumor antigens such as CA-125 for ovarian cancer and PSA for castration-resistant prostate cancer will be tested during screening and every 
8 weeks ± 7 days after the first dose of pamiparib in local laboratories. 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. 
18. Testing will be performed by local laboratory at screening and as clinically indicated and will include HBV/HCV serology (hepatitis B surface antigen, 
hepatitis B surface antibody, hepatitis B core antibody, and HCV antibody) and viral load assessment (HBV DNA and HCV RNA). 
19. Concurrent medications will be collected during screening and on the first day of study. Changes to Concurrent medications will be collected during 
subsequent clinic visits. 
20. Pharmacokinetic (PK) samples will be collected at the following timepoints: For pamiparib: ≤ 30 min before pamiparib and TMZ dosing, 1 (± 15 min), 
2 hours (± 30 min), and 4 hours (± 30 min) after pamiparib dose on Cycle 1 Day 1 and Cycle 1 Day 15; For TMZ: on Cycle 1 Day 1 and Day 7 at ≤ 30 min 
before dosing and 1 hour (± 15 min) after TMZ dose. 
21. Blood samples must be collected at screening or on Day 1 for the assessment of germline BRCA and/or other mutation analysis (8 ml). In addition, two 
blood samples (10 mL each) must be collected for plasma markers (e.g., CNA), TMZ treatment, and PARP inhibition before study treatment on Day 1 and 
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Day 15, and at the EOT visit (unless one had been collected within 14 days). Instructions for the processing, storage, and shipping of samples will be 
provided in the Study Manual. 
22. For patients in Expansion Cohorts 1 (ovarian cancer), 2 (TNBC), and 3 (mCRPC) with unknown BRCA mutation or HRD status, collection of archival 
tumor tissue is required during pre-screening to determine eligibility. For patients in Dose escalation and Cohorts 4 and 5, collection of archival tumor 
tissue for the purpose of biomarker analysis is required, if available and can be collected on screening or Cycle 1 Day 1. For patients in Cohort 6, collection 
of an archival tumor tissue sample is mandatory for prospective HRD testing to determine eligibility and should be collected during the prescreening 
period. Specific instructions for tissue collection and shipment are provided in the Study Manual. Any tissue provided during pre-screening period will 
not be re-collected during screening stage. 
23. For patients in Dose escalation, and patients in Dose expansion Cohorts 4 and 5: a fresh baseline biopsy of a tumor lesion is highly recommended if 
archival tissue is not available. Written patient consent is required for fresh tumor biopsies.                                                                                                                                     
For patients with unknown mutation or HRD status in Expansion Cohorts 1 (ovarian cancer), 2 (TNBC), and 3 (mCRPC) or patients in 
Expansion Cohort 6:  if archival tumor tissue is not available, a fresh biopsy must be provided for prospective HRD testing at prescreening. Patients will 
only be required to sign the prescreening consent form. Any tissue taken during pre-screening period will not be re-collected during screening stage.  
Dose escalation and Dose expansion Cohorts 1-5: An optional biopsy for pharmacodynamics analysis on Cycle 1 Day 1 and, if agreeable, also on Cycle 
1 Day 15 is highly recommended. Optional biopsy will also be taken, if agreeable, at the EOT visit for the patients who have confirmed disease 
progression during the study from accessible tumor sites to obtain samples to explore resistance mechanisms. If feasible, any follow up biopsy should be 
ideally taken from the same tumor lesion as the baseline biopsy (See Section 7.9.2) 
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Appendix 1 Table 2: 
Schedule of Assessments and Procedures for PK Intensive Visit (Days -2 to 1): Only for 
Approximately 20 Patients - Dose Escalation ONLY 
Assessments 
Day -2 (± 3 days) 1 
Day -1 
Day 1 
Time 
Pre-dose 
0 h 
0.5 h 
1 h 
2 hr 
4 h 
6 h 
24 h 
48 h 
Allowed time window 
 
 
± 5 min 
± 15 min 
± 30 min 
± 30 min 
± 30 min 
± 2 h 
± 2 h 
Concurrent medications 
X 
 
 
 
 
 
 
 
 
Complete Physical examination2 
X 
 
 
 
 
 
 
 
 
Limited physical examination3 
 
 
 
 
 
 
 
 
X 
Vital signs (including weight) 
X 
 
 
 
 
 
X 
X 
X 
ECOG performance status 
X 
 
 
 
 
 
 
 
 
Hematology 
X 
 
 
 
 
 
 
 
 
Clinical chemistry 
X 
 
 
 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
 
Urinalysis4 
X 
 
 
 
 
 
 
 
 
Blood sample collection for biomarkers5 
X 
 
 
 
 
 
 
 
 
Computed tomography or MRI6 
X 
 
 
 
 
 
 
 
 
Triplicate ECGs7 
X 
 
 
X 
X 
X 
X 
 
 
Pamiparib PK assessments8 
X 
 
X 
X 
X 
X 
X 
X 
X 
Pamiparib Dosing9 
 
X 
 
 
 
 
 
 
X 
Archival Tumor Tissues10 
X 
 
 
 
 
 
 
 
 
Fresh Tumor Tissues11 (additional consent required) 
X 
 
 
 
 
 
 
 
 
Adverse events 
X 
 
 
 
 
 
 
X 
X 
TMZ Dosing12 
 
 
 
 
 
 
 
 
X 
TMZ PK assessments13 
 
 
 
 
 
 
 
 
X 
CT: Computerized tomography; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; MRI: magnetic resonance imaging; PK: 
pharmacokinetic;  
TMZ: Temozolomide; X: to be performed. 
Notes: All assessments except for post-dose ECGs and PK samples and biopsies must occur before pamiparib administration. ECGs must occur before PK sampling and biopsies 
must be performed after all ECGs have been completed on Day -2. For patients enrolled into the PK intensive part of the study, the pre-dose biopsy must occur after the patient 
was approved for enrollment and before dosing on Cycle 1 Day -2. 
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1. 
Screening must occur within 28 days of Day -2. Assessments obtained within 4 days of Day -2 do not have to be repeated on Day -2. Patient registration 
may occur as late as Day -2 prior to any study treatment. 
2. 
Complete 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; 11) neurological status.  
3. 
A limited physical examination should be directed at the evaluation of symptoms or specific safety issues. Changes from baseline abnormalities should be recorded at each 
subsequent physical examination. New or worsening abnormalities should be recorded as AEs if appropriate. 
4. 
If urine protein is ≥ 2+ by dipstick, a 24-hour urine for total protein and a random urine for total protein and creatinine will be obtained and evaluated (Section 7.6.3). 
5. 
Blood samples will be collected before study treatment on Day -2 for the assessment of germline BRCA and/or other mutation analysis (8 ml). In addition, two blood 
samples (10 mL each) must be collected for plasma markers (e.g., CNA), TMZ treatment, and PARP inhibition. Instructions for the processing, storage, and shipping of 
samples will be provided in the Study Manual. 
6. 
A computed tomography (CT) or MRI scan of the thorax, abdomen, and pelvis plus other relevant evaluations as appropriate will be performed.  
7. 
ECGs will be performed in triplicate on Day -2 within a 5-minute window 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 -2. Triplicate ECGs will be sent to a central reader. 
8. 
Pamiparib PK samples will be collected at the following timepoints: For pamiparib: ≤ 30 min before dosing on Day -2 and post-dose at 30 min (± 5 min); 1 hour (± 15 min); 
2 hours (± 30 min), 4 hours (± 30 min), and 6 hours (± 30 min), 24 hours (± 2 h) on Day -1, and 48 hours (± 2 h) on Day 1. 
9. 
Pamiparib dosing must occur after the collection of the 48-hour post-dose PK sample on Day 1. 
10. 
Collection of archival tumor tissue for purpose of biomarker analysis is highly recommended. Specific instructions for tissue collection and shipment are provided in the 
Study Manual. 
11. 
In the absence of archival tumor tissues, a fresh baseline biopsy of a tumor lesion is highly recommended. Any tissues taken during pre-screening period will not be re-
collected during baseline. An optional biopsy for biomarker analysis after treatment on Cycle 1 and if agreeable, also on Cycle 1 Day 15, and EOT is highly recommended. 
Optional biopsy will also be taken at the EOT visit for the patients who have confirmed disease progression during the study from accessible tumor sites to obtain samples to 
explore resistance mechanisms. If feasible, any follow up biopsy should be ideally taken from the same tumor lesion as the baseline biopsy. Written patient consent is 
required for fresh tumor biopsies. Fresh biopsies should be limited to readily accessible tumor lesions (e.g., skin, peripheral lymph nodes, lung, liver or internal lymph node 
metastases which can be readily accessed using CT guidance). If performed, a tissue cylinder should be obtained that has proper size for histological examination and 
biomarker analysis.  
12. 
TMZ dosing must occur after the collection of the 48-hour post-dose PK sample on Day 1. 
13. 
TMZ PK samples will be collected at the following timepoints: pre-dose (within 30 min prior to dose) and 1 hour (± 15 min) post dose. 
 
