Clinical trial NCT03150862
Conditions: Brain and Central Nervous System Tumors
Keywords: Adult glioblastoma, adult giant cell glioblastoma, adult gliosarcoma, glioma neoplasms recurrent adult brain tumor neoplasms, central nervous system neoplasms, neoplasms by histologic type, neoplasms by site astrocytoma neuroepithelial neuroectodermal tumors germ cell and embryonal antineoplastic agents glandular and epithelial nerve tissue, nervous system diseases temozolomide BGB-290 alkylating, alkylating agents molecular mechanisms of pharmacological action Poly(ADP-ribose) polymerase inhibitors enzyme inhibitors
Sponsor: BeiGene USA, Inc.
Start date: 2017-07-24; Completion date: 2021-03-17
Enrollment: 116 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the safety, efficacy and clinical activity of Pamiparib in combination with radiation therapy (RT) and/or temozolomide (TMZ) in participants with newly diagnosed or recurrent/refractory glioblastoma.

Detailed description:
An open-label, multiple-dose, dose-escalation study to determine the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of Pamiparib in combination with radiation therapy (RT) and/or TMZ.

In dose escalation/Phase 1b, Pamiparib will be combined with RT (Arm A) or RT and TMZ (Arm B) in participants with newly diagnosed unmethylated glioblastoma (GBM) and in Arm C of the study Pamiparib will be combined with TMZ in participants with methylated or unmethylated recurrent/refractory GBM.

The dose expansion/Phase 2 phase will enroll up to 4 cohorts: participants with newly diagnosed unmethylated GBM in Arms A and B, and 2 cohorts of participants with recurrent/refractory GBM grouped by O-6-methylguanine-DNA methyltransferase (MGMT) status - unmethylated or methylated - in Arm C.

Participants in Arms A and B are treated until completion of RT and participants in Arm C may continue treatment in the absence of safety concerns and disease progression.

Arms: arm 1: Participants with newly diagnosed unmethylated GBM will receive Pamiparib and radiation therapy. arm 2: Participants with newly diagnosed unmethylated GBM will receive Pamiparib, radiation therapy (RT) and temozolomide (TMZ). arm 3: Participants with newly diagnosed unmethylated GBM will receive Pamiparib and radiation therapy. arm 4: Participants with recurrent/refractory methylated or unmethylated GBM will receive Pamiparib and TMZ. arm 5: Participants with recurrent/refractory methylated or unmethylated GBM will receive Pamiparib and TMZ.
Interventions: intervention 1: Pamiparib intervention 2: TMZ intervention 3: Radiation
Intervention descriptions: intervention 1: Administered as specified in the treatment arm intervention 2: Administered as specified in the treatment arm intervention 3: Up to 60 Gy (total) over 6 - 7 weeks

Protocol documents:
Prot_000.pdf: 
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CLINICAL STUDY PROTOCOL 
 
 
 
Protocol Title: 
A Phase 1b/2 study to assess the safety, tolerability 
and efficacy of BGB-290 in combination with radiation 
therapy and/or temozolomide in subjects with first-line 
or recurrent/refractory glioblastoma 
Protocol Number: 
BGB-290-104 
Investigational Product 
Pamiparib (BGB-290) 
Original Protocol (Version 1.0): 
17 February 2017 
Protocol Version 2.0 
23 July 2018 (Final) 
IND No.: 
135006 
EudraCT No.:  
2017-001554-33 
Study Phase: 
1b/2 
Sponsor: 
BeiGene USA, Inc. 
2115 Linwood Avenue  
Fort Lee, NJ 07024 
United States 
 
Sponsor Medical Monitor:  
 
 
 
 
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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 USA Inc. Your acceptance of this document constitutes 
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from BeiGene USA Inc. 




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SYNOPSIS 
Name of 
Sponsor/Company: 
BeiGene USA, Inc. 
Name of Finished 
Product: 
Pamiparib (BGB-290) 
Name of Active 
Ingredient: 
Pamiparib (BGB-290) 
Title of Study: 
A Phase 1b/2 study to assess the safety, tolerability and efficacy of BGB-290 in 
combination with radiation therapy and/or temozolomide in subjects with 
first-line or recurrent/refractory glioblastoma 
Protocol No: 
BGB-290-104 
Number of Patients: 
Approximately 300 patients (60 in Phase 1b and 240 in Phase 2) may be 
enrolled. The actual sample size in Phase 1b will depend on the number of 
cohorts enrolled per arm. 
Study Centers: 
Approximately 15 to 40 centers in the United States, Europe, and/or Australia 
Study Phase: 
Phase 1b/2 
Treatment Duration: 
Arm A (dose escalation and dose expansion): Patients will be treated with 
pamiparib (also known as BGB-290) + radiation therapy (RT) for a maximum 
of 6 to 7 weeks.  
Arm B (dose escalation and dose expansion): Patients will be treated with 
pamiparib + RT + temozolomide (TMZ) for a maximum of 6 to 7 weeks.   
In Arms A and B of the dose-escalation phase, after RT is completed, at the 
discretion of the investigator and after discussion with the medical monitor, 
patients may continue to receive pamiparib in combination with TMZ 
(maintenance).  In the Arm A expansion phase of the study, continuation of 
treatment (with pamiparib in combination with TMZ) will be at the discretion 
of the Investigator after discussion with the Medical Monitor.  In the Arm B 
expansion phase of the study, maintenance treatment will be mandatory for all 
patients. 
Arm C (dose escalation and dose expansion): Patients will be treated with 
pamiparib + TMZ. 
In all 3 arms, patients will continue receiving study drug(s) until progressive 
disease (PD), unacceptable toxicity or death, withdrawal of consent, loss to 
follow-up, or study termination by sponsor. 


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Objectives: 
Primary: 
Phase 1b 
Arm A (pamiparib + RT): Patients with first-line glioblastoma multiforme (GBM) with unmethylated 
MGMT promoter (unmethylated GBM) 
 
To assess safety and tolerability of pamiparib combined with RT 
 To identify dose-limiting toxicity (ies) (DLTs) and determine the maximum tolerated dose (MTD) or 
maximum administered dose (MAD) for pamiparib combined with RT 
 To select the recommended Phase 2 schedule for pamiparib combined with RT 
Arm B (pamiparib + RT + TMZ): Patients with first-line unmethylated GBM 
 To assess safety and tolerability of pamiparib combined with RT and TMZ 
 To identify DLTs and determine the MTD or MAD for TMZ when combined with RT and the 
MTD/MAD of pamiparib determined in Arm A 
 To select the recommended phase 2 dose (RP2D) for TMZ when combined with RT and the MTD/MAD 
for pamiparib determined in Arm A 
Arm C (pamiparib + TMZ): Patients with recurrent/refractory GBM 
 To assess safety and tolerability of pamiparib combined with TMZ 
 To identify DLTs and determine the MTD or MAD for TMZ combined with pamiparib 
 To select the RP2D for TMZ combined with pamiparib 
Phase 2 
Arm A, Expansion 1 (pamiparib + RT): Patients with first-line unmethylated GBM 
 To make a preliminary assessment of efficacy of pamiparib combined with RT 
Arm B, Expansion 1 (pamiparib + RT + TMZ): Patients with first-line unmethylated GBM 
 To make a preliminary assessment of efficacy of pamiparib combined with RT and TMZ 
Arm C, Expansion 1 (pamiparib + TMZ): Patients with recurrent/refractory unmethylated GBM 
 To make a preliminary assessment of efficacy of pamiparib combined with TMZ 
Arm C, Expansion 2 (pamiparib + TMZ): Patients with recurrent/refractory methylated GBM 
 To make a preliminary assessment of efficacy of pamiparib combined with TMZ 
Secondary: 
Phase 1b, all Arms 
 To characterize the pharmacokinetics (PK) of pamiparib in combination with RT and/or TMZ 
 To make a preliminary assessment of pamiparib efficacy in combination with RT and/or TMZ 
 


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Phase 2, all Arms 
 To further characterize the efficacy, safety and tolerability of pamiparib in combination with RT  
and/or TMZ 
 To further characterize the PK of pamiparib in combination with RT and/or TMZ 
Exploratory: 
Study Design: 
This is an open-label, multi-center, multiple-dose, dose-escalation Phase 1b/2 study to determine the 
safety, PK, and pharmacodynamics of pamiparib in combination with RT and/or TMZ with two initial 
arms (Arms A and C) and a potential third arm (Arm B). In Arm A, pamiparib will be combined with RT 
in patients with first-line GBM with unmethylated MGMT promoter (unmethylated GBM). In Arm B, 
depending on the safety of the Arm A combination, pamiparib will be combined with both TMZ and RT 
in patients with first-line unmethylated GBM. In Arm C, pamiparib will be combined with TMZ in 
patients with recurrent/refractory GBM with methylated or unmethylated MGMT promoter. 
Dose Escalation Phase 
The dose escalation phase consists of the following: 
Arm A: 
Pamiparib (60 mg BID) administered continuously at increasing exposures of 2, 4, and 
6 weeks in combination with RT administered for 6 to 7 weeks. 
Arm B: 
Depending on the safety of the Arm A combination, the following combination may be 
explored: pamiparib (at the exposure determined as safe in Arm A) in combination with RT administered 
for 6 to 7 weeks and increasing doses of TMZ. 
In both Arms A and B, after RT is completed, patients will receive no further RT.  
Maintenance Treatment for Arms A and B:  Following completion of RT, at the discretion of the 
investigator and after discussion with the medical monitor, patients in Arm A escalation and expansion 
and Arm B escalation phases of the study may continue to receive pamiparib in combination with TMZ.  
In the Arm B expansion phase of the study, maintenance treatment will be mandatory for all patients.  
Dosing for this maintenance regimen should begin after the 4-week rest period (+ 7 days) to allow for 
recovery from RT treatment (as per Appendix 1 Table 4). 
Arm C: 
Pamiparib (60 mg BID, administered continuously) in combination with increasing doses 
of TMZ administered on Days 1 to 21 of each 28-day cycle.  
Approximately 60 patients may be enrolled during the dose escalation phase. The actual sample size in 
this phase will depend on the number of dose escalation cohorts enrolled per arm. 
Dose Expansion Phase 
Once the safety, tolerability, PK, pharmacodynamic, and preliminary antitumor activity have been 
reviewed for the dose escalation cohorts of each of the arms, up to approximately 60 patients may be 
enrolled in expansion cohorts for each of the 3 arms at a dose level below or equal to the MTD or MAD 
for that arm. In Arm C, 2 expansion cohorts may be opened, one for unmethylated GBM and one for 


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methylated GBM (Protocol Section 4.3). Therefore, a total of approximately 240 patients may be enrolled 
in the dose expansion phase.  
Adverse events (AEs) during and after the treatment period with study drug(s) will be followed and 
documented as outlined in Protocol Section 8.4 and Section 10. AEs will be graded according to National 
Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v4.03. To determine the 
PK properties of pamiparib, blood samples will be obtained coinciding with specific PK time points as 
outlined in Protocol Section 8.5 and Protocol Appendix 1. 
Disease status will be assessed using Response Assessment in Neuro-Oncology (RANO) criteria 
(Appendix 2). Patients will undergo tumor assessments at Screening and then every 8 weeks, or as 
clinically indicated.  
Patients in Arms A and B who have completed all study treatments per protocol and do not continue on 
pamiparib in combination with TMZ (maintenance) will have their end-of-treatment (EOT) visit at the 
end of the Rest Phase, 28 days after RT was completed, unless they do not complete the full study 
treatment; in such a case they should have the EOT visit within 7 days of stopping all study treatment. All 
other patients who have discontinued all study treatments should return to the clinic for an EOT visit 
within 7 days of stopping all treatment. After the EOT visit, all patients should have regular follow-up for 
safety, efficacy, and survival as outlined in Protocol Section 6.6.  
Patients will be followed for survival and further anticancer therapy information post progression via 
phone contact (with the patient’s guardian, if applicable) approximately every 12 weeks as per Protocol 
Appendix 1. 
Study Population: 
Inclusion criteria 
Patients must meet all of the following criteria to be eligible for the study: 
For all patients 
1. 
Signed Informed Consent Form (ICF) 
2. 
Age 18 years 
3. 
Histopathologically confirmed glioblastoma (World Health Organization [WHO] Grade IV) (Louis et 
al, 2016) 
 
Tumor must have a supratentorial component. 
4. 
5. 
Ability to undergo serial magnetic resonance imaging (MRI) scans (computerized tomography [CT] 
cannot substitute for MRI) 
6. 
Brain MRI scan ≤ 14 days prior to Day 1 
 
Patients requiring glucocorticoids must be on a daily dose equivalent of dexamethasone 4 mg 
twice daily or less that has been stable for ≥ 7 days prior to the MRI. 
7. 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 (Protocol Appendix 3) 
8. 
Ability to swallow whole capsules 


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9. 
Adequate hematologic and end-organ function, as defined by the following laboratory results 
(obtained ≤ 2 weeks prior to Day 1): 
 
Absolute neutrophil count (ANC)  1.5 x 109/L 
 
Platelet count  100 x 109/L 
 
Hemoglobin ≥ 9 g/dL ≥ 14 days after growth factor support or transfusion if appropriate 
 
Serum creatinine  1.5 x upper limit of normal (ULN) or estimated creatinine clearance 
 50 mL/min (calculated using the institutional standard method) 
 
Total serum bilirubin  1.5 x ULN (≤ 4 x ULN, if Gilbert’s syndrome) 
 
Aspartate and alanine aminotransferase (AST and ALT)  3 x ULN 
 
Albumin ≥ 3 g/dL 
 
International Normalized Ratio (INR) ≤ 1.5 and activated partial thromboplastin time 
(aPTT) ≤ 1.5 x ULN 
10. Female patients of childbearing potential and female partners of male study patients must agree to 
practice highly effective methods of birth control (Protocol Appendix 4) for the duration of the study 
and for ≥ 6 months after the last study treatment. In addition, non-sterile male patients must agree to 
practice highly effective methods of birth control (Protocol Appendix 4) and avoid sperm donation 
for the duration of the study and for ≥ 6 months after the last dose of study drug 
11. Willingness and ability to comply with all protocol-specified requirements  
→For patients in Arms A and B (NOT applicable to Arm C) 
12. 
No previous treatment except surgery (ie, no previous RT, local chemotherapy, or systemic 
therapy for lower grade central nervous system tumors) 
13. 
Ability to initiate RT ≤ 49 days after surgery, but ≥ 14 days after a biopsy or ≥ 28 days after an 
open biopsy or a craniotomy with adequate wound healing 
14. 
Documentation of unmethylated MGMT promoter status 
 
In escalation cohorts, it is preferable to determine MGMT status by quantitative methylation-
specific polymerase chain reaction (MS-PCR). Other acceptable platforms include 
pyrosequencing methodologies and methylation sensitive high-resolution melting 
(MS-HRM) assays with comparable sensitivity, applied to archival or fresh tumor tissue. 
Sponsor must be notified prior to utilizing alternate assays or if data from acceptable 
alternate platforms are available.   
 
In expansion cohorts, archival or fresh tumor tissue must be submitted for central analysis of 
MGMT status. 
→For patients in Arm C Escalation (NOT applicable to Arms A and B) 
15. 
Documentation of MGMT promoter status 
 
It is preferable to determine MGMT status by MS-PCR. Other acceptable platforms include 
pyrosequencing methodologies and MS-HRM assays with comparable sensitivity, applied to 
archival or fresh tumor tissue. Sponsor must be notified prior to utilizing alternate assays or 
if data from acceptable alternate platforms are available. 


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16. 
No prior systemic chemotherapy, other than TMZ, for glioblastoma (including investigational 
cytotoxic chemotherapy), and no prior anti-angiogenic therapy 
 
Prior use of Optune device is allowed with a minimum of 1 week since last Tumor Treating 
Fields application 
17. 
Histologically confirmed secondary glioblastoma will be allowed during the dose escalation 
phase only 
18. 
Disease that is evaluable or measurable as defined by RANO criteria (Protocol Appendix 2) 
→For patients in Arm C Expansion 
19. 
Histologically confirmed de novo (primary) glioblastoma with unequivocal first progressive 
disease (PD) after RT with concurrent/adjuvant TMZ chemotherapy as defined by one or more 
of the following: 
 
PD ≥ 3 months after the end of radiotherapy 
 
PD that is clearly outside the radiation field 
 
PD that has been unequivocally proven by surgery/biopsy 
20. 
Disease that is measurable as defined by RANO criteria (Protocol Appendix 2) 
 
Patients with recurrent disease must have at least one bi-dimensionally measurable 
contrast-enhancing lesion with clearly defined margins by MRI scan, with minimal 
diameters of 10 mm, visible on 2 or more axial slices 
21. 
Documentation of MGMT promoter status 
 
Tumor tissue (archival or fresh) must be submitted for central analysis of MGMT status 
 
Patients will be enrolled into 1 of 2 expansion cohorts based on MGMT methylation status 
Exclusion criteria 
Patients will be excluded from the study for any of the following reasons: 
For all patients 
1. Chemotherapy, biologic therapy, immunotherapy, or investigational agent ≤ 21 days (or 
≤ 5 half-lives, whichever is shorter) prior to Day 1  
2. Unresolved acute effects of any prior therapy of Grade ≥ 2, except for AEs not constituting a safety 
risk by investigator judgement 
3. Major surgical procedure, open biopsy, or significant traumatic injury ≤ 28 days 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 
4. 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 


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diagnosed >2 years ago with no current evidence of disease and no therapy ≤ 2 years prior to 
Day 1 
5. Active infection requiring systemic treatment 
6. Have known human immunodeficiency virus (HIV) infection or serologic status reflecting active viral 
hepatitis infection:  
 
Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers whose 
HBV DNA is > 500 IU/mL or patients with active hepatitis C virus (HCV) should be excluded. 
Note: Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B 
(HBV DNA ≤ 500 IU/mL), and cured patients with hepatitis C can be enrolled.  
7. 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 (see Protocol Appendix 5) 
≤ 6 months prior to Day 1 
 
Grade ≥ 2 ventricular arrhythmia ≤ 6 months prior to Day 1 
 
Cerebral vascular accident (CVA) or transient ischemic attack (TIA) ≤ 6 months prior to Day 1 
8. Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease, or 
previous gastric resection or lap-band surgery 
 
Gastroesophageal reflux disease under treatment with proton-pump inhibitors is allowed 
(assuming no drug interaction potential) 
9. Active bleeding disorder, including gastrointestinal bleeding, as evidenced by hematemesis, 
significant hemoptysis, or melena ≤ 6 months prior to Day 1 
10. Anticoagulation with heparin, warfarin, or other anticoagulants other than the following: 
 
Low-dose aspirin and/or non-steroidal anti-inflammatory agents are allowed 
 
Use of thrombolytics to establish patency of indwelling venous catheters is allowed 
 
Prophylactic anticoagulation for venous access devices is allowed as long as INR is  1.5 and 
aPTT  1.5  institutional ULN 
 
Low molecular weight heparin for treatment of thromboembolic events 
11. Use ≤ 10 days (or ≤ 5 half-lives, whichever is shorter) prior to Day 1 or anticipated need for food or 
drugs known to be strong or moderate CYP3A inhibitors or strong CYP3A inducers including known 
enzyme inducing anti-epileptic drugs (Protocol Appendix 6) 
12. Pregnancy or nursing 
 
Females of childbearing potential require a negative serum pregnancy test ≤ 7 days before 
Day 1. 
13. Significant intercurrent illness that may result in the patient’s death prior to death from glioblastoma 
14. Known history of intolerance to the excipients of the pamiparib capsule 


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→For patients in Arm B and C (NOT applicable to Arm A) 
15. Known hypersensitivity to any temozolomide component or to dacarbazine (DTIC) 
16. Have hereditary problems of galactose intolerance, the Lapp lactase deficiency, or 
glucose-galactose malabsorption 
Study Drug and 
Treatment: 
Pamiparib: 
Arm A, Arm B, and Arm C: 60 mg will be administered orally (PO) twice 
daily (BID), once in the morning and once in the evening. The time difference 
between 2 consecutive doses should be approximately 8 to 12 hours. 
Radiation therapy: 
Arm A and Arm B: RT will be administered once daily (QD)  5 days/week 
for 6 to 7 weeks with 1.8 or 2 Gy/fraction for a total target dose of between 58 
Gy and 64 Gy.  
Temozolomide: 
Arm B and Arm C: flat-dosing will be used for TMZ. For Arm C, the first 
dose level of 40 mg PO 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, 
corresponding to 46 mg/m2 and 69 mg/m2, respectively, will be administered 
PO QD. For Arm B, the first dose level of TMZ will be lower than or equal to a 
dose that has been determined to be safe and tolerable in Arm C. 
Dose Modifications: 
RT should only be modified for AEs determined to be solely or mostly related to RT as typically done per 
standard of care. 
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. 
Criteria for treatment modifications and suggested guidelines for the management of toxicities related to 
pamiparib and/or TMZ are summarized below. 
Dose 
level 
Temozolomide (TMZ)1 
 
Dose 
level 
Pamiparib2 
Flat dosing 
QD 
Dose 
equivalent 
 
BID 
QD 
-1 
20 mg 
12 mg/m2 
 
-2 
20 mg 
40 mg 
1 
40 mg 
23 mg/m2 
 
-1 
40 mg 
80 mg 
2 
80 mg 
46 mg/m2 
 
1 
60 mg 
120 mg 
3 
120 mg 
69 mg/m2 
 
 
- 
- 
4 
TBD 
- 
 
 
- 
- 
Note: TMZ will be dose-reduced first for a maximum of 2 dose reductions. After discussions with the medical monitor, 
pamiparib may be dose-reduced next for a maximum of 2 dose reductions. Depending on the toxicity that is triggering a 
second TMZ dose reduction, the possibility of a concurrent pamiparib dose reduction should be discussed with the medical 
monitor. Once a dose of pamiparib or TMZ has been reduced, re-escalation is not allowed. A patient must discontinue 


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treatment with pamiparib and TMZ, if, after treatment is resumed at a lower dose, the toxicity recurs with the same or worse 
severity.  
BID = twice daily; QD = once daily; TBD = to be determined 
1  Flat dosing of TMZ is used in this study. Dose equivalent information is provided for reference only and assumes an 
average body surface area of 1.73 m2. The starting dose for Arm C is dose level 1. For Arm B, the first dose level of 
TMZ will be lower than or equal to a dose that has been determined to be safe and tolerable in Arm C. 
2  The dose for pamiparib used in this study is 60 mg BID. A QD schedule may be explored as outlined in Protocol 
Section 4.2.1. 
The hold and discontinue guidelines for pamiparib (without TMZ) also apply in Arm A. After a toxicity 
has adequately resolved, the decision in Arm A of resuming pamiparib treatment at the same dose level 
versus dose-reducing pamiparib should be made in discussion with the Medial Monitor. 
Concomitant Therapy and Clinical Practice: 
Permitted Medications 
All treatments and supportive care, including glucocorticoids, 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 case report 
form (CRF) including all prescription and over-the-counter (OTC) drugs, herbal supplements, and IV 
medications and fluids. If changes occur during the study period, documentation of that change in drug 
dosage, frequency, route, and date will also be included on the CRF. 
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 treatment should be recorded. 
Prohibited Concomitant Therapy 
Patients are not allowed to receive other anticancer therapy, including surgery, RT (other than 
protocol-specified), and cytotoxic, biologic, or hormone therapy. Hormone replacement therapy is 
allowed.  
Therapeutic anticoagulation with heparin, warfarin, or other anticoagulants is not allowed, with the 
exception of low molecular weight heparin for treatment of patients with thromboembolic events. 
Low-dose aspirin, non-steroidal anti-inflammatory agents, and thrombolytics to establish patency of 
indwelling venous catheters are allowed, as is prophylactic anticoagulation for venous access devices as 
long as INR is 1.5 and aPTT 1.5  institutional ULN (Protocol Section 5.1). 
Concomitant Use of CYP Inhibiting Drugs 
The primary metabolic pathway for pamiparib involves the CYP3A isoform. The concurrent 
administration of strong/moderate inhibitors of CYP3A or strong CYP3A inducers is not allowed. In 
addition, pamiparib is an inhibitor of CYP2C9; careful monitoring should be used when co-prescribing 
CYP2C9 substrates with a narrow therapeutic index, such as phenytoin and warfarin. 
Criteria for Evaluation: 
Efficacy: 
Tumor assessments will include all known or suspected disease sites. MRIs will be performed at 
screening (within 14 days of Day 1) and every 8 weeks (7 days), unless otherwise specified in 
Appendix 1. Non-contrast cranial MRI may only be used to document disease in those patients who are 
allergic to contrast. Tumor assessments should be repeated at the end of treatment visit if more than 4 
weeks have passed since the last evaluation. The same imaging technique used at screening should be 


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used throughout the study. 
Anti-tumor activity will be assessed through radiologic tumor assessments conducted at screening, during 
treatment as specified in the Schedule of Activity, whenever disease progression is suspected (eg, 
symptomatic deterioration), and at the time of withdrawal from treatment (if not done in the previous 
4 weeks). 
Assessment of response will be made using the RANO criteria (Protocol Appendix 2). Responses should 
be confirmed with 2 assessments at least 4 weeks apart. Efficacy evaluations using the RANO criteria 
involve post-contrast MRI findings, non-contrast T1 and T2 FLAIR images, use of corticosteroid dose, 
and clinical status per RANO (Ellingson et al 2015).  
Following initial evidence of radiographic progressions and due to the potential for pseudo-progression 
patients may, at the discretion of the investigator, remain on treatment until further imaging is performed 
at 4 to 8 weeks (at the discretion of the investigator) after the initial determination of potential 
progression. 
A central independent radiology facility (IRF) may evaluate imaging studies and supportive clinical data 
in a central and independent fashion. The IRF will comprise board-certified radiologists who will identify 
baseline lesions and assign post-baseline time point responses. 
Safety: 
Safety will be monitored throughout the study. Safety assessments include AE monitoring and reporting, 
physical examinations, vital sign measurements, electrocardiograms (ECGs), and clinical laboratory tests. 
Endpoints: 
Primary Endpoints: 
Phase 1b, all Arms 
 
Incidence and nature of DLTs  
 
Incidence, nature, and severity of AEs, graded according to the NCI-CTCAE, v4.03 
 
Number of cycles (Arm C only) and the dose intensity of each component of the treatment 
regimens, and changes in vital signs and clinical laboratory test results during and following study 
treatment  
Phase 2, Arm A (pamiparib + RT) and Arm B (pamiparib + RT + TMZ) 
 
Modified disease control rate (DCR) as assessed using the RANO criteria (Appendix 2) 
Phase 2, Arm C (pamiparib + TMZ) 
 
Objective response rate (ORR) as assessed using RANO criteria 
Secondary Endpoints 
Phase 1b, all Arms 
 
PK parameter for pamiparib: Ctrough  
 
Modified DCR (Arms A and B), DCR (Arm C), ORR, and clinical benefit rate (CBR) 
 
Time-to-event endpoints: duration of response (DOR), progression-free survival (PFS), and overall 
survival (OS) 


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Phase 2, Arm A (pamiparib + RT) and Arm B (pamiparib + RT + TMZ) 
 
ORR and CBR as assessed using RANO criteria 
 
Time-to-event endpoints: DOR, PFS, and OS 
 
Incidence, nature, and severity of AEs, graded according to NCI-CTCAE, v4.03 
 
The dose intensity of each component of the treatment regimens, and changes in vital signs and 
clinical laboratory test results during and following study treatment  
 
PK parameter for pamiparib: Ctrough 
Phase 2, Arm C (pamiparib + TMZ) 
 
DCR and CBR as assessed using RANO criteria 
 
Time-to-event endpoints: DOR, PFS, and OS  
 
Incidence, nature, and severity of AEs, graded according to NCI-CTCAE, v4.03 
 
Number of cycles and the dose intensity of each component of the treatment regimens, and changes 
in vital signs and clinical laboratory test results during and following study treatment  
 
PK parameter for pamiparib: Ctrough 
Exploratory Endpoints 
Statistical Methods: 
Hypothesis testing will be performed in Phase 2. In addition, descriptive statistics will be used in 
describing the antitumor activity and tolerability of the combination regimens in each Phase. Confidence 
intervals will be constructed to describe the precision of the point estimates of interest (eg, ORR). 
Tumor assessments by investigators according to RANO will be used to calculate ORR, modified DCR 
(Arms A and B), DCR (Arm C), PFS, DOR, and CBR, as well as time-point estimate PFS-6m. OS and 
OS at 6 months and 12 months (OS-6m and OS-12m), will be summarized in the efficacy analysis. An 
optional independent read of the MRI scans may be performed and will be analyzed in the same fashion. 
Populations: 
 
The Safety Analysis Set includes all patients who received any study treatment (pamiparib, RT, 
and/or TMZ). The Safety Analysis Set will be used for all efficacy and safety analyses. 
 
The Efficacy-evaluable Analysis Set includes patients in the Safety Analysis Set who had baseline 
and at least one post-baseline tumor assessment, unless discontinued treatment or study early due to 
clinical progression or death prior to tumor assessment. 
 
The DLT-evaluable Analysis Set includes patients who received ≥ 42 Gy of RT (Arms A and B) and 
≥ 70% of scheduled pamiparib (Arms A, B, and C) and TMZ (Arms B and C) during the DLT 
assessment window with sufficient safety assessments. All patients who had a DLT event will be 
considered DLT-evaluable regardless of study treatment intensity.  
 
The PK Analysis Set includes all patients for whom valid pamiparib PK parameters can be estimated. 


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Primary Efficacy Analysis: 
Phase 1b 
As described in the protocol objectives, the trial is designed to establish the safety and tolerability of 
pamiparib in combination with RT and/or TMZ. Evidence of any antitumor activity will be documented 
and summarized for the Safety Analysis Set as secondary endpoints of the trial. 
Phase 2 (Arms A and B) 
Modified DCR is the primary efficacy endpoint in Arms A and B. It is defined as the proportion of 
patients with CR, PR, or SD as the response assessment at the EOT visit, as scheduled per protocol. 
Patients with no EOT tumor assessment, as scheduled per protocol (due to any reason), will be considered 
non-responders for modified DCR. Modified DCR of pamiparib combination therapy is assumed as 60% 
in the study population. The historical rate in a similar population is estimated as 40% (Rivera et al, 
2010).  
The null and alternative hypotheses are set as follows: 
 H0: Modified DCR = 40% 
 Ha: Modified DCR > 40% 
A binomial exact test will be performed for hypothesis testing in each arm separately in the Safety 
Analysis Set. If the obtained one-sided p-value is < 0.025, it will be concluded that pamiparib 
combination therapy showed a statistically significant increase of modified DCR compared to historical 
control. Therefore, the superiority of pamiparib combination therapy will be demonstrated in this arm. 
Two-sided binomial exact 95% confidence interval (CI) of modified DCR will be constructed to assess 
the precision of the rate estimate.  
The primary efficacy analysis will be conducted when mature response rate data have been observed, 
which will be determined by the sponsor. 
Sensitivity analysis of modified DCR will be carried out in the Efficacy-evaluable Analysis Set. 
Phase 2 (Arm C) 
ORR is the primary efficacy endpoint in Arm C. ORR of pamiparib combination therapy is assumed as 
25% in the study population. The historical rate in a similar population is estimated as 10% (Chen et al 
2013)  
The null and alternative hypotheses are set as follows: 
 H0: ORR = 10% 
 Ha: ORR > 10% 
A binomial exact test will be performed similarly to that described for Arms A and B. 
Secondary Efficacy Analysis: 
Descriptive statistics will be used to summarize the secondary efficacy analysis.  
DCR is defined as the proportion of patients with best overall response (BOR) of CR, PR, or SD. BOR is 
defined as the best response recorded from the start of study treatment until data cutoff or start of new 
anti-cancer therapy. 
CBR is defined as the proportion of patients with BOR of CR, PR, or durable SD (SD ≥ 24 weeks).  
Exact 95% CIs will be calculated for the rate variables: ORR for patients with measurable disease at 
baseline, DCR and CBR in the Safety Analysis Set. 


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PFS is defined as the time from the date of first study treatment to disease progression or death, 
whichever occurs first.  
PFS censoring rule will follow the 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 an MRI, if possible, to correlate radiographic findings with the clinical findings. Data for patients 
without disease progression or death at the time of analysis will be censored at the time of the last tumor 
assessment. Data for patients who are lost to follow-up prior to documented disease progression will be 
censored at the last tumor assessment date when the patient was known to be progression-free. Data for 
patients who started new anti-cancer therapy will be censored at the last tumor assessment date prior to 
the introduction of new therapy. More details will be provided in the statistical analysis plan.  
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 first study treatment to death from any cause. 
Time-to-event variables PFS, DOR, and OS will be estimated using the Kaplan-Meier method in the 
Safety Analysis Set. Kaplan-Meier estimates of PFS, DOR, and OS will be plotted over time. Median 
PFS, DOR, and OS for each arm will be presented (if possible to estimate), along with their 2-sided 95% 
CIs using generalized Brookmeyer and Crowley method. The PFS-6m, OS-6m, and OS-12m, defined as 
the percentages of patients in the analysis population who remain alive and progression-free at 6 months 
(or alive at 6 or 12 months for OS-6m and OS-12m), will be estimated using Kaplan-Meier method along 
with the corresponding 95% CI constructed using Greenwood’s formula. OS will be assessed by 6-month 
intervals until the last patient enrolled on the study had died. 
Selected efficacy endpoints will be summarized in the Efficacy-evaluable Analysis Set as sensitivity 
analysis. 
In Phase 2, modified DCR (in Arms A and B) and ORR (in Arm C) will be summarized in the specified 
subgroups: sex, age group (<65 vs. ≥ 65 years of age), race, ECOG performance status (0 vs. ≥ 1), prior 
surgery status, baseline corticosteroid use, mutations, and geographic region. In addition, ORR (in Arm 
C) will be summarized by relapse status. 
Pharmacokinetic Analyses: 
Population PK analysis may be carried out to include plasma concentrations from this trial in an existing 
model. PK parameters such as minimum observed plasma concentration (Cmin) will be summarized, and 
additional PK parameters such as apparent clearance of the drug from plasma (CL/F) and area under the 
plasma concentration-time curve from zero to 24 hours post-dose (AUC0-24) may be derived from the 
population PK analysis if supported by data. 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by data. 
Exploratory Efficacy Analyses: 
Safety Analysis: 
Safety will be assessed by monitoring and recording of all AEs graded by CTCAE v4.03. Laboratory 
values (hematology, clinical chemistry, coagulation, and urinalysis), vital signs, physical examinations, 
and ECG findings will also be used in determining the safety of study treatment. 
Sample Size: 
Approximately 300 patients (60 in Phase 1b and 240 in Phase 2) may be enrolled. The actual sample size 


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in Phase 1b will depend on the number of cohorts enrolled per arm.  
In Phase 2, the sample size calculation is carried out using modified DCR in Arms A and B and ORR in 
Arm C.  
 
Assuming modified DCR of 60% in Arms A and B vs. 40% in historical control, the power of a 
binomial exact test is 0.874 in each arm when n = 60. 
 
Assuming ORR of 25% in Arm C vs. 10% in historical control, the power of a binomial exact test is 
0.847 when n = 60 per expansion cohort. 
With the above assumptions, the binomial exact 95% CI of modified DCR is (46.5%, 72.4%) in Arms A 
and B and the binomial exact 95% CI of ORR is (14.7%, 37.9%) in each expansion cohort of Arm C. 
Interim Analysis: 
A brief data summary will be performed once the Phase 1b dose escalation portion is completed. In 
Phase 2, an interim analysis will be implemented in each arm after approximately the first 20 patients in 
that arm complete ≥ 2 tumor assessments. This analysis is for futility only. No recruitment stop is planned 
for this interim analysis. If the conditional or predictive power of demonstrating the final efficacy is 
< 10%, enrollment in this arm will be halted and safety and efficacy data will be further evaluated before 
making the decision of whether to stop the arm permanently. Otherwise, the enrollment will be continued 
to approximately 60 patients in this arm. 
 
 


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TABLE OF CONTENTS 
SIGNATURES ...................................................................................................................................... 2 
Synopsis ................................................................................................................................................. 3 
TABLE OF CONTENTS .................................................................................................................... 17 
TABLE OF TABLES .......................................................................................................................... 22 
TABLE OF FIGURES ........................................................................................................................ 22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................... 24 
1. 
INTRODUCTION ................................................................................................................. 27 
1.1. 
Biology of Glioblastoma ....................................................................................................... 27 
1.2. 
Imaging and Treatment of Glioblastoma ............................................................................... 27 
1.2.1. Overview and Key Data for Glioblastoma ................................................................ 27 
1.2.2. Imaging of Glioblastomas ......................................................................................... 28 
1.2.3. O6-methylguanine-DNA Methyltransferase Status and Treatment Response ........... 29 
1.2.3.1. Methylation of the O6-methylguanine-DNA Methyltransferase (MGMT) 
Gene Promoter ............................................................................................ 29 
1.2.3.2. MGMT Methylation Status and Significance for Newly Diagnosed 
Glioblastoma ............................................................................................... 30 
1.2.3.3. MGMT Methylation Status and Significance for Recurrent Glioblastoma 32 
1.2.4. Treatment Toxicity .................................................................................................... 32 
1.2.4.1. Toxicity of Dose-dense Temozolomide Regimens ..................................... 32 
1.3. 
Background on Poly (ADP-ribose) Polymerase Inhibitors and Pamiparib (BGB-290) ........ 33 
1.3.1. Poly (ADP-ribose) Polymerase (PARP) and Pamiparib............................................ 33 
1.3.2. PARP Inhibitors and Glioblastoma ........................................................................... 33 
1.3.3. PARP Inhibitors in Combination with Temozolomide or Radiation ........................ 34 
1.3.4. Nonclinical Data for Pamiparib ................................................................................. 36 
1.3.4.1. Nonclinical Safety Data .............................................................................. 36 
1.3.4.2. Nonclinical Activity Data ........................................................................... 37 
1.3.5. Clinical Data for Pamiparib ....................................................................................... 40 
1.3.5.1. Pharmacokinetics Data for BGB-290-AU-002 ........................................... 41 
1.3.5.2. Exploratory Biomarker Data ....................................................................... 42 
1.3.5.3. Clinical Safety and Preliminary Efficacy for BGB-290-AU-002 ............... 42 
1.3.5.4. Pamiparib Dose Selection ........................................................................... 43 
1.4. 
Study Rationale ..................................................................................................................... 44 
1.5. 
Risk-Benefit Assessment ....................................................................................................... 44 
1.6. 
Study Conduct ....................................................................................................................... 44 
2. 
STUDY OBJECTIVES ......................................................................................................... 45 
2.1. 
Primary Objectives ................................................................................................................ 45 
2.1.1. Phase 1b ..................................................................................................................... 45 
2.1.2. Phase 2  ..................................................................................................................... 45 


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2.2. 
Secondary Objectives ............................................................................................................ 46 
2.3. 
Exploratory Objectives .......................................................................................................... 46 
3. 
STUDY ENDPOINTS ........................................................................................................... 46 
3.1. 
Primary Endpoints ................................................................................................................. 46 
3.2. 
Secondary Endpoints ............................................................................................................. 47 
3.3. 
Exploratory Endpoints ........................................................................................................... 47 
4. 
STUDY DESIGN .................................................................................................................. 47 
4.1. 
Summary of Study Design ..................................................................................................... 47 
4.1.1. Dose Escalation Phase (Phase 1b) ............................................................................. 49 
4.1.2. Dose Expansion Phase (Phase 2) ............................................................................... 49 
4.2. 
Details of Dose-Escalation Stage .......................................................................................... 50 
4.2.1. Starting Dose and Dose-Escalation Approach........................................................... 50 
4.2.2. Rules for Dose Escalation.......................................................................................... 51 
4.2.3. Assessment of Dose-Limiting Toxicity ..................................................................... 52 
4.2.4. Definition of Dose-Limiting Toxicity ....................................................................... 53 
4.3. 
Details of Cohort-Expansion Stage ....................................................................................... 53 
4.4. 
Duration of Study .................................................................................................................. 54 
5. 
STUDY POPULATION ........................................................................................................ 54 
5.1. 
Inclusion Criteria ................................................................................................................... 54 
5.2. 
Exclusion Criteria .................................................................................................................. 56 
6. 
STUDY PHASES FROM SCREENING TO END OF STUDY .......................................... 58 
6.1. 
Screening ............................................................................................................................... 58 
6.2. 
Enrollment ............................................................................................................................. 59 
6.3. 
Treatment ............................................................................................................................... 59 
6.4. 
Unscheduled Visit ................................................................................................................. 59 
6.5. 
Permanent Discontinuation of Study Treatment ................................................................... 59 
6.5.1. Reasons for Permanent Discontinuation of Study Treatment ................................... 59 
6.5.2. End of Treatment Visit .............................................................................................. 60 
6.6. 
Follow-Up Phase ................................................................................................................... 60 
6.6.1. Safety Follow-Up ...................................................................................................... 60 
6.6.2. Efficacy Follow-Up ................................................................................................... 60 
6.6.3. Survival Follow-Up ................................................................................................... 61 
6.6.4. Lost to Follow-Up ..................................................................................................... 61 
6.7. 
End of Study .......................................................................................................................... 61 
7. 
STUDY TREATMENT ......................................................................................................... 62 
7.1. 
Study Treatments ................................................................................................................... 62 


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7.1.1. Pamiparib ................................................................................................................... 62 
7.1.1.1. Packaging and Labeling .............................................................................. 62 
7.1.1.2. Handling and Storage .................................................................................. 62 
7.1.1.3. Dosage and Administration ......................................................................... 62 
7.1.2. Temozolomide ........................................................................................................... 63 
7.1.2.1. Packaging and Labeling .............................................................................. 63 
7.1.2.2. Handling and Storage .................................................................................. 63 
7.1.2.3. Dosage and Administration ......................................................................... 63 
7.1.2.4. Temozolomide and Pamiparib Drug-drug Interaction Potential ................. 63 
7.1.3. Radiation Therapy ..................................................................................................... 64 
7.1.4. Radiation Therapy Adverse Events ........................................................................... 66 
7.1.4.1. Acute 
 ................................................................................................... 66 
7.1.4.2. Early Delayed .............................................................................................. 67 
7.1.4.3. Late Delayed ............................................................................................... 67 
7.1.5. Dose Holds and Modifications of Study Treatments ................................................ 67 
7.1.5.1. General Considerations for Modifications of Study Treatments ................ 67 
7.1.5.2. Dose Modification Considerations for Combinations with Radiation 
Therapy 
 ................................................................................................... 67 
7.1.5.3. Dose Modification Guidelines for Temozolomide and Pamiparib ............. 68 
7.1.6. Compliance and Accountability ................................................................................ 72 
7.1.7. Disposal and Destruction ........................................................................................... 72 
7.1.8. Treatment of Overdose from Study Drugs ................................................................ 73 
7.1.9. Occupational Safety ................................................................................................... 73 
7.2. 
Concomitant Medications and Non-Drug Therapies ............................................................. 73 
7.2.1. Permitted Medications and Supportive Care ............................................................. 73 
7.2.2. Pneumocystis jirovecii Pneumonia Prophylaxis........................................................ 73 
7.2.3. Prohibited Medications .............................................................................................. 74 
7.2.4. Medications to Be Used with Caution ....................................................................... 74 
8. 
STUDY ASSESSMENTS ..................................................................................................... 75 
8.1. 
Study Flow and Visit Schedule ............................................................................................. 75 
8.2. 
Patient Demographics and Other Baseline Characteristics ................................................... 75 
8.2.1. Demographics ............................................................................................................ 75 
8.2.2. Medical History ......................................................................................................... 75 
8.2.3. Other Baseline Characteristics .................................................................................. 75 
8.3. 
Tumor Assessments ............................................................................................................... 75 
8.3.1. Magnetic Resonance Imaging (MRI) ........................................................................ 75 
8.3.2. Central Independent Radiology Facility (IRF) .......................................................... 76 
8.4. 
Safety ..................................................................................................................................... 77 
8.4.1. Adverse Events .......................................................................................................... 77 
8.4.2. Physical Examination, Vital Signs, ECOG Performance Status, Weight and Height ... 
 
 ..................................................................................................................... 77 
8.4.3. Electrocardiograms .................................................................................................... 77 
8.4.4. Laboratory Studies ..................................................................................................... 77 


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8.4.4.1. Hematology ................................................................................................. 78 
8.4.4.2. Chemistry  ................................................................................................... 78 
8.4.4.3. Coagulation ................................................................................................. 78 
8.4.4.4. Urinalysis with Dipstick .............................................................................. 78 
8.4.4.5. Hepatitis B Serology Test ........................................................................... 78 
8.4.4.6. Pregnancy Testing ....................................................................................... 78 
8.5. 
Pharmacokinetics ................................................................................................................... 78 
8.6. 
Biomarkers ............................................................................................................................ 79 
8.7. 
Appropriateness of Measurements ........................................................................................ 79 
9. 
DATA HANDLING AND QUALITY ASSURANCE ......................................................... 80 
9.1. 
Data Collection ...................................................................................................................... 80 
9.2. 
Data Management/Coding ..................................................................................................... 80 
9.3. 
Quality Assurance ................................................................................................................. 81 
10. 
SAFETY MONITORING AND REPORTING .................................................................... 82 
10.1. Adverse Events ...................................................................................................................... 82 
10.1.1. Definition and Reporting of an Adverse Event ......................................................... 82 
10.1.2. Assessment of Severity .............................................................................................. 82 
10.1.3. Assessment of Causality ............................................................................................ 83 
10.1.4. Follow-Up of Adverse Events ................................................................................... 84 
10.1.5. Laboratory Test Abnormalities .................................................................................. 84 
10.2. Definition of a Serious Adverse Event .................................................................................. 85 
10.3. Timing, Frequency, and Method of Capturing Adverse Events and Serious Adverse Events
 ............................................................................................................................................... 86 
10.3.1. Adverse Event Reporting Period ............................................................................... 86 
10.3.2. Eliciting Adverse Events ........................................................................................... 86 
10.4. Specific Instructions for Recording Adverse Events and Serious Adverse Events ............... 86 
10.4.1. Disease Progression ................................................................................................... 86 
10.4.2. Death 
86 
10.5. Prompt Reporting of Serious Adverse Events ....................................................................... 87 
10.5.1. Timeframes for Submitting Serious Adverse Events ................................................ 87 
10.5.2. Completion and Transmission of the Serious Adverse Event Report ....................... 87 
10.5.3. Regulatory Reporting Requirements for Serious Adverse Events ............................ 87 
10.6. Pregnancy Reporting ............................................................................................................. 88 
10.7. Poststudy Adverse Events ..................................................................................................... 89 
10.8. Expedited Reporting to Health Authorities, Ethics Committees and Investigators .............. 89 
11. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN .................................. 90 
11.1. Primary, Secondary and Exploratory Study Endpoints ......................................................... 90 
11.2. Statistical Analysis ................................................................................................................ 90 


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11.2.1. Analysis Set ............................................................................................................... 90 
11.2.2. Patient Disposition ..................................................................................................... 90 
11.2.3. Demographics and Other Baseline Characteristics ................................................... 91 
11.2.4. Prior and Concomitant Therapy ................................................................................ 91 
11.2.5. Efficacy Analyses ...................................................................................................... 91 
11.2.5.1. Primary Efficacy Analysis .......................................................................... 91 
11.2.5.2. Secondary Efficacy Analysis ...................................................................... 92 
11.2.6. Pharmacokinetic Analyses ......................................................................................... 93 
11.2.7. Exploratory Analyses ................................................................................................ 94 
11.3. Safety Analyses ..................................................................................................................... 94 
11.3.1. Extent of Exposure .................................................................................................... 94 
11.3.2. Dose-limiting Toxicity .............................................................................................. 94 
11.3.3. Adverse Events .......................................................................................................... 94 
11.3.4. Laboratory Analyses .................................................................................................. 95 
11.3.5. Physical Examinations ............................................................................................... 95 
11.3.6. Vital Signs ................................................................................................................. 95 
11.3.7. Electrocardiogram ..................................................................................................... 95 
11.4. Sample Size Consideration .................................................................................................... 95 
11.5. Interim Analysis .................................................................................................................... 96 
11.6. Other Statistical Issues .......................................................................................................... 96 
12. 
STUDY ADMINISTRATION AND INVESTIGATOR OBLIGATIONS .......................... 97 
12.1. Regulatory Authority Approval ............................................................................................. 97 
12.2. Investigator Responsibilities ................................................................................................. 97 
12.2.1. Good Clinical Practice ............................................................................................... 97 
12.2.2. Ethical Conduct of the Study and Ethics Approval ................................................... 97 
12.2.3. Informed Consent ...................................................................................................... 98 
12.2.4. Investigator Reporting Requirements ........................................................................ 98 
12.2.5. Confidentiality ........................................................................................................... 98 
12.2.6. Electronic Case Report Forms ................................................................................... 99 
12.2.7. Drug Accountability .................................................................................................. 99 
12.2.8. Inspections ............................................................................................................... 100 
12.2.9. Protocol Adherence ................................................................................................. 100 
12.3. Sponsor Responsibilities ..................................................................................................... 100 
12.3.1. Protocol Modifications ............................................................................................ 100 
12.3.2. Use of Information and Publication ........................................................................ 100 
12.4. Study and Study Center Closure .......................................................................................... 101 
12.5. Records Retention and Study Files ...................................................................................... 102 
12.5.1. Study Files and Retention of Records ..................................................................... 102 
12.5.2. Provision of Study Results and Information to Investigator ................................... 103 
12.6. Information Disclosure and Inventions ............................................................................... 103 
12.7. Joint Investigator/Sponsor Responsibilities ........................................................................ 104 


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12.7.1. Access to Information for Monitoring ..................................................................... 104 
12.7.2. Access to Information for Auditing or Inspections ................................................. 104 
13. 
REFERENCES .................................................................................................................... 105 
14. 
APPENDICES ..................................................................................................................... 111 
Appendix 1. 
STUDY ASSESSMENTS ....................................................................................... 112 
Appendix 2. 
RESPONSE ASSESSMENT FOR NEURO-ONCOLOGY (RANO)  
CRITERIA FOR TIME POINT RESPONSES ................................................................................. 128 
Appendix 3. 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE  STATUS ............................................................................................................ 133 
Appendix 4. 
CONTRACEPTION GUIDELINES AND DEFINITION OF 
CHILDBEARING  POTENTIAL ..................................................................................................... 134 
Appendix 5. 
NEW YORK HEART ASSOCIATION CLASSIFICATION ................................ 135 
Appendix 6. 
PROHIBITED MEDICATIONS ............................................................................... 136 
Appendix 7. 
MEDICATIONS TO BE USED WITH CAUTION .................................................. 137 
Appendix 8. 
SIGNATURE OF INVESTIGATOR ...................................................................... 138 
Appendix 9. 
LIST OF COUNTRY-SPECIFIC AMENDMENTS ............................................... 139 
 
TABLE OF TABLES 
Table 1: 
O6-methylguanine-DNA Methyltransferase (MGMT) Status and Clinical Benefit in 
Newly Diagnosed Glioblastoma ............................................................................... 31 
Table 2: 
PK Parameters for the Food Effect Cohort ............................................................... 41 
Table 3: 
Individual Dose Levels for Temozolomide and Pamiparib ...................................... 69 
Table 4: 
Criteria for Modification of Pamiparib and Temozolomide Dosing ........................ 70 
Table 5: 
Timeframes and Documentation Methods for Reporting Serious Adverse Events to 
the Sponsor or Designee ........................................................................................... 87 
 
TABLE OF FIGURES 
Figure 1: 
DNA-Trapping Activity of Pamiparib and Other PARP Inhibitors ......................... 37 
Figure 2: 
Simulation of Pamiparib Concentrations in Human Organs .................................... 38 
Figure 3: 
Combination Activity of Pamiparib and Temozolomide in H209 Small Cell Lung 
Cancer Xenograft Model .......................................................................................... 39 
Figure 4: 
Combination Activity of Pamiparib and Temozolomide in H209-T Intracranial Model
 
 ......................................................................................................................... 40 
Figure 5: 
Correlation of PAR Inhibition in Peripheral Blood Mononuclear Cells with Pamiparib 
Dose  ......................................................................................................................... 42 


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Figure 6  
Phase 1b/2 Study Overview for Pamiparib with Radiation Therapy and/or 
Temozolomide in Patients with First-Line or Recurrent/Refractory Glioblastoma . 48 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
AUC0-24h 
area under the plasma concentration-time curve from zero to 24 
hours post-dose 
BER 
base excision repair 
BGB-290 
study drug code (also known as pamiparib) 
BID 
twice daily 
BOR 
best overall response 
CBR 
clinical benefit rate 
CL 
clearance 
CL/F 
apparent clearance 
Cmin 
minimum observed plasma concentration 
Cmax 
maximum observed plasma concentration 
Ctrough 
lowest observed plasma concentration 
CI 
confidence interval 
CR 
complete response 
CSR 
clinical study report 
CT 
computed tomography 
CYP 
cytochrome P450 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
DSB 
Double-strand break 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
(e)CRF 
(electronic) case report form 
EDC 
electronic data capture 


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EGFR 
epidermal growth factor receptor 
EOT 
end-of-treatment 
FDA 
Food and Drug Administration 
FLAIR 
fluid attenuated inversion recovery 
GBM 
glioblastoma multiforme 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HR 
homologous recombination 
IB 
Investigator’s Brochure 
IC50 
half inhibitory concentration 
ICH 
International Conference of Harmonisation 
ICF 
informed consent form 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRF 
Independent Radiology Facility 
MAD 
maximum administered dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGMT 
O6-methylguanine-DNA methyltransferase 
MMR 
Mismatch Repair 
MRI 
magnetic resonance imaging 
MS-PCR 
methylation-specific polymerase chain reaction 
MTD 
maximum tolerated dose 
NCI-CTCAE 
National Cancer Institute Common Toxicity Criteria for Adverse 
Events 
ORR 
objective response rate 
OS 
overall survival 
Pamiparib 
BGB-290 
PAR 
poly(ADP-ribose) 
PARP 
poly(ADP-ribose) polymerase 
PBMCs 
peripheral blood mononuclear cells 
PD 
progressive disease 


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PFS 
progression-free survival 
PI3K 
phosphatidylinositol-3-OH kinase 
PK 
pharmacokinetic(s) 
PK/PD 
pharmacokinetic/pharmacodynamic 
PO 
orally 
PR 
partial response 
PT 
Preferred Term 
PTV 
planning target volume 
QD 
once daily 
QTc 
QT interval corrected for heart rate 
RANO 
Response Assessment in Neuro-Oncology 
RP2D 
recommended Phase II dose 
RT 
radiation therapy 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
System Organ Class 
SSB 
single-strand break 
TEAE 
treatment-emergent adverse event 
TMZ 
temozolomide 
TPR 
Time Point Response 
ULN 
upper limit of normal 
US 
United States 
WBC 
white blood cell 
 
 


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1. 
INTRODUCTION 
1.1. 
Biology of Glioblastoma 
Glioblastomas multiforme (GBM), the most aggressive subtype of gliomas, harbor a range of 
oncogenic mutations. These mutations are associated with resistance to both chemotherapy and 
radiation therapy (RT). A substantial number of these genetic alterations affect key players in DNA 
repair pathways. 
 Methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter 
and Mismatch Repair (MMR) gene mutations: MGMT promoter methylation was 
associated with a profound shift in the nucleotide substitution spectrum of treated GBMs. 
Notably, high occurrence of MMR gene mutations was observed in MGMT-
hypermethylated tumors (Cancer Genome Atlas Research Network 2008). 
 Downregulation of the p53 signaling pathway: Around 70% of GBM patients were 
reported to have somatic mutations affecting the p53 pathway. Inactivation of the p53 
pathway was due to ARF deletion in 55%, MDM2 amplification in 11%, and MDM4 
amplification in 4% of GBM patients (Cancer Genome Atlas Research Network 2008). 
 Downregulation of the retinoblastoma (RB) signaling pathway: RB1 and its paralogs p107 
and p130 play a central role in DNA double-strand break (DSB) repair by non-
homologous end joining (NHEJ) (Huang et al 2015). A high frequency of mutations 
affecting the RB pathway was reported for GBM. The most common alterations were 
deletion of the CDKN2A and CDKN2B loci on chromosome 9p21 in 55% and 53% of the 
cases, respectively, followed by amplification of the CDK4 locus in 14% (Cancer Genome 
Atlas Research Network 2008). 
 Upregulation of the epidermal growth factor receptor (EGFR)/Ras/phosphatidylinositol-3-
OH kinase (PI3K) signaling pathway through PTEN alterations: PTEN alterations have 
been reported in 34% of GBM (Smith et al 2001). PTEN loss leads to defects in DNA 
DSB repair by homologous recombination (HR). 
The high frequency of genetic alterations in GBM affecting DNA repair pathways suggests that 
DNA-damaging agents or agents interfering with DNA repair may be able to provide clinical benefit 
for GBM patients. This hypothesis is supported by the current standard of care for GBM patients but 
has not been adequately explored for other classes of drugs, such as inhibitors of poly(ADP-ribose) 
polymerase (PARP). 
1.2. 
Imaging and Treatment of Glioblastoma 
1.2.1. 
Overview and Key Data for Glioblastoma 
GBM is the most common primary malignant brain tumor in adults with approximately 10,000 cases 
diagnosed annually in the United States (US) and with a dismal prognosis despite aggressive 


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treatment (CBTRUS 2012). Because of the infiltrative nature of GBM, surgery alone is never 
curative. Therefore, the majority of patients are subsequently treated with RT with or without 
chemotherapy. In 2005, Stupp and colleagues published a landmark study demonstrating a 
2.5-month overall survival (OS) benefit with the addition of the alkylating agent temozolomide 
(TMZ) to surgery and RT (Stupp et al 2005). The results of this large trial established the role of 
TMZ, along with maximal safe resection and RT, for the treatment of newly diagnosed GBM 
patients <65 years old. Preliminary evidence that inactivation of the MGMT protein conferred 
sensitivity to TMZ (Esteller et al 2000; Hegi et al 2004) and TMZ’s efficacy in recurrent glioma 
(Yung et al 2000) served as supporting data for this large, randomized, Phase 3 trial. Subset analyses 
confirmed improved survival and sensitivity to TMZ for tumors deficient in MGMT (defined by 
MGMT promoter methylation) compared to those with adequate MGMT expression (defined by an 
unmethylated MGMT promoter) (Hegi et al 2005).  
Since the added benefit with use of TMZ is limited in the MGMT promoter unmethylated 
glioblastoma population, the risk-benefit ratio of combined modality treatment in these patients (eg, 
myelosuppression and an increased risk of pseudo-progression events) has been questioned. In 
contrast, a recently published randomized study of short-course radiation plus TMZ in elderly 
patients with GBM (Perry et al 2017) demonstrated the benefit of chemoradiotherapy in patients with 
either methylated or unmethylated MGMT status. Hence, significant regional debate remains with 
respect to whether incorporation of TMZ should be based upon MGMT methylation status alone 
(Newlands et al 1997, Stupp et al 2001). The current European Association for Neuro-Oncology 
guidelines for glioma do acknowledge the option of radiotherapy only for newly diagnosed MGMT 
promoter unmethylated glioblastoma.  This reverses the older European Society for Medical 
Oncology guideline that reserved this option for patients treated within clinical trials (Weller et al 
2017; Stupp et al 2014). More recently, several clinical trials evaluated an investigational agent in 
combination with RT but without TMZ in patients with newly diagnosed glioblastoma and 
unmethylated MGMT promoter (Wick et al 2016; Herrlinger et al 2016; Nabors et al 2015). 
1.2.2. 
Imaging of Glioblastomas 
An important aspect to the treatment of glioblastoma is appropriate imaging and detection of 
response. Standard-of-care GBM neuroimaging includes the following. 
1. After initial primary debulking surgery, magnetic resonance imaging (MRI) of the brain 
without and with contrast can serve as baseline imaging prior to start of RT ± chemotherapy. 
2. After surgery and RT, MRI of the brain without and with contrast is usually performed 2 to 6 
weeks following completion of treatment, and then every 2 months. 
3. During chemotherapy or a course of RT, MRI of the brain without and with contrast every 8 
weeks is the usual approach. Standard-of-care surveillance MRI of the brain without and with 
contrast is then repeated every 3 months for 3 years, followed by every 6 months for an 
additional 2 years, and then annually. 


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Notwithstanding standardization of imaging, challenges in the neuroimaging evaluation of patients 
undergoing treatment for GBM remain. In particular, differentiating a treatment response from tumor 
progression can be problematic, and a validated neuroimaging method to clearly distinguish between 
pseudo-progression and tumor progression has unfortunately not been found to date. 
In multicenter MRI studies, standardization of MR scanners and parameters (eg, field strength, 
gradient system, manufacturer, and sequences) must be considered. It is well known that even minor 
differences in hardware or sequence timing may result in significant changes in image contrast and 
analysis. Lesion contrast is also dependent on the magnetic field strength of the scanner, with higher 
field strengths showing higher contrast-to-noise compared with lower field strength scanners (eg, 3 T 
vs 1.5 T). 
Ellingson and colleagues have provided recommendations for brain tumor MRI acquisition for use in 
multicenter clinical trials to reduce variability associated with response assessment 
(Ellingson et al 2015). The protocol was designed to allow flexibility in terms of adding subsequent 
imaging techniques, such as the addition of perfusion MRI prior to acquisition of post-contrast 
3D T1-weighted images, the addition of susceptibility-weighted or gradient-echo acquisition before 
contrast injection, or acquisition of post-contrast, 2D T1-weighted turbo spin-echo (TSE) images 
following post-contrast 3D T1-weighted image acquisition. 
1.2.3. 
O6-methylguanine-DNA Methyltransferase Status and Treatment Response 
1.2.3.1. 
Methylation of the O6-methylguanine-DNA Methyltransferase (MGMT) Gene 
Promoter 
TMZ and other alkylating agents, including the nitrosoureas carmustine and lomustine, are 
commonly used cytotoxic chemotherapies for newly diagnosed and recurrent GBM. They induce 
apoptosis and cell death by methylating guanine at the O6 position, initiating a DSB in the DNA and 
cell cycle arrest. The MGMT protein removes the damaging alkyl groups from the O6 position of 
guanine and repairs the DNA. The alkylated protein is then degraded, requiring constant 
replenishment for DNA repair to be effective. 
High expression of MGMT in cancer cells, including glioma cells, account for the predominant 
mechanism of resistance to alkylating agents. Consistent with this finding, lack of MGMT protein 
correlates with increased sensitivity to DNA-damaging agents, like temozolomide or XRT. The 
absence of MGMT protein in GBM has been determined to be almost exclusively caused by 
methylation of the promoter of the MGMT gene (Hegi et al 2005) referred to hereafter as ‘MGMT 
methylation’ or ‘methylated GBM.’ 
Conversely, patients with an unmethylated MGMT promoter or higher levels of MGMT protein in 
their tumors are less likely to respond to alkylating agents resulting in shorter survival compared 
with patients with a methylated MGMT promoter or lower levels of MGMT protein (Table 1).  
It is known that MGMT is inactivated after each reaction (ie, suicide enzyme). Therefore, if the rate 
of DNA alkylation were to outpace the rate of MGMT protein synthesis, the enzyme could, in theory, 


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be depleted. Several studies have shown that prolonged exposure to TMZ can deplete MGMT 
activity in blood cells, a process that could potentially increase the antitumor activity of the drug 
(Brandes et al 2006; Gilbert et al 2013; Strik et al 2008; Tolcher et al 2003). This resistance to TMZ 
remains a critical barrier to the effective treatment of glioblastoma. 
1.2.3.2. 
MGMT Methylation Status and Significance for Newly Diagnosed Glioblastoma 
Despite differences in the diagnostic methods used to detect MGMT methylation, studies have 
consistently demonstrated improved outcomes for patients with methylated GBM regardless of 
treatment, showed added benefit with TMZ, and suggested that MGMT methylation is both 
prognostic and predictive (Table 1). 