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APPENDIX 2. CONTRACEPTION GUIDELINES AND DEFINITION OF 
CHILDBEARING POTENTIAL 
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 
− Oral, intravaginal, or transdermal 
• Progestogen-only hormonal contraception associated with the inhibition of ovulation 
− 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 Patient’s usual 
and preferred lifestyle. Periodic abstinence (e.g., 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 3. NEW YORK HEART ASSOCIATION CLASSIFICATION 
 
NYHA Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. 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. 
NYHA = New York Heart Association  
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APPENDIX 4. PROHIBITED MEDICATIONS 
 
Strong and Moderate CYP3A Inhibitors and Strong CYP3A Inducers 
 
Strong CYP3A Inhibitors 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals: boceprevir, telaprevir 
Other: cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone, 
Protease Inhibitors: indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir 
Strong CYP3A Inducers 
Avasimibe , carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. John’s wort 
(hypericum perforatum) 
Moderate CYP3A Inhibitors 
Antibiotics: ciprofloxacin, erythromycin 
Antifungals: fluconazole 
Protease inhibitors: amprenavir, atazanavir, darunavir, fosamprenavir 
Calcium channel blockers: diltiazem, verapamil 
Tyrosine kinase inhibitors (anticancer): imatinib 
Food products: grapefruit juice (citrus paradisi fruit juice) 
Herbal medications: Schisandra sphenanthera 
Others: aprepitant, casopitant, cimetidine, cyclosporine, dronedarone, tofisopam 
 
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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;45:228-47. 
DEFINITIONS 
Response and progression will be evaluated in this study using the international criteria proposed 
by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee (Version 1.1). 
Changes in only the largest diameter (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. 
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. 
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• 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. Study 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 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 
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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 (e.g., “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 (e.g., 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 study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung. 
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g., 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 studies 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 
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guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA 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 studies 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 (e.g., 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 
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: 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 progressive disease, 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 
reports 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 progressive disease, 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 (e.g., 2 mm). However, sometimes lesions or lymph nodes 
which are recorded as target lesions at baseline become so faint on CT scans 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 
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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. 
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 timepoints specified in the protocol. 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker levels. All lymph nodes must be non-pathological in size (< 10 mm short axis). 
Non-CR/Non-progressive disease: Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease: 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 the 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 III 
studies when it is not a criterion of study entry to have measurable disease. The same general 
concepts apply 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 progressive disease for measurable disease: i.e., an increase in tumor burden 
representing an additional 73% increase in “volume” (which is equivalent to a 20% increased 
diameter in a measurable lesion). Examples include an increase in a pleural effusion from “trace” 
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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 progressive disease at 
that point. While it 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: i.e., 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 study 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 study has a CT or MRI brain 
ordered which reveals metastases. The patient’s brain metastases are considered to be evidence 
of progressive disease 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 truly represents 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 
progressive disease 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 
progressive disease. 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 progressive disease 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 progressive disease. 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study until the end of 
the study 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 
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In studies where confirmation of response is required, repeated ‘NE’ timepoint assessments may 
complicate best response determination. The analysis plan for the study must address how 
missing data/assessments will be clearly explained in determination of response. For example, in 
most studies it is reasonable to consider a patient with timepoint responses of PR-NE-PR as a 
confirmed response. Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document objective progression 
even after discontinuation of treatment. Symptomatic deterioration is not a descriptor of an 
objective response, it is a reason for stopping study therapy. 
Conditions that define “early progression, early death, and unevaluability” are study 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 (e.g., very small and uncertain new lesions, cystic changes, 
or necrosis in existing lesions), treatment may continue until the next scheduled assessment. If at 
the next scheduled assessment, progression is confirmed, the date of progression should be the 
earlier date when progression was suspected. 
 
CONFIRMATORY MEASUREMENT/DURATION OF RESPONSE 
In non-randomized studies 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 studies. However, in all other circumstances, i.e., in randomized studies 
(phase II or III) or studies 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 study 
results. However, elimination of the requirement for response confirmation may increase the 
importance of central review to protect against bias, in particular in studies which are not 
blinded. In the case of SD, measurements must have met the SD criteria at least once after study 
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 studies, 
from date of randomization) until the criteria for progression are met, taking as reference the 
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smallest sum on study (if the baseline sum is the smallest, this is the reference for calculation of 
progressive disease). 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 study, 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 studies are to be made. 
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APPENDIX 6. DRUGS THAT PROLONG THE QT INTERVAL AND/OR 
INDUCE TORSADES DE POINTES PROHIBITED 
MEDICATIONS 
 
Antiarrhythmics 
 
amiodarone 
disopyramide 
dofetilide 
flecainide 
ibutilide 
procainamide 
quinidine 
sotalol 
Anticancer 
 
arsenic trioxide 
vandetanib 
Antihistamines 
 
astemizole 
terfenadine 
Antibiotics 
 
azithromycin 
clarithromycin 
erythromycin 
moxifloxacin 
sparfloxacin 
Antianginal 
bepridil 
Antimalarial 
 
chloroquine 
halofantrine 
Antipsychotics 
 
chlorpromazine 
haloperidol 
mesoridazine 
pimozide 
thioridazine 
Antinausea 
 
domperidone 
droperidol 
dolasetron (intravenous and oral) 
Anti-infective 
pentamidine 
Antilipemic 
probucol 
Antidepressants 
citalopram 
Opiate agonists 
 
levomethadyl 
methadone 
GI stimulant 
cisapride 
 
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APPENDIX 7. 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 (e.g., Torsade de Pointes). 
 
 
Strong CYP2C8 Inhibitors 
 
gemfibrozil 
 
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APPENDIX 8. EASTERN COOPERATIVE ONCOLOGY GROUP 
(ECOG) PERFORMANCE STATUS 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
As published by (Oken et al 1982). Eastern Cooperative Oncology Group, Robert Comis M.D., 
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APPENDIX 9. 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 v1.1 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 anti-mouse antibody4, 5) or if there has 
been medical and/or surgical interference with their peritoneum or pleura during the previous 28 
days (e.g., paracentesis). If assessing therapy that includes 2 treatment modalities for relapse 
(e.g., 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 
responders. In Appendix 9 Table 1 and Appendix 9 Table 2 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 have not had a CA-125 response and cannot therefore be classified as a CA-125 complete 
responder. 
Reporting of response according to GCIG criteria that integrate CA-125 response with RECIST 
v1.1 is shown in Appendix 9 Table 1 and Appendix 9 Table 2. 
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Appendix 9 Table 1: Evaluation of best overall response in patients without initial 
measurable disease and who are evaluable by CA-125 
CA-125 
Nontarget 
Lesions* 
New 
Lesions 
Overall 
Serological 
Response 
Best Response for This 
Category Also 
Requires 
Response and 
Normalized 
CR 
No 
CR 
Confirmed and 
maintained for at least 28 
days 
Response 
Non- 
progressive 
disease 
No 
PR 
 
Normalized but no 
response 
Non-CR/Non- 
progressive 
disease 
No 
SD 
 
Non-PR/non- 
progressive disease 
Non- 
progressive 
disease 
No 
SD 
 
Progressive disease 
Any 
Yes or No 
progressive disease 
 
Any 
progressive 
disease † 
Yes or No 
progressive disease 
 
Any 
Any 
Yes 
progressive disease 
 
1. *Nontarget lesions include ascites and peritoneal thickening, which are not measurable 
according to RECIST. 
2. †Unequivocal progression in nontarget lesions may be accepted as disease progression. 
3. CR: Complete response; PR: partial response; SD: stable disease. 
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Appendix 9 Table 2: 
Best overall response in patients with measurable disease and who 
are also evaluable by CA-125 
Target 
Lesion* 
Nontarget 
Lesions† 
New 
Lesions 
CA-125 
Overall 
Best 
Response 
Best Response for 
This Category Also 
Requires 
CR 
CR 
No 
Normal 
CR 
Best RECIST v1.1 
response for CR and PR 
also required it to be 
confirmed and 
maintained for at least 
28 days if response is 
primary end point 
CR  
Non-CR 
Non-
progressive 
disease 
No 
Not 
progressive 
disease 
PR 
CR  
CR 
No 
PR but not 
normal 
PR 
CR  
NE 
No 
PR 
PR 
PR  
Non- 
progressive 
disease or 
NAE 
No 
Not 
progressive 
disease 
PR 
NAE  
Non- 
progressive 
disease 
No 
PR 
PR 
Progressive disease or New >28 days from 
CA-125 PR‡ 
PR 
PR 
SD§  
Non- 
progressive 
disease 
No 
PR 
PR 
SD§  
Non- 
progressive 
disease or 
NAE 
No 
Not PR and 
not 
progressive 
disease 
SD 
Progressive disease or New >28 days from 
CA-125 PR‡ 
PR 
progressive 
disease 
Progressive 
disease  
Any 
Yes or 
No 
Any 
progressive 
disease 
Any  
progressive 
disease 
Yes or 
No 
Any 
progressive 
disease 
Any  
Any 
Yes 
Any 
progressive 
disease 
Any  
Any 
Yes or 
No 
progressive 
disease 
progressive 
disease 
1. *Target lesions include up to 5 measurable lesions (2 per organ) as deﬁned by RECIST v1.1. 
2. †Nontarget lesions include ascites and peritoneal thickening which are not measurable according to 
RECIST v1.1. 
3. ‡Patients who have a CA-125 response that occurs more than 28 days from PD according to 
RECIST v1.1 are considered a PR, according to best response, but PD if the RECIST v1.1 PD is 
within 28 days of CA-125 response. 
4. §The protocol should specify the minimum time interval between 2 measurements for classiﬁcation as 
stable disease. NE, Not evaluated; NAE, not all evaluated. 
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APPENDIX 10. PROSTATE CANCER CLINICAL STUDIES WORKING 
GROUP 2 (PCWG2) CRITERIA TO GUIDE ASCRIBING 
DISEASE RESPONSE 
The table below is modified from the following reference:  
Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical studies for patients with 
progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate 
Cancer Clinical Trials Working Group. J Clin Oncol, 2008. 26(7): 1148-59. 
Variable 
PCWG2 (2007) 
PSA 
On this study serial PSA measurements will be done every 
8 weeks ± 7 days after the first dose of Pamiparib in the first 
year and every 9 weeks ± 7 days afterwards. Increases and 
decreases will be tracked in order to assess disease response. 
The PSA readings on its own will not be used to define 
progression in this protocol. PSA response and PSA 
progression will be defined according to the consensus 
guidelines of the PCWG 2: 
• PSA partial response is defined as a ≥ 50% decline in 
PSA from Cycle 1 Day 1 (baseline) PSA value. This PSA 
decline much be confirmed to be sustained by a second 
PSA value obtained 4 or more weeks later. 
• PSA progression date is defined as the date that a ≥ 25% 
increase and an absolute increase of ≥ 2 ng/mL above the 
nadir is documented, which is confirmed by a second 
consecutive value obtained 4 or more weeks later. The 
first PSA reading will be obtained at week 12. 
 
Duration of PSA Response: 
Duration of PSA response is calculated from the time the 
PSA value first declines by at least 50% of the Cycle 1 Day 1 
(baseline) value that has been confirmed by a second value 
until the time there is an increase of 25% of PSA nadir, 
provided the absolute increase is at least 2 ng/mL. The 
increase must be confirmed by a second consecutive 
measurement that is at least 25% above the nadir. If the PSA 
never shows a 25% increase over the nadir value, then the 
patient will be assessed at the last PSA measurement. 
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Target Lesions 
Nodal or visceral progression sufficient for study entry 
independent of PSA measurable lesions not required for entry. 
Use RECIST to record soft-tissue (nodal and visceral) lesions 
as target or non-target. 
Only lymph nodes ≥ 2 cm in diameter should be used to assess 
for a change in size. 
Record presence of nodal and/or visceral disease separately. 
Progression at any scheduled reassessment  12 weeks does 
not need to be confirmed. 
Bone 
≥ 2 new lesions at the first scheduled reassessment  13 weeks 
from Cycle 1 Day 1 compared with baseline must be 
confirmed by a second scan performed 6 or more weeks later.  
Confirmatory scans should show an additional 2 new lesions 
compared to the first post-treatment scan (i.e. a total of 
≥ 4 new lesions compared with the baseline bone scan).  
Confirm ambiguous results by other imaging modalities (e.g., 
CT or MRI).  
Investigators are highly encouraged to maintain the patient’s 
treatment with study medication unless progression is 
confirmed. 
≥ 2 new lesions at the first scheduled reassessment > 13 weeks 
from Cycle 1 Day 1 compared with baseline must be 
confirmed by a second scan performed 6 or more weeks later.  
Confirmatory scans should confirm the presence of the 2 new 
lesions compared to the baseline scan. (i.e. a total of ≥ 2 new 
lesions compared with the baseline bone scan).  
Confirm ambiguous results by other imaging modalities (e.g., 
CT or MRI).  
Investigators are highly encouraged to maintain the patient’s 
treatment with study medication unless progression is 
confirmed. 
CT: computed tomography; MRI: magnetic resonance imaging; PCWG2: Prostate Cancer Clinical Trials Working 
Group 2;  
PET: positron emission tomography; PSA: prostate-specific antigen; PSA-DT: PSA doubling-time;  
RECIST: Response Evaluation Criteria in Solid Tumors 
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APPENDIX 11. SIGNATURE OF INVESTIGATOR 
 
Protocol Title: 
A Phase 1b Study to Assess the Safety, Tolerability, and Clinical 
Activity of BGB-290 in Combination with Temozolomide (TMZ) 
in Subjects with Locally Advanced or Metastatic Solid Tumors 
Protocol Number: 
BGB-290-103 
 
This protocol is a confidential communication of BeiGene, Ltd., and its subsidiaries. I confirm 
that I have read this protocol, I understand it, and I will work according to this protocol and the 
terms of the clinical study agreement governing the study. I will also work consistently with the 
ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
good clinical practices and the applicable laws and regulations. Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from BeiGene, Ltd., or one of its subsidiaries. 
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator: 
_______________________________ Date: _____________ 
Printed Name: 
_______________________________ 
Investigator Title: 
_______________________________ 
Name/Address of Center: 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
 
_______________________________ 
Instructions for Investigator: Please SIGN and DATE this signature page prior to 
implementation of this sponsor-approved protocol. PRINT your name, title, and the name and 
address of the center in which the study will be conducted. 
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Clinical Study Report (Final Database Lock Date (Data Extraction Date): 16 May 2023) 
BeiGene 
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16.1.9 
DOCUMENTATION OF STATISTICAL METHODS 


 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-290-103 
Study Protocol 
Title: 
A Phase 1b Study to Assess the Safety, Tolerability, and Clinical Activity of 
BGB-290 in Combination with Temozolomide (TMZ) in Subjects with Locally 
Advanced or Metastatic Solid Tumors 
 