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Table 1: 
O6-methylguanine-DNA Methyltransferase (MGMT) Status and Clinical Benefit 
in Newly Diagnosed Glioblastoma 
Study 
(Phase) 
Age, 
median 
(range) 
Treatment  
arm 
PFS 
OS 
uMGMT 
(months) 
mMGMT 
(months) 
uMGMT 
(months) 
mMGMT 
(months) 
Stupp 
(Phase 3) 
56 
(19–71) 
Radiation 
4.4 
5.9 
11.8 
15.3 
Chemotherapy 
5.3 
10.3 
12.7 
21.7 
NOA-08  
(Phase 3) 
72 
(66–84) 
Radiation 
4.6 (EFS) 
4.6 (EFS) 
10.4 
9.6 
Chemotherapy 
3.3 (EFS) 
8.4 (EFS) 
7 
Not 
reached 
Nordic 
(Phase 3) 
70 
(60–88) 
Radiation 
Not 
reported 
Not 
reported 
7.0 
8.2 
Chemotherapy 
Not 
reported 
Not 
reported 
6.8 
9.7 
ANOCEF  
(Phase 2) 
77 
(80–87) 
Chemotherapy 
2.6 
6.0 
4.4 
7.2 
Brandes 
(Phase 2) 
68 
(65–82) 
Chemoradiation 
9.5 
22.9 
13.7 
Not 
reached 
German 
Glioma 
Network  
(Observational) 
74 
(70–86.6) 
Radiation 
5.2 
4.5 
8.8 
7.8 
Chemotherapy 
0.5 
6.8 
2.6 
7.2 
Chemoradiation 
7.2 
7.3 
10.4 
13.1 
Perry et al  
(Phase 3) 
73 
(65–90) 
Radiation 
Chemoradiation 
Not 
reported 
Not 
reported 
7.9 
7.7 
Sources: General: Chen et al 2013; Stupp: Stupp et al 2005; NOA-08: Wick et al 2012; Nordic: Malmström et al 
2012; ANOCEF: Gállego Pérez-Larraya et al 2011; Brandes: Brandes et al 2009; GGN: Weller et al 2009; 
Perry et al 2017. 
EFS = event-free survival; mMGMT = methylated O6-methylguanine-DNA methyltransferase promoter; OS = 
overall survival; PFS = progression-free survival; uMGMT = unmethylated O6-methylguanine-DNA 
methyltransferase promoter  
In several studies on improving treatment of patients with newly diagnosed GBM without MGMT 
promoter methylation (and thus little or no benefit at all of the addition of TMZ to be expected), 
TMZ has been left out of the investigational arm. Multiple European-led trials have used RT alone, 
rather than RT with chemotherapy, as the comparative arm in trials of novel targets to replace TMZ 


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(Herrlinger et al 2014; Wick et al 2014, Wick et al 2013). The GLARIUS trial, a randomized Phase 2 
study of irinotecan, bevacizumab, and RT versus TMZ and RT in newly diagnosed unmethylated 
GBM found a significantly prolonged median progression-free survival (mPFS) of 9.7 months in the 
experimental arm versus 5.9 months in the standard arm (Herrlinger et al 2014). Despite the mPFS 
benefit observed in this study, the median overall survival (mOS) between the two groups was 
comparable (16.6 months compared with 17.3 months, respectively). This suggested that it is 
reasonable to omit TMZ in newly diagnosed unmethylated patients without adversely impacting the 
patients’ survival (Herrlinger et al 2014). 
1.2.3.3. 
MGMT Methylation Status and Significance for Recurrent Glioblastoma 
In the recurrent setting, MGMT methylation status has yet to guide treatment. Preliminary data 
suggested that prolonged exposure to TMZ may suppress MGMT activity, therefore making the cells 
more susceptible than the standard 5-day regimen (Days 1 to 5 of a 28-day cycle) (Hegi 2005). This 
hypothesis led to a series of studies of dose-dense schedules to prevent repletion of MGMT and 
improve sensitivity to TMZ and shift the outcome of unmethylated GBM patients toward methylated 
GBM patients (Perry et al 2010; Weller et al 2010; Weller et al 2013). A large, randomized trial of 
dose-dense TMZ (21 days on and 7 days off at 100 mg/m2) in the adjuvant setting (RTOG 0525) in 
newly diagnosed GBM patients resolved the conflicting data on timing of standard temozolomide 
and efficacy of alternative dosing. No improvement was seen in mPFS or mOS with dose-dense 
TMZ, regardless of MGMT promoter methylation status (Gilbert et al 2013). These findings, in 
addition to results from dose-dense TMZ at recurrence (Wick et al 2009) suggest that unmethylated 
tumors cannot be ‘sensitized’ to TMZ by solely intensifying the dose. 
The standard dosing of TMZ (Days 1 to 5 of a 28-day cycle) has shown a favorable safety profile 
and modest efficacy in clinical trials. TMZ in increased dose density schedules in maintenance after 
RT and for recurrent tumors that have evaded from prior standard therapy that may include TMZ 
appears to be a rational approach. 
1.2.4. 
Treatment Toxicity 
The dose-limiting factor associated with chemotherapy for GBM is bone marrow toxicity. Daily, 
low-dose TMZ given concomitantly with RT rarely affects platelet or neutrophil counts, but patients 
usually experience some degree of lymphopenia. In contrast, the standard TMZ dosing and schedule 
(Stupp et al 2005) used for adjuvant treatment frequently causes neutropenia and/or 
thrombocytopenia.  
To achieve clinical benefit, it is imperative that the magnitude of any sensitizing effect for TMZ is 
significantly greater in the tumor than in the critical normal tissues. Targeting DNA repair pathways 
might be predicted to achieve tumor-specific chemo- and/or radio-sensitization.  
1.2.4.1. 
Toxicity of Dose-dense Temozolomide Regimens 
Studies have been conducted to assess the safety concerns (Neyns et al 2010). The greater dose 
intensity achieved in these studies does not appear to significantly increase the frequency of 


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thrombocytopenia or neutropenia (Gilbert et al 2013). Available data from Phase 2 trials indicate a 
high incidence of lymphopenia (8% to 68%), a common TMZ toxicity, and a slight increase in 
fatigue. Grade 3 or 4 lymphopenia in trials using the 21 of 28 days TMZ schedule (75 mg/m2) 
occurred in 24% to 53% of cases, and Grade 4 lymphopenia, which may increase the risk of 
opportunistic infections, was reported in 47% in one study for recurrent anaplastic astrocytoma or 
oligoastrocytoma (Neyns et al 2008). 
In the RTOG 0525 study, adverse events (AEs) were evaluated separately during the concurrent 
chemo- and radiotherapy and the adjuvant treatment phase. Grade 3 or 4 lymphopenia was the most 
common toxicity occurring in 12% of patients but without significant opportunistic infections. 
Serious neutropenia and thrombocytopenia occurred in 3.6% and 6.8%, respectively, of all patients 
undergoing RT. There was one treatment-related death as a result of neutropenia (Gilbert et al 2013). 
1.3. 
Background on Poly (ADP-ribose) Polymerase Inhibitors and Pamiparib (BGB-290) 
1.3.1. 
Poly (ADP-ribose) Polymerase (PARP) 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 into double-strand breaks during DNA replication. DNA-bound 
PARP1/2 catalyzes the synthesis of poly (ADP-ribose) (PAR) onto a range of DNA-associated 
proteins that mediate DNA repair. PARP1 also undergoes auto-PARylation, a molecular change that 
ultimately leads to its release from DNA (Leonetti et al 2012). 
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 the clinic, PARP inhibitors, including olaparib, rucaparib, niraparib, and 
talazoparib, have demonstrated sustained antitumor responses as a single agent in patients with 
BRCA1- or BRCA2-mutant tumors, while achieving a favorable safety profile. Olaparib and 
rucaparib are two PARP inhibitors that are approved as a single agent for patients with advanced 
ovarian cancer who have a germline mutation in the BRCA gene (Approved product prescribing 
information; available online). 
Pamiparib (also known as BGB-290) is a highly potent and selective inhibitor of PARP1 and PARP2 
with demonstrated brain penetrance in nonclinical studies (see Section 1.3.4.1). As such it has the 
potential to differentiate from other PARP inhibitors by combining potent PARP-trapping activity 
with significant brain penetrance. This brain penetrance is particularly relevant within a GBM 
population where few cytotoxic drugs have demonstrated efficacy, thought to be due, at least in part, 
to the blood-brain barrier preventing adequate delivery to these tumors. 
1.3.2. 
PARP Inhibitors and Glioblastoma 
As summarized in Section 1.1, GBMs have a high prevalence of genetic alterations affecting DNA 
repair pathways, raising the possibility that PARP inhibitors may be able to contribute to clinical 
benefit for GBM patients. Whereas this hypothesis has not been adequately explored in the clinic, 


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nonclinical data for one such alteration, PTEN loss, support the concept of synthetic lethality of 
PARP inhibition with other pathways aside from BRCA1/2. Deletions in chromosome 10 
encompassing the PTEN gene have been frequently observed in GBM (Endersby and Baker 2008; 
Li and Ross 2007) and have been estimated to occur in about one third of GBMs (Huang et al 2015). 
PTEN is a lipid phosphatase with a role in dampening PI3K/Akt signaling, and PTEN loss results in 
PI3K/Akt pathway hyperactivation. However, PTEN also plays a role in the maintenance of genome 
stability as demonstrated using mouse embryonic PTEN-/- cells. This phenotype was related to a 
defect in the regulation of the expression of RAD51, an important HR component (Shen et al 2007). 
Synthetic lethality of PTEN loss and PARP inhibition is supported by data that the PARP inhibitor 
veliparib is very effective in reducing the survival of PTEN-/- human GBM cell lines, whereas 
astrocytes with the intact PTEN gene are less sensitive to veliparib. PTEN-deficient astrocytes and 
GBM cells were also more sensitive to the methylating agent N-methyl-N′-nitro-N-nitrosoguanidine 
(MNNG) with a mechanism of action very similar to TMZ (McEllin et al 2010). These data suggest 
that GBMs with defects in DNA repair pathways may be sensitive to PARP inhibition, in particular 
when combined with DNA-damaging agents. 
1.3.3. 
PARP Inhibitors in Combination with Temozolomide or Radiation 
PARP-1 and PARP-2 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 limit TMZ cytotoxicity. The 
first step of the BER process is the excision of the modified base by N-methylpurine glycosylase 
(MPG) resulting in an apurinic/apyrimidinic (AP) site that is subsequently cleaved by 
apurinic/apyrimidinic endonuclease. The resultant DNA nicks are finally repaired by the coordinate 
intervention of PARP-1, DNA polymerase, XRCC1 and ligase III. Inhibition of PARP activity 
hampers PARylation of PARP-1 and PARP-2, interrupting the completion of the repair process 
mediated by BER (Kim and Wilson 2012). Combining PARP inhibition with DNA-damaging TMZ 
leads to increased DNA damage that 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 (Tentori et al 1999; Tentori et al 2001). This mechanism might further 
enhance the cytotoxic effects of TMZ combined with a PARP inhibitor. 
Since the discovery of synthetic lethality of PARP inhibitors in BRCA-deficient cells, accumulation 
of unrepaired single-strand breaks (SSBs) resulting from catalytic PARP inhibition has been 
considered central to the mechanism of action of PARP inhibitors. More recently, it has been 
demonstrated that PARP inhibitors also trap PARP1- and PARP2-DNA complexes at DNA damage 
sites and that PARP trapping can be more cytotoxic than unrepaired SSBs (Kedar et al 2012; Murai 
et al 2012; Murai et al, 2014a; Fojo and Bates 2013). Murai and colleagues investigated whether 
PARP trapping is important for chemotherapy combinations that are currently being studied in the 
clinic. To this purpose, a PARP inhibitor with potent PARP-trapping activity, olaparib, was 
compared to a PARP inhibitor with similar catalytic PARP inhibition but significantly less PARP-
trapping activity, veliparib. Both drugs showed highly synergistic effects with the toposisomerase I 
inhibitor camptothecin, consistent with catalytic PARP inhibition being important for the activity of 


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this combination. However, in combination with the alkylating agent TMZ, olaparib was 
significantly more effective than veliparib indicating that PARP trapping was essential for the 
combination activity (Murai et al 2014b). Gill and colleagues similarly showed that sensitivity to a 
PARP inhibitor was due to DNA-trapping activity and that TMZ-mediated potentiation of PARP 
inhibitor activity was associated with enhanced trapping of PARP1-DNA complexes (Gill et al 
2015). These data suggest that combinations of TMZ with PARP inhibitors with potent DNA-
trapping activity may be of particular interest. 
In glioma cells, pharmacological modulation of PARP activity increased growth inhibition by TMZ 
in both p53-wild-type and p53-mutant glioblastoma cells and markedly lowered the TMZ IC50 to 
levels below the concentration of TMZ that can be detected in the plasma or brain of treated patients. 
The most pronounced effect was observed in tumor cells resistant to TMZ due to high MGMT levels 
or to MMR deficiency. In fact, in short-term primary cultures of glioma cells derived from surgical 
specimens, the enhancement of chemosensitivity to TMZ induced by a PARP inhibitor was 
especially evident in MGMT-proficient cells. Moreover, in an MMR-deficient glioma cell line, in 
which an MGMT inhibitor would have been ineffective, the combination of TMZ with the PARP 
inhibitor reverted resistance to the methylating compound (Tentori et al 2001; Tentori et al 2002; 
Tentori et al 2003). These data suggest that GBM patients who derive less benefit from current 
standard of care because of lack of MGMT promoter methylation may benefit from a combination 
regimen that includes a PARP inhibitor.  
Several clinical studies have been conducted with PARP inhibitors (olaparib, rucaparib, and 
veliparib) in combination with TMZ. 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 (DLTs), and observed 
anti-tumor activity was only modest (Gabrielson et al 2015; Gojo et al 2017; Hussain et al 2014; 
Middleton et al 2015; Plummer et al 2013; Su et al 2014). This is contrasted by a recent study for 
talazoparib, a PARP inhibitor with very good DNA-trapping activity. Standard doses of talazoparib 
(0.5 to 1 mg) were administered with low doses of TMZ in patients with non-BRCA1/2-mutated 
cancers (Wainberg et al 2016) The starting dose of TMZ was 25 mg/m2, approximately 12.5% of the 
therapeutic dose, and the MTD was determined 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 partial response or stable disease. 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.  
Ionizing radiation used in the clinical treatment of GBM generates mostly SSBs and to a minor 
extent DSBs. Single-strand breaks are repaired through the BER pathway, operating via either the 
short patch or the long patch repair sub-pathways, which differ in the size of the repair patch and the 
enzymes involved. A PARP-1 role in the short patch is well established, but its contribution in the 
long patch is still unclear. In non-replicating cells, PARP inhibition only delays the repair of SSBs 


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induced by radiation with a minimal impact on cell survival. On the contrary, PARP inhibition 
markedly enhances radiosensitivity of proliferating cells since unrepaired SSBs collide with the 
DNA replication machinery, generating DSBs. Thus, PARP inhibitors have the potential to increase 
the anti-tumor effect of RT by preventing DNA damage repair and increasing cytotoxic DNA 
damage (Godon et al 2008; Noel et al 2006; Dungey et al 2008). 
1.3.4. 
Nonclinical Data for Pamiparib 
1.3.4.1. 
Nonclinical Safety Data 
The nonclinical toxicity and toxicokinetic profile of pamiparib was characterized in single and up to 
91-day repeat-oral-dose studies in rats and dogs, and in a core battery of genotoxicity tests, including 
in vitro Ames and chromosomal aberration assays, and in vivo bone marrow micronucleus assays in 
rats. Safety pharmacology assessments included in vitro hERG channel activity assays and in vivo 
studies of cardiovascular function in dogs, as well as central nervous system and respiratory system 
function tests in rats. 
The main toxicity findings were bone marrow inhibition that correlated with clinical pathology 
changes and gastrointestinal toxicity that presented as emesis, decreased food consumption and 
decreased body weight. The systemic exposure increased dose-proportionally without apparent sex 
differences or accumulation. The MTD was considered to be 6 mg/kg in rats and 3 mg/kg in dogs for 
both 28-day and 91-day toxicity studies.  
Pamiparib was not mutagenic in the in vitro Ames (bacterial reverse mutation) assay, but clastogenic 
in the in vitro chromosomal aberration assay in mammalian Chinese hamster ovary cells and in the in 
vivo bone marrow micronucleus assay in rats, which is consistent with its mechanism of action. 
PARP enzymes are involved in normal cellular homeostasis, such as DNA transcription, cell cycle 
regulation and DNA damage repair. Pamiparib interacts with and inhibits the enzymatic repair 
machinery that carries out detection and repair of single-strand DNA breaks (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 
planning as it was not considered essential because of its genotoxicity and bone marrow inhibition. 
There was no apparent inhibition of pamiparib on hERG channel as the value of half-maximal 
inhibition 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 ECGs were noted in telemetry-
instrumented conscious dogs. No effects on the central nervous system or respiratory functions were 
noted in Sprague-Dawley rats. No abnormal changes in the cardiovascular, central nervous system, 
and respiratory system 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. 




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concentration ratio calculated by partial area under the concentration-time curve (AUC1~4h) was 
18%. In a tissue distribution study in rats, pamiparib was detected in all organs checked after oral 
administration. Specifically, in individual rat brains, the ratio of brain to blood concentration ranged 
from 21% to 63% over time (0.5 to 24 hours) with a mean brain/blood ratio (AUC1~4h) of 26%.  
A population pharmacokinetic/pharmacodynamic (PK/PD) model was developed based on clinical 
PK data from Phase 1 trial BGB-290-AU-002 (Section 1.3.5) and tissue distribution data from rats. 
Simulated brain concentration-time profiles in a typical patient suggested that trough brain 
concentration at 60 mg BID was above the threshold of 0.5 M identified from a sensitive animal 
model for efficacy (Figure 2). 
Figure 2: 
Simulation of Pamiparib Concentrations in Human Organs 
Simulated PK profiles:  
bottom profile in red = brain;  
top profile in black = plasma;  
horizontal green line = threshold of 0.5 µM identified from a sensitive animal model for efficacy 
 
Single-Agent Antitumor Activity of Pamiparib 
Pamiparib as a single agent has demonstrated excellent in vitro activity against tumor cell lines with 
defects of the HR pathway. In vivo, pamiparib showed strong antitumor activity against a 
BRCA1-mutant mouse xenograft model (MDA-MB-436 breast cancer) and was 16-fold more potent 
than olaparib. In a PK/PD study, oral (PO) administration of pamiparib resulted in time- and 
dose dependent inhibition of PARylation in MDA-MB-436 breast cancer xenografts in mice. 


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Inhibition of PARylation in the tumor tissues correlated well with tumor drug concentrations of 
pamiparib. 
Combination Antitumor Activity of Pamiparib with Temozolomide 
The anti-proliferative effect of pamiparib in combination with TMZ was evaluated in 8 human GBM 
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 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 3). 
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 
3 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 
antitumor activity and delayed resistance.  
Figure 3: 
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 


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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 
Given the significant brain penetrance of pamiparib, its activity was further explored in an 
intracranial tumor model in nude mice for H209-T small cell lung cancer xenografts (Figure 4). 
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 (p<0.01), with 
median survival of 54 days. The result suggests pamiparib in combination with TMZ can overcome 
TMZ resistance in this intracranial model. 
Figure 4: 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 
1.3.5. 
Clinical Data for Pamiparib 
Pamiparib is currently being studied in two Phase 1a studies (BGB-290-AU-002 in Australia, n = 53 
[as of 30 September 2016] and BGB-290-102 in China, n = 15 [as of 25 September 2017]), as well 
as one Phase 1 study (BGB-A317/BGB-290_Study_001) for the combination of pamiparib with 
BGB-A317, an anti-PD-1 antibody (n = 41 [as of 02 February 2017]); one Phase 1b study 


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(BGB-290-103) for the combination of pamiparib with TMZ in patients with solid tumors (n = 10 [as 
of 01 December 2017]); and one Phase 1b/2 study (BGB-290-104) for the combination of pamiparib 
with RT and/or TMZ in patients with glioblastoma (n = 4 [as of 02 February 2017]). The study data 
from BGB-290-AU-002 are the most mature and key interim results are summarized below. 
1.3.5.1. 
Pharmacokinetics Data for BGB-290-AU-002 
In the first in human Phase 1 study, interim PK data of pamiparib showed that pamiparib is rapidly 
absorbed and eliminated after oral administration. The maximum serum concentration (Cmax) and the 
drug exposure (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 h, 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 
approximately 2-fold accumulation.  
The impact of administration of a high-fat meal on the PK of pamiparib after a 60-mg dose is being 
assessed. Preliminary data from 13 patients enrolled in the food effect cohort of 
study BGB-290-AU-002 show that after administration with a high-fat meal, the rate of absorption 
was slower, as indicated by a delay in time to maximum concentration (Tmax) from 2 to 7 hours, and 
lower maximum concentration (Cmax), and AUC0-∞ after a high-fat meal was 15% lower than fasted 
(Table 2). 
Table 2: 
PK Parameters for the Food Effect Cohort 
PK Parameter 
Fed 
(N = 13) 
Fast 
(N=13) 
Treatment 
Comparison 
GMR (90% CI) 
AUC [ng•h/mL], Geo mean (CV, %) 
25003 (58) 
29419 (62) 
0.85 (0.74 - 0.98) 
 
Cmax [ng/mL], Geo mean (CV, %) 
1185 (32) 
2013 (32) 
0.59 (0.53 - 0.66) 
 
Tmax [h], Median (range) 
7.0 (2.0 - 7.1) 
2.0 (1.0 - 4.1) 
 
 
T½ [h], Geo mean (range) 
12.6 (5 - 22) 
12.4 (5 - 23) 
 
 
Abbreviations: AUC, area under the concentration-time curve; Cmax, maximum observed concentration; CV = coefficient 
of variation; GMR, geometric mean ratio; h, hours; T1/2, terminal half-life; Tmax, time to maximum concentration 
Based on pharmacodynamic data, with an apparent flat exposure-response for PAR inhibition and 
objective responses observed at lower dose levels, the decrease in Cmax and the modest decrease of 
15% in overall exposure with high-fat meal is not considered to be clinically significant. However, 
since pamiparib is not a substrate to known active transporters, and its brain penetration is thought to 
be driven by passive diffusion through a concentration gradient, in a brain tumor population where 
brain pentrance is key, the reduction in Cmax may reduce brain penetration of pamiparib. Therefore, 
in GBM studies, patients will continue to be required to fast for 1 hour before and 2 hours after 
pamiparib administration. 


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1.3.5.2. 
Exploratory Biomarker Data 
 
1.3.5.3. 
Clinical Safety and Preliminary Efficacy for BGB-290-AU-002 
BGB-290-AU-002 is a first-in-human trial evaluating pamiparib to characterize the safety, the MTD, 
preliminary anti-tumor activity and the pharmacokinetics of pamiparib given as a monotherapy in a 
3+3 dose escalation scheme. Pamiparib was administered in doses ranging from 2.5 mg PO BID up 
to 120 mg PO BID. 
The study is being conducted in 5 Australian study centers, and preliminary data for 45 patients are 
available (cutoff date of 30 September 2016).  
The preliminary safety data indicate that the most frequent adverse events (AEs) (≥ 10% of patients) 
assessed as related to pamiparib 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 are of interest in this study. The most frequent hematologic AEs (≥ 10% of 
patients) assessed as related to pamiparib were anemia (22%, n = 10) and neutropenia (11%, n = 5). 


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Hematologic AEs, regardless of relatedness, were reported in 40% of patients (n = 18). Anemia was 
most frequent (33%, n = 15), followed by neutropenia (11%, n = 5) and thrombocytopenia (2%, 
n = 1). 
Twenty-six patients experienced Grade 3 AEs (regardless of relatedness), and no Grade 4 AEs were 
reported. Eleven Grade 3 AEs in 9 patients (20%) were considered related to pamiparib: anemia 
(n = 5), neutropenia (n = 3), hypophosphatemia (n = 1), nausea (n = 1) and fatigue (n = 1). Serious 
AEs (SAEs) reported as related to pamiparib included anemia (n = 2) and nausea (n = 1). 
SAEs were reported in 25 patients, and for 3 patients they were considered related to BGB 290: 
anemia (n = 2) and nausea (n = 1). Three patients discontinued study drug because of an AE: 
vomiting (n = 1), oral paresthesia (n = 1), and right neck cutaneous metastases (n = 1). 
Four patients experienced a fatal AE ≤ 28 days after the last pamiparib dose. All deaths were due to 
complications of the underlying malignancy, and none was considered related to pamiparib. 
Four patients experienced AEs that were considered DLTs: Grade 2 nausea that persisted despite 
optimal standard medical therapy in 2 patients; Grade 2 anorexia and Grade 2 nausea in 1 patient, 
and Grade 2 nausea and Grade 2 paresthesia in 1 patient. Based on the encountered DLTs and the 
overall safety profile of BGB-290, the MTD of BGB-290 was determined to be 80 mg PO BID (160 
mg/day). 
Ten patients achieved either a CR (n = 2) or PR (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). 
1.3.5.4. 
Pamiparib Dose Selection 
Based upon the overall safety, efficacy, and PK profile of pamiparib, the dose of pamiparib 60 mg 
PO BID was selected using available clinical data from Study BGB-290-AU-002 (Section 1.3.5.3). 
The study determined the MTD of pamiparib to be 80 mg PO BID (160 mg/day). The dose of 60 mg 
BID was selected for further evaluation based on the following findings: 
 A linear PK profile observed up to 80 mg BID 
 Similar toxicity profiles at 60 mg and 80 mg BID with the following exceptions: 
o Fewer patients at 60 mg BID experienced treatment-related treatment-emergent 
adverse events (TEAEs) of anemia and neutropenia. 
o There was a slightly higher rate of dose interruptions at 80 mg vs 60 mg BID for 
anemia and nausea. 
 Responses were observed across the dose range evaluated.  
For additional and updated clinical information to date, please refer to the most current versions of 
the Pamiparib IB. 


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1.4. 
Study Rationale 
Aside from surgical resection and RT as main standards of care, TMZ is the only systemic agent 
approved for first-line patients but only patients with methylated MGMT promoter benefit from 
TMZ. Glioblastomas have a high prevalence of alterations affecting DNA repair. There is strong 
scientific rationale that PARP inhibitors may provide antitumor activity in GBM, in particular when 
combined with standard-of-care DNA-damaging RT and/or TMZ. These novel combinations may 
furthermore be able to overcome resistance in GBMs with unmethylated MGMT promoter. 
Pamiparib is a promising PARP inhibitor to study in GBM as it is a potent and selective inhibitor of 
PARP1 and PARP2, exhibits excellent DNA-trapping activity and shows brain penetrance in 
nonclinical experiments. In the clinic, pamiparib has shown favorable PK properties, has been 
well-tolerated and achieved maximum pharmacodynamic target modulation in PBMCs at a dose 
level well below the regimen for this study (10 mg versus 60 mg BID). PK modeling predicts that 
the 60 mg pamiparib dose will achieve brain concentrations required for antitumor activity. 
Nonclinical and preliminary clinical data suggest that maximizing PARP inhibition with lower doses 
of TMZ to induce DNA damage may provide antitumor activity with an acceptable safety profile. 
For these reason, the regimens of this study will try to maximize brain penetrance and PARP 
inhibition in tumor tissue by investigating full dose pamiparib with lower TMZ dose levels. In 
summary, pamiparib is an excellent candidate to determine the effects of combining PARP inhibition 
with RT and/or TMZ in this unmet medical need.  
1.5. 
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 at least partial overlap with the safety profile of RT 
and/or TMZ. Therefore, patients of this study may experience AEs typical for these study treatments 
at a higher frequency and/or severity. In addition, patients may encounter AEs that are uniquely 
caused by the novel combination(s). Given the dire prognosis of GBM patients and the limited 
treatment options, the risk of combining pamiparib with RT and/or 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 Sections 1.3 and 1.4, 
scientific rationale and supportive data are strong for combining PARP inhibitors with RT and/or 
TMZ in GBM. This warrants evaluation of these combinations in GBM patients, as the overall 
risk-benefit assessment appears favorable. 
1.6. 
Study Conduct 
This study will be conducted in compliance with the protocol approved by the Institutional Review 
Board (IRB) or Independent Ethics Committee (IEC) and regulatory authorities, and in accordance 
with Good Clinical Practice (GCP) standards.  