Date: 
January 27, 2021 
Version: 
2.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
1 
INTRODUCTION 
6 
2 
FOR THESE ANALYSES AND WILL BE ATTACHED TO THE CLINICAL 
STUDY REPORT STUDY OVERVIEW 
6 
3 
STUDY OBJECTIVES 
7 
3.1 
Primary Objective 
7 
3.2 
Secondary Objectives 
7 
3.3 
Exploratory Objectives 
7 
4 
STUDY ENDPOINTS 
7 
4.1 
Primary Endpoints 
7 
4.2 
Secondary Endpoints 
8 
4.3 
Exploratory Endpoints 
8 
5 
SAMPLE SIZE CONSIDERATIONS 
8 
6 
STATISTICAL METHODS 
9 
6.1 
Analysis Populations 
9 
6.2 
Data Analysis General Considerations 
9 
6.2.1 
Definitions and Computations 
9 
6.2.2 
Conventions 
10 
6.2.3 
Handling of Missing Data 
10 
6.2.4 
Multiplicity Adjustment 
11 
6.2.5 
Patient Disposition 
11 
6.2.6 
Protocol Deviations 
11 
6.2.7 
Demographics and Other Baseline Characteristics 
12 
6.2.8 
Disease History 
12 
6.2.9 
Prior Anti-Cancer Systemic Therapies 
12 
6.2.10 
Prior and Concomitant Medications 
12 
6.2.11 
Medical History 
13 
6.3 
Efficacy Analysis 
13 
6.3.1 
Primary Efficacy Endpoints 
13 
6.3.2 
Secondary Efficacy Endpoints 
14 
6.3.3 
Subgroup Analyses 
15 
6.3.4 
CA-125 Assessment 
15 
6.3.5 
PSA Assessment 
15 
6.3.6 
Pharmacokinetic Endpoints 
15 
6.3.7 
Exploratory Endpoints 
16 
6.4 
Safety Analyses 
16 
6.4.1 
Extent of Exposure 
16 
6.4.2 
Dose Limiting Toxicity 
17 
6.4.3 
Adverse Events 
17 
6.4.4 
Laboratory Values 
18 
6.4.5 
Vital Signs 
18 
6.4.6 
Electrocardiograms 
19 
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6.4.7 
ECOG Performance Status 
19 
7 
INTERIM ANALYSIS 
19 
8 
CHANGES IN THE PLANNED ANALYSIS 
19 
9 
REFERENCES 
20 
10 
APPENDICES 
21 
10.1 
Handling Missing Date Information 
21 
10.2 
Censoring Rules 
24 
 
 
Tables 
Table 1 Estimated Objective Response Rate and 90% Confidence Interval for 20-25 
Patients 
8 
Table 2  Serum Chemistry and Hematology Laboratory Tests 
18 
 
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
AUC 
area under the plasma concentration-time curve (drug exposure) 
AUC0-12 
area under the plasma concentration-time curve from 0 to 12 hours postdose 
BGB-290    
pamiparib 
CI 
confidence interval 
CKD-EPI 
Chronic Kidney Epidemiology Collaboration 
CR 
complete response 
CSR 
clinical study report 
CT 
computed tomography 
CTC 
circulating tumor cell 
CTC-HRD-negative 
or CTC-HRD- 
circulating tumor cells negative for homologous recombination deficiency per Epic 
Sciences assay 
CTC-HRD-positive 
or CTC-HRD+ 
circulating tumor cells positive for homologous recombination deficiency per Epic 
Sciences assay 
CYP 
cytochrome P450 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
End-of-Treatment (Visit) 
FDG 
fluorine-18 [F-18]fluorodeoxyglucose 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HRD 
homologous recombination deficiency 
IC50 
half-maximal inhibition concentration 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IRC 
Independent Review Committee 
mCRPC 
metastatic castration-resistant prostate cancer 
MDRD STUDY EQ 
Modification of Diet in Renal Disease study equation 
MDS 
myelodysplastic syndrome 
MRI 
magnetic resonance imaging 
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Abbreviation 
Definition 
NCI-CTCAE 
National Cancer Institute-Common Terminology Criteria for Adverse Events 
NE 
not evaluable 
ORR 
objective response rate 
OS 
overall survival 
PAR 
poly (ADP-ribose) 
PARP 
poly (ADP-ribose) polymerase 
PCWG3 
Prostate Cancer Clinical Trials Working Group 3 
PD 
progressive disease 
PET 
positron-emission tomography 
PK 
pharmacokinetic 
PR 
partial response 
PSA 
prostate-specific antigen 
QTcF 
QT interval with Fridericia's correction 
RECIST 
Response Evaluation Criteria in Solid Tumors 
rPFS 
radiographic progression-free survival 
SAE 
serious adverse event 
SD 
stable disease 
TEAE 
treatment-emergent adverse event 
TMZ 
Temozolomide 
ULN 
upper limit of normal 
US or USA 
United States or United States of America 
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1 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze the efficacy and safety endpoints for protocol BGB-290-103: 
A Phase 1b Study to Assess the Safety, Tolerability, and Clinical Activity of BGB-290 in 
combination with Temozolomide (TMZ) in Subjects with Locally Advanced or Metastatic Solid 
Tumors. The focus of this SAP is for the planned primary, secondary and exploratory efficacy 
and safety analyses. 
 
The analysis details for Pharmacokinetic (PK), Pharmacodynamics, Pharmacogenomics, and 
Biomarker analyses may not be fully described within this SAP. Separate analysis plans may be 
provided if applicable. 
 
2 
FOR THESE ANALYSES AND WILL BE ATTACHED TO THE 
CLINICAL STUDY REPORT STUDY OVERVIEW 
This is an open-label, multi-center Phase 1b study to evaluate the combined use of pamiparib 
(also known as BGB-290), a poly (ADP-ribose) polymerase, e.g., PARP, inhibitor, with a 
deoxyribonucleic acid (DNA)-alkylating agent, TMZ, in subjects with locally advanced and 
metastatic solid tumors. The study consists of two phases, a dose escalation phase and a dose 
expansion phase. The dose escalation phase of the study will evaluate the safety, tolerability, 
preliminary efficacy, and PK in addition to determining the maximum tolerated dose (MTD) 
and/or maximum administered dose (MAD) for the combination. In the dose expansion phase of 
this study, the safety, preliminary efficacy and PK profile of the combination will be evaluated 
further. Preliminary biomarkers for efficacy will also be explored through both phases of the 
study. 
 
Dose Escalation: 
The dose escalation phase of the study consists of a modified 3+3 dose escalation scheme 
utilizing a fixed dose of BGB-290 in combination with escalating doses of TMZ. The following 
two arms were planned to undergo dose escalation independently:  
 
• Arm A: TMZ will be administered once a day during Days 1 to 7 of each 28-day cycle 
(pulse dosing of TMZ)  
• Arm B: TMZ will be administered once a day continuously during each 28-day cycle 
(continuous dosing of TMZ) 
 
Dose Expansion: 
The dose expansion phase of the study will further evaluate the safety and anti-tumor activity of 
BGB-290 in combination with TMZ at the dose and schedule that will be chosen based on all 
data available including the dose escalation phase. This dose expansion phase will enroll patients 
in 6 different cohorts according to indication and/or homologous recombination deficiency 
(HRD) status as follows:  
 
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• Cohort 1: HRD positive (HRD+) ovarian cancer;  
• Cohort 2: HRD+ triple-negative breast cancer (TNBC);  
• Cohort 3: HRD+ metastatic castration-resistant prostate cancer (mCRPC);  
• Cohort 4: Extensive Stage Small Cell Lung Cancer;  
• Cohort 5: Gastric/Gastroesophageal Junction Cancer; and  
• 
Cohort 6: patients who have HRD+ nonsquamous non-small cell lung cancer (NSCLC), 
squamous NSCLC, esophageal cancer, squamous head and neck cancer or soft-tissue 
sarcomas. Enrollment into these cohorts will occur simultaneously and independently. 
 
For the interim clinical study report (CSR), only cohort 1 to 5 will be included. All cohorts will 
be included in the final CSR. 
 
3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVE  
• To determine the safety and tolerability of pamiparib (also known as BGB-290) when 
given orally in combination with temozolomide (TMZ) (pulsed and continuous) 
• To determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) 
for pamiparib combined with TMZ (pulsed and continuous) 
• To select the recommended Phase 2 dose (RP2D) and schedule of pamiparib in 
combination with TMZ 
• To determine the preliminary antitumor activity of pamiparib in combination with TMZ 
3.2 
SECONDARY OBJECTIVES  
• To characterize the PK of BGB-290 and TMZ 
3.3 
EXPLORATORY OBJECTIVES 
• To evaluate candidate biomarkers in tumor tissue and in peripheral circulation as 
potential makers of response, resistance, or disease progression 
 
4 
STUDY ENDPOINTS 
4.1 
PRIMARY ENDPOINTS 
• Escalation: Incidence and nature of DLTs 
• Escalation and Expansion: Incidence, nature, and severity of AEs, graded according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCICTCAE) v.4.03 and  
• Objective response rate (ORR), as assessed using RECIST v1.1 
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4.2 
SECONDARY ENDPOINTS 
• Pharmacokinetic parameters of BGB-290 and TMZ, including but not limited to Ctrough 
• Time-to event- endpoints: e.g., duration of response (DOR), disease control rate (DCR), 
progression-free survival (PFS), and overall survival (OS) 
4.3 
EXPLORATORY ENDPOINTS 
• Candidate predictive biomarkers, including, but not limited to, expression and mutations 
of genes in the DNA damage response pathway, and relationship to efficacy and 
resistance 
5 
SAMPLE SIZE CONSIDERATIONS 
It is expected that approximately 250 patients will be enrolled in the entire study.  
 