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
2.1.1. 
Phase 1b 
Arm A (pamiparib + RT): Patients with first-line glioblastoma with unmethylated MGMT 
promoter (unmethylated GBM) 
 To assess safety and tolerability of pamiparib combined with RT 
 To identify DLTs and determine the MTD or maximum administered dose (MAD) for 
pamiparib combined with RT 
 To select the recommended Phase 2 schedule for pamiparib combined with RT 
Arm B (pamiparib + RT + TMZ): Patients with first-line unmethylated GBM 
 To assess safety and tolerability of pamiparib combined with RT and TMZ 
 To identify DLTs and determine the MTD or MAD for TMZ when combined with RT and 
the MTD/MAD of pamiparib as determined in Arm A 
 To select the RP2D for TMZ when combined with RT and the MTD/MAD of pamiparib 
determined in Arm A 
Arm C (pamiparib + TMZ): Patients with recurrent/refractory GBM 
 To assess safety and tolerability of pamiparib combined with TMZ 
 To identify DLTs and determine the MTD or MAD for TMZ combined with pamiparib 
 To select the RP2D for TMZ combined with pamiparib 
2.1.2. 
Phase 2 
Arm A, Expansion 1 (pamiparib + RT): Patients with first-line unmethylated GBM 
 To make a preliminary assessment of efficacy of pamiparib combined with RT 
Arm B, Expansion 1 (pamiparib + RT + TMZ): Patients with first-line unmethylated GBM 
 To make a preliminary assessment of efficacy of pamiparib combined with RT and TMZ 
Arm C, Expansion 1 (pamiparib + TMZ): Patients with recurrent/refractory unmethylated GBM 
 To make a preliminary assessment of efficacy of pamiparib combined with TMZ 
Arm C, Expansion 2 (pamiparib + TMZ): Patients with recurrent/refractory methylated GBM 
 To make a preliminary assessment of efficacy of pamiparib combined with TMZ 


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2.2. 
Secondary Objectives 
Phase 1b, all Arms 
 To characterize the PK of pamiparib in combination with RT and/or TMZ 
 To make a preliminary assessment of pamiparib efficacy in combination with RT and/or 
TMZ 
Phase 2, all Arms 
 To further characterize the efficacy, safety, and tolerability of pamiparib in combination 
with RT and/or TMZ 
 To further characterize the PK of pamiparib in combination with RT and/or TMZ 
2.3. 
Exploratory Objectives 
3. 
STUDY ENDPOINTS 
3.1. 
Primary Endpoints 
Phase 1b, all Arms 
 Incidence and nature of DLTs  
 Incidence, nature, and severity of AEs, graded according to the NCI-CTCAE, v4.03 
 Number of cycles (Arm C only) and the dose intensity of each component of the treatment 
regimens, and changes in vital signs and clinical laboratory test results during and following 
study treatment  
Phase 2, Arm A (pamiparib + RT) and Arm B (pamiparib + RT + TMZ) 
 Modified disease control rate (DCR) as assessed using the Response Assessment in Neuro-
Oncology (RANO) criteria (Appendix 2) 
Phase 2, Arm C (pamiparib + TMZ) 
 Objective response rate (ORR) as assessed using RANO criteria 


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3.2. 
Secondary Endpoints 
Phase 1b, all Arms 
 PK parameter for pamiparib of Ctrough  
 
Modified DCR (Arms A and B), DCR (Arm C), ORR, and clinical benefit rate (CBR)  
 Time-to-event endpoints: duration of response (DOR), PFS, and OS 
Phase 2, Arm A (pamiparib + RT) and Arm B (pamiparib + RT + TMZ) 
 ORR and CBR as assessed using RANO criteria 
 Time-to-event endpoints: DOR, PFS, and OS 
 Incidence, nature, and severity of AEs, graded according to NCI-CTCAE, v4.03 
 The dose intensity of each component of the treatment regimens, and changes in vital signs 
and clinical laboratory test results during and following study treatment  
 PK parameter for pamiparib: Ctrough 
Phase 2, Arm C (pamiparib + TMZ) 
 DCR and CBR as assessed using RANO criteria 
 Time-to-event endpoints: DOR, PFS, and OS  
 Incidence, nature, and severity of AEs, graded according to NCI-CTCAE, v4.03 
 Number of cycles and the dose intensity of each component of the treatment regimens, and 
changes in vital signs and clinical laboratory test results during and following study 
treatment  
 PK parameter for pamiparib: Ctrough 
3.3. 
Exploratory Endpoints 
4. 
STUDY DESIGN 
4.1. 
Summary of Study Design 
This is an open-label, multi-center, multiple-dose, dose-escalation Phase 1b/2 study to determine the 
safety, pharmacokinetics (PK) and pharmacodynamics of pamiparib in combination with RT and/or 


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TMZ. Two initial arms (Arms A and C) and a potential third arm (Arm B) will be enrolled in the 
study (Figure 6). In Arm A, pamiparib will be combined with RT in patients with first-line GBM 
with unmethylated MGMT promoter (unmethylated GBM). In Arm B, depending on the safety of the 
Arm A combination, pamiparib will be combined with both TMZ and RT in patients with first-line 
unmethylated GBM. In Arm C, pamiparib will be combined with TMZ in patients with 
recurrent/refractory GBM with methylated or unmethylated MGMT promoter. 
Patients will continue receiving pamiparib in combination with RT and/or TMZ until progressive 
disease (PD), unacceptable toxicity or death, withdrawal of consent, loss to follow-up, or study 
termination by sponsor. 
Figure 6  
Phase 1b/2 Study Overview for Pamiparib with Radiation Therapy and/or 
Temozolomide in Patients with First-Line or Recurrent/Refractory Glioblastoma 
 
* During dose escalation (Phase 1b), both unmethylated and methylated GBM are allowed in Arm C. 
290 = pamiparib; 1L = first-line; methylated = glioblastoma with methylated MGMT promoter; rec./ref. = 
recurrent/refractory; RT = radiation therapy; TBD = to be determined; unmethylated = glioblastoma with 
unmethylated MGMT promoter; wks = weeks 
 


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4.1.1. 
Dose Escalation Phase (Phase 1b) 
The Phase 1b, dose escalation phase consists of the following: 
Arm A: Pamiparib (60 mg BID) administered continuously at increasing exposures of 2, 4, and 6 
weeks in combination with RT administered for 6 to 7 weeks. 
Arm B: Depending on the safety of the Arm A combination, the following combination may be 
explored: pamiparib (at the exposure determined as safe in Arm A) in combination with 
RT administered for 6 to 7 weeks and increasing doses of TMZ (Section 4.2.1). 
In both Arms A and B, after RT is completed, patients will receive no further RT.  
Maintenance Treatment for Arms A and B 
Following completion of RT, at the discretion of the investigator and after discussion with the 
medical monitor, patients in the Arm A escalation and expansion and patients in Arm B escalation 
phases of the study may continue to receive pamiparib in combination with TMZ. TMZ will be given 
at a dose level lower than or equal to a dose that has been determined to be safe and tolerable in Arm 
C of study. 
In the Arm B expansion phase of the study, maintenance treatment with pamiparib in combination 
with TMZ will be mandatory for all patients.  
Dosing for this maintenance treatment should begin after the 4-week rest period (+ 7 days) to allow 
for recovery from RT treatment (please refer to Appendix 1 Table 4). 
Arm C: Pamiparib (60 mg BID, administered continuously) in combination with increasing doses 
of TMZ (Section 4.2.1). TMZ will be administered on Days 1 to 21 of each 28-day cycle.  
Approximately 60 patients may be enrolled in the 3 arms of the dose escalation phase. The actual 
sample size in this phase will depend on the number of dose escalation cohorts enrolled per arm. 
4.1.2. 
Dose Expansion Phase (Phase 2) 
Once the safety, tolerability, PK, pharmacodynamic, and preliminary antitumor activity have been 
reviewed for the dose escalation cohorts of each of the arms, up to approximately 60 patients may be 
enrolled in expansion cohorts for each of the 3 arms at a dose level below or equal to the MTD or 
MAD for that arm. In Arm C, 2 expansion cohorts may be opened, one for unmethylated GBM and 
one for methylated GBM (Section 4.3).  
Approximately 60 patients may be enrolled during the dose escalation phase, and in each of the 
4 dose-expansion cohorts totalling 240 patients in the dose expansion phase, for an approximate total 
of 300 patients enrolled in the entire study. 
Adverse events (AEs) during and after the treatment period with study drug(s) will be followed and 
documented as outlined in Section 8.4 and Section 10. AEs will be graded according to National 
Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) v4.03.  


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To determine the PK properties of pamiparib, blood samples will be taken at various time points as 
outlined in Section 8.5 and Appendix 1. To determine pharmacodynamic effects of pamiparib, blood 
samples will be obtained coinciding with specific PK time points as outlined in Section 8.5 and 
Appendix 1. 
Disease status will be assessed using Response Assessment in Neuro-Oncology (RANO) criteria 
(Appendix 2). Patients will undergo tumor assessments at screening and then every 8 weeks, or as 
clinically indicated.  
In Arm B expansion phase of the study, maintenance treatment (pamiparib in combination with 
TMZ) will be mandatory for all patients.  In Arm A expansion phase of the study, continuation of 
treatment (with pamiparib in combination with TMZ) will be at the discretion of the investigator 
after discussion with the Medical Monitor. 
Following completion of RT, all patients in Arms A and B who continue on pamiparib in 
combination with TMZ should follow the schedule of assessments for maintenance treatment 
(Appendix 1 Table 4).  
Patients in Arms A and B who have completed all study treatments per protocol and do not continue 
on pamiparib in combination with TMZ (maintenance) should have their EOT visit at the end of the 
Rest Phase, 28 days after RT was completed, unless they do not complete the full study treatment; in 
such a case, they should have the end-of-treatment (EOT) visit within 7 days of stopping all study 
treatment.  
All other patients who have discontinued all study treatments should return to the clinic for an EOT 
visit within 7 days of stopping all study treatment. 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.  
After the EOT visit, all patients should have regular follow-up for safety, efficacy, and survival as 
outlined in Section 6.6. 
Study procedures and assessments are further detailed in Section 8. 
4.2. 
Details of Dose-Escalation Stage 
4.2.1. 
Starting Dose and Dose-Escalation Approach 
Arm A 
RT will be administered QD  5 days/week for 6 to 7 weeks with 1.8 or 2 Gy/fraction for a total 
target dose of between 58 Gy and 64 Gy. 
The starting dose for pamiparib will be the 60 mg PO BID based on the rationale outlined in 
Sections 1.3 and 1.4. In Cohort 1, exposure to pamiparib will be limited to the first 2 weeks of RT. In 
Cohorts 2 and 3, pamiparib will be given for the first 4 and 6 weeks of RT, respectively. If 2, 4, or 
6 weeks of combination treatment exceeds the MTD, alternative regimens for pamiparib may be 
explored after discussions with all investigators based on which regimen exceeded the MTD and 


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what toxicities were observed. For example, if 2 weeks of pamiparib are not tolerated, a schedule of 
1 week on, 1 week off, or 1 week on and 3 weeks off may be explored. Depending on data available 
at that time, a lower dose level of pamiparib may also be explored.  
Arm B 
The opening of Arm B will depend on the safety of the Arm A combination, and Arm B may be 
enrolled at the initial dose and schedule of pamiparib found to be safe and tolerable in Arm A. RT 
will be administered as for Arm A. 
The first dose level of TMZ will be lower than or equal to a dose that has been determined to be safe 
and tolerable in Arm C, and dose escalation will proceed as described for Arm C. The time period of 
TMZ administration may be the same or shorter than that for pamiparib administration. Similar to 
Arms A and C, alternative regimens may be explored with adjustments of dose and/or schedule as 
outlined for Arms A and C.  
Arm C 
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 to 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. TMZ will be given on Days 1 
to 21 of each 28-day cycle based on data and rationale discussed in Sections 1.2, 1.3, and 1.4.  
Following the same rationale for pamiparib dosing as for Arms A and B, all patients will receive 
pamiparib of 60 mg PO BID continuously. 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, such as a lower dose of pamiparib, a lower dose of TMZ, and/or 
alternative dosing schedules for either drug. 
Depending on emerging safety data from this and other pamiparib Phase 1 studies, the pamiparib 
regimen may be switched to QD for one or more of the 3 arms at any time during or after dose 
escalation. The QD dose of pamiparib may be escalated according to the dose escalation rules in 
Section 4.2.2 of the protocol. 
Once Arm C dose escalation identifies the RP2D for the combination, that combination regimen 
may be applied in Phase 2 Arm A and B patients (see Section 4.3). Additionally, data emerging 
from other ongoing studies with pamiparib may be used to determine the combination regimen. 
4.2.2. 
Rules for Dose Escalation 
Dose escalation in all 3 arms will occur in accordance with the following modified 3+3 dose 
escalation rules. 
A minimum of 3 patients will be initially enrolled per cohort. 


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 If none of the first 3 evaluable patients enrolled in a given cohort experience a DLT, 
dose escalation may proceed. 
 If one of the first 3 evaluable patients enrolled in a given cohort experiences a DLT, 
additional patients (for a minimum of 6 evaluable patients) will be enrolled in that cohort.  
o If less than one-third of evaluable patients in a given cohort experiences a DLT (eg, 
DLTs in fewer than 2 of 6 patients), escalation will proceed to the next higher dose 
level. 
If a DLT is observed in one-third or more of patients (eg, 2 or more of up to 6 patients), the MTD 
will have been exceeded, and dose escalation will be stopped. 
1. Additional patients (for a minimum of 6 evaluable patients) will then be assessed for DLTs at 
the preceding dose level (if a minimum of 6 evaluable patients had not already been assessed at 
that dose level).  
2. 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 (eg, DLTs in fewer than 2 of 6 patients) 
will be declared the MTD. 
If less than one-third of evaluable patients (eg, DLTs in fewer than 2 of 6 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 pamiparib (Arm A) or TMZ (Arms B and 
C), including AEs, laboratory assessments, and PK analyses (as available), will be reviewed by the 
medical monitor, PK scientist, Safety Scientist and Biostatistician with input from other members of 
the team as appropriate. 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 treatments for all cohorts. The following assessments must be obtained at the end of the 
DLT assessment window: complete physical examination, vital signs and weight, Eastern 
Cooperative Oncology Group (ECOG) performance status, ECG, hematology, chemistry, 
coagulation, urinalysis, AEs, and concomitant medications. 
For Arm A, the DLT assessment window will depend on the time period of pamiparib administration 
during RT and will consist of the time period of combination treatment plus 4 weeks after the last 
scheduled combination treatment, eg, 6 weeks for Cohort 1 of Arm A when pamiparib is given 
during the first 2 weeks of RT, and 10 weeks for Cohort 3 of Arm A when pamiparib is given during 
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For Arm B, the DLT assessment window will depend on the time period of combined administration 
of pamiparib and TMZ during RT and will otherwise follow Arm A rules, eg, if TMZ will be given 
only for the first 3 weeks of pamiparib and RT, then the DLT assessment window will be 7 weeks.  
For Arm C, 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 experience a 
DLT and who do not receive ≥ 42 Gy of RT (Arms A and B) and ≥ 70% of scheduled pamiparib 
(Arms A, B and C) and TMZ (Arms B and C) 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 DLT assessment. 
4.2.4. 
Definition of Dose-Limiting Toxicity 
A DLT is defined as one of the following toxicities occurring during the DLT assessment window 
(as defined for each of the arms and cohorts; Section 4.2.3) and considered by the investigator to be 
related to pamiparib:  
 Grade 3 non-hematologic, non-hepatic major organ AE, with the following exceptions:  
o Grade 3 nausea, vomiting, or diarrhea that resolves to Grade 1 with optimal medical 
management within 3 days  
o Grade 3 electrolyte disturbances that respond to correction within 3 days  
 Grade 4 neutropenia lasting > 7 days  
 Grade  3 febrile neutropenia 
 Grade 3 thrombocytopenia with clinically significant bleeding 
 
Grade 4 thrombocytopenia lasting  3 days and requiring transfusion, or any decreased platelet count 
<15,000/mm3/ <15.0 x 109/L 
 Grade  4 anemia 
 Grade  3 total bilirubin or hepatic transaminases (ALT [SGPT] or AST [SGOT]) with the 
following exceptions: 
o For patients with Grade 1 hepatic transaminase levels at baseline, a hepatic transaminase 
level of  7.5  upper limit of normal (ULN) will be considered a DLT. 
4.3. 
Details of Cohort-Expansion Stage 
Expansion cohorts (up to approximately 60 patients each) may be enrolled at a dose level below or 
equal to the MTD or MAD of pamiparib (Arm A) or TMZ (Arms B and C) to better characterize 
the safety and tolerability of pamiparib in combination with RT, RT and TMZ or TMZ alone, and to 
make a preliminary determination of the efficacy of these combinations.  


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Arms A and B may have one expansion cohort each, and only patients with unmethylated GBM will 
be allowed to enroll. After dose escalation in Arm C for GBM patients regardless of MGMT 
methylation status, Arm C may have two expansion cohorts, one for unmethylated GBM and one for 
methylated GBM. 
The rules for continued dosing in the cohort-expansion stage will be identical to those in the 
dose-escalation stage. 
If the frequency of Grade ≥ 3 toxicities or other unacceptable chronic toxicities in the cohort 
expansion stage of a given arm suggest 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 approximately 60 patients) into an expansion cohort at a lower dose level. 
4.4. 
Duration of Study 
The duration of the study from first enrolled patient to final analysis of OS is estimated to be 
approximately 4 years. 
5. 
STUDY POPULATION 
5.1. 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for the study: 
For all patients 
1. Signed Informed Consent Form (ICF) 
2. 
Age  18 years 
3. 
Histopathologically confirmed glioblastoma (World Health Organization [WHO] Grade IV) 
(Louis et al 2016) 
 Tumor must have a supratentorial component. 
4. 
5. 
Ability to undergo serial MRI scans (computerized tomography [CT] cannot substitute for 
MRI) 
6. 
Brain MRI scan ≤14 days prior to Day 1 
 Patients requiring glucocorticoids must be on a daily dose equivalent of dexamethasone 
4 mg twice daily or less that has been stable for ≥ 7 days prior to the MRI 
7. 
ECOG performance status ≤ 1 (Appendix 3) 


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8. 
Ability to swallow whole capsules 
9. 
Adequate hematologic and end-organ function, as defined by the following laboratory results 
(obtained ≤ 2 weeks prior to Day 1): 
 Absolute neutrophil count (ANC)  1.5 x 109/L 
 Platelet count  100 x 109/L 
 Hemoglobin ≥ 9 g/dL ≥ 14 days after growth factor support or transfusion if appropriate 
 Serum creatinine  1.5 x ULN or estimated creatinine clearance 50 mL/min (calculated 
using the institutional standard method) 
 Total serum bilirubin  1.5 x ULN (≤ 4 x ULN, if Gilbert’s syndrome) 
 Aspartate and alanine aminotransferase (AST and ALT)  3 x ULN 
 Albumin ≥ 3 g/dL 
 International Normalized Ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) 
≤ 1.5 x ULN 
10. Female patients of childbearing potential and female partners of male study patients must agree 
to practice highly effective methods of birth control (Appendix 4) for the duration of the study, 
and for ≥ 6 months after last study treatment. In addition, non-sterile male patients must agree to 
practice highly effective methods of birth control (Appendix 4) and avoid sperm donation for the 
duration of the study and for ≥ 6 months after the last dose of study drug. 
11. Willingness and ability to comply with all protocol-specified requirements  
→ For patients in Arms A and B (NOT applicable to Arm C) 
12. No previous treatment except surgery (ie, no previous RT, local chemotherapy, or 
systemic therapy for lower grade central nervous system tumors) 
13. Ability to initiate RT ≤ 49 days after surgery, but ≥ 14 days after a biopsy or ≥ 28 days 
after an open biopsy or a craniotomy with adequate wound healing 
14. Documentation of unmethylated MGMT promoter status 
 In escalation cohorts, it is preferable to determine MGMT status by quantitative 
methylation-specific polymerase chain reaction (MS-PCR). Other acceptable 
platforms include pyrosequencing methodologies and methylation sensitive high-
resolution melting (MS-HRM) assays with comparable sensitivity, applied to archival 
or fresh tumor tissue. Sponsor must be notified prior to utilizing alternate assays or if 
data from acceptable alternate platforms are available. 
 In expansion cohorts, archival or fresh tumor tissue must be submitted for central 
analysis of MGMT status. 


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→ For patients in Arm C Escalation (NOT applicable to Arms A and B) 
15. Documentation of MGMT promoter status 
 It is preferable to determine MGMT status by MS-PCR. Other acceptable platforms 
include pyrosequencing methodologies and MS-HRM assays with comparable 
sensitivity, applied to archival or fresh tumor tissue. Sponsor must be notified prior to 
utilizing alternate assays or if data from acceptable alternate platforms are available.  
16. No prior systemic chemotherapy, other than TMZ, for glioblastoma (including 
investigational cytotoxic chemotherapy) and no prior anti-angiogenic therapy  
 Prior use of Optune device is allowed with a minimum of 1 week since last Tumor 
Treating Fields application 
17. Histologically confirmed secondary glioblastoma will be allowed during the dose 
escalation phase only 
18. Disease that is evaluable or measurable as defined by Response Assessment in 
Neuro-Oncology (RANO) criteria (Appendix 2) 
→ For patients in Arm C Expansion  
19. Histologically confirmed de novo (primary) glioblastoma with unequivocal first 
progressive disease (PD) after RT with concurrent/adjuvant TMZ chemotherapy as defined 
by one or more of the following: 
 PD ≥ 3 months after the end of radiotherapy 
 PD that is clearly outside the radiation field 
 PD that has been unequivocally proven by surgery/biopsy 
20. Disease that is measurable as defined by RANO criteria (Appendix 2) 
 Patients with recurrent disease must have at least one bi-dimensionally measurable 
contrast-enhancing lesion with clearly defined margins by MRI scan, with minimal 
diameters of 10 mm, visible on 2 or more axial slices 
21. Documentation of MGMT promoter status 
 Tumor tissue (archival or fresh) must be submitted for central analysis of MGMT 
status 
 Patients will be enrolled into 1 of 2 expansion cohorts based on MGMT methylation 
status 
5.2. 
Exclusion Criteria 
Patients will be excluded from the study for any of the following reasons: 


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For all patients 
1. Chemotherapy, biologic therapy, immunotherapy, or investigational agent ≤ 21 days (or 
≤ 5 half-lives, whichever is shorter) prior to Day 1  
2. 
Unresolved acute effects of any prior therapy of Grade ≥ 2, except for AEs not constituting a 
safety risk by investigator judgement 
3. 
Major surgical procedure, open biopsy, or significant traumatic injury ≤ 28 days 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. 
4. 
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 
5. 
Active infection requiring systemic treatment  
6. 
Have known human immunodeficiency virus (HIV) infection or serologic status reflecting 
active viral hepatitis infection: 
 Patients with untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers whose 
HBV DNA is > 500 IU/mL or patients with active hepatitis C virus (HCV) should be 
excluded. Note: Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable 
hepatitis B (HBV DNA ≤ 500 IU/mL), and cured patients with hepatitis C can be enrolled.  
7. 
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 (see Appendix 5) 
≤ 6 months prior to Day 1 
 Grade ≥ 2 ventricular arrhythmia ≤ 6 months prior to Day 1 
 Cerebral vascular accident (CVA) or transient ischemic attack (TIA) ≤ 6 months prior to 
Day 1 
8. 
Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease or 
previous gastric resection or lap-band surgery 
 Gastroesophageal reflux disease under treatment with proton-pump inhibitors is allowed 
(assuming no drug interaction potential) 


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9. 
Active bleeding disorder, including gastrointestinal bleeding, as evidenced by hematemesis, 
significant hemoptysis or melena ≤ 6 months prior to Day 1 
10. Anticoagulation with heparin, warfarin, or other anticoagulants other than the following: 
 Low-dose aspirin and/or non-steroidal anti-inflammatory agents are allowed 
 Use of thrombolytics to establish patency of indwelling venous catheters is allowed 
 Prophylactic anticoagulation for venous access devices is allowed as long as INR is 
 1.5 and aPTT  1.5  institutional ULN 
 Low molecular weight heparin for treatment of thromboembolic events 
11. Use ≤ 10 days (or ≤ 5 half-lives, whichever is shorter) prior to Day 1 or anticipated need for 
food or drugs known to be strong or moderate CYP3A inhibitors or strong CYP3A inducers 
including known enzyme inducing anti-epileptic drugs (Appendix 6)  
12. Pregnancy or nursing 
 Females of childbearing potential require a negative serum pregnancy test ≤ 7 days before 
Day 1 
13. Significant intercurrent illness that may result in the patient’s death prior to death from 
glioblastoma 
14. Known history of intolerance to the excipients of the pamiparib capsule 
→ For patients in Arms B and C (NOT applicable to Arm A) 
15. 
Known hypersensitivity to any temozolomide component or to dacarbazine (DTIC) 
16. 
Have hereditary problems of galactose intolerance, the Lapp lactase deficiency, or 
glucose-galactose malabsorption 
6. 
STUDY PHASES FROM SCREENING TO END OF STUDY 
6.1. 
Screening 
As part of the screening visit, study center personnel will explain to the potential patient all aspects 
of the study, obtain signed informed consent, and document the informed consent process in the 
patient’s source documents before any study-specific procedures are conducted. 
The signed ICF initiates screening that must occur within 28 days of enrollment (Day -28 to Day -1). 
Study center personnel will access the Interactive Response Technology (IRT) system to obtain a 
screening identification number for the potential patient, which is generated by IRT.  
Required screening assessments, some with shorter screening windows, are listed in Appendix 1. 
Assessments obtained within 14 days of Day 1 (pregnancy and laboratory assessments: within 7 days 


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of Day 1) do not have to be repeated on Day 1. Results of standard of-care tests or examinations 
performed before obtaining informed consent and within the screening windows may be used and do 
not have to be repeated as long as they meet protocol specifications.  
It is highly recommended that general screening assessments such as physical examination and 
laboratory assessments should be conducted first to rule out ineligibility based on those grounds 
before more involved and/or invasive procedures are carried out. 
The investigator must assess the potential patient for eligibility. Screen failures and consent 
withdrawals must be documented in the patients’ source documents. 
6.2. 
Enrollment 
After determination of eligibility, the investigator will complete the treatment authorization form and 
supporting documentation and provide them to the sponsor and/or designee for review and 
subsequent approval. No eligibility waivers will be granted. 
6.3. 
Treatment 
Day 1 of Cycle 1 is the first day of any study treatment administration (there is no Day 0 in this 
protocol).  
Details on study treatment are provided in Section 7.1. 
Study procedures of each clinic visit are outlined in Appendix 1. 
On days with PK assessments, study drug should be administered in the clinic in accordance with the 
schedule for the PK samples. Assessments should be obtained before study drug administration 
unless stated otherwise in Appendix 1 and should be performed in order of least invasive to most 
invasive assessment. All safety-related assessments must be reviewed and dose modifications, if 
necessary, be made by the investigator or subinvestigator before study drug administration. 
6.4. 
Unscheduled Visit 
Unscheduled visits may occur any time as necessary as per investigator decision or patient’s request 
for reasons such as additional assessment or follow-up of AEs. If PD is suspected an MRI should be 
performed  
6.5. 
Permanent Discontinuation of Study Treatment 
6.5.1. 
Reasons for Permanent Discontinuation of Study Treatment 
Patients may permanently discontinue study treatment for any of the following reasons: 
 Disease progression 
 Adverse event(s) 
 Death 


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 Pregnancy 
 Major protocol deviations 
 Patient withdrew consent for study treatment 
o Patients may voluntarily withdraw consent from study treatment at any time 
 
If a patient withdraws consent from the Treatment Phase they should 
continue with all follow-up visits including survival follow-up 
 Start of other anticancer therapy 
Other than for treatment completion (Arms A and B), the reason for discontinuation from treatment 
will be recorded on the electronic case report form (eCRF).  Every effort must be made to encourage 
the patient to complete their EOT visit and appropriate safety follow-ups. 
6.5.2. 
End of Treatment Visit 
Patients in Arms A and B who have completed all study treatments per protocol and do not continue 
on pamiparib in combination with TMZ will have their EOT visit at the end of the Rest Phase, 
28 days after RT was completed. Patients continuing on pamiparib in combination with TMZ 
(maintenance) should follow the schedule of assessments for maintenance treatment 
(Appendix 1 Table 4). 
All other patients with any of the reasons for discontinuation of study treatment listed above will 
undergo an EOT visit within 7 days after stopping all study treatments.  
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 MRI showed PD may be used as the EOT visit provided that all required assessments were 
performed. 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 PD. ECG does not have to be repeated if it was 
performed within 14 days of the EOT visit.  
6.6. 
Follow-Up Phase 
6.6.1. 
Safety Follow-Up 
Approximately 30 days after the last day of study drug or before initiation of new anticancer therapy, 
whichever occurs first, a safety follow-up will occur with the safety assessments outlined in 
Appendix 1. If new anticancer therapy is inadvertently initiated before this safety follow-up (eg, 
without the knowledge of the study center team), a safety follow-up should be scheduled as soon as 
possible. 
6.6.2. 
Efficacy Follow-Up 
Patients who were not discontinued from study treatment due to PD and meet criteria otherwise (eg, 
discontinued for AE and no new anticancer therapy) will be followed every 8 weeks (±7 days) until 


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disease progression, administrative issues, start of other anticancer therapy or any other reason listed 
in Section 6.7, whichever occurs first.  
For efficacy assessments as per protocol, refer to Section 8.3 and Appendix 1. 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. 
6.6.3. 
Survival Follow-Up 
Patients will be followed for survival and further anticancer therapy information post progression via 
phone contact or other means (with the patient’s guardian, if applicable) approximately every 12 
weeks as per Appendix 1. 
6.6.4. 
Lost to Follow-Up 
If attempts to contact the patient by phone are unsuccessful, the following additional attempts should 
be made to obtain protocol-required follow-up information. The patient should be contacted by mail 
in a manner that provides proof of receipt by the patient. If unsuccessful, other contacts should be 
explored, such as referring physicians or relatives. Attempts of contact should be documented in the 
patient’s source documents. If a patient cannot be contacted despite all attempts, the patient will be 
considered lost to follow-up, and death information should be obtained through a public record 
search if local agencies permit. 
6.7. 
End of Study 
Premature discontinuation from the study without EOT and any follow-up visits may occur under the 
following circumstances: 
 Patient withdrew consent for study participation 
o Patients may voluntarily withdraw consent from the study at any time. 
 Investigator’s discretion 
 Lost to follow-up 
o The investigator should show due diligence by documenting in the source 
documents steps taken to contact the patient, eg, dates of telephone calls or 
registered letters (Section 6.6.4) 
 Death 
 Study termination by sponsor 
 Other, as per the discretion of the sponsor or health authority 
 
 


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7. 
STUDY TREATMENT  
7.1. 
Study Treatments 
7.1.1. 
Pamiparib 
7.1.1.1. 
Packaging and Labeling 
Pamiparib capsules are provided in a container with a child-resistant closure. Patients will receive 
pamiparib as 20 mg or 60 mg capsules, depending on dose level and availability. The contents of the 
label will be in accordance with all applicable local regulatory requirements. The label will include 
at a minimum: drug name, dose strength, contents, sponsor, protocol number, batch number, 
directions for use, storage conditions, caution statements, retest or expiration date, and space to enter 
the patient number, visit number, and name of investigator. 
7.1.1.2. 
Handling and Storage 
The instructions for drug ordering are in the Pharmacy Binder. The IRT system will also be used for 
drug supply management. The study drug will be dispatched to a study center only after receipt of 
the required documents in accordance with applicable regulatory requirements and the sponsor’s 
procedures. The investigator or pharmacist/designated personnel is responsible for maintaining the 
drug supply inventory and acknowledging receipt of all study drug shipments. All study drugs must 
be stored in a secure area with access limited to the investigator and authorized study center 
personnel and under physical conditions that are consistent with study drug specific requirements. 
Pamiparib must be kept at 15°C to 30°C (59°F to 86°F) and protected from light. An accurate study 
drug accountability log must be maintained and kept up to date at all times. 
7.1.1.3. 
Dosage and Administration 
Pamiparib 60 mg will be administered PO BID, once in the morning and once in the evening. The 
time difference between 2 consecutive doses should be approximately 8 to 12 hours.   
Patients will be instructed to swallow the capsules whole, in rapid succession, with water. Patients will be 
required to fast for at least 1 hour before and 2 hours 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, the morning dose of pamiparib should be administered in the 
clinic in accordance with the schedule for PK samples (Appendix 1). 