• 
Dose Escalation Phase: Approximately 50 patients may be enrolled. More patients may be 
enrolled if additional doses/schedules are to be evaluated based on emerging data. 
 
• 
Dose Expansion Phase: Approximately 200 patients in total will be treated in 6 cohorts. 
Each cohort will enroll approximately 20-25 patients each and will be evaluated 
separately. Cohorts can be closed due to futility or clinical efficacy based on statistical 
evaluation or due to insufficient patient recruitment. Cohorts can be also further 
expanded based on emerging data.  
 
A sample size of 20-25 patients in an expansion cohort will provide the half width of the 
90% confidence interval of the ORR approximately 13% to 20% when the observed ORR 
is approximately 40%. Hence, the low bound is above 20%. This is considered adequate 
in the preliminary assessment of anticancer activity of pamiparib and TMZ combination 
therapy. The following Table 1 gives the 90% confidence interval for estimated objective 
response rate between 36% to 41% for different sample sizes. 
 
Table 1 Estimated Objective Response Rate and 90% Confidence Interval for 20-25 
Patients 
Sample Size 
No. of 
Responders 
Response Rate 
90% Confidence Interval 
Lower Limit 
Upper Limit 
20 
8 
40% 
22% 
61% 
21 
8 
38% 
21% 
58% 
 
9 
43% 
24% 
63% 
22 
8 
36% 
20% 
56% 
 
9 
41% 
23% 
60% 
23 
9 
39% 
22% 
58% 
 
10 
43% 
26% 
62% 
24 
9 
38% 
21% 
56% 
 
10 
42% 
25% 
60% 
25 
10 
40% 
24% 
58% 
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6 
STATISTICAL METHODS 
No formal hypothesis testing will be conducted in this study. Data will be described mainly using 
descriptive statistics. Confidence intervals will be constructed to describe the precision of the 
point estimates of interest (e.g., objective response rate and disease control rate). Efficacy and 
safety analyses will be performed by dose escalation and dose expansion phases accordingly. 
Within dose escalation phase, data will be summarized by dose level within a dosing cohort or 
all combined. Within dose expansion phase, data will be summarized by cohort. 
6.1 
ANALYSIS POPULATIONS 
• Safety Analysis Set (SAF): includes all patients enrolled into the study who receive any 
dose of pamiparib and/or TMZ. The Safety Analysis Set will be used for overall survival 
analysis and safety analyses. 
• Efficacy-Evaluable Analysis Set: includes patients in the SAF who had evaluable disease 
in the dose escalation phase (or measurable disease in the dose expansion phase) at 
baseline and had at least one postbaseline tumor assessment unless discontinued 
treatment due to clinical progression or death prior to tumor assessment.  
Evaluable disease means patients may have measurable (target lesions) or non-
measurable lesions (non-target lesions); measurable disease means patients must have at 
least 1 measurable lesion (target lesions) and may or may not have non measurable 
lesions (non-target lesions). 
• DLT Evaluable Analysis Set: includes patients who received ≥ 70% of BGB-290 and 
TMZ during the DLT assessment window (Cycle 1). Additionally, patients who had a 
DLT event during the DLT assessment window despite receiving < 70% of the scheduled 
dose will also be included. 
• PK Analysis Set: includes patients who received any dose of BGB-290 or TMZ, and 
contributed at least one plasma concentration.   
6.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
6.2.1 
Definitions and Computations 
Study day: Study day will be calculated in reference to the date of the first combination treatment 
of BGB-290 and TMZ (e.g., Cycle 1 Day 1). For assessments conducted on or after the date of 
the first combination treatment, study day will be calculated as (assessment date – date of first 
dose of combination treatment + 1). For BGB-290 PK intensive group, BGB-290 is administered 
starting from 2 days prior to Cycle 1 Day 1 and noted as Study Day -2. For this group, study day 
will still be calculated from Cycle 1 Day 1 when both BGB-290 and TMZ are administered. 
There is no study day 0. 
 
In the situation where the event date is partial or missing, the date will appear partial or missing 
in the listings. Study day and any corresponding durations will be presented based on the 
imputations specified in Appendix 10.1.   
 
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Treatment duration: The treatment duration will be calculated per different dosing scheme of 
BGB-290 and TMZ. Refer to Section 0for more detail. 
Treatment-emergent period: The treatment-emergent period is defined as the period of time from 
the date of the first dose of either pamiparib or TMZ through 30 days after the last dose of 
pamiparib (permanent discontinuation of pamiparib) or initiation of new anti-cancer therapy. The 
treatment-emergent period will be used in the summaries of treatment-emergent adverse events 
(TEAEs) and concomitant medications.  
 
TEAE: An AE started or worsened during the treatment-emergent period. Treatment-related 
SAEs occurred after treatment-emergent period will also be counted as TEAEs. 
 
Baseline: Unless otherwise specified, a baseline value is defined as the last non-missing value 
collected before or on the date of first dose of any treatment.  
All calculations and analyses will be conducted using SAS version 9.4 or higher. 
6.2.2 
Conventions 
Unless otherwise specified, the following conventions will be applied to all analyses:   
 
• 1 year = 365.25 days. Number of years is calculated as (days/365.25) rounded up to 1 
decimal place.   
• 1 month = 30.4375 days. Number of months is calculated as (days/30.4375) rounded up 
to 1 decimal place.   
• P-values will be rounded to 4 decimal places.  P-values that round to 0.0000 will be 
presented as ‘< 0.0001’ and p-values that round to 1.000 will be presented as ‘> 0.9999’.   
• Duration of imaging-based event endpoints (such as PFS) will be based on the actual date 
the radiograph was obtained rather than the associated visit date.   
• Missing efficacy or safety data will not be imputed unless otherwise specified.   
• For laboratory results collected as < or >, a numeric value, 0.0000000001 will be 
subtracted or added, respectively, to the value.   
• For by-visit observed data analyses, percentages will be calculated based on the number 
of patients with nonmissing data as the denominator, unless otherwise specified.   
• For continuous endpoints, summary statistics will include n, mean, standard deviation, 
median, Q1, Q3 and range (minimum and maximum).  For PK analysis, both geometric 
mean and geometric CV will be included. 
• For discrete endpoints, summary statistics will include frequencies and percentages. 
6.2.3 
Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in the SAP. Missing dates 
or partially missing dates will be imputed conservatively for adverse events and 
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prior/concomitant medications/procedures.  Specific rules for handling of missing or partially 
missing dates for adverse events and prior/concomitant medications/procedures are provided in 
Appendix 10.1. 
By-visit endpoints will be analyzed using observed data, unless otherwise specified. For 
observed data analyses, missing data will not be imputed and only the observed records will be 
included.  
When summarizing categorical variables, patients with missing data are included in the 
denominator to calculate percentages unless otherwise specified. When needed, the category of 
“Missing” is created and the number of patients with missing data is presented. 
When summarizing continuous variables, patients with missing data are not included in 
calculations. No imputations are made. 
6.2.4 
Multiplicity Adjustment 
No multiplicity adjustments will be made in this study. Two-sided 90% confidence interval (CI) 
will be used to describe the precision of the rate estimate whenever appropriate.  
6.2.5 
Patient Disposition 
The following patient disposition information will be summarized: 
• Number of patients treated 
• Number (%) of treated patients who discontinued from treatment  
• Reason(s) for treatment discontinuation 
• Number (%) of treated patients who discontinued from study 
• Reason(s) for study discontinuation 
• Number (%) of treated patients who remain in study 
• Study follow-up time: defined as the time from the first dose date to death date or end of 
study date (whichever occurred first) for patients who discontinued study or the data 
cutoff date for ongoing patient 
 
6.2.6 
Protocol Deviations 
Major protocol deviation criteria will be established and patients with major protocol deviations 
will be identified and documented before the database lock. Major protocol deviations will be 
summarized for the SAF. Also a listing of Covid-19 related protocol deviations will be 
summarized if applicable. 
 
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6.2.7 
Demographics and Other Baseline Characteristics 
Demographics and baseline characteristics including following variables will be summarized 
using descriptive statistics:  
• Age (years) and age group (years) as < 65, ≥ 65  
• Gender 
• Race 
• Baseline Eastern Cooperative Oncology Group (ECOG) performance status  
• Ethnicity 
• Tobacco use 
• Height 
• Weight 
 
6.2.8 
Disease History 
The number (percentage) of subjects reporting a history of disease and characteristic, as recorded 
on the eCRF, will be summarized in the SAF. Disease characteristics include time from initial 
diagnosis to study entry, type of solid tumor (if applicable), locations of metastases, MSI-H 
mutation, hormone status, tumor histology/cytology, Germline BRCA mutation, somatic BRCA 
mutation and HRD status.  
 
A subject data listing of disease history will be provided.  
 
6.2.9 
Prior Anti-Cancer Systemic Therapies  
The number of patients with prior anticancer surgeries, prior systemic therapies, prior radiation 
therapies will be summarized by cohort and all patients for the SAF. The therapies and surgeries 
with the same sequence/regimen number are counted as one prior therapy/surgery.   
A subject data listing of prior anticancer drug therapies, prior anticancer surgeries and prior 
radiation therapies will be provided. 
 
6.2.10 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the version of World Health Organization 
Drug Dictionary (WHO DD) drug codes currently in effect at BeiGene at the time of database 
lock and will be further classified to the appropriate Anatomical Therapeutic Chemical (ATC) 
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The number and percentage of patients reporting prior and concomitant medications will be 
summarized by ATC medication class and WHO DD preferred term for the Safety Analysis Set 
by cohort and overall. Prior medications are defined as medications that started and ended before 
the first dose date. Concomitant medications will be defined as medications that (1) started 
before the first dose of study treatment and were continuing at the time of the first dose of study 
treatment, or (2) started on or after the date of the first dose of study treatment up to 30 days after 
the patient’s last dose of pamiparib or initiation of a new anticancer therapy. A listing of prior 
and concomitant medications will be provided.   
6.2.11 
Medical History 
Medical History will be coded using MedDRA (version 23.0). The number and percentage of 
patients reporting a history of any medical condition, as recorded on the CRF, will be 
summarized by system organ class (SOC) and preferred term (PT) for the Safety Analysis Set by 
cohort and overall. A listing of medical history will be provided.   
 
6.3 
EFFICACY ANALYSIS 
6.3.1 
Primary Efficacy Endpoints 
Escalation:  
• Dose-limiting toxicity in the DLT evaluation period will be used to determine the dose 
and schedule of pamiparib plus TMZ in the expansion cohorts. The DLT events will be 
listed for patients in the DLT Evaluable Analysis Set. 
 
All phases:  
• Incidence, nature, and severity of AEs will be summarized. Refer to Section 6.4.3 for 
more detail. The outputs for AEs will be summarized in SAF. 
• Overall Response Rate (ORR) by investigator 
Tumor status evaluation including response and progression will be assessed using 
RECIST v1.1 by investigator throughout this study. This criterion will be used to 
calculate rumor assessment endpoints including ORR, DCR, DOR and PFS.  
 
            ORR is defined as the proportion of subjects who have a best overall response (BOR) of  
complete response (CR) or partial response (PR), where BOR is defined as the best 
response recorded from the first postbaseline tumor assessment until data cutoff date, 
disease progression or start of new anticancer treatment. For a confirmed ORR, 
confirmation of CR or PR at next tumor scan (at least 4 weeks from initial documentation) 
is required. 
 
Two-sided binomial exact 90% confidence intervals (CI) of ORR will also be constructed 
for the statistical inference of the point estimate in each cohort.   
 
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Tables for confirmed and nonconfirmed ORR will be summarized in Efficacy Evaluable 
Analysis Set. In addition, a listing of the tumor assessment data in SAF will also be 
provided. Patients without evaluable postbaseline tumor assessment will be considered as 
non-responders in the safety analysis set. Maximum tumor shrinkage per patient will be 
presented in waterfall plots. 
 
6.3.2 
Secondary Efficacy Endpoints 
• Pharmacokinetic parameters of BGB-290 and TMZ, including but not limited to Ctrough 
Refer to Section 6.3.6 for more detail. 
 
• Disease Control Rate (DCR) by investigator 
 
DCR is defined as the proportion of subjects with BOR of CR, PR, or stable disease (SD). 
Similar to ORR, two-sided binomial exact 90% confidence intervals will be calculated 
for DCR in each cohort. The table for DCR will be summarized in both SAF and Efficacy 
Evaluable Analysis Set. Patients without evaluable postbaseline tumor assessment will be 
considered as non-responders in the safety analysis set. 
 
• Duration of Response (DOR) by investigator 
 
DOR is defined as the time (month) from the date of the earliest documented CR or PR 
(that is subsequently confirmed) to disease progression or death due to any cause, 
whichever occurs earlier. The tables for confirmed and nonconfirmed DOR will be 
summarized in efficacy evaluable set and only responders will be included in the DOR 
calculation.  
Kaplan-Meier method will be used to estimate DOR, and corresponding quartiles 
(including the median) in the responders. A two-sided 90% CIs of median will be 
calculated for each cohorts using generalized Brookmeyer and Crowley method 
(Brookmeyer & Crowley, 1982). 
 
Censoring rule for DOR will follow PFS censoring rule mentioned in FDA Guidance for 
Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2018). 
The censoring rules are described in Appendix 10.2. 
• PFS and PFS-6m by investigator 
 
PFS is defined as the time (months) from the date of the first dose of combination 
treatment to disease progression or death due to any cause, whichever occurs first. The 
PFS-6m is defined as the percentages of subjects who remain alive and progression-free 
at 6 months. PFS censoring rules are described in Appendix 10.2. If a patient meets the 
criteria for more than 1 censoring rule, PFS will be censored at the earliest censoring date. 
The tables for PFS and PFS-6m will be summarized in Efficacy Evaluable Analysis Set. 
 
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Kaplan-Meier method will be used to estimate PFS and PFS-6m, and corresponding 
quartiles (including the median) in the responders. A two-sided 90% CIs of median, Q1 
and Q3 will be calculated for each cohorts using generalized Brookmeyer and Crowley 
method (Brookmeyer & Crowley, 1982). Event free rate at the specified time point (e.g., 3, 
6, 9 or 12 months) will be estimated using the Kaplan-Meier method along with the 
corresponding 90% CI constructed using Greenwood’s formula. 
• OS and OS-6m 
OS is defined as the time (months) from the date of the first dose of combination 
treatment to death due to any cause. Deaths that occur on or before the data cutoff date 
will be considered as an event. Data from patients who are alive on or before the data 
cutoff date will be censored at the last known alive date. The OS-6m is defined as the 
percentages of subjects in the analysis population who remain alive and progression-free 
at 6 months. The tables for OS and OS-6m will be summarized in SAF. 
 
Kaplan-Meier method will be used to estimate OS and OS-6m, and corresponding 
quartiles (including the median) in the responders. A two-sided 90% CIs of median, Q1 
and Q3 will be calculated for each cohorts using generalized Brookmeyer and Crowley 
method (Brookmeyer & Crowley, 1982). Event free rate at the specified time point (e.g., 3, 
6, 9 or 12 months) will be estimated using the Kaplan-Meier method along with the 
corresponding 90% CI constructed using Greenwood’s formula. 
 
6.3.3 
Subgroup Analyses 
ORR and DCR will be summarized for patients with SCLC in the expansion stage in subgroups 
of  
•  chemosensitivity 
•  number of prior regimens for advanced or metastatic disease (1, ≥ 2) 
 
6.3.4 
CA-125 Assessment 
For subjects with ovarian cancer, the CA-125 assessment result including elevated/normal and 
change from baseline (%) will be provided for each patient in a listing in SAF. 
 
6.3.5 
PSA Assessment 
For subjects with prostate cancer, PSA will be evaluated. The PSA assessment result including 
change from baseline and nadir (%) will be provided for each patient in a listing in SAF. 
 