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7.1.2. 
Temozolomide 
7.1.2.1. 
Packaging and Labeling 
Capsules of TMZ are available in 20 and 100 mg. Please refer to the package insert for detailed 
information. 
7.1.2.2. 
Handling and Storage 
Please refer to the package insert for detailed information. 
7.1.2.3. 
Dosage and Administration 
Temozolomide will be administered PO QD, preferably during the same time frame each day (ie 
always in the morning or always in the evening). The daily dose and schedule will be determined by 
arm and stage of study as outlined in Section 4.2.1. 
On days with PK assessments, TMZ should be administered in the clinic. 
Patients will be instructed to swallow the capsules whole, in rapid succession, with water.  
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. 
Antiemetic prophylaxis is usually not required for TMZ. However, prophylaxis with a 5-HT3 
antagonist is recommended prior to administration of the first few TMZ doses and should be 
administered orally 30 to 60 minutes before TMZ treatment. Most patients report optimal nausea 
control with the use of a 5-HT3 antagonist. If optimal nausea control cannot be achieved, any 
alternative dosing schedule, such as TMZ administration at night, should be discussed with the 
medical monitor before implementation. 
For patients receiving TMZ (Arms B & C), Pneumocystis jirovecii pneumonia prophylaxis is 
required as outlined in Section 7.2.2. 
7.1.2.4. 
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 temozolomide 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 
temozolomide and MTIC (USPI). 
CYP phenotyping study using human liver microsomes with selective CYP inhibitors and 
recombinant CYP enzymes suggests that CYP3A was the major CYP isoform responsible for 
pamiparib metabolism while CYP2C8 contribute to pamiparib metabolism to a lesser extent. 
Pamiparib is a moderate inhibitor for CYP2C9 (IC50 = 6.48 M) while its IC50 for other CYP 


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isozymes are all greater than 10 M. Pamiparib is not a time-dependent CYP inhibitor of the 7 major 
CYP isozymes tested (please see the Pamiparib IB).  
Consequently, the drug-drug interaction potential between pamiparib and TMZ is believed to be low 
when coadministered. 
7.1.3. 
Radiation Therapy 
All patients in Arms A and B will receive RT using either standardized 3-dimensional conformal 
radiotherapy (3DCRT) technique, intensity modulated radiotherapy (IMRT), volumetric modulated 
arc therapy (VMAT) or other 3D conformal technique on a linear accelerator delivering a beam 
energy of ≥ 6 MV. Radiation therapy, associated 3D radiation therapy planning and 
stabilization/immobilization procedures will be performed as per local guidelines and taking into 
account local institutional standard of care. 
Patients will receive radiation therapy 5 days per week, in once daily fractions, 1.8 or 2 Gy per 
fraction, to a total target dose between 58 Gy and 64 Gy in 29 to 33 fractions, for a total duration of 
up to 7 weeks. The radiation dose should be prescribed to the tumor and its immediate surrounding 
tissue abnormalities.  
Treatment planning should ideally be carried out based on results of the MRI. The target volume 
should at a minimum encompass the contrast-enhancing lesion (and/or surgical cavity) on T1-
weighted post-contrast MRI and an acceptable margin, and may include surrounding tissue 
abnormalities as demarcated on T2w or FLAIR MR images.  
Target Volumes 
Recognizing variation in target volume definitions exists, the definition of volumes will be in 
accordance to recognized standard and local guidelines with appropriate reference to the European 
Society for Radiotherapy and Oncology (ESTRO)-Advisory Committee on Radiation Oncology 
Practice (ACROP) guideline for “Target delineation of Glioblastomas” (Niyazi et al, 2016) and the 
American Society for Radiation Oncology (ASTRO) Evidence-Based Clinical Practice Guideline 
“Radiation Therapy for Glioblastoma” (Cabrera et al, 2016). 
North American radiation oncology cooperative groups generally treat patients in 2 phases, with an 
initial phase directed at edema (hyperintense region on T2/FLAIR on MRI) in addition to the 
resection cavity and gross residual tumor (enhancing lesion on T1) followed by a boost directed only 
at the resection cavity and gross residual tumor. T2 hyperintense regions are targeted in this 
paradigm because of evidence that T2 hyperintensity sometimes reflects infiltrative and/or low-grade 
tumor. Some institutions, however, utilize a two-phase treatment paradigm targeting resection cavity 
and gross tumor alone without specifically targeting edema, citing similar patterns of failure with 
this approach. (Cabrera et al, 2016). Institutional standards may consist of delivery of a simultaneous 
integrated boost (SIB) that targets the T2w/FLAIR hyperintense regions and T1w contrast 
enhancement and resection cavity at the same time. 


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The European Organization for Research and Treatment of Cancer (EORTC) has adopted a 
single-phase approach, targeting the enhancing tumor plus cavity with a wide margin throughout the 
entire treatment, without specifically targeting edema. (Niyazi et al, 2016). 
The following are recommendations for target volume definitions. 
Gross tumor volume 
The gross tumor volume (GTV) is defined by: 
 The region of enhancement (without oedema) on post-operative CT/ T1-weighted MRIs 
(if available) or the region of enhancement (without oedema) on pre-operative 
CT/T1-weighted MRIs if post op imaging is not available (usually contained in the 
above),  
Plus 
 The tumor resection margin (usually contained in the above) 
In some tumors no area of enhancement can be seen and the GTV is defined entirely on the T2 
abnormality.  
For newly diagnosed GBM and in case of complete or subtotal removal, the position of the tumor 
bed can have shifted, and the GTV should take the new position of the abnormalities on the planning 
CT scan and any post-operative imaging into account. Post-operative imaging is not mandatory, and 
it is acceptable to define GTV based on preoperative scans and a planning CT, the latter ideally with 
IV-contrast. 
Clinical target volume 
The clinical target volume (CTV) is defined as the GTV plus a margin to account for microscopic 
spread. This will usually be in the order of 2 to 3 cm but should include all areas of persisting 
oedema (T2 weighted area on MRI/hypo dense area on CT), but can be reduced in anatomical 
regions where spread is unlikely (eg, below the tentorium cerebelli) and keeping the volume within 
the skull.  
The CTV extends to the contralateral hemisphere only when midline structures such as the corpus 
callosum and the contralateral hemisphere are invaded by tumor. The tentorium and meninges should 
be considered as anatomical borders and therefore a margin of 3-10 mm is sufficient to encompass 
the microscopic spread at these borders, always keeping the volume within the outer table of the 
skull. 
Planning target volume 
The planning target volume (PTV) will provide a margin around the CTV to compensate the 
uncertainties of the setup and the delivery. This margin should be based upon known individual 
departmental evaluations. In case it was not investigated the PTV should be defined as CTV plus 
3-5 mm margins to all directions.  To ensure that surface dose inaccuracies of the treatment planning 


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system are avoided, the PTV border should be collapsed to inside the natural barriers by limiting to 
3 mm from the skin surface. 
Additional target volumes and cone downs as and if defined per local standards. 
Organs at Risk 
To minimize radiation exposure, organ(s) at risk, including eyes, optic nerves, optic chiasm, left and 
right cochlea, brain stem, and normal brain should be contoured during treatment planning. Every 
attempt should be made to shield the contoured organs at risk during radiotherapy planning to 
minimize their dose after satisfying planning requirements for the respective volumes. The 
maximum administered doses to the organ at risk must be as follows (Scottianti et al, 2015): 
Organ at Risk 
Maximum Dose (Gy) 
Lenses 
7 
Optic nerves/Optic chiasma 
56 
Cochlea 
≤ 45 (< 34 to contralateral cochlea) 
Brainstem 
60 
Retina 
< 45 
Lacrimal gland 
< 40 
The maximal dose to non-specified normal tissues, such as skin and any uninvolved brain 
hemisphere, is 105% of the prescription dose. 
Compliance Criteria 
Radiation therapy will be given regardless of the administration of pamiparib (Arm A) and 
pamiparib in combination with TMZ (Arm B). For example, if administration of pamiparib and/or 
TMZ has been modified or delayed due to toxicity related to study drugs only, RT may continue. 
Interruptions in RT that may be necessitated by skin reaction, brain edema, or other acute reactions 
are permitted for up to a total of 7 days but the reason for the interruption should be clearly 
documented in the patient chart and CRF. For interruptions of 8 days or greater, a deviation will be 
assigned. 
For additional details, please see the study Radiation Manual. 
7.1.4. 
Radiation Therapy Adverse Events 
Toxicities arising during or after the completion of radiation therapy and attributed to radiation will 
be assessed according to NCI-CTCAE v4.03 criteria. 
7.1.4.1. 
Acute 
Expected acute radiation-induced toxicities include hair loss, fatigue, and erythema or soreness of 
the scalp. Potential acute toxicities include nausea and vomiting as well as temporary aggravation of 
brain tumor symptoms such as headaches, seizures, and weakness. Reactions in the ear canals and on 


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the ear should be observed and treated symptomatically; these reactions could result in short-term 
hearing impairment. Dry mouth or altered taste have been occasionally reported. 
7.1.4.2. 
Early Delayed 
Possible early delayed radiation effects include lethargy and transient worsening of existing 
neurological deficits occurring 1-3 months after radiotherapy treatment. 
7.1.4.3. 
Late Delayed 
Possible late delayed effects of radiotherapy, typically occurring >3 months after completion of RT, 
include radiation necrosis, endocrine dysfunction, and radiation-induced neoplasms. In addition, 
neurocognitive deficits, which could lead to mental slowing and behavioral change, are possible. 
Permanent hearing impairment and visual damage are rare. Cataracts can be encountered. 
7.1.5. 
Dose Holds and Modifications of Study Treatments 
7.1.5.1. 
General Considerations for Modifications of Study Treatments 
AEs should be assessed as best as possible regarding their relatedness to one or more study 
treatment(s). Investigators should discuss potential dose modifications with the medical monitor 
prior to implementation, if feasible. Regardless of discontinuation of one, two or all study 
treatment(s), patients should continue on study with regular follow-up as outlined in Section 6.5.2 
and Section 6.6. 
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 treatment after the DLT 
assessment window, may temporarily suspend study treatment. Depending on the toxicity, study 
treatment 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. 
Criteria for treatment 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. 
Once a dose of pamiparib or TMZ has been reduced, re-escalation is not allowed. 
7.1.5.2. 
Dose Modification Considerations for Combinations with Radiation Therapy 
For the patient populations of Arms A and B, RT is an important cornerstone of treatment and should 
not be compromised because of administration of pamiparib and/or TMZ. Consequently, RT should 
only be modified for AEs determined to be solely or mostly related to RT as typically done per 
standard of care. 


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If AEs are encountered that are considered related to pamiparib and/or TMZ, dosing modifications 
for pamiparib and/or TMZ should be implemented as outlined in Table 3 and Table 4. 
If RT is temporarily interrupted for reasons unrelated to pamiparib and TMZ (if applicable), then treatment 
with pamiparib and TMZ should continue as scheduled. If RT is permanently interrupted for reasons 
unrelated to pamiparib and TMZ (if applicable), the investigator may consult the medical monitor on the 
appropriateness of initiating maintenance treatment with pamiparib and TMZ.  
7.1.5.3. 
Dose Modification Guidelines for Temozolomide and Pamiparib 
As outlined in Sections 1.2.3, 1.3.1, 1.3.2, and 1.3.4, and discussed in Section 1.5, PARP inhibitors, 
including pamiparib, show at least partial overlap with the safety profile of TMZ. Therefore, patients in 
Arms B and C of this study may experience AEs typical for these two drug classes 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. 
As outlined in Section 1.2.3, TMZ is considered a treatment option but not a strongly established standard 
of care for the patient populations of this study. In the context of this study, the role of TMZ is to sensitize 
GBM cells to pamiparib through DNA damage that can be caused by relatively low doses of TMZ. Given 
these considerations, the decision to hold study drugs will always be made for both pamiparib and TMZ 
combined. 
Given the favorable safety profile of pamiparib (Sections 1.3.4 and 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 
2 TMZ dose reductions will be allowed. 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 2 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 should be discussed with the medical monitor. A patient must discontinue 
treatment with pamiparib and TMZ, if, after treatment is resumed at a lower dose, the toxicity recurs 
with the same or worse severity. Dose levels for TMZ and pamiparib are summarized in Table 3. 


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Table 3: 
Individual Dose Levels for Temozolomide and Pamiparib 
Dose 
level 
Temozolomide (TMZ)1 
 
Dose 
level 
Pamiparib2 
Flat dosing QD 
Dose equivalent 
 
BID 
QD 
-1 
20 mg 
12 mg/m2 
 
-2 
20 mg 
40 mg 
1 
40 mg 
23 mg/m2 
 
-1 
40 mg 
80 mg 
2 
80 mg 
46 mg/m2 
 
1 
60 mg 
120 mg 
3 
120 mg 
69 mg/m2 
 
 
 
 
4 
TBD 
- 
 
 
 
 
Note: TMZ will be dose-reduced first for a maximum of 2 dose reductions. After discussions with the medical monitor, 
pamiparib may be dose-reduced next for a maximum of 2 dose reductions. Depending on the toxicity that is triggering a second 
TMZ dose reduction, the possibility of a concurrent pamiparib dose reduction should be discussed with the medical monitor. 
Once a dose of pamiparib or TMZ has been reduced, re-escalation is not allowed. 
BID = twice daily; QD = once daily; TBD = to be determined 
1  Flat dosing of TMZ is used in this study. Dose equivalent information is provided for reference only and assumes an average 
body surface area of 1.73 m2. The starting dose for Arm C is dose level 1. For Arm B, the first dose level of TMZ will be 
lower than or equal to a dose that has been determined to be safe and tolerable in Arm C. 
2  The dose for pamiparib used in this study is 60 mg BID. A QD schedule may be explored as outlined in Section 4.2.1. 
TMZ and pamiparib will be dose-modified as outlined in Table 4. The hold and discontinue guidelines 
also apply to pamiparib (without TMZ) in Arm A. After a toxicity has adequately resolved, the 
decision in Arm A of resuming pamiparib treatment at the same dose level versus dose-reducing 
pamiparib should be made in discussion with the Medial Monitor. 


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Table 4: 
Criteria for Modification of Pamiparib and Temozolomide Dosing 
Toxicity 
Recommended Dose Modification 
Hematologic 
Anemia (hemoglobin, Hb) 
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) 
 
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 (life-threatening 
consequences; urgent intervention 
indicated) 
Hold pamiparib and TMZ until resolved to Grade ≤1 or baseline and 
 TMZ by 1 dose level 
Neutropenia (absolute neutrophil count, ANC) 
Grade 3 (ANC <1.0 - 0.5 x 109/L) 
Hold pamiparib and TMZ until resolved to Grade ≤2 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 
Thrombocytopenia (platelet count, PLT) 
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 
 


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Table 4: 
Criteria for Modification of Pamiparib and Temozolomide Dosing (Continued) 
Toxicity 
Recommended Dose Modification 
Renal 
Serum creatinine 
 
2-3 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  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  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 (eg review of peripheral blood 
smear and haptoglobin determination), then  TMZ by 1 dose level and 
continue treatment at the discretion of the investigator 
AST and/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, permanently discontinue pamiparib and TMZ 
 If persistent for >14 days, permanently discontinue pamiparib and 
TMZ 
Grade 4 (>20 x ULN) 
Permanently discontinue pamiparib and TMZ 
 


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Table 4: 
Criteria for Modification of Pamiparib and Temozolomide Dosing (Continued) 
Toxicity 
Recommended Dose Modification 
Pancreatic 
Pancreatitis 
Grade 3 or 4 
 
Permanently discontinue pamiparib and TMZ 
Cardiac 
Cardiac - Prolonged QTc interval 
QTcF >500 msec or >60 msec from 
the higher of the baseline or 
predose value 
 
 Obtain triplicate ECGs (5 minutes apart) ~1 hour after initial ECG  
 If mean QTcF >500 ms or >60 msec from baseline value, hold 
pamiparib and TMZ until evaluation of ECGs by cardiologist  
 Cardiology evaluation as soon as practical but within 7 days of 
initial abnormal ECG  
 If mean QTcF >500 ms or >60 msec from baseline value confirmed by 
cardiologist, permanently 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 
 
7.1.6. 
Compliance and Accountability 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient. 
The investigator and/or study personnel 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. 
7.1.7. 
Disposal and Destruction 
After completion of the study, all unused pamiparib will be inventoried and packaged for return 
shipment by the hospital unit pharmacist or other designated study personnel. 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. 


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7.1.8. 
Treatment of Overdose from Study Drugs 
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 because 
of an overdose should be reported to the medical monitor as well as being included in standard AE 
reporting. 
7.1.9. 
Occupational Safety 
Pamiparib is not expected to pose significant occupational safety risk to the study center personnel 
under normal conditions of use and administration. A material safety data sheet describing occupational 
hazards and recommended handling precautions will be provided to the investigator, where this is 
required by local laws, or is available upon request from the sponsor. 
7.2. 
Concomitant Medications and Non-Drug Therapies 
7.2.1. 
Permitted Medications and Supportive Care 
All treatments and supportive care, including glucocorticoids, 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 case report form (CRF) including all prescription and over-the-counter (OTC) drugs, herbal 
supplements, and IV medications and fluids. If changes occur during the study period, 
documentation of that change in drug dosage, frequency, route, and date will also be included on the 
CRF. 
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 treatment 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. 
7.2.2. 
Pneumocystis jirovecii Pneumonia Prophylaxis 
Glioblastoma patients receiving concomitant chemoradiotherapy with TMZ 75 mg/m2 during 6 to 
7 weeks or dose-dense TMZ regimens especially in combination with chronic use of corticosteroids 
have a high risk for developing Pneumocystis jirovecii pneumonia (previously known as 
Pneumocystis carinii). 
For that reason, all patients in Arms B and C are required to receive Pneumocystis jirovecii 
pneumonia prophylaxis as per the package insert for TMZ. The choice of prophylactic medications 
will be left to the discretion of the investigator.  


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7.2.3. 
Prohibited Medications 
Patients are not allowed to receive other anticancer therapy, including surgery, RT (other than 
protocol-specified), and cytotoxic, biologic, or hormone therapy. Hormone replacement therapy is 
allowed.  
Therapeutic anticoagulation with heparin, warfarin, or other anticoagulants is not allowed, with the 
exception of low molecular weight heparin for the treatment of patients with thromboembolic events. 
Low-dose aspirin, non-steroidal anti-inflammatory agents and thrombolytics to establish patency of 
indwelling venous catheters are allowed, as is prophylactic anticoagulation for venous access devices 
as long as INR is 1.5 and aPTT 1.5  institutional ULN (Section 5.1). 
The primary metabolic pathway for pamiparib involves the CYP3A isoform. The concurrent 
administration of compounds/substances presented in Appendix 6 are prohibited, as they are 
associated with possible interactions with pamiparib through the CYP3A metabolic pathway, as well 
as other various metabolic interactions. 
7.2.4. 
Medications to Be Used with Caution 
The primary metabolic pathway for pamiparib involves the CYP3A isoform. Concurrent 
administration of strong/moderate inhibitors of CYP3A or strong CYP3A inducers is not allowed. 
Pamiparib is an inhibitor of CYP2C9; 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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8. 
STUDY ASSESSMENTS 
8.1. 
Study Flow and Visit Schedule 
The study-specific assessments and procedures with allowed time windows for Arm A, Arm B, and 
Arm C, and maintenance treatment for Arms A and B are outlined in Appendix Table 1, Appendix 
Table 2, Appendix Table 3, and Appendix Table 4, respectively. Assessment of safety of the 
combination therapies will be based on AE monitoring and reporting (including attribution of AEs 
and serious adverse events [SAEs]), clinical laboratory testing, vital signs, ECGs, physical 
examinations, and PK assessments as outlined in Sections 8.2, 8.4, and 8.5, as well as Appendix 1. 
Assessments of efficacy will occur as outlined in Section 8.3 and Appendix 1. 
8.2. 
Patient Demographics and Other Baseline Characteristics 
8.2.1. 
Demographics 
Demographic data will include gender, date of birth (or age), and race/ethnicity. 
8.2.2. 
Medical History 
Clinically significant medical history findings (eg, previous diagnoses, diseases or surgeries) started 
before signing the informed consent, and 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 that require treatment or follow-up, or the 
presence of signs or symptoms that require medical intervention. Concurrent medical signs and 
symptoms must be documented to establish baseline severities. 
For the GBM history, the date of initial diagnosis and current disease status, staging, sites of disease, 
prior anticancer therapies, dates administered, responses and duration of response to these treatments 
will also be recorded. 
8.2.3. 
Other Baseline Characteristics 
Information will also be collected regarding prior medications/significant non-drug therapies, 
childbearing potential (Appendix 4) and any other assessments that are done for the purpose of 
eligibility for inclusion into the study. For further details on eligibility assessments, please see 
Section 5 and Appendix 1. 
8.3. 
Tumor Assessments 
8.3.1. 
Magnetic Resonance Imaging (MRI) 
Tumor assessments will include all known or suspected disease sites. The minimum recommended 
MRI sequences include: (i) parameter-matched precontrast and post-contrast inversion 
recovery-prepared, isotropic 3D T1-weighted gradient-recalled echo; (ii) axial 2D T2-weighted turbo 
spin-echo acquired after contrast injection and before post-contrast 3D T1-weighted images to 
control timing of images after contrast administration; (iii) precontrast, axial 2D T2-weighted 


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fluid-attenuated inversion recovery; and (iv) precontrast, axial 2D, 3-directional diffusion-weighted 
images. MRIs will be performed at screening (within 14 days of Day 1) and every 8 weeks 
(7 days), unless otherwise specified in Appendix 1. 
Non-contrast cranial MRI may only be used to document disease in those patients who are allergic to 
contrast. Tumor assessments should be repeated at the end of treatment visit if more than 4 weeks 
have passed since the last evaluation. 
The same imaging technique used at screening should be used throughout the study.  
Anti-tumor activity will be assessed through radiologic tumor assessments conducted at screening, 
during treatment as specified in the Schedule of Activity, whenever disease progression is suspected 
(eg, symptomatic deterioration), and at the time of withdrawal from treatment (if not done in the 
previous 4 weeks). All patients’ files and radiologic images (in Digital Imaging and Communications 
in Medicine [DICOM] format) must be available for source verification and for central review. 
Assessment of response will be made using the RANO criteria (Appendix 2). Responses should be 
confirmed with two assessments at least 4 weeks apart. Efficacy evaluations using the RANO criteria 
involve post-contrast MRI findings, non-contrast T1 and T2 FLAIR images, use of corticosteroid 
dose, and clinical status per RANO (Ellingson et al 2015).  
Following initial evidence of radiographic progressions and due to the potential for 
pseudo-progression patients may, at the discretion of the investigator, remain on treatment until 
further imaging is performed 4 to 8 weeks (at the discretion of the investigator) after the initial 
determination of potential progression. 
8.3.2. 
Central Independent Radiology Facility (IRF) 
An IRF may evaluate imaging studies and supportive clinical data in a central and independent 
fashion. The IRF will comprise board-certified radiologists who will identify baseline lesions and 
assign post-baseline time point responses. Details regarding IRF member qualification, training, 
methods, procedures, and other issues relevant to IRF will be described in the IRF Charter. 
The IRF will not perform independent clinical evaluations. The IRF may be asked to evaluate 
response status and may request select clinical data solely to aid in the interpretation of radiographic 
images. All scans should be sent to the IRF within 1-3 business days of acquisition (as detailed in the 
Study Manual). 
All radiologic studies acquired at all scheduled time points and any additional (unscheduled) 
radiologic images acquired to evaluate for potential metastatic disease also must be sent to the IRF.  
Minimal standards for imaging platform and machine settings as well as information regarding 
transfer of scan files to the IRF can be found in the Study Imaging Manual. 
Assessment of response will be made using the RANO criteria as outlined in Appendix 2.  


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8.4. 
Safety  
8.4.1. 
Adverse Events 
Safety assessments should be performed at the study center visits throughout the study. See 
Appendix 1 for the schedule of assessments and windows for assessments. 
All AEs and SAEs, regardless of the relationship to study treatment, will be collected per the process 
and for the time periods outlined in Section 10. The accepted regulatory definition of AEs, SAEs, 
and important additional requirements for SAE reporting are outlined in Section 10. 
8.4.2. 
Physical Examination, Vital Signs, ECOG Performance Status, Weight and Height 
A complete or limited physical examination, vital signs (systolic and diastolic blood pressure, pulse 
rate and oral, temporal or tympanic temperature), weight, height and ECOG performance status will 
be performed at time points specified in Appendix 1. 
A complete physical examination should include an evaluation of head, eyes, ears, nose and throat, 
neck, heart, chest (including lungs), abdomen, extremities, skin, lymph nodes, cardiovascular status 
and neurological status. A limited physical examination should include neurological status and 
additionally be directed at the evaluation of symptoms or specific safety issues. Changes from 
baseline abnormalities should be recorded at each subsequent physical examination. New or 
worsened abnormalities should be recorded as AEs if appropriate. 
ECOG performance status will be determined as outlined in Appendix 3. 
8.4.3. 
Electrocardiograms 
Single 12-lead ECGs with assessment of PR interval, QRS duration, and QTc interval will be 
obtained as outlined in Appendix 1. Additional ECGs will be performed if clinically indicated. To 
minimize postural variability, it is important that patients are resting and in a semi-recumbent 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. Screening 
ECG must be performed within 14 days of Day 1. For the scheduled ECG assessment at the EOT 
visit, ECG does not have to be repeated if it was performed within 14 days of the EOT visit. 
8.4.4. 
Laboratory Studies 
Samples for hematology, chemistry, and coagulation profiles will be drawn and analyzed locally. All 
other required blood samples will be sent to a 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 material such as test tubes and labels is provided in the laboratory manual. 
Laboratory studies will be performed at the time points specified in Appendix 1 (including allowed 
windows of assessment) and may also be performed as medically necessary. Laboratory assessments 
should be done before study treatment. Screening blood and urine tests must be performed within 


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14 days of Day 1. If they were performed within 7 days of Day 1, they do not need to be repeated on 
Day 1. 
8.4.4.1. 
Hematology 
Hematology includes hemoglobin, platelet count, white blood cell count, neutrophil count, and 
lymphocyte count. 
8.4.4.2. 
Chemistry 
Chemistry includes albumin, alkaline phosphatase, AST, ALT, blood urea nitrogen, chloride, 
creatinine, glucose, lactic acid dehydrogenase, phosphate, potassium, sodium, total bilirubin, and 
total protein.  
8.4.4.3. 
Coagulation 
The coagulation profile includes INR and aPTT. 
8.4.4.4. 
Urinalysis with Dipstick 
Urinalysis will be assessed using urine dipstick. Urine microscopy will be performed if urine 
dipstick is abnormal. Urinalysis includes blood, protein, ketones, glucose, red blood cells, and white 
blood cells.  
8.4.4.5. 
Hepatitis B Serology Test 
Testing for hepatitis B will be performed by the local laboratory at Screening and will include HBV 
serology (HBsAg, HBsAb and HBcAb) and viral load assessment (HBV DNA).  
8.4.4.6. 
Pregnancy Testing 
The Clinical Trials Facilitation Group’s recommendations related to contraception and pregnancy 
testing in clinical trials include for females with childbearing potential the use of highly effective 
forms of birth control (Appendix 4) and testing for pregnancy every 28 days. For women of 
childbearing potential, a screening serum pregnancy test must be obtained within 7 days prior of 
Day 1. For subsequent pregnancy testing on study and at end of treatment, urine pregnancy tests are 
allowed. If a urine pregnancy test is positive, a confirmatory serum pregnancy test is required. 
8.5. 
Pharmacokinetics 
Pharmacokinetic samples will be collected from patients in all cohorts at the following time points 
(Appendix 1): predose (within 30 min prior to dose) and 2 hours (± 30 min) post-dose on both Day 1 
and Day 15 (collection takes place in Cycle 1 for Arm C). If pamiparib treatment is administered 
only for a 2-week (14-day) time period, PK samples will be collected on Day 1 and Day 14 instead. 
The time of study drug administration on the day prior to Day 15 (Day 14 for patients receiving only 
2 weeks of pamiparib) must be recorded on the eCRF. Details concerning collection, handling, and 
processing of the PK plasma samples will be provided in the laboratory manual. 


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8.6. 
Biomarkers 
Patients are required to provide archival tumor tissues for the analysis of candidate predictive 
biomarkers. This is optional and dependent upon tissue availability in the dose escalation phase but 
mandatory in the dose expansion phase. Archival tumor tissue, either a formalin-fixed 
paraffin-embedded block with tumor tissue (preferred) or, ideally, around 15 unstained slides will be 
sent to the central laboratory for biomarker testing. 
Candidate markers will include, but are not limited to: 
1. Markers of disease (eg, DNA hypermethylation, PTEN loss or mutational status, 
EGFR/EGFRviii) 
2. Markers related to response or resistance to TMZ (eg, MGMT levels and methylation status, 
APNG, gH2Ax) 
3. Markers related to response or resistance to PARP inhibitors (eg, HRD, BRCA loss or 
mutational status, ATM, MRE11, RAD51) 
Patients will also provide blood samples to be processed into serum, plasma and cell fractions for the 
analysis of germline mutations, such as, but not limited to, BRCA, and circulating markers, such as, 
but not limited to, circulating tumor cells (CTCs) and circulating nucleic acids [CNAs]. 
Instructions for the processing, storage, and shipping of samples will be provided in the laboratory 
manual. 
8.7. 
Appropriateness of Measurements 
All safety and PK assessments used in this study are standard, and generally recognized as reliable, 
accurate, and relevant. 
 
 


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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. Study center audits may be made periodically by the sponsor’s or the contract research 
organization’s qualified compliance auditing team, which is an independent function from the study 
team responsible for conduct of the study. 
9.1. 
Data Collection 
Data will be entered into the eCRFs in an electronic data capture (EDC) system.  
Data collection on the eCRF must follow the instructions described in the eCRF Completion 
Guidelines. The investigator has ultimate responsibility for the collection and reporting of all clinical 
data entered on the eCRF. The investigator or designee must sign the completed casebooks to attest 
to its accuracy, authenticity, and completeness. 
Data contained in the eCRFs are the sole property of BeiGene and should not be made available in 
any form to third parties without written permission from BeiGene, except for authorized 
representatives of BeiGene or appropriate regulatory authorities. 
9.2. 
Data Management/Coding 
All final patient data, both eCRF and external data (eg, laboratory data), collected according to the 
protocol, will be stored at BeiGene at the end of the study.  
Standard procedures (including following data review guidelines, computerized validation to 
produce queries, and maintenance of an audit file, which includes all database modifications) will be 
followed to support accurate data collection. Data will be reviewed for outliers, logic, data 
inconsistencies, and completeness. 
During the course of the study, a study monitor will make study center visits to review protocol 
compliance, compare eCRFs against individual patient’s medical records, and ensure that the study 
is being conducted according to pertinent regulatory requirements. 
eCRF entries will be verified with source documentation. The review of medical records will be 
performed in a manner to ensure that patient confidentiality is maintained. Checking the eCRFs for 
completeness, clarity, and cross checking with source documents is required to monitor the progress 
of the study. Direct access to source data is also required for inspections and audits, and will be 
carried out giving due consideration to data protection and medical confidentiality. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®) 
Version 18.1 or higher. Concomitant medications will be coded using the World Health Organization 
Drug Dictionary. Concomitant diseases/medical history will be coded using the MedDRA 
Version 18.1 or higher. 


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9.3. 
Quality Assurance 
To ensure compliance with GCP and all applicable regulatory requirements, the sponsor may 
conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection of 
this study. Such audits/inspections can occur at any time during or after completion of the study. If 
an audit or inspection occurs, the investigator and institution agree to allow the auditor/inspector 
direct access to 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 
(eg, hospital progress notes, laboratory results and diagnostics reports) relative to the AE or SAE. 
The investigator will then record all relevant information regarding an AE or SAE in the eCRF. 
However, there may be instances when copies of medical records for certain cases are requested by 
the sponsor. In this instance, all patient identifiers will be blinded on the copies of the medical 
records before submission to the sponsor.  
10.1.2. 
Assessment of Severity 
The investigator will make an assessment of severity for each AE and SAE reported during the 
study. AEs and SAEs should be assessed and graded based upon the NCI-CTCAE Version 4.03 or 
higher. 
Toxicities that are not specified in the NCI-CTCAE will be defined as follows: 
 Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated  
 Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living  
 Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily 
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 Grade 4: Life-threatening consequences; urgent intervention indicated  
 Grade 5: Death related to AE  
NOTE: The terms “severe” and “serious” are not synonymous. Severity is a measure of intensity (eg, 
grade of a specific AE, mild [Grade 1], moderate [Grade 2], severe [Grade 3], or life-threatening 
[Grade 4]); whereas seriousness is classified by the criteria based on the regulatory definitions. 
Seriousness serves as the guide for defining regulatory reporting obligations from the sponsor to 
applicable regulatory authorities as described in Section 10.2. 
10.1.3. 
Assessment of Causality 
The investigator is obligated to assess the relationship between the study drug and the occurrence of 
each AE or SAE. The investigator will use clinical judgement to determine the relationship. 
Alternative causes, such as natural history of the underlying diseases, concomitant therapy, and other 
risk factors, and the temporal relationship of the AE or SAE to the study drug will be considered and 
investigated. The investigator will also consult the IB and/or Product Information, for marketed 
products, in the determination of his/her assessment. 
There may be situations when an SAE has occurred, and the investigator has minimal information to 
include in the initial report to the sponsor. However, it is very important that the investigator always 
provides assessment of causality for every SAE before transmission of the SAE report/eCRF to the 
sponsor since the causality assessment is one of the criteria used when determining regulatory 
reporting requirements. The investigator may change his/her opinion of causality 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 at least “a reasonable possibility” that the AE may 
have been caused by the study drug (ie, there are facts, evidence, or arguments to suggest possible 
causation, or a causal relationship between the AE and the drug cannot be ruled out). A number of 
factors should be considered in making this assessment, including: 
 Temporal relationship of the AE to the administration of study treatment/study procedure 
 Whether an alternative etiology has been identified  
 Mechanism of action of the study drug 
 Biological plausibility 
An AE should be considered ”related” to study drug if any of the following are met, otherwise the 
event should be assessed as not related: 
 There is clear evidence to suggest a causal relationship, and other possible contributing factors 
can be ruled out. 
 There is evidence to suggest a causal relationship, and the influence of other factors is unlikely. 


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 There is some evidence to suggest a causal relationship (eg, the AE occurred within a 
reasonable time after administration of the study drug). However, the influence of other factors 
may have contributed to the AE (eg, the patient’s clinical condition or other concomitant AEs). 
10.1.4. 
Follow-Up of Adverse Events 
When treatment is interrupted or permanently discontinued due to an AE or abnormal laboratory 
value the patient must be followed at a frequency as medically indicated until resolution or 
stabilization of the event, whichever comes first.  
All patients will be followed for AEs and SAEs for at least 30 days following the last dose of 
pamiparib or initiation of new anticancer therapy, whichever occurs first. For prolonged 
hematological toxicities, treatment should be interrupted and blood counts should be monitored 
weekly until recovery.  
If the levels have not recovered to CTCAE Grade ≤ 1 or baseline after 4 weeks, the patient should be 
referred to a hematologist for further investigations, including bone marrow analysis and blood 
sample for cytogenetics. If myelodysplastic syndrome/acute myeloid leukemia is diagnosed, the 
event should be reported as an SAE regardless of causality. 
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 eCRF page(s) will be updated. The investigator will 
ensure that follow-up includes any supplemental investigations as may be indicated to elucidate the 
nature and/or causality of the AE or SAE. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals. 
The sponsor may request that the investigator perform or arrange for the conduct of supplemental 
measurements and/or evaluations to elucidate as fully as possible the nature and/or causality of the 
AE or SAE. The investigator is obligated to assist. If a patient dies during participation in the study 
or during a recognized follow-up period, the sponsor will be provided with a copy of any 
postmortem findings, including histopathology. 
New or updated information will be recorded on the originally completed SAE report, with all 
changes signed and dated by the investigator. The updated SAE report should be resent to the 
sponsor within the time frames outlined in Section 10.5.1. 
10.1.5. 
Laboratory Test Abnormalities 
Abnormal laboratory findings (eg, chemistry, hematology, coagulation) or other abnormal 
assessments (ECGs, X-rays, vital signs) that are judged by the investigator as clinically significant 
will be recorded as AEs or SAEs. This includes clinically significant abnormal laboratory findings or 
other abnormal assessments that are present at baseline and significantly worsen during the study.  
The definition of clinically significant is left to the judgement of the investigator; in general, these 


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are the abnormalities that are associated with clinical signs or symptoms, require active medical 
intervention, or lead to dose interruption or discontinuation, or require close observation, or more 
frequent follow-up assessments, or further diagnostic investigation.  
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.  
o Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an SAE. 
o Hospitalization for social/convenience considerations is not considered an SAE.  
o Scheduled therapy for the target disease of the study, including admissions for transfusion 
support or convenience, is not considered an SAE.  
 Results in disability/incapacity.  
NOTE: The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of relatively minor 
medical significance, such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle), which may interfere or prevent everyday life 
functions, but do not constitute a substantial disruption.  
 Is a congenital anomaly/birth defect.  
 Is considered a significant medical AE by the investigator based on medical judgement (eg, 
may jeopardize the patient or may require medical/surgical intervention to prevent one of the 
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10.3. 
Timing, Frequency, and Method of Capturing Adverse Events and Serious Adverse 
Events 
10.3.1. 
Adverse Event Reporting Period 
After the ICF has been signed but before study treatment, only SAEs should be reported, as required 
per Section 10.5. 
After initiation of study treatment, all AEs and SAEs, regardless of relationship to study treatment, 
will be reported until 30 days after the last study treatment or initiation of new anticancer therapy, 
whichever occurs first. After this period, the investigator should report any SAEs that are believed to 
be related to prior study treatment. 
10.3.2. 
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?  
10.4. 
Specific Instructions for Recording Adverse Events and Serious Adverse Events 
10.4.1. 
Disease Progression 
Disease progression and death due to disease progression, which is expected in this study population 
and measured as an efficacy endpoint, should not be reported as an event term. Instead, the 
symptoms, signs or clinical sequelae that result from disease progression should be reported as the 
events.  
For instance, a patient presents with pleural effusion resulting from disease progression of metastasis 
to lungs. The event term should be reported as “pleural effusion” instead of disease progression. If a 
patient experienced a fatal multi-organ failure due to disease progression, the term “multi-organ 
failure” should be reported as the SAE with death as outcome instead of reporting “fatal disease 
progression” or “death due to disease progression”.  
10.4.2. 
Death 
Death is an outcome and not usually considered an AE. If the only information available is death and 
the cause of death is unknown, then the death is reported as an event, eg “death”, “death of unknown 
cause”, or “death unexplained”. 


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10.5. 
Prompt Reporting of Serious Adverse Events 
10.5.1. 
Timeframes for Submitting Serious Adverse Events 
As soon as the investigator determines that the AE meets the protocol definition of an SAE, the event 
must be reported promptly (within 24 hours) to the sponsor or designee as described in Table 5.  
Table 5: 
Timeframes and Documentation Methods for Reporting Serious Adverse Events 
to the Sponsor or Designee 
 
Timeframe for 
Making Initial 
Report  
Documentation 
Method  
Timeframe for 
Making Follow-up 
Report 
Documentation 
Method 
 
Reporting 
Method 
 
All SAEs 
Within 24 hours of 
first knowledge of 
the AE  
SAE Report 
As expeditiously as 
possible 
SAE Report 
Email or fax 
SAE form or 
Pregnancy form 
Abbreviations: AE, adverse event; SAE, serious adverse event. 
10.5.2. 
Completion and Transmission of the Serious Adverse Event Report 
Once an investigator becomes aware that an SAE has occurred in a patient, he/she is to report the 
information to the sponsor within 24 hours as outlined above 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 time frames.  
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 must always provide an assessment of causality at the time of the initial report as 
described in Section 10.1.1. 
The sponsor will provide contact information for SAE receipt. 
10.5.3. 
Regulatory Reporting Requirements for Serious Adverse Events 
The investigator will promptly report all SAEs to the sponsor in accordance with the procedures 
detailed in Section 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. Prompt notification of SAEs by the investigator to the appropriate project contact for 
SAE receipt is essential so that legal obligations and ethical responsibilities towards the safety of 
other patients are met. 


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The investigator, or responsible person according to local requirements, will comply with the 
applicable local regulatory requirements related to the reporting of SAEs to regulatory authorities 
and the IRB/IEC. 
This protocol is being filed under an Investigational New Drug (IND) protocol amendment with the 
United States Food and Drug Administration (FDA). Once active, a given SAE may qualify as an 
IND safety report if the SAE is both attributable to the study drug and unexpected. In this case, all 
investigators filed to the IND (and associated INDs for the same compound) will receive an 
expedited investigator safety report, identical in content to the IND safety report submitted to the 
FDA. 
Expedited investigator safety reports are prepared according to the sponsor’s policy and are 
forwarded to investigators as necessary. The purpose of the report is to fulfill specific regulatory and 
GCP requirements regarding the product under investigation. 
When a study center receives an initial or follow-up report or other safety information (eg, revised 
IB) from the sponsor, the responsible person according to local requirements is required to promptly 
notify his/her IRB or IEC. 
Expedited Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
BeiGene, as study sponsor, is responsible for reporting suspected, unexpected, serious adverse 
reactions involving the study drug to all regulatory authorities and participating investigators in 
accordance with International Council for Harmonisation (ICH) Guidelines and/or local regulatory 
requirements, as applicable. In addition, BeiGene or authorized designee will be responsible for the 
submission of safety letters to central independent ECs (IECs). 
The sponsor (or authorized designee) will notify investigators of all reportable SAEs. This 
notification will be in the form of an expedited safety report. Upon receiving such notices, the 
investigator must review and retain the notice with other study-related documentation. 
The investigator and IRB/EC will determine whether the informed consent requires revision. The 
investigator should also comply with the IRB/EC procedures for reporting any other safety 
information. 
Suspected serious adverse reactions and other significant safety issues reported from the 
investigational product development program will be reported by the sponsor or its designated 
representative, either as expedited safety reports and/or in aggregate reports—to the relevant, 
competent health authorities in all concerned countries. 
10.6. 
Pregnancy Reporting 
If a female patient or the partner of a male patient becomes pregnant while receiving study treatment 
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. Any premature 
termination of the pregnancy will be reported. 


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While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE. 
An abortion, whether accidental, therapeutic, or spontaneous should be always reported as an SAE. 
Similarly, any congenital anomaly/birth defect in a child born to a patient exposed to the study drug 
should be recorded and reported as an SAE.  
10.7. 
Poststudy Adverse Events 
A poststudy AE or SAE is defined as any AE that occurs outside of the AE/SAE reporting period, as 
defined in Section 10.3.1. 
Investigators are not obligated to actively seek AEs or SAEs in former patients. However, if the 
investigator learns of any SAE, including a death, at any time after a patient has been discharged 
from the study, and he/she considers the SAE related to the study drug, the investigator will notify 
the sponsor. 
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 Pamiparib IB. 
 
 


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11. 
STATISTICAL CONSIDERATIONS AND ANALYTICAL PLAN 
All data will be presented by Phase, summarized by arm and cohort in Phase 1b and by arm and 
expansion cohort in Phase 2. Most of the analysis methods described in this section are directed to 
the Phase 2 portion of the trial. However, they will be applied to the Phase 1 portion of data analyses 
whenever appropriate.  
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 
Hypothesis testing will be performed in Phase 2. In addition, descriptive statistics will be used in 
describing the antitumor activity and tolerability of the combination regimens in each Phase. CIs will 
be constructed to describe the precision of the point estimates of interest (eg ORR). 
11.2.1. 
Analysis Set 
 The Safety Analysis Set includes all patients who received any study treatment 
(pamiparib, RT, and/or TMZ). The Safety Analysis Set will be used for all efficacy and 
safety analyses. 
 The Efficacy-evaluable Analysis Set includes patients in the Safety Analysis Set who had 
baseline and at least one post-baseline tumor assessment, unless discontinued treatment or 
study early due to clinical progression or death prior to tumor assessment. 
 The DLT-evaluable Analysis Set includes patients who received ≥ 42 Gy of RT (Arms A 
and B) and ≥ 70% of scheduled pamiparib (Arms A, B and C) and TMZ (Arms B and C) 
during the DLT assessment window with sufficient safety assessments. All patients who 
had a DLT event will be considered DLT-evaluable regardless of study treatment 
intensity.  
 The PK Analysis Set includes all patients for whom valid pamiparib PK parameters can 
be estimated. 
11.2.2. 
Patient Disposition 
The number of patients enrolled, treated and discontinued from study drug, as well as those with 
major protocol deviations will be counted by arm. 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. 


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11.2.3. 
Demographics and Other Baseline Characteristics 
Demographics and other baseline characteristics will be summarized by arm in the Safety Analysis 
Set using descriptive statistics. Continuous variables include age, weight, vital signs, time since 
initial tumor diagnosis, categorical variables include sex, age group (< 65 vs. ≥ 65 years), race, 
ECOG performance status, prior therapy for GBM, geographic region, and systemic corticosteroids 
at baseline. 
11.2.4. 
Prior and Concomitant Therapy 
Concomitant medications will be assigned an 11-digit code using the World Health Organization 
Drug Dictionary 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 that stopped before 
the first dose of study drug. Concomitant medications will be defined as medications that 1) started 
before first study treatment and were continuing at the time of first study treatment, or 2) started on 
or after the date of first study treatment up to 30 days after last study treatment. A listing of prior and 
concomitant medications will be included in the CSR. 
11.2.5. 
Efficacy Analyses 
Tumor assessments by investigators according to RANO will be used to calculate ORR, modified 
DCR (Arms A and B), DCR (Arm C), PFS, DOR, and CBR, as well as time-point estimate PFS-6m. 
OS and OS at 6 and 12 months (OS-6m and OS-12m) will be summarized in the efficacy analysis. 
An optional independent read of the MRI scans may be performed and will be analyzed in the same 
fashion. 
11.2.5.1. Primary Efficacy Analysis 
Phase 1b 
As described in the protocol objectives, the trial is designed to establish the safety and tolerability of 
pamiparib in combination with RT and/or TMZ. Evidence of any antitumor activity will be 
documented and summarized for the Safety Analysis Set as secondary endpoints of the trial. 
Phase 2 (Arms A and B) 
Modified DCR is the primary efficacy endpoint in Arms A and B. It is defined as the proportion of 
patients with CR, PR, or SD as the response assessment at the EOT visit, as scheduled per protocol. 
Patients with no EOT tumor assessment, as scheduled per protocol (due to any reason), will be 
considered non-responders for modified DCR. Modified DCR of pamiparib combination therapy is 
assumed as 60% in the study population. The historical rate in a similar population is estimated as 
40% (Rivera et al 2010).  
The null and alternative hypotheses are set as follows: 


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 H0: Modified DCR = 40% 
 Ha: Modified DCR > 40% 
A binomial exact test will be performed for hypothesis testing in each arm separately in the Safety 
Analysis Set. If the obtained one-sided p-value is < 0.025, it will be concluded that pamiparib 
combination therapy showed a statistically significant increase of modified DCR compared to 
historical control. Therefore, the superiority of pamiparib combination therapy will be demonstrated 
in this arm. 
Two-sided binomial exact 95% confidence interval (CI) of modified DCR will be constructed to 
assess the precision of the rate estimate.  
The primary efficacy analysis will be conducted when mature response rate data have been observed, 
which will be determined by the sponsor. 
Sensitivity analysis of modified DCR will be carried out in the Efficacy-evaluable Analysis Set. 
Phase 2 (Arm C) 
ORR is the primary efficacy endpoint in Arm C. ORR of pamiparib combination therapy is assumed 
as 25% in the study population. The historical rate in a similar population is estimated as 10% (Chen 
et al 2013).  
The null and alternative hypotheses are set as follows: 
 H0: ORR = 10% 
 Ha: ORR > 10% 
A binomial exact test will be performed within each expansion cohort of Arm C similarly to that 
described for Arms A and B. 
11.2.5.2. Secondary Efficacy Analysis 
Descriptive statistics will be used to summarize the secondary efficacy analysis.  
DCR is defined as the proportion of patients with best overall response (BOR) of CR, PR, or SD. 
BOR is defined as the best response recorded from the start of study treatment until data cutoff or 
start of new anticancer therapy. 
CBR is defined as the proportion of patients with BOR of CR, PR, or durable SD (SD ≥24 weeks).  
Exact 95% CIs will be calculated for the rate variables: ORR for patients with measurable disease at 
baseline, DCR, and CBR in the Safety Analysis Set. 
PFS is defined as the time from the date of first study treatment 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 an MRI, if possible, to correlate radiographic findings with the clinical findings. 


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Data for patients without disease progression or death at the time of analysis will be censored at the 
time of the last tumor assessment. Data for patients who are lost to follow-up prior to documented 
disease progression will be censored at the last tumor assessment date when the patient was known 
to be progression-free. Data for patients who started new anticancer therapy will be censored at the 
last tumor assessment date prior to the introduction of new therapy. More details will be given in the 
SAP.  
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 first study treatment to death of any cause. 
Time-to-event variables PFS, DOR, and OS will be estimated using the Kaplan-Meier method in the 
Safety Analysis Set. Kaplan-Meier estimates of PFS, DOR, and OS will be plotted over time. 
Median PFS, DOR, and OS for each arm will be presented (if possible to estimate), along with their 
2-sided 95% CIs using generalized Brookmeyer and Crowley method. The PFS-6m, OS-6m, and 
OS-12m, defined as the percentages of patients in the analysis population who remain alive and 
progression-free at 6 months (or alive at 6 or 12 months for OS-6m and OS-12m), will be estimated 
using Kaplan-Meier method along with the corresponding 95% CI constructed using Greenwood’s 
formula. OS will be assessed by 6-month intervals until the last patient enrolled on the study had 
died. 
Selected efficacy endpoints will be summarized in the Efficacy-evaluable Analysis Set as sensitivity 
analysis. 
In Phase 2, modified DCR (in Arms A and B) and ORR (in Arm C) will be summarized in the 
specified subgroups: sex, age group (< 65 vs. ≥ 65), race, ECOG performance status (0 vs. ≥ 1), prior 
surgery status, baseline corticosteroid use, mutations, and geographic region. In addition, ORR (in 
Arm C) will be summarized by relapse status. 
11.2.6. 
Pharmacokinetic Analyses 
Population PK analysis may be carried out to include plasma concentrations from this trial in an 
existing model. PK parameters such as minimum observed plasma concentration (Cmin) will be 
summarized, and additional PK parameters such as apparent clearance of the drug from plasma 
(CL/F) and area under the plasma concentration-time curve from zero to 24 hours post-dose 
(AUC0-24) may be derived from the population PK analysis if supported by data. 
Exposure-response (efficacy or safety endpoints) analysis may be carried out if supported by data. 
The results of the population PK and exposure-response analyses may be reported separately from 
the CSR. Details of the PK analyses will be provided in a separate SAP.  


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11.2.7. 
Exploratory Analyses 
11.3. 
Safety Analyses 
Safety will be assessed by monitoring and recording of all AEs graded by CTCAE v4.03. Laboratory 
values, vital signs, physical examinations and ECG findings will also be used in determining the 
safety of the study treatment. 
11.3.1. 
Extent of Exposure 
Extent of exposure to each study treatment will be summarized in each arm descriptively as the 
number of cycles received (number and percentage of patients) in Arm C, duration of exposure 
(days), cumulative total dose received per patient (mg for pamiparib and TMZ and Gy for RT), dose 
intensity (mg/day for pamiparib and TMZ) and relative dose intensity. 
The number (percentage) of patients requiring dose reductions, dose holds, and permanent drug 
discontinuation due to AEs will be summarized by arm. Frequency of dose reductions and study drug 
withholding 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 toxicities in the DLT evaluation period will be summarized descriptively for each dose 
level in the DLT-evaluable population. 
11.3.3. 
Adverse Events 
Adverse Events will be coded using MedDRA Version 18.1 or higher and graded using NCI-CTCAE 
Version 4.03 or higher. A treatment-emergent adverse event (TEAE) is defined as an AE that had an 
onset date on or after first study treatment or was worsening in severity from baseline (pretreatment) 
up to 30 days following permanent study treatment discontinuation or initiation of new anticancer 
therapy, whichever occurs first. All TEAEs will be included in summary tables and in patient data 
listings. 
The incidence of TEAEs will be reported as the number (percentage) of patients with TEAEs by 
system organ class (SOC) and preferred term (PT). A patient will be counted only once by the 
highest grade according to NCI-CTCAE Version 4.03 or higher 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 treatment. Treatment-
related AEs include those events considered by the investigator to be related to study treatment or 
with missing assessment of the causal relationship. Serious AEs, deaths, TEAE of Grade  3, related 


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TEAEs and TEAEs that led to study drug/treatment discontinuation, dose reduction or treatment 
delay will be summarized. 
11.3.4. 
Laboratory Analyses 
Clinical laboratory (eg, hematology and chemistry) values will be evaluated as specified in the SAP 
and collected in the EDC system. Collected values may be a subset of all the values obtained in the 
requested sampling, eg, a complete blood count with differential may be requested for the evaluation 
of neutrophils only. Analyzed laboratory values will be flagged and identified as those outside 
(above or below) the normal range. 
Laboratory parameters that are graded in NCI-CTCAE Version 4.03 will be summarized by 
NCI-CTCAE grade. Shift tables will be provided as appropriate. 
11.3.5. 
Physical Examinations 
Physical examination results collected in association with an AE will be listed and summarized. 
11.3.6. 
Vital Signs  
Specific vital signs, eg, blood pressure and temperature, will be summarized and listed. The change 
from baseline will also be presented. 
11.3.7. 
Electrocardiogram 
Electrocardiogram assessments will be performed as outlined in Appendix 1. The percentage of 
patients with abnormal and clinically significant ECG findings will be presented. 
11.4. 
Sample Size Consideration 
Approximately 300 patients (60 in Phase 1b and 240 in Phase 2) may be enrolled. The actual sample 
size in Phase 1b will depend on the number of cohorts enrolled per arm.  
In Phase 2, the sample size calculation is carried out using modified DCR in Arms A and B and ORR 
in each expansion cohort of Arm C.  
 Assuming modified DCR of 60% in Arms A and B vs. 40% in historical control, the power 
of a binomial exact test is 0.874 in each arm when n = 60. 
 Assuming ORR of 25% in Arm C vs. 10% in historical control, the power of a binomial 
exact test is 0.847 when n = 60 per expansion cohort. 
With the above assumptions, the binomial exact 95% CI of modified DCR is (46.5%, 72.4%) in 
Arms A and B and the binomial exact 95% CI of ORR is (14.7%, 37.9%) in each expansion cohort 
of Arm C.  


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11.5. 
Interim Analysis 
A brief data summary will be performed once the Phase 1b dose escalation portion is completed. In 
Phase 2, an interim analysis will be implemented in each arm after approximately the first 
20 patients in that arm completed ≥ 2 tumor assessments. This analysis is for futility only. No 
recruitment stop is planned for this interim analysis. If the conditional or predictive power of 
demonstrating the final efficacy is < 10%, enrollment in this arm will be halted and safety and 
efficacy data will be further evaluated before making the decision of whether to stop the arm 
permanently. Otherwise, the enrollment will be continued to approximately 60 patients in this arm. 
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 
The investigator will ensure that this study is conducted in accordance with the principles of the 
“Declaration of Helsinki” ICH guidelines, and that the basic principles of “Good Clinical Practice,” 
as outlined in 21 Code of Federal Regulations (CFR) 312, Subpart D, “Responsibilities of Sponsors 
and Investigators,” 21 CFR, Part 50, and 21 CFR, Part 56, are adhered to. 
Investigators and all subinvestigators must provide documentation of their financial interest or 
arrangements with BeiGene, or proprietary interests in the drug being studied. This documentation 
must be provided before participation of the investigator and any subinvestigator. The investigator 
and subinvestigator agree to notify BeiGene or its authorized representative of any change in 
reportable interests during the study and for 1 year following completion of the study. Study 
completion is defined as the date that the last patient has completed the protocol defined activities. 
12.2.2. 
Ethical Conduct of the Study and Ethics Approval 
This study will be conducted by the principal investigator and the study center in accordance with 
GCP and all applicable regulatory requirements, including, where applicable, the current version of 
the Declaration of Helsinki. 
The investigator (or sponsor, where applicable) is responsible for ensuring that this protocol, the 
study center’s ICF, and any other information that will be presented to potential patients (eg, 
advertisements or information that supports or supplements the ICF) are reviewed and approved by 
the appropriate IEC/IRB. 
The IEC/IRB must be constituted in accordance with all applicable regulatory requirements. The 
sponsor will provide the investigator with relevant document(s)/data that are needed for IEC/IRB 
review and approval of the study. 
Before the study drug(s) can be shipped to the study center, the sponsor or its authorized 
representative must receive copies of the IEC/IRB approval, the approved ICF, and any other 
information that the IEC/IRB has approved for presentation to potential patients. 
If the protocol, the 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 


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ICF including obtaining IEC/IRB approval of the amended form before new patient consent to take 
part in the study using this version of the form. Copies of the IEC/IRB approval of the amended 
ICF/other information and the approved amended ICF/other information must be forwarded to the 
sponsor promptly. 
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 ICF for documenting written informed consent. Each ICF will be 
appropriately signed and dated by the patient or the patient’s legally authorized representative and 
the person obtaining consent. 
Informed consent will be obtained before the patient can participate in the study. The contents and 
process of obtaining informed consent will be in accordance with all applicable regulatory 
requirements. 
During the informed consent process, male patients on Arms B and C 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. 
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 
Information on maintaining patient confidentiality in accordance to individual local and national 
patient privacy regulations must be provided to each patient as part of the informed consent process, 
either as part of the ICF or as a separate signed document (for example, in the US, a study-center 
specific HIPAA consent may be used). The investigator must assure that patients’ anonymity will be 
strictly maintained and that their identities are protected from unauthorized parties. Only patient 
initials, date of birth, and an identification code (ie, not names) should be recorded on any form or 
biological sample submitted to the sponsor, IRB, or laboratory. The investigator must keep a 
screening log showing codes, names, and addresses for all patients screened and for all patients 
enrolled in the study. 
The investigator agrees that all information received from BeiGene, including but not limited to the 
IB, this protocol, eCRFs, the IND, and any other study information, remain the sole and exclusive 
property of BeiGene during the conduct of the study and thereafter. This information is not to be 
disclosed to any third party (except employees or agents directly involved in the conduct of the study 


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or as required by law) without prior written consent from BeiGene. The investigator further agrees to 
take all reasonable precautions to prevent the disclosure by any employee or agent of the study site 
to any third party or otherwise into the public domain. 
If a written contract for the conduct of the study 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. 
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 on the eCRF. If a patient is withdrawn from the study because of a treatment-limiting AE, 
thorough efforts should be made to clearly document the outcome. 
The eCRFs exist within an EDC system with controlled access managed by BeiGene or its 
authorized representative for this study. Study staff will be appropriately trained in the use of eCRFs 
and applications of electronic signatures before the study start and before being given access to the 
EDC system. Original data and any changes of data will be recorded using the EDC system, with all 
changes tracked by the system and recorded in an electronic audit trail. The investigator attests that 
the information contained in the eCRFs is true by providing an electronic signature within the EDC 
system. After final database lock, the investigator will receive a copy of the patient data on 
CD-ROMs for archiving the data at the study center. 
12.2.7. 
Drug Accountability 
The investigator or designee (ie, pharmacist) is responsible for ensuring adequate accountability of 
all used and unused study drug. This includes acknowledgment of receipt of each shipment of study 
product (quantity and condition), patient dispensing records and returned or destroyed study product. 
Dispensing records will document quantities received from BeiGene, quantities dispensed to 
patients, and quantities destroyed or returned to BeiGene, including lot number, date dispensed, 
patient identifier number, patient initials, and the initials of the person dispensing the medication. 
At study initiation, the monitor will evaluate the study center’s standard operating procedure for 
study drug disposal/destruction in order to ensure that it complies with BeiGene requirements. At the 
end of the study, following final drug inventory reconciliation by the monitor, the study center will 
dispose of and/or destroy all unused study drug supplies, including empty containers, according to 
these procedures. If the study center cannot meet BeiGene’s requirements for disposal, arrangements 
will be made between the study center and BeiGene or its representative for destruction or return of 
unused study drug supplies. 
All drug supplies and associated documentation will be periodically reviewed and verified by the 
study monitor over the course of the study. 


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12.2.8. 
Inspections 
The investigator should understand that source documents for this study should be made available to 
appropriately qualified personnel from BeiGene or its representatives, to IRBs/IECs, or to regulatory 
authority or health authority inspectors.   
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 assert 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. 
12.3. 
Sponsor Responsibilities 
12.3.1. 
Protocol Modifications 
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
initiated only by BeiGene. All protocol modifications must be submitted to regulatory authorities and 
the IRB/IEC together with, if applicable, a revised model ICF in accordance with local requirements. 
As applicable by local requirements, written documentation of regulatory authorities, IRB/IEC and 
required study center approval must be obtained by the sponsor before changes can be implemented. 
Information on any change in risk and /or change in scope must be provided to patients already 
actively participating in the study, and they must read, understand and sign each revised ICF 
confirming his/her willingness to remain in the study. 
12.3.2. 
Use of Information and Publication 
A CSR will be prepared and provided to the regulatory agency(ies) of participating countries. 
BeiGene will ensure that the report meets the standards set out in the ICH Guideline for Structure 
and Content of Clinical Study Reports (ICH E3). Note that an abbreviated report may be prepared in 
certain cases. 
The results of this study will be published or presented at scientific meetings in a timely, objective, 
and clinically meaningful manner that is consistent with good science, industry and regulatory 
guidance, and the need to protect the intellectual property of BeiGene (sponsor), regardless of the 
outcome of the study.  The data generated in this clinical study are the exclusive property of the 
sponsor and are confidential.  For multicenter studies, the first publication or disclosure of study 
results shall be a complete, joint multicenter publication or disclosure coordinated by the sponsor.  
Thereafter, any secondary publications will reference the original publication(s).  Authorship will be 
determined by mutual agreement and all authors must meet the criteria for authorship established by 


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the International Committee of Medical Journal Editors Uniform Requirements for Manuscripts or 
stricter local criteria (International Committee of Medical Journal Editors 2016). 
After conclusion of the study and without prior written approval from BeiGene, investigators in this 
study may communicate, orally present, or publish in scientific journals or other scholarly media 
only after the following conditions have been met: 
 The results of the study in their entirety have been publicly disclosed by or with the consent 
of BeiGene in an abstract, manuscript, or presentation form; or 
 The study has been completed at all study sites for at least 2 years. 
 No such communication, presentation, or publication will include BeiGene’s confidential 
information.  
 Each investigator agrees to submit all manuscripts or congress abstracts and 
posters/presentations to the sponsor prior to submission.  This allows the sponsors to protect 
proprietary information, provide comments based on information from other studies that may 
not yet be available to the investigator, and ensure scientific and clinical accuracy.  The 
details of the processes of producing and reviewing reports, manuscripts, and presentations 
based on the data from this trial will be presented in the investigator’s clinical study 
agreement. 
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. 
 Resolve and close all data queries. 
 Accountability, reconciliation, and arrangements for unused study drug(s). 
 Review of study records for completeness. 
 Return of treatment codes to the sponsor. 
 Shipment of PK samples to assay laboratories. 
In addition, the sponsor reserves the right to temporarily suspend or prematurely discontinue this 
study either at a single study center or at all study centers at any time for reasons including, but not 
limited to, safety or ethical issues or severe noncompliance. If the sponsor determines such action is 
needed, the sponsor will discuss this with the investigator (including the reasons for taking such 
action) at that time. When feasible, the sponsor will provide advance notification to the investigator 
of the impending action before 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 


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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, ICF, drug records, staff curriculum vitae 
and authorization forms, and other appropriate documents and correspondence. 
Patient clinical source documents (usually defined by the project in advance to record key 
efficacy/safety parameters independent of the eCRFs) would include (although not be limited to) the 
following: patient hospital/clinic records, physician’s and nurse’s notes, appointment book, original 
laboratory reports, ECG, electroencephalogram, X-ray, pathology and special assessment reports, 
consultant letters, screening and enrollment log, etc. 
Following closure of the study, the investigator must maintain all study records in a safe and secure 
location. The records must be maintained to allow easy and timely retrieval, when needed (eg, audit 
or inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with 
assessment of the facility, supporting systems, and personnel.  
The sponsor will inform the investigator of the time period for retaining these records to comply with 
all applicable regulatory requirements. The minimum retention time will meet the strictest standard 
applicable to that study center for the study, as dictated by any institutional requirements or local 
laws or regulations, or the sponsor’s standards/procedures; otherwise, the retention period will 
default to 15 years. 
The investigator must notify the sponsor of any changes in the archival arrangements, including, but 
not limited to, the following: archiving at an off-site facility and transfer of ownership of, or 
responsibility for, the records in the event the investigator leaves the study center. 
If the investigator cannot guarantee this archiving requirement at the study site for any or all of the 
documents, arrangements must be made between the investigator and BeiGene to store these in 


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secure containers outside of the study center so that they can be returned to the investigator in case of 
a regulatory audit. When source documents are required for the continued care of the patient, 
appropriate copies should be made for storage outside of the study center. 
Biological samples at the conclusion of this study may be retained as outlined in the agreement with 
the contract research organization managing the biological samples.  
12.5.2. 
Provision of Study Results and Information to Investigator 
When the CSR is completed, the sponsor will provide the major findings of the study to the 
investigator. 
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 that are conceived or reduced to practice by the study center personnel during the course of or 
as a result of the study are the sole property of the sponsor, and are hereby assigned to the sponsor. 
If a written contract for the conduct of the study that includes ownership provisions inconsistent with 
this statement is executed between the sponsor and the study center, that contract’s ownership 
provisions shall apply rather than this statement. 
All information provided by the sponsor and all data and information generated by the study center 
as part of the study (other than a patient’s medical records) will be kept confidential by the 
investigator and other study center personnel. This information and data will not be used by the 
investigator or other study center personnel for any purpose other than conducting the study without 
the prior written consent of the sponsor. 
These restrictions do not apply to: 
 Information which becomes publicly available through no fault of the investigator or 
study center personnel. 
 Information which is necessary to disclose in confidence to an IEC/IRB solely for 
the evaluation of the study. 
 Information which is necessary to disclose in order to provide appropriate medical care to 
a patient. 
 Study results that may be published as described in Section 12.3.2. 