6.3.6 
Pharmacokinetic Endpoints 
For subjects in BGB-290 PK intensive group who contributed full PK profiles up to 48 hours 
postdose of Cycle 1 Day 1, and up to 6 hours on Cycle 1 Day 15, the following PK parameters 
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will be derived: Cmax, C2h, Tmax, T1/2, AUC0-4h, AUC0-inf (Day 1), AUClast, apparent clearance 
CL/F, and Vz/F (Day 1). 
 
For the remaining subjects, PK parameters such as Cmin will be summarized. Population PK 
analysis may be carried out to include plasma concentrations from this study in an existing 
model, and additional PK parameters such as apparent clearance of the drug from plasma (CL/F) 
and AUC may be derived if supported by data. Population PK analysis may be reported 
separately from the final CSR. 
 
Trough and/or peak plasma concentrations of TMZ will be summarized and compared with 
appropriate historical control. 
 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by 
data. 
 
A summary of concentration for pamiparib (sparse and intensive sampling separately) and TMZ, 
and PK parameters for pamiparib, listings for concentration (pamiparib and TMZ separately) and 
parameters for pamiparib and figures of concentration vs time for intensive pamiparib PK 
sampling will be provided. 
 
6.3.7 
Exploratory Endpoints 
Exploratory endpoints include blood and tumor biomarkers will be analyzed using the SAF. The 
correlation of predictive biomarkers with efficacy endpoints for study treatment will be explored. 
 
6.4 
SAFETY ANALYSES 
All safety analyses will be performed by dose level in dose escalation phase and by cohort in 
dose expansion phase and by total (dose escalation and expansion phases combined). Safety will 
be assessed by monitoring and recording of all AEs graded by CTCAE v4.03. Laboratory values 
(hematology, serum chemistry, coagulation, and urinalysis), vital signs, physical exams and 
ECGs findings will also be used in determining the safety.  Patients in SAF will be included for 
safety analyses. 
 
6.4.1 
Extent of Exposure 
Extent of exposure to study drug will be summarized descriptively as the duration of exposure 
(months), cumulative total dose received per subject (mg), actual dose intensity (mg/day), 
relative dose intensity (%), dose reduction, dose interruption, and dose missed per patient. 
 
Duration of exposure (months) is determined for each patient and study medication based on 
dosing schedule. For daily dosing of both BGB-290 and TMZ, it will be calculated as (date of 
last dose – date of first dose + 1)/30.4375. For the dosing schedule of TMZ administered 7 days 
a cycle, it will be calculated as (date of last dose – date of first dose + 22)/30.4375. For the 
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dosing schedule of TMZ administered 14 days a cycle, it will be calculated as (date of last 
dose – date of first dose + 15)/30.4375. 
Dose intensity per subject is defined for each study medication as sum of actual dose received 
divided by duration of treatment. Relative dose intensity is defined as total actual dose received 
divided by total planned dose.  
 
The number (percentage) of patients who had missed doses, dose reductions and dose 
interruptions summarized. Frequency of reductions and dose interruptions 
will be summarized by categories (1, 2, 3, ≥4). 
 
Subject data listings will be provided for all dosing records and for calculated summary statistics. 
 
6.4.2 
Dose Limiting Toxicity 
Dose-limiting toxicity in the DLT evaluation period will be used to determine the dose and 
schedule of BGB-290 plus TMZ in the expansion cohorts. DLTs will be taken from the adverse 
event eCRF. Number and percentage of patients with DLT events will be listed at each 
combination dosing level in the DLT evaluable analysis set.   
 
6.4.3 
Adverse Events 
The AE verbatim descriptions (investigator terms from the eCRF) will be classified into 
standardized medical terminology using Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events will be coded to MedDRA (Version 23.0) lower level term closest to 
the verbatim term. The linked MedDRA preferred term (PT) and primary system organ class 
(SOC) are also captured in the database. 
 
A treatment emergent adverse event (TEAE) is defined as an AE that had an onset date or 
worsened during the treatment-emergent period (refer to Section 6.2.1). Treatment-related SAEs 
occurred after treatment-emergent period will also be counted as TEAEs. Only those AEs that 
were treatment emergent will be included in summary tables. All AEs, treatment emergent or 
otherwise, will be presented in subject data listings. 
 
An overview table, including the incidence of and the number of subjects with TEAEs, 
treatment-emergent serious adverse events (SAEs), treatment-related TEAEs, TEAEs with grade 
3 or above, and treatment-related SAEs will be provided. Treatment-related AEs include those 
events considered by the investigator to be possibly or probably related to study drug or with 
missing assessment of the causal relationship. 
 
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs by 
SOC, PT and CTCAE grade. A subject will be counted only once by the highest severity grade 
according to CTCAE v.4.03 within an SOC and PT, even if the subject experienced more than 1 
TEAE within a specific SOC and PT. 
 
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The number (percentage) of subjects with treatment-emergent SAEs, treatment-related TEAEs, 
TEAEs with grade 3 or above, and treatment-related SAEs will be summarized by SOC, PT and 
CTCAE grade. TEAEs with grade 3 or above will also be summarized by PT in descending order. 
Incidence of TEAEs of interest will be summarized by SOC and PT. TEAEs of interest, if 
needed, will be defined before database lock. 
 
Subject data listings of all AEs, SAEs, treatment-related AEs, grade 3 or above AEs, AEs that 
led to death and AEs that led to treatment discontinuation, dose reduction or dose interruption 
will be provided. 
 
6.4.4 
Laboratory Values 
Laboratory safety tests will be evaluated for selected parameters. 
Laboratory parameters listed in Table 2 will be graded in NCI CTCAE v4.03. A shift table 
(baseline grade to maximum grade after dosing on Cycle 1 Day 1) will be provided for 
hemoglobin, platelet count, white blood cell count, neutrophil and lymphocyte. Patient data 
listings of selected hematology and serum chemistry parameters, urinalysis and coagulation will 
be provided.   
Table 2  Serum Chemistry and Hematology Laboratory Tests 
Serum Chemistry 
Hematology 
Alkaline phosphatase (ALP) 
Hemoglobin 
Alanine aminotransferase (ALT) 
Platelet counts 
Aspartate aminotransferase (AST) 
White blood cell (WBC) count 
Albumin 
Neutrophil (Absolute) 
Total bilirubin 
Blood Urea Nitrogen 
Lymphocyte (Absolute) 
Monocyte (Absolute) 
Creatinine 
Sodium 
Basophil (Absolute) 
Eosinophil (Absolute) 
Phosphate 
 
Glucose 
 
Lactate dehydrogenase 
 
Total Protein 
 
Potassium 
 
6.4.5 
Vital Signs 
Vital sign parameters (systolic and diastolic blood pressure [BP], temperature, height and weight) 
will be listed by subjects and visits. 
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6.4.6 
Electrocardiograms 
During the BGB-290 PK intensive period (Day -2) and cycle 1, ECGs will be performed in 
triplicate on a machine provided by the sponsor. ECG findings at baseline, postbaseline will be 
listed by visit and/or time point. In addition, single ECG and abnormal QT interval with 
Fridericia's correction (QTcF) derived from triplicate ECG will also be listed. 
6.4.7 
ECOG Performance Status 
ECOG scores and change from baseline will be listed by visit for the SAF. 
 
7 
INTERIM ANALYSIS 
In dose escalation phase, before the dose is escalated to the next level, the safety review team 
will review the safety data to determine the next dose level. The recommended dose for dose 
expansion phase will be determined by the safety review team before the dose expansion phase. 
Interim CSR may be conducted for the purpose of safety and/or efficacy review. 
 
8 
CHANGES IN THE PLANNED ANALYSIS 
There are some changed in the planned analysis and they are listed below:  
• DLT will be provided in a listing and no descriptive statistics will be provided. 
• Subgroup analysis for ORR will only be done for SCLC patients in chemosensitivity and 
number of prior regimens. 
• All by-visit analyses will be removed, and the following will be performed: hematology 
data will be presented in a shift table and serum chemistry will be provided in a listing. 
ECG will be listed. A listing of QTcF will be provided for patients with abnormal 
postbaseline values and abnormal changes from baseline. ECOG and vital signs will be 
provided in listings. 
• Ninety percent CIs will be presented instead of 95% CIs. 
• OS analyses will be conducted in SAF instead of Efficacy Evaluable Analysis Set. Only 
PFS and OS analyses will be conducted and not PFS-6m and OS-6m analyses.  
• Efficacy analyses such as ORR, PFS and DOR will be based on radiographic responses 
or radiographic progression. 
• Treatment-emergent SAEs, treatment-related TEAEs, TEAEs with grade 3 or above, and 
treatment-related SAEs will be summarized by SOC, PT and CTCAE grade. AEs that led 
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to death and AEs that led to treatment discontinuation, dose reduction or dose 
interruption will only be listed. 
• Number of treatment cycles will not be summarized. Instead, reasons for dose reduction, 
dose interruption and missed dose will be summarized. 
 