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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 CRFs at regular intervals throughout the study to 
verify adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered on them. The monitor should have access to any patient records needed to verify the entries 
on the eCRFs. The investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved. 
12.7.2. 
Access to Information for Auditing or Inspections 
Representatives of regulatory authorities or of BeiGene may conduct inspections or audits any time 
during or after completion of this clinical study. If the investigator is notified of an inspection by a 
regulatory authority the investigator agrees to notify the sponsor or its designee immediately. The 
investigator agrees to provide to representatives of a regulatory agency or BeiGene access to records, 
facilities, and personnel for the effective conduct of any inspection or audit. 


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Food and Drug Administration Center for Drug Evaluation Research (CDER) and Center for 
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Fojo T and Bates S. Mechanisms of resistance to PARP inhibitors–three and counting. Cancer 
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Gojo I, Beumer JH, Pratz KW, 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.  
Hegi ME, Diserens AC, Godard S, et al. Clinical trial substantiates the predictive value of O-6-
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Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in 
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Herrlinger U, Schaefer N, Steinbach JP, et al. Survival and quality of life in the randomized, 
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Huang PH, Cook R, Mittnacht S. RB in DNA repair. Oncotarget. 2015;6(25):20746-47.  
Hussain M, Carducci MA, Slovin S, et al. Targeting DNA repair with combination veliparib 
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International Committee of Medical Journal Editors. Recommendations for the Conduct, Reporting, 
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Kedar PS, Stefanick DF, Horton JK, et al. Increased PARP-1 association with DNA in alkylation 
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Kim YJ, Wilson DM 3rd. Overview of base excision repair biochemistry. Curr Mol Pharmacol. 
2012;5(1):3-13. 


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Leonetti C, Biroccio A, Graziani G, et al. Targeted therapy for brain tumours: role of PARP 
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Li L, Ross AH. Why is PTEN an important tumor suppressor? J Cell Biochem. 
2007;102(6):1368-74. 
Louis DN, Ohgaki H, Wiestler OD, et al. World Health Organization Histological Classification of 
Tumours of the Central Nervous System. International Agency for Research on Cancer, France. 
2016. 
Malmström A, Grønberg BH, Marosi C, et al. Temozolomide versus standard 6-week radiotherapy 
versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic 
randomised, phase 3 trial. Lancet Oncol. 2012;13(9):916-26.  
McEllin B, Camacho CV, Mukherjee B, et al. PTEN loss compromises homologous recombination 
repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) 
polymerase inhibitors. Cancer Res. 2010;70(13):5457-64. 
Middleton MR, Friedlander P, Hamid O, et al. Randomized phase II study evaluating veliparib 
(ABT-888) with temozolomide in patients with metastatic melanoma. Ann Oncol. 
2015;26(10):2173-9. 
Murai J, Huang SY, Das BB, et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. 
Cancer Res. 2012;72:5588–99. 
Murai J, Huang SY, Renaud A, et al. Stereospecific PARP Trapping by BMN 673 and Comparison 
with Olaparib and Rucaparib. Mol Cancer Ther. 2014a;13:433–43. 
Murai J, Zhang Y, Morris J, et al. Rationale for poly(ADP-ribose) polymerase (PARP) inhibitors in 
combination therapy with camptothecins or temozolomide based on PARP trapping versus catalytic 
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Newlands ES, Stevens MF, Wedge SR, et al. Temozolomide: a review of its discovery, chemical 
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Niyazi M, Brada M, Chalmers AJ, et al. ESTRO-ACROP guideline “target delineation of 
glioblastomas”. Radiother Oncol. 2016;118(1):35-42. 


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Noel G, Godon C, Fernet M, et al. Radiosensitization by the poly(ADPribose) polymerase inhibitor 
4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA 
synthesis. Mol. Cancer Ther. 2006,5:564-74. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55.  
Perry JR, Bélanger K, Mason WP, et al. Phase II trial of continuous dose-intense temozolomide in 
recurrent malignant glioma: RESCUE study. J Clin Oncol. 2010;28(12):2051-7. 
Perry JR, Laperriere NL, O’Callaghan J, et al. Short-course radiation plus temozolomide in elderly 
patients with glioblastoma. N Engl J Med. 2017;376(11):1027-37. 
Plummer R, Lorigan P, Steven N, et al. A phase II study of the potent PARP inhibitor, Rucaparib 
(PF-01367338, AG014699), with temozolomide in patients with metastatic melanoma demonstrating 
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Rivera AL, Pelloski CE, Gilbert MR, et al. MGMT promoter methylation is predictive of response to 
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Tentori L, Turriziani M, Franco D, et al. Treatment with temozolomide and poly (ADP-ribose) 
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14. 
APPENDICES 
 


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APPENDIX 1. 
STUDY ASSESSMENTS 
 


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Appendix Table 1: Schedule of Assessments for Arm A (Pamiparib and Radiation Therapy) 
Study Phase 
Screeninga 
Radiation Therapy (RT)b 
Restc 
End of 
Treatmentd 
Safety 
Follow-upe 
Long-Term 
Follow-upe 
Day of Phase 
-28 to -1 
RT 
D1 
RT 
D8 
RT 
D15 
RT 
D22 
RT 
D29 
RT 
D36 
RT 
D43 
Rest 
D1 
Rest 
D15 
Rest 
D29 
 
 
Allowed time window 
 
 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
+ 3 
± 3 
+ 3 
 
 
Study Day 
-28 to -1 
1 
8 
15 
22 
29 
36 
43 
43-50 
57-64 
71-78 
Variese 
Variese 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient enrollment 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examinationf 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Limited physical examinationf 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
 
 
Vital signs and weightg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance status  
X 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
12-lead ECG 
X (-14 to -1) 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Hematologyh 
X (-14 to -1) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistryi 
X (-14 to -1) 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
 
Coagulation (INR and aPTT) 
X (-14 to -1) 
 
 
 
 
 
 
 
 
 
X 
  
 
Hepatitis B Serologyj 
 
X (-14 to -1) 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisk 
X (-14 to -1) 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Pregnancy testingl 
X (-7 to -1) 
 
 
 
X 
 
 
 
X 
 
X 
X  
 
MRI scanm 
X (-14 to -1) 
 
 
 
 
 
 
 
 
 
X 
 
X 
(q8w ±7d) 
Patient registration 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
RTb 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Pamiparibn,d 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Adverse eventso 
Xo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xo 
Xo 


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Appendix Table 1: Schedule of Assessments for Arm A (Pamiparib and Radiation Therapy) (Continued) 
Study Phase 
Screeninga 
Radiation Therapy (RT)b 
Restc 
End of 
Treatmentd 
Safety 
Follow-upe 
Long-Term 
Follow-upe 
Day of Phase 
-28 to -1 
RT 
D1 
RT 
D8 
RT 
D15 
RT 
D22 
RT 
D29 
RT 
D36 
RT 
D43 
Rest 
D1 
Rest 
D15 
Rest 
D29 
 
 
Concomitant medication(s) p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xp 
X (~q12w)p  
Pharmacokineticsq 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Blood for biomarkersr 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
Tumor tissues 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
X (~q12w) 
-7/-14 to -1, Day -7/-14 to Day -1 of screening; aPTT, activated partial thromboplastin time; CSF, cerebrospinal fluid; D, day; ECG, electrocardiogram; ECOG, Eastern 
Cooperative Oncology Group; INR, International Normalized Ratio; MRI, magnetic resonance imaging; q8w ±7d, every 8 weeks ± 7 days; ~q12w, approximately every 
12 weeks; RT, radiation therapy 
a Screening must occur within 28 days of Day 1. Some assessments have a narrower screening window as shown in the table. Assessments obtained within 14 days of 
Day 1 (pregnancy and laboratory assessments: within 7 days) do not have to be repeated on Day 1. It is highly recommended that general screening assessments such 
as physical examination and laboratory assessments should be conducted first to rule out ineligibility based on those grounds before more involved and/or invasive 
procedures are carried out. 
b RT will be administered once daily (QD)  5 days/week for 6 to 7 weeks with 1.8 or 2 Gy/fraction for a total target dose of between 58 Gy and 64 Gy. If the time 
period of RT extends beyond 6 weeks, a clinic visit on Day 43 will be required (gray italics in table).   
c Day 1 of Rest Phase is defined as the day after RT is completed.  
d For patients who have completed all study treatment per protocol and who do not continue on maintenance treatment with pamiparib in combination with TMZ, as 
described further below, the end-of-treatment (EOT) visit will occur at the end of the Rest Phase, 28 days after RT was completed. Patients who discontinued study 
treatment for any other reason outlined in Section 6.5.1 will undergo the EOT visit within 7 days after stopping all study treatments. 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 MRI showed progressive disease (PD) may be used as the EOT visit provided that all required assessments were performed. 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 PD. ECG does not have to be repeated if it was performed 
within 14 days of the EOT visit. 
After RT is completed, patients will receive no further RT. However, at the discretion of the investigator and after discussion with the medical monitor, patients may 
continue to receive pamiparib in combination with TMZ until PD, unacceptable toxicity or death, withdrawal of consent, loss to follow-up, or study termination by 
sponsor, as described in Section 4.1.1 and Section 4.1.2.. This maintenance treatment should begin after the 4-week rest period post-completion of RT (+7 days) to 
allow for recovery from RT treatment. Patients should follow the Schedule of Assessments for the maintenance treatment (Appendix 1 Table 4). 
e Safety Follow-up: All patients who discontinue study treatment for reasons other than completion of RT per protocol will have a safety follow-up visit approximately 


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30 (±7) days after the last day of study treatment to collect AEs and SAEs that may have occurred after the patient discontinued from the study treatment. For patients 
who have completed all study treatments per protocol, this safety follow-up coincides with the EOT visit. 
 Long-Term Follow-up: Patients who were not discontinued from study treatment due to PD and meet criteria otherwise (eg, 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 6.7, whichever occurs first. 
 Patients will be followed for survival and further anticancer therapy information post progression via phone contact (with the patient’s guardian, if applicable) 
approximately every 12 weeks. 
f A complete physical examination should include an evaluation of head, eyes, ears, nose and throat, neck, heart, chest (including lungs), abdomen, extremities, skin, 
lymph nodes, cardiovascular status and neurological status. A limited physical examination should include neurological status, and additionally be directed at the 
evaluation of symptoms or specific safety issues. Changes from baseline abnormalities should be recorded at each subsequent physical examination. New or worsened 
abnormalities should be recorded as AEs if appropriate. 
g Vital signs (systolic and diastolic blood pressure; pulse rate; and oral, temporal or tympanic temperature) will be taken before study treatment and approximately 
15 minutes prior to each collection of PK blood samples, if applicable, during the treatment period. 
h Hematology includes hemoglobin, platelet count, white blood cell (WBC) count, neutrophil count, and lymphocyte count.  
i Chemistry includes albumin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), chloride, 
creatinine, glucose, lactic acid dehydrogenase (LDH), phosphate, potassium, sodium, total bilirubin, and total protein.  
j Testing will be performed by the local laboratory at Screening and will include HBV serology (HBsAg, HBsAb, and HBcAb) and viral load assessment (HBV DNA). 
k Urinalysis will be assessed using urine dipstick. Urine microscopy will be performed if any assessment on the urine dipstick is abnormal. Urinalysis includes glucose, 
protein, ketones, blood, red blood cells, and white blood cells.  
l  For women of childbearing potential, a serum pregnancy test must be performed during screening ≤ 7 days prior to Day 1. For subsequent pregnancy testing while on 
study treatment and at end of treatment, urine pregnancy tests are acceptable. If a urine pregnancy test is positive, a confirmatory serum pregnancy test is required. 
m Tumors will be assessed at screening by MRI per RANO criteria within 14 days prior to Day 1 and then approximately 4 weeks after completion of RT as part of the 
EOT visit. Patients without PD at the EOT visit must then be followed with MRIs every 8 weeks (± 7 days) during the Follow-up Phase. 
n All patients will receive daily pamiparib concurrent with RT starting on Day 1 for a time period that is determined by the Cohort a patient was enrolled into. Patients in 
Cohort 1 will receive daily pamiparib for the first 2 weeks of RT only (black X), patients in subsequent cohorts will receive pamiparib for longer time periods (gray 
italics X) as outlined in Section 4. Patients will be required to fast for at least 1 hour before and 2 hours 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 should be administered in the clinic. 
o Adverse events and laboratory safety measurements will be recorded at each study visit, graded per NCI-CTCAE Version 4.03 and assessed as outlined in Section 10. 
After informed consent has been signed but prior to study treatment, only SAEs should be reported. After initiation of study treatment, all AEs and SAEs, regardless 
of relationship to study treatment, will be reported until 30 days after last study treatment or initiation of new anticancer therapy, whichever occurs first. After this 
period, the investigator should report any SAEs that are believed to be related to prior study treatment. 
p Concomitant medications will be recorded at each study visit. 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 treatment should be recorded. The eCRF entry must include the dose, regimen, route, indication, and start and stop dates of use of the 


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prior and concomitant medications. Concomitant medications include subsequent anticancer therapy information acquired during the Follow-up Phase. 
q Pharmacokinetic samples will be collected from patients in all cohorts at the following time points: predose (within 30 min prior to dose) and 2 hours (± 30 min) post-
dose on both Day 1 and Day 15. Where pamiparib treatment is administered for only a 2-week (14-day) time period, the PK samples will be collected on Day 1 and 
Day 14 instead. The time of study drug administration on the day prior to Day 15 (Day 14 for patients receiving only 2 weeks of pamiparib) must be recorded on the 
eCRF. Details concerning collection, processing, and handling of the PK plasma samples will be provided in the laboratory manual. 
r Blood samples must be collected at screening or on Day 1 (5 mL) for the assessment of germline mutations. Additionally, 3 blood samples (10 mL each) must be 
collected for the assessment of circulating tumor cells (CTCs) and plasma markers (eg, circulating nucleic acids, CNAs) of GBM, TMZ treatment, and PARP 
inhibition at screening or on Day 1 before study treatment, and 2 blood samples (10 mL each) must be collected for the assessment of plasma markers (eg, CNAs) on 
Day 15 and Day 36 before study treatment 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 laboratory manual.  
s 
 
 
 


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Appendix Table 2: Schedule of Assessments for Arm B (Pamiparib, Radiation Therapy and Temozolomide) 
Study Phase 
Screening a 
Radiation Therapy (RT)b 
Restc 
End of 
Treatmentd 
Safety 
Follow-upe 
Long-Term 
Follow-upe 
Day of Phase 
-28 to -1 
RT 
D1 
RT 
D8 
RT 
D15 
RT 
D22 
RT 
D29 
RT 
D36 
RT 
D43 
Rest 
D1 
Rest 
D15 
Rest 
D29 
 
 
Allowed time window 
 
 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
+ 3 
± 3 
+ 3 
 
 
Study Day 
-28 to -1 
1 
8 
15 
22 
29 
36 
43 
43-50 
57-64 
71-78 
Variese 
Variese 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Patient enrollment 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examinationf 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Limited physical examinationf 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
 
 
Vital signs and weightg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance status  
X 
X 
 
 
X 
 
 
 
X 
 
X 
 
 
12-lead ECG 
X (-14 to -1) 
X 
 
 
 
 
X 
 
 
 
X 
 
 
Hematologyh 
X (-14 to -1) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistryi 
X (-14 to -1) 
X 
X 
X 
X 
X 
X 
  
X 
 
X 
X 
 
Coagulation (INR and aPTT) 
X (-14 to -1) 
 
 
 
 
 
 
 
 
 
X 
 
 
Hepatitis B serologyj 
X (-14 to -1) 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisk 
X (-14 to -1) 
 
 
 
X 
 
 
 
X 
 
X 
 
 
Pregnancy testingl 
X (-7 to -1) 
 
 
 
X 
 
 
 
X 
 
X 
X  
 
MRI scanm 
X (-14 to -1) 
 
 
 
 
 
 
 
 
 
X 
 
X 
(q8w ±7d) 
Patient registration 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
RTb 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Pamiparibn,d 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
Temozolomide (TMZ)o,d 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 


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Appendix Table 2: Schedule of Assessments for Arm B (Pamiparib, Radiation Therapy, and Temozolomide) 
Study Phase 
Screening a 
Radiation Therapy (RT)b 
Restc 
End of 
Treatmentd 
Safety 
Follow-upe 
Long-Term 
Follow-upe 
Day of Phase 
-28 to -1 
RT 
D1 
RT 
D8 
RT 
D15 
RT 
D22 
RT 
D29 
RT 
D36 
RT 
D43 
Rest 
D1 
Rest 
D15 
Rest 
D29 
 
 
Adverse eventsp 
Xp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xp 
Xp 
Concomitant medication(s)q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xq 
X (~q12w)q 
Pharmacokineticsr 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
Blood for biomarkerss 
X 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
Tumor tissuet 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
X (~q12w) 
-7/-14 to -1 = Day -7/-14 to Day -1 of screening; aPTT, activated partial thromboplastin time; CSF, cerebrospinal fluid; D, day; ECG, electrocardiogram; ECOG, Eastern 
Cooperative Oncology Group; INR, International Normalized Ratio; MRI, magnetic resonance imaging; q8w ±7d, every 8 weeks ± 7 days; ~q12w, approximately every 
12 weeks; RT, radiation therapy 
a Screening must occur within 28 days of Day 1. Assessments obtained within 14 days of Day 1 (pregnancy and laboratory assessments: within 7 days) do not have to 
be repeated on Day 1. Some assessments have a narrower screening window as shown in the table. It is highly recommended that general screening assessments such 
as physical examination and laboratory assessments should be conducted first to rule out ineligibility based on those grounds before more involved and/or invasive 
procedures are carried out. 
b RT will be administered once daily (QD)  5 days/week for 6 to 7 weeks with 1.8 or 2 Gy/fraction for a total target dose of between 58 Gy and 64 Gy. If the time 
period of RT extends beyond 6 weeks, a clinic visit on Day 43 will be required (gray italics in table).  
c Day 1 of Rest Phase is defined as the day after RT is completed.  
d For patients who have completed all study treatment per protocol and do not continue on maintenance treatment with pamiparib in combination with TMZ, the end-of-
treatment (EOT) visit will occur at the end of the Rest Phase, 28 days after RT was completed.  Patients who discontinued study treatment for any other reason 
outlined in Section 6.5.1 will undergo the EOT visit within 7 days after stopping all study treatments. 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 MRI showed 
progressive disease (PD) may be used as the EOT visit provided that all required assessments were performed. 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 PD. ECG does not have to be repeated if it was performed within 14 days of the 
EOT visit. 
After RT is completed, patients will receive no further RT. However, at the discretion of the investigator and after discussion with the medical monitor, patients in the 
escalation phase may continue to receive pamiparib in combination with TMZ until PD, unacceptable toxicity or death, withdrawal of consent, loss to follow-up, or 
study termination by sponsor. In the expansion phase, continuation of treatment is mandatory. This maintenance treatment should begin after the 4-week rest period 
post-completion of RT (+7 days) to allow for recovery from RT treatment. Patients should follow the Schedule of Assessments for the maintenance treatment 


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(Appendix 1 Table 4). 
e Safety Follow-Up: All patients who discontinue study treatment for reasons other than completion of RT per protocol will have a safety follow-up visit approximately 
30 (±7) days after the last day of study treatment to collect AEs and SAEs that may have occurred after the patient discontinued from the study treatment. For patients 
who have completed all study treatments per protocol, this safety follow-up coincides with the EOT visit. 
 Long-Term Follow-up: Patients who were not discontinued from study treatment due to PD and meet criteria otherwise (eg, 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 6.7, whichever occurs first. 
 Patients will be followed for survival and further anticancer therapy information post progression via phone contact (with the patient’s guardian, if applicable) 
approximately every 12 weeks. 
f A complete physical examination should include an evaluation of head, eyes, ears, nose and throat, neck, heart, chest (including lungs), abdomen, extremities, skin, 
lymph nodes, cardiovascular status and neurological status. A limited physical examination should include neurological status, and additionally be directed at the 
evaluation of symptoms or specific safety issues. Changes from baseline abnormalities should be recorded at each subsequent physical examination. New or worsened 
abnormalities should be recorded as AEs if appropriate. 
g Vital signs (systolic and diastolic blood pressure; pulse rate; and oral, and temporal or tympanic temperature) will be taken before study treatment and approximately 
15 minutes prior to each collection of PK blood samples, if applicable, during the treatment period. 
h Hematology includes hemoglobin, platelet count, white blood cell (WBC) count, neutrophil count, and lymphocyte count. Per the Temodar package insert, 
hematology also needs to be completed on Day 43, which is 21 days after the second dose. 
i Chemistry includes albumin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), chloride, 
creatinine, glucose, lactic acid dehydrogenase (LDH), phosphate, potassium, sodium, total bilirubin, and total protein. 
j Testing will be performed by the local laboratory at Screening and will include HBV serology (HBsAg, HBsAb, and HBcAb) and viral load assessment (HBV DNA). 
k Urinalysis will be assessed using urine dipstick. Urine microscopy will be performed if any assessment on the urine dipstick is abnormal. Urinalysis includes glucose, 
protein, ketones, bilirubin, blood, red blood cells, and white blood cells.  
l For women of childbearing potential, a serum pregnancy test must be performed during screening ≤ 7 days prior to Day 1. For subsequent pregnancy testing while on 
study treatment and at end of treatment, urine pregnancy tests are acceptable. If a urine pregnancy test is positive, a confirmatory serum pregnancy test is required. 
m Tumors will be assessed at screening by MRI per RANO criteria within 14 days prior to Day 1 and then approximately 4 weeks after completion of RT as part of the 
EOT visit. Patients without PD at the EOT visit must then be followed with MRIs every 8 weeks (± 7 days) during the Follow-up Phase. 
n All patients will receive daily pamiparib concurrent with RT starting on Day 1 for a time period that will be defined following review of the safety data obtained in 
Arm A, as outlined in Section 4. Patients will be required to fast for at least 1 hour before and 2 hours 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 should be administered in the clinic. 
o All patients will receive temozolomide (TMZ) at a dose level as outlined in Section 4.2.1on the same schedule as pamiparib. Instructions for TMZ administration are the 
same as for pamiparib. Antiemetic prophylaxis may be provided as described in Section 7.1.2.3. On days with PK assessments, TMZ should be administered in the clinic. 
p  Adverse events and laboratory safety measurements will be recorded at each study visit, graded per NCI-CTCAE Version 4.03 and assessed as outlined in Section 10. 


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After informed consent has been signed but prior to study treatment, only SAEs should be reported. After initiation of study treatment, all AEs and SAEs, regardless 
of relationship to study treatment, will be reported until 30 days after last study treatment or initiation of new anticancer therapy, whichever occurs first. After this 
period, the investigator should report any SAEs that are believed to be related to prior study treatment. 
q Concomitant medications will be recorded at each study visit. 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 treatment 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. Concomitant medications include subsequent anticancer therapy information acquired during the Follow-up Phase. 
r Pharmacokinetic samples will be collected from patients in all cohorts at the following time points: predose (within 30 min prior to dose) and 2 hours (± 30 min) post-
dose on both Day 1 and Day 15. If pamiparib treatment is administered only for a 2-week (14-day) time period, PK samples will be collected on Day 1 and Day 14 
instead. The time of study drug administration on the day prior to Day 15 (Day 14 for patients receiving only 2 weeks of pamiparib) must be recorded on the eCRF. 
Details concerning collection, processing, and handling of the PK plasma samples will be provided in the laboratory manual. 
s Blood samples must be collected at screening or on Day 1 (5 mL) for the assessment of germline mutations. Additionally, 3 blood samples (10 mL each) must be 
collected for the assessment of circulating tumor cells (CTCs) and plasma markers (eg, circulating nucleic acids [CNAs]) of GBM, TMZ treatment, and PARP 
inhibition at screening or on Day 1 before study treatment, and 2 blood samples (10 mL each) must be collected for the assessment of blood markers (eg CNAs) on 
Day 15 and Day 36 before study treatment 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 laboratory manual.  
t 
 
 


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Appendix Table 3: Schedule of Assessments for Arm C (Pamiparib and Temozolomide) 
Study Phase 
Screeninga 
Treatmentb 
End of 
Treatmentc 
Safety 
Follow-upd 
Long-Term 
Follow-upd 
Day of Phase 
-28 to -1 
Cycle 1 
Cycle 2 
Cycle ≥3 
 
 
 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
D15 
 
Allowed time window 
 
 
± 2 
± 2 
± 2 
+ 2 
± 2 
± 3 
± 3 
 
 
 
Study Day 
-28 to -1 
1 
8 
15 
22 
29 
43 
57 
71 
Varies 
Variesd 
Variesd 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Patient enrollment 
Xa 
 
 
 
 
 
 
 
 
 
 
 
Demographics and medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete physical examinatione 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
Limited physical examinatione 
 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
Vital signs and weightf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance status  
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
12-lead ECG 
X (-14 to -1) 
 X 
 
 
 
X 
 
X 
 
X 
 
 
Hematologyg 
X (-14 to -1) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Chemistryh 
X (-14 to -1) 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Coagulation (INR and aPTT) 
X (-14 to -1) 
 
 
 
 
X 
 
 
 
X 
 
 
Hepatitis B serologyi 
X (-14 to -1) 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisj 
X (-14 to -1) 
  
 
 
 
X 
 
X 
 
X 
 
 
Pregnancy testingk 
X (-7 to -1) 
 
 
 
 
X 
 
X 
 
X 
X  
 
MRI scanl 
X (-14 to -1) 
 
 
 
 
 
 
X 
(q8w ±7d) 
 
X 
 
X 
(q8w ±7d) 
Patient registration 
Xa 
 
 
 
 
 
 
 
 
 
 
 
Pamiparibm 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Temozolomide (TMZ)n 
 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
Adverse eventso 
Xo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xo 
Xo 


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Appendix Table 3: Schedule of Assessments for Arm C (Pamiparib and Temozolomide) (Continued) 
Study Phase 
Screeninga 
Treatmentb 
End of 
Treatmentc 
Safety 
Follow-upd 
Long-Term 
Follow-upd 
Day of Phase 
-28 to -1 
Cycle 1 
Cycle 2 
Cycle ≥3 
 
 
 
D1 
D8 
D15 
D22 
D1 
D15 
D1 
D15 
 
Concomitant medication(s)p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xp 
X (~q12w)p 
Pharmacokineticsq 
 
X 
 
X 
 
 
 
 
 
 
 
 
Blood for biomarkersr 
X 
X 
 
X 
 
 
 
X 
 
X 
 
 
Tumor tissue s 
X 
 
 
 
 
 
 
 
 
 
 
 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
X (~q12w) 
7/-14 to -1, Day -7/-14 to Day -1 of screening; aPTT, activated partial thromboplastin time; CSF, cerebrospinal fluid; D, day; ECG, electrocardiogram; ECOG, Eastern 
Cooperative Oncology Group; INR, International Normalized Ratio; MRI, magnetic resonance imaging; q8w ±7d, every 8 weeks ± 7 days; ~q12w, approximately 
every 12 weeks   
a Screening must occur within 28 days of Day 1. Assessments obtained within 14 days of Day 1 (pregnancy and laboratory assessments: within 7 days) do not have to be 
repeated on Day 1. Some assessments have a narrower screening window as shown in the table. It is highly recommended that general screening assessments such as 
physical examination and laboratory assessments should be conducted first to rule out ineligibility based on those grounds before more involved and/or invasive 
procedures are carried out. 
b Cycle 1 encompasses the dose-limiting toxicity (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). 
c The end-of-treatment (EOT) visit will occur within 7 days after a patient discontinued study treatment for any of the reasons outlined in Section 6.5.1. A visit should be 
scheduled as soon as possible, but the EOT visit may occur later after discussion with the medical monitor for specific circumstances, such as prolonged 
hospitalization. The visit at which MRI showed progressive disease (PD) may be used as the EOT visit provided that all required assessments were performed. 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 PD. ECG does not have to be 
repeated if it was performed within 14 days of the EOT visit. 
d Safety Follow-up: all patients who discontinue study treatment will have a safety follow-up visit approximately 30 (±7) days after the last day of study treatment to 
collect AEs and SAEs that may have occurred after the patient discontinued from the study treatment. 
 Long-Term Follow-up: Patients who were not discontinued from study treatment due to PD and meet criteria otherwise (eg, 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 6.7, whichever occurs first. 
 Patients will be followed for survival and further anticancer therapy information post progression via phone contact (with the patient’s guardian, if applicable) 
approximately every 12 weeks. 
e A complete physical examination should include an evaluation of head, eyes, ears, nose and throat, neck, heart, chest (including lungs), abdomen, extremities, skin, 


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lymph nodes, cardiovascular status and neurological status. A limited physical examination should include neurological status, and additionally be directed at the 
evaluation of symptoms or specific safety issues. Changes from baseline abnormalities should be recorded at each subsequent physical examination. New or worsened 
abnormalities should be recorded as AEs if appropriate. 
f Vital signs (systolic and diastolic blood pressure; pulse rate; and oral, temporal or tympanic temperature) will be taken before study treatment and approximately 
15 minutes prior to each collection of PK blood samples, if applicable, during the treatment period. 
g Hematology includes hemoglobin, platelet count, white blood cell (WBC) count, neutrophil count, and lymphocyte count. For cycle 2 and beyond hematology is only 
required on Days 1 and 15 however should be measured more frequently based on the patient’s blood counts and need for additional monitoring. Per the Temodar 
prescribing information, hematology also needs to be completed on Day 22 which is 21 days after the first dose. 
h Chemistry includes albumin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), chloride, 
creatinine, glucose, lactic acid dehydrogenase (LDH), phosphate, potassium, sodium, total bilirubin, and total protein. 
i Testing will be performed by the local laboratory at Screening and will include HBV serology (HBsAg, HBsAb, and HBcAb) and viral load assessment (HBV DNA). 
j Urinalysis will be assessed using urine dipstick. Urine microscopy will be performed if any assessment on the urine dipstick is abnormal. Urinalysis includes glucose, 
protein, ketones, bilirubin, blood, red blood cells, and white blood cells.  
k For women of childbearing potential, a serum pregnancy test must be performed during screening ≤ 7 days prior to Day 1. For subsequent pregnancy testing while on 
study treatment and at end of treatment, urine pregnancy tests are acceptable. If a urine pregnancy test is positive, a confirmatory serum pregnancy test is required. 
l Tumors will be assessed at screening by MRI per RANO criteria within 14 days prior to Day 1, then every 8 weeks (± 7 days) and as part of the EOT visit. Patients 
without PD at the EOT visit must then be followed with MRIs every 8 weeks (± 7 days) during the Follow-up Phase. 
m All patients will receive daily pamiparib as outlined in Section 4. Patients will continue receiving pamiparib in combination with TMZ in Arm C until PD, 
unacceptable toxicity or death, withdrawal of consent, loss to follow-up, or study termination by sponsor. Patients will be required to fast for at least 1 hour before and 2 
hours 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 should be administered in the clinic. 
n All patients will receive temozolomide (TMZ) at a dose level as outlined in Section 4. TMZ will be given for Days 1 to 21 of each 28-day cycle. Instructions for TMZ 
administration are the same as for pamiparib. Antiemetic prophylaxis may be provided as described in Section 7.1.2.3. On days with PK assessments, TMZ should be 
administered in the clinic. 
o Adverse events and laboratory safety measurements will be recorded at each study visit, graded per NCI-CTCAE Version 4.03 and assessed as outlined in Section 10. 
After informed consent has been signed but prior to study treatment, only SAEs should be reported. After initiation of study treatment, all AEs and SAEs, regardless of 
relationship to study treatment, will be reported until 30 days after last study treatment or initiation of new anticancer therapy, whichever occurs first. After this period, 
the investigator should report any SAEs that are believed to be related to prior study treatment. 
p Concomitant medications will be recorded at each study visit. 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 treatment 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. Concomitant medications include subsequent anticancer therapy information acquired during the Follow-up Phase. 
q Pharmacokinetic samples will be collected from patients in all cohorts at the following time points: predose (within 30 min prior to dose) and 2 hours (± 30 min) post-
dose on both Cycle 1 Day 1 and Cycle 1 Day 15. If pamiparib treatment is administered for only 2 weeks (14-day) time period, PK sampes will be collected on Day 1 
and Day 14 instead. The time of study drug administration on the day prior to Cycle 1 Day 15 (Day 14 if pamipraib is administered for 2 weeks) must be recorded on 


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the eCRF. Details concerning collection, processing, and handling of the PK plasma samples will be provided in the laboratory manual. 
r Blood samples must be collected at screening or on Day 1 (5 mL) for the assessment of germline mutations. Additionally, 3 blood samples (10 mL each) must be 
collected for the assessment of circulating tumor cells (CTCs) and plasma markers (eg, circulating nucleic acids [CNAs]) of GBM, TMZ treatment, and PARP 
inhibition at screening or on Day 1before study treatment, and 2 blood samples (10 mL each) must be collected for the assessment of plasma markers (eg, CNAs) of 
GBM on Day 15 and Cycle 3 Day 1 before study treatment 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 laboratory manual.  
s 


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Appendix Table 4: Schedule of Assessments for Maintenance Treatment for Arms A and B (Pamiparib In Combination With 
Temozolomide) 
Study Phase 
Re-Screeninga 
Treatment 
End of 
treatment 
(EOT) 
Visitb 
Safety 
Follow-upc 
Long-term 
Follow-upc 
Day of Phase 
-7 to -1 
Cycle 1 
Cycle 2 
Cycle ≥3 
Day 1 
Day 15 
Day 1 
Day 15 
Day 1 
Allowed time window 
 
 
± 3 
± 3 
± 3 
± 3 
Re-Treatment Study Day 
 
1 
15 
28 
43 
57 
Varies 
Variesc 
Variesc 
Patient enrollment 
X 
 
 
 
 
 
 
 
 
Complete physical examinationd 
X 
X 
X 
X 
X 
X 
 
 
 
Vital signs and weighte 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG 
X  
X 
 
 
 
 
X 
 
 
Hematologyf 
X  
X 
X 
X 
X 
X 
X 
X 
 
Chemistryg 
X  
X 
X 
X 
X 
X 
X 
X 
 
Urinalysish 
X  
X 
 
 
 
 
X 
 
 
Pregnancy testingi 
X  
 
 
X 
 
X 
X 
X 
 
MRI scanj  
X 
 
 
 
 
X (q8w ±7d) 
X 
 
X (q8w ±7d) 
Pamiparibk 
 
X 
X 
X 
X 
X 
 
 
 
Temozolomide (TMZ)l 
 
X 
X 
X 
X 
X 
 
 
 
Adverse eventsm 
X 
X 
X 
X 
X 
X 
X 
Xm 
Xm 
Concomitant medication(s)n 
X 
X 
X 
X 
X 
X 
X 
Xn 
X (~q12w)n 
Survival follow-up 
 
 
 
 
 
 
 
 
X (~q12w) 
Tumor tissueo 
 
 
 
 
 
 
Xo 
 
 
 
 


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Appendix Table 4: Schedule of Assessments for Maintenance Treatment for Arms A and B (Pamiparib In Combination With 
Temozolomide) (Continued) 
7/-14 to -1, Day -7/-14 to Day -1 of screening; aPTT, activated partial thromboplastin time; CSF, cerebrospinal fluid; D, day; ECG, electrocardiogram; ECOG, Eastern 
Cooperative Oncology Group; INR, International Normalized Ratio; MRI, magnetic resonance imaging; q8w ±7d, every 8 weeks ± 7 days; ~q12w, approximately every 
12 weeks 
 
a Maintenance treatment should commence following the 4-week rest period post-completion of RT (+7 days) to allow for recovery from RT treatment. A re-screening 
to confirm continued eligibility must occur within 7 days prior to commencing maintenance treatment. The EOT visit post-completion of the post RT rest period may 
be considered the re-screening visit provided all assessments were completed. Patients’ must continue to meet eligibility criteria prior to commencing maintenance 
treatment. 
b The end-of-treatment (EOT) visit will occur within 7 days after a patient discontinued study treatment for any of the reasons outlined in Section 6.5.1. A visit should be 
scheduled as soon as possible, but the EOT visit may occur later after discussion with the medical monitor for specific circumstances, such as prolonged 
hospitalization. The visit at which MRI showed progressive disease (PD) may be used as the EOT visit provided that all required assessments were performed. 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 PD. ECG does not have to be 
repeated if it was performed within 14 days of the EOT visit. 
c Safety Follow-up: all patients who discontinue study treatment will have a safety follow-up visit approximately 30 (±7) days after the last day of study treatment to 
collect AEs and SAEs that may have occurred after the patient discontinued from the study treatment. 
 Long-Term Follow-up: Patients who were not discontinued from study treatment due to PD and meet criteria otherwise (eg, 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 6.7, whichever occurs first. 
 Patients will be followed for survival and further anticancer therapy information post progression via phone contact (with the patient’s guardian, if applicable) 
approximately every 12 weeks. 
d A limited physical examination should include neurological status, and additionally be directed at the evaluation of symptoms or specific safety issues. Changes from 
the EOT visit of the escalation portion should be recorded. New or worsened abnormalities should be recorded as AEs if appropriate. 
e Vital signs (systolic and diastolic blood pressure; pulse rate; and oral, temporal, or tympanic temperature) will be taken before study treatment during the treatment 
period. 
f Hematology includes hemoglobin, platelet count, white blood cell (WBC) count, neutrophil count, and lymphocyte count. For maintenance cycle 2 and beyond 
hematology is only required on Days 1 and 15 however should be measured more frequently based on the patient’s blood counts and need for additional monitoring. 
Per the Temodar prescribing information, hematology also needs to be completed on Day 22 which is 21 days after the first dose. 
g Chemistry includes albumin, alkaline phosphatase, aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), chloride, 
creatinine, glucose, lactic acid dehydrogenase (LDH), phosphate, potassium, sodium, total bilirubin, and total protein. 
h Urinalysis will be assessed using urine dipstick. Urine microscopy will be performed if any assessment on the urine dipstick is abnormal. Urinalysis includes glucose, 
protein, ketones, bilirubin, blood, red blood cells, and white blood cells.  
i For women of childbearing potential, a serum pregnancy test must be performed during re-screening ≤ 7 days prior to Day 1. For subsequent pregnancy testing while 


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on study treatment and at end of treatment, urine pregnancy tests are acceptable. If a urine pregnancy test is positive, a confirmatory serum pregnancy test is required. 
j The scheduling of MRIs during the maintenance phase should continue on an 8 week schedule; ie, the first MRI during maintenance should be completed 8 weeks after 
the EOT MRI conducted after the rest period following completion of RT. Tumors will be assessed by MRI per RANO criteria every 8 weeks (± 7 days). Patients 
without PD at the EOT visit must be followed with MRIs every 8 weeks (± 7 days) during the Follow-up Phase. The EOT MRI should only be collected if an MRI has 
not been performed within 8 weeks or if PD is suspected. 
k All patients will receive daily pamiparib as outlined in Section 4. Patients will continue receiving pamiparib in combination with TMZ until PD, unacceptable toxicity 
or death, withdrawal of consent, loss to follow-up, or study termination by sponsor. Patients will be required to fast for at least 1 hour before and 2 hours 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.  
l All patients will receive temozolomide (TMZ) at a dose level lower than or equal to a dose that has been determined to be safe and tolerable in Arm C of study. 
m Adverse events and laboratory safety measurements will be recorded at each study visit, graded per NCI-CTCAE Version 4.03 and assessed as outlined in Section 10. 
After initiation of study treatment, all AEs and SAEs, regardless of relationship to study treatment, will be reported until 30 days after last study treatment or initiation 
of new anticancer therapy, whichever occurs first. After this period, the investigator should report any SAEs that are believed to be related to prior study treatment. 
n Concomitant medications will be recorded at each study visit. All concomitant medications taken by or administered to the patient until 30 days after the last day of study 
treatment 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.  
o If the patient undergoes repeat resection on completion of the maintenance phase, tumor tissue may be collected for the assessment of markers related to GBM, TMZ 
treatment, and PARP inhibitors. 
 
 


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APPENDIX 2. 
RESPONSE ASSESSMENT FOR NEURO-ONCOLOGY (RANO) 
 
CRITERIA FOR TIME POINT RESPONSES 
1. Definitions and Baseline Classification 
Baseline is defined as the screening assessment performed immediately prior to commencement of 
any study treatment. 
The following definitions are to be applied: 
Measurable Lesions 
Measurable lesions are enhancing lesions that can be measured bi-dimensionally with clearly defined 
margins by computed tomography (CT) or magnetic resonance imaging (MRI). 
Minimal Diameter: 
Lesions must have two perpendicular diameters of at least 10 mm, visible on two or more axial slices 
that are preferably, at most, 5 mm apart with 0-mm skip. 
Note: After baseline, target lesions that become smaller than the minimum requirement for 
measurement or become no longer amenable to bi-dimensional measurement are to be recorded at 
the default value of 5 mm for each diameter below 5 mm until the lesion disappears (recorded as 
0  0 mm).  
Multicentric Lesions 
Multicentric lesions are lesions where there is normal intervening brain tissue between the two (or 
more) lesions. If there is no normal brain tissue between these two (or more) lesions, they will be 
considered the same lesion. 
For multicentric lesions that are discrete foci of enhancement, no more than 3 separately enhancing 
lesions should be identified and the sum of the product of the diameters (SPD) measured. 
Non-Measurable Lesions 
All other lesions that do not meet the criteria for measurable disease as defined, as well as all non-
enhancing and other truly non-measurable lesions, are considered non-measurable. 
A non-measurable lesion will include foci of enhancement that are less than the specified smallest 
diameter, non-enhancing lesions seen on T2-weighted or fluid attenuated inversion recovery 
(FLAIR) images, hemorrhagic or predominantly cystic or necrotic lesions, and leptomeningeal 
tumor. Hemorrhagic lesions often have intrinsic T1-weighted hyperintensity that could be 


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misinterpreted as enhancing tumor, and for this reason, the pre-contrast T1-weighted image must be 
examined to exclude baseline or interval sub-acute hemorrhage.  
At baseline, lesions are to be identified as follows: 
a. Target lesions: Up to 5 measurable lesions, each at least 10  10 mm, representative of the 
patient’s disease 
 
b. Non-target lesions: All other lesions, including all non-measurable lesions and any measurable 
lesions not chosen as Target lesions 
2. Post-Treatment Evaluation 
At each evaluation, a time point response is to be determined for target lesions, non-target lesions, 
and new lesion. The RANO criteria and associated conventions for each post-treatment time point 
assessment are provided in Appendix Table 5. Overall time point response is derived as described in 
Appendix Table 6. 
Unless progression is observed, overall response can only be determined when all lesions are 
assessed.  
3. Confirmation 
Confirmation assessments for overall time point responses of complete response (CR) and partial 
response (PR) are to be performed no less than 4 but no more than 8 weeks after the initial time point 
at which a response is seen. 
4. Best Response 
Best response, incorporating confirmation requirements, will be derived from the series of time point 
responses and need not be considered when assigning response at each time point. 
 
 


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Appendix Table 5: 
RANO Criteria For Time Point Responses (TPR) 
Prerequisite 
If the daily dose of glucocorticoids is not the same for each of the 5 days preceding the current MRI, 
target or non-target lesion TPR is to be designated NE (not evaluable). To avoid this designation, 
MRI should be delayed until these glucocorticoid criteria can be met, and every effort should be 
made to ensure the MRI is performed on schedule while meeting these criteria.  
 
Target Enhancing Lesion (T1/post-contrast) Time Point Response (TPR) 
Target 
Lesion 
TPR 
Criteria 
NA 
No Target enhancing lesions identified at baseline 
PD 
≥25% increase in sum of the products of perpendicular diameters (SPD) of the target 
enhancing lesions compared to the prior MRI (since and including baseline) with the nadir 
SPD for the target enhancing lesions and on a stable or increasing dose of glucocorticoids. 
 
(If the glucocorticoid dose is neither stable nor increased, a Target Lesion TPR of NE is to 
be assigned.) 
NE 
≥ 1 target enhancing lesions were not assessed unless progression is observed 
 
CR 
Disappearance of all enhancing target lesion(s); and, 
 
No glucocorticoids (other than a physiologic replacement dose of a maximum of 1.2 mg 
dexamethasone equivalent dose per day) taken for the 5 days immediately preceding the date 
of the current MRI. 
 
(If glucocorticoid dose is greater than a physiologic replacement dose, a Target lesion TPR 
of PR is to be assigned.) 
PR 
≥50% decrease in the SPD of all target enhancing lesions compared to the baseline MRI; 
and glucocorticoids stable or decreased, 
 
(If the glucocorticoid dose is neither stable nor decreased, a Target Lesion TPR of SD is to 
be assigned.) 
SD 
Target lesion TPR not qualify for PD, NE, CR or PR 
CR, complete response; MRI, magnetic resonance imaging; NA, not applicable; NE, not evaluable, PD = 
progressive disease, PR, partial response; SD, stable disease; TPR, time point response. 
 


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Appendix Table 5: 
RANO Criteria For Time Point Responses (TPR) (Continued) 
Non-Target Enhancing Lesion (T1/post-contrast) Time Point Response (TPR)  
Non-Target Lesion TPR 
Criteria 
NA 
No Non-Target enhancing lesions identified at baseline 
PD 
MRI: Non-target 
enhancing 
(T1/post-contrast) 
Unequivocal progression (not due to co-morbid events) of one more non-
target enhancing lesions compared to the prior MRI (since and including 
baseline) with the nadir for the non-target enhancing lesions; 
and on stable or increasing dose of glucocorticoids. 
 
(If the glucocorticoid dose is neither stable nor increased, a Non-Target 
Lesion TPR of NE is to be assigned.) 
NE 
≥ 1 non-target enhancing lesions were not assessed unless progression is observed 
CR 
MRI: Non-target 
enhancing 
(T1/post-contrast) 
Disappearance of all enhancing non-target lesion(s); and, 
 
No glucocorticoids (other than a physiologic replacement dose of a maximum 
of 1.2 mg dexamethasone equivalent dose per day) taken for the 5 days 
immediately preceding the date of the current MRI. 
 
(If glucocorticoid dose is greater than a physiologic replacement dose, a Non-
Target lesion TPR of PR is to be assigned.) 
SD 
Non-Target TPR does not qualify for PD, NE, CR or PR 
CR, complete response; MRI, magnetic resonance imaging; NA, not applicable; NE, not evaluable, PD; progressive 
disease, PR, partial response; SD, stable disease; TPR, time point response. 
Time Point Response (TPR) (New Lesions) 
New Lesion TPR 
Criteria 
Yes 
1. One or more new lesions (enhancing (T1/post-contrast) or non-enhancing 
(T1/pre-contrast or T2/FLAIR)) compared to the baseline MRI, regardless 
of glucocorticoid dose 
 
2. Significant increase on T2/FLAIR (including mass effects) not due to co-
morbid events (eg, radiation therapy, demyelination, ischemic injury, 
infection, seizures, postoperative changes, or other treatment effects based 
upon a review of all prior T2/FLAIR images) compared to the T2/FLAIR 
image at the prior time point (since and including baseline) with the nadir 
SPD for the target enhancing lesions; and on stable or increasing dose of 
glucocorticoids steroids. 
 
If #2 is met and glucocorticoid dose is neither stable nor increased, a time point 
response of NE is to be assigned. 
 
NE 
Absence of new lesions was not established or T2/FLAIR not assessed. 
No 
No new lesions compared to baseline MRI and no significant increase onT2/FLAIR 
(including mass effects) 
MRI, magnetic resonance imaging; FLAIR, Fluid-Attenuated Inversion Recovery; NE, not evaluable, TPR, time point 
response. 


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Appendix Table 6: 
Overall Time Point Response 
Criterion 
CR 
PR 
SD 
PD 
T1 gadolinium enhancing disease 
None 
≥ 50% ↓ 
< 50% ↓ but < 25% ↑ 
  ≥ 25% ↑ 
T2/Flair 
Stable or ↓ 
Stable or ↓ 
Stable or ↓ 
↑* 
New lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or ↓ 
Stable or ↓ 
NAǂ 
Clinical Status 
Stable or ↑ 
Stable or ↑ 
Stable or ↑ 
↓* 
Requirement for response 
All 
All 
All 
Any* 
CR, Complete Response; FLAIR, Fluid-Attenuated Inversion Recovery; NA, Not Applicable; PD, Progressive Disease; 
PR, Partial Response; SD, Stable Disease 
* Progression occurs when this criterion is present 
ǂ  Increase in corticosteroids alone will not be taken into account in determining progression in the absence of persistent 
clinical deterioration 
 
Reference: Wen PY, Macdonald DR, Reardon DA et al. Updated response assessment criteria for high-grade 
gliomas: response assessment in neuro-oncology working group. J. Clin. Oncol. 2010;28 (11):1963-72). 
 
 
 


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APPENDIX 3. 
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, eg, light house work, 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., Group 
Chair. 
 
 


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APPENDIX 4. 
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 
o Oral, intravaginal or transdermal 
 Progestogen-only hormonal contraception associated with the inhibition of ovulation 
o Oral, injectable, implantable 
 An intrauterine device (IUD) 
 Intrauterine hormone-releasing system (IUS) 
 Bilateral tubal occlusion 
 Vasectomized partner 
 Sexual abstinence (defined as refraining from heterosexual intercourse during the entire period 
of exposure associated with the study treatment). Total sexual abstinence should only be used 
as a contraceptive method if it is in line with the patients’ usual and preferred lifestyle. Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of exposure to study drug, and withdrawal are not acceptable 
methods of contraception. 
Of note, barrier contraception (including male and female condoms with or without spermicide) is 
not considered a highly effective method of contraception and if used, this method must be used in 
combination with another acceptable method listed above. 
Definition of childbearing potential 
Childbearing potential is defined as being physiologically capable of becoming pregnant. No 
childbearing potential is defined as one or both of the following criteria: 
 Surgically sterile (bilateral salpingectomy, bilateral oophorectomy, or hysterectomy) 
 Post-menopausal, defined as 
o ≥55 years of age with no spontaneous menses for ≥12 months OR 
o <55 years of age with no spontaneous menses for ≥12 months AND with a 
post-menopausal follicle-stimulating (FSH) concentration >30 IU/mL 
 
 


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APPENDIX 5. 
NEW YORK HEART ASSOCIATION CLASSIFICATION 
 
NYHA Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, eg no shortness of 
breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, eg walking short 
distances (20-100 m). Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. 
 
 
 


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APPENDIX 6. 
PROHIBITED MEDICATIONS 
Strong and Moderate CYP3A Inhibitors and Strong CYP3A Inducers 
Strong CYP3A Inhibitors 
Antibiotics: clarithromycin, telithromycin, troleandomycin 
Antifungals: itraconazole, ketoconazole, posaconazole, voriconazole 
Antivirals: boceprevir, telaprevir 
Other: cobicistat, conivaptan, elvitegravir, mibefradil, nefazodone 
Protease Inhibitors: indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir 
Strong CYP3A Inducers 
Avasimibe, carbamazepine, mitotane, phenobarbital, phenytoin, rifabutin, rifampin (rifampicin), St. John’s 
wort (Hypericumperforatum) 
Moderate CYP3A Inhibitors 
Antibiotics: ciprofloxacin, erythromycin 
Antifungals: fluconazole 
Protease inhibitors: amprenavir, atazanavir, darunavir, fosamprenavir 
Calciumchannel 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 
Data compiled from the FDA’s “Guidance for Industry, Drug Interaction Studies;” 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664 htm 
from the Indiana University School of Medicine’s “Clinically Relevant” Table 
http://medicine.iupui.edu/flockhart/table htm; from the University of Washington’s Drug Interaction Database 
www.druginteractioninfo.org 
 
 
 


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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 coadministered with 
a known potent inhibitor. 
2 
Substrates with narrow therapeutic index (NTI): Drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns (eg, Torsade de 
Pointes). 
 
 
Strong CYP2C8 Inhibitors 
 
 gemfibrozil 
 
Data compiled from the FDA’s “Guidance for Industry, Drug Interaction Studies;” 
http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664 htm 
from the Indiana University School of Medicine’s “Clinically Relevant” Table 
http://medicine.iupui.edu/flockhart/table htm; from the University of Washington’s Drug Interaction Database 
www.druginteractioninfo.org 
 
 
 


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APPENDIX 8. 
SIGNATURE OF INVESTIGATOR 
 
PROTOCOL TITLE: 
A Phase 1b/2 study to assess the safety, tolerability and efficacy of 
BGB-290 in combination with radiation therapy and/or temozolomide 
in subjects with first-line or recurrent/refractory glioblastoma 
 
PROTOCOL NO: 
BGB-290-104 
This protocol is a confidential communication of BeiGene USA, Inc. I confirm that I have read this 
protocol, I understand it, and I will work according to this protocol. I will also work consistently with 
the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with 
good clinical practices and the applicable laws and regulations. Acceptance of this document 
constitutes my agreement that no unpublished information contained herein will be published or 
disclosed without prior written approval from BeiGene USA, Inc. 
 
 
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
 
Signature of Investigator:  
 
  
Printed Name:  
 
  
Investigator Title: 
 
  
Name/Address of Center:  
 
 
Date:  
 
 
 
 
 
 
Instructions to the Investigator: Please SIGN and DATE this signature page. PRINT your name, title, and the 
name of the center in which the study will be conducted. Return the signed copy to BeiGene, USA. 


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APPENDIX 9. 
LIST OF COUNTRY-SPECIFIC AMENDMENTS 
 
Amendment 1.1 (UK) – 15 December 2017 
 
 


Signature Page for VV-CLIN-002114 v1.0
Signature Page for VV-CLIN-002114 v1.0
Approval
Biomarker/Translation Research
25-Jul-2018 03:03:29 GMT+0000
Approval
Regulatory Affairs
25-Jul-2018 03:46:48 GMT+0000
Approval
Drug Supply
25-Jul-2018 04:42:57 GMT+0000
Approval
Clinical Operations
25-Jul-2018 11:54:05 GMT+0000
Approval
Clinical Development
25-Jul-2018 19:31:41 GMT+0000
Approval
Clinical Pharmacology
25-Jul-2018 20:51:09 GMT+0000
Approval
Biometrics
26-Jul-2018 22:23:47 GMT+0000
Approval
Drug Safety
27-Jul-2018 22:20:29 GMT+0000


Signature Page for VV-CLIN-002114 v1.0
Signature Page for VV-CLIN-002114 v1.0
Approval
Clinical Development
27-Jul-2018 23:17:31 GMT+0000

SAP_001.pdf: 
 
BeiGene USA, Inc 
 BGB-290-104 
Statistical Analysis Plan 
 
 
Version 1.0:  04/20/2020 
Page 1 of 24  
CONFIDENTIAL 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
BGB-290-104 
Study Protocol 
Title: 
A Phase 1b/2 study to assess the safety, tolerability and efficacy of BGB-
290 in combination with radiation therapy and/or temozolomide in 
subjects with first-line or recurrent/refractory glioblastoma 
 
 
Date: 
April 20, 2020 
Version: 
1.0 
 
 
DocuSign Envelope ID: 8450D441-98ED-4167-AFF9-13F2214EF32D




 
BeiGene USA, Inc 
 BGB-290-104 
Statistical Analysis Plan 
 
 
Version 1.0:  04/20/2020 
Page 3 of 24  
CONFIDENTIAL 
 
 
TABLE OF CONTENTS 
1 
INTRODUCTION 
7 
2 
STUDY OVERVIEW 
7 
3 
STUDY OBJECTIVES 
7 
3.1 
Primary Objectives 
7 
3.2 
Secondary Objectives 
8 
4 
STUDY ENDPOINTS 
8 
4.1 
Primary Endpoints 
8 
4.2 
Secondary Endpoints 
9 
5 
SAMPLE SIZE CONSIDERATIONS 
10 
6 
STATISTICAL METHODS 
10 
6.1 
Analysis Populations 
10 
6.2 
Data Analysis general considerations 
11 
6.2.1 
Definitions and Computations 
11 
6.2.2 
Conventions 
12 
6.2.3 
Handling of Missing Data 
13 
6.2.4 
Handling of Treatment Cycles 
13 
6.2.5 
Adjustment for Covariates 
13 
6.2.6 
Data Integrity 
13 
6.3 
Patient Characteristics 
13 
6.3.1 
Patient Disposition 
13 
6.3.2 
Protocol Deviations 
13 
6.3.3 
Demographic and Other Baseline Characteristics 
14 
6.3.4 
Prior and Concomitant Medications 
14 
6.3.5 
Prior GBM Related Therapy (arm C only) 
15 
6.3.6 
Medical History 
15 
6.4 
Efficacy Analysis 
15 
6.4.1 
Primary Efficacy Endpoints 
15 
6.4.2 
Secondary Efficacy Endpoints 
16 
6.4.3 
Subgroup Analyses 
17 
6.5 
Safety Analyses 
18 
6.5.1 
Extent of Exposure 
18 
6.5.2 
Dose Limiting Toxicity 
18 
6.5.3 
Adverse Events 
18 
6.5.4 
Laboratory Values 
20 
6.5.5 
Vital Signs 
21 
6.5.6 
Electrocardiograms (ECG) 
21 
6.5.7 
Eastern Cooperative Oncology Group (ECOG) 
21 
6.6 
Pharmacokinetic Analyses 
21 
6.6.1 
Plasma Concentrations 
21 
7 
INTERIM ANALYSIS 
21 
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Page 4 of 24  
CONFIDENTIAL 
 
8 
CHANGES IN THE PROTOCOL PLANNED ANALYSIS 
21 
9 
REFERENCES 
22 
10 
APPENDIX 
22 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
BOR 
best overall response 
CBR 
clinical benefit rate 
CI 
confidence interval 
CR 
complete response 
CTCAE 
common Terminology Criteria for Adverse Events 
Ctrough 
lowest concentration reached before the next dose administered 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
GBM 
glioblastoma 
KM 
Kaplan-Meier 
MAD 
maximum administered dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MGMT 
O6-methylguanine-DNA methyltransferas 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PK 
pharmacokinetic  
PFS 
progression-free survival 
PR 
partial response 
PT 
preferred term 
RANO 
Response Assessment in Neuro-Oncology 
RT 
radiotherapy 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
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SOC 
system Organ Class 
SPD 
sum of the products of the perpendicular diameter 
TEAE 
treatment-emergent adverse event 
TMZ 
temozolomide 
unmethylated GBM 
GBM with unmethylated MGMT promoter 
 
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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 and report results for 
BGB-290-104 protocol Version 2.0, dated July 23rd 2018: A Phase 1b/2 study to assess the 
safety, tolerability and efficacy of pamiparib in combination with radiation therapy (RT) and/or 
temozolomide (TMZ) in patients with first-line or recurrent/refractory glioblastoma (GBM). The 
focus of this SAP is for the planned primary, secondary efficacy and safety analyses specified in 
the study protocol. 
2 
STUDY OVERVIEW 
This is an open-label, multicenter, multiple-dose, dose-escalation Phase 1b/2 study to determine 
the safety and pharmacokinetics (PK) of pamiparib in combination with radiation therapy and/or 
temozolomide with two initial arms (arms A and C) and a potential third arm (arm B). In arm A, 
pamiparib will be combined with RT in patients with first-line GBM with unmethylated MGMT 
promoter (‘unmethylated GBM’). In arm B, depending on the safety of the arm A combination, 
pamiparib will be combined with both TMZ and RT in patients with first-line unmethylated GBM. 
In arm C, pamiparib will be combined with TMZ in patients with recurrent/refractory GBM with 
methylated or unmethylated MGMT promoter.  
On completion of escalation cohorts, the study planned to  enroll expansion cohorts for arm C 
and depending upon the emerging data, either arm A or arm B. Under protocol Version 2.0, 
dated July 23rd 2018, following completion of radiation treatment in Arms A and B , at the 
discretion of the investigator and after discussion with the medical monitor, patients may 
continue to receive pamiparib in combination with TMZ (maintenance).  
 
Disease status will be assessed using Response Assessment in Neuro-Oncology (RANO) criteria. 
Patients will undergo tumor assessments at screening and then every 8 weeks, or as clinically 
indicated. 
3 
STUDY OBJECTIVES 
3.1 
PRIMARY OBJECTIVES  
3.1.1. Phase 1b  
Arm A (pamiparib + RT): Patients with first-line unmethylated GBM 
• To assess safety and tolerability of pamiparib combined with RT  
• To identify dose-limiting toxicities (DLTs) and determine the maximum tolerated dose 
(MTD) or maximum administered dose (MAD) and length of treatment for pamiparib 
combined with RT  
• To select the recommended Phase