9 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time, Biometrics 1982; 
38(1): 29-41. 
 
Eisenhauer EA, Therasse P, Bogaerts J Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009; 
45:228-47. 
 
Food and Drug Administration Center for Drug Evaluation Research CDER and Center for 
Biologics 
 
Evaluation and Research (2007). FDA Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics (2007). 
 
Kaplan E, Meier P. Nonparametric estimation from incomplete observations. Journal of 
American Statistical Association. 1958;53:457-81. 
 
Greenwood M. “The natural duration of cancer”. Reports on Public Health and Medical 
Subjects (London: Her Majesty’s Stationery Office). 1926; 33:1-26. 
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10 
APPENDICES 
10.1 
HANDLING MISSING DATE INFORMATION 
In general, missing or partial dates will not be imputed at data level. The following rules will 
apply for the specific analysis and summary purposes mentioned below only.   
10.1.1 Prior/Concomitant Medications, Disease and Medical History, Prior Therapy (Drug, 
Surgery/Procedure, Radiotherapy) 
When the start date or end date of a medication/therapy/procedure is partially missing, the date 
will be imputed to determine whether the medication/therapy/procedure is prior or concomitant. 
The following rules will be applied to impute missing or partial dates for medications 
/therapy/procedure: 
 
Missing 
Impute 
Exception 
Start Date 
Day 
01 
N/A 
 
Day/Month 
January 01 
N/A 
 
Day/Month/Year or 
Year only 
Do not impute 
N/A 
End Date 
Day 
Last day of the 
month 
N/A 
 
Day/Month 
December 31 
N/A 
 
Day/Month/Year or 
Year only 
Do not impute 
N/A 
 
If the imputed start date becomes after end date, then update start date same as end date. And if 
the imputed start date or end date becomes after death date, then set to death date. 
 
For disease history, medical history and prior therapy, including initial diagnosis date, therapy 
date (start/end date), or surgery date, if the imputed start date or end date becomes after first dose 
date, then set to first dose date - 1.  
 
 
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10.1.2 Initial Diagnosis and Most Recent Progression 
For initial diagnosis date and most recent progression date, which has no duration and only start 
date is available, impute the date using the following rule: 
 
 
Missing 
Impute 
Exception 
Initial Diagnosis Date/ 
Most Recent Progression 
Date 
Day 
01 
N/A 
Day/Month 
January 01 
N/A 
Day/Month/Year or 
Year only 
Do not impute 
N/A 
If the imputed initial diagnosis date or most recent progression date is on or after the treatment 
start date, then set to treatment start date - 1. 
10.1.3 Adverse Events 
The imputation rule for the safety analyses will be used to address the issues with partial dates. 
When the start date or end date of an adverse event is partially missing, the date will be imputed 
to determine whether the adverse event is treatment-emergent. When in doubt, the adverse event 
will be considered treatment emergent by default. The following rules will be applied to impute 
missing or partial dates for adverse events: 
 
Missing 
Impute 
Exception 
Start Date 
Day 
01 
If Month and Year 
= Month and Year 
of treatment start 
date, then set to 
treatment start date 
 
Day / Month 
January 01 
If Year = Year of 
treatment start date, 
then set to 
treatment start date 
 
Day / Month / Year 
or Year only 
Do not impute 
If AE End Date > 
treatment start date, 
then set to 
treatment start date   
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End Date 
Day 
Last day of the 
month 
N/A 
 
Day / Month 
December 31 
N/A 
 
Day / Month / Year 
or Year only 
Do not impute 
N/A 
If the imputed AE start date becomes after AE end date, then update AE start date same as AE 
end date. And if the imputed start date or end date becomes after death date, then set to death 
date. 
The following rule will be applied to impute missing toxicity grade of AE:   
1. The highest grade will be used from patient’s AEs with the same preferred term.   
2. If patient has no AEs with the same preferred terms, the highest grade of the AEs with the 
same SOC will be used. 
3. If patient has no same SOC, the highest grade of all AEs from that patient will be used.  
4. If it is the single AE reported for that patient, no imputation for the missing grade will be 
done. 
10.1.4 Deaths 
In case complete death dates are not recorded, impute as follows: 
• If year, month and day are all missing, then impute the death date as the last date of 
patient known to be alive + 1 for efficacy analyses, e.g., DOR, PFS and OS. 
• If both month and day are missing, then the imputed month and day will be 01Jan or the 
last date of the last date of patient known to be alive + 1, whichever is later. 
• If only day is missing, the death will be assumed to be on the first day of the month or the 
last date of patient known to be alive + 1, whichever is later.  
10.1.5 New Anticancer therapy 
If the start day of a subsequent anticancer therapy is incomplete or missing, impute as follows:  
• if both month and day are missing,  
1) impute the date as 31Dec, if the year is earlier than the year of the first PD date + 1 
or the treatment end date + 1, whichever is later 
2) impute the date as 01Jan, if the year is later than the year of the first PD date or the 
treatment end date + 1, whichever is later 
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3) impute the date as the first PD date + 1 or the treatment end date + 1, whichever is 
later, if the year is the same year of first PD date + 1 or the treatment end date + 1, 
whichever is later 
• if only day is missing, 
4) impute the date as the first day of the month if year and month are available and 
partial new anticancer therapy date still could indicate it is at least one month later 
than the first PD date +1 or the treatment end date +1, whichever is later.  
5) impute the date as the last day of the month if year and month are available and 
partial new anticancer therapy date still could indicate it is at least one month earlier 
than the first PD date +1 or the treatment end date +1, whichever is later. 
6) Impute the date as the first PD date +1 or the treatment end date +1, whichever is 
later, if the year and month are the same year and month of first PD date +1 or the 
treatment end date +1, whichever is later. 
• The treatment end date refers to the last dose date of pamiparib. 
10.2 
CENSORING RULES 
Table 3 shows the primary censoring rules for the derivation of PFS.   
Table 3 
Censoring Rules for Analysis of PFS 
No. Situation 
Date of Progression or Censoring 
Outcome 
1 
No baseline tumor assessments or no 
post baseline tumor assessment 
Reference start date (e.g., C1D1) 
Censored 
2 
Progression documented on scheduled 
visit or between scheduled visits 
Date of first radiologic PD 
assessment 
Progressed 
3 
No progression at the time of data cutoff 
or withdrawal from study 
Date of last adequate radiologic 
assessment prior to or on date of data 
cutoff or withdrawal from study 
Censored 
4 
Treatment discontinuation for 
undocumented progression 
Date of last radiological assessment 
of measured lesions 
Censored 
5 
New anticancer treatment started 
Date of last radiological assessment 
of measured lesions prior to or on 
date of new anticancer treatment 
Censored 
6 
Death before first PD assessment 
Date of death 
Progressed 
7 
Death between adequate assessment 
visits* 
Date of death 
Progressed 
8 
Death or PD after two or more 
consecutive missed visit** 
Date of last adequate radiologic 
assessment before missed tumor 
assessments 
Censored 
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BeiGene USA, Inc 
                       BGB-290-103 
              (Statistical Analysis Plan) 
 
 
Version 2.0:  01/27/2021 
Page 25 of 25  
CONFIDENTIAL 
 
9 
A patient meets the criteria for more than 
1 censoring rules above 
 
Date of the earliest censoring date 
among all events 
Censored 
Abbreviations: CR=complete response, PD=progressive disease, PR=partial response, SD=stable disease. 
*Adequate tumor assessment is a radiologic assessment of CR, PR, SD, non-CR/non-PD or PD as determined by investigators or 
by IRC.  
**More than one missed visit is defined if the duration between the last tumor assessment and death or PD is longer than 2 
scheduled visits, which is 17 weeks (119 days). 
 
 
 
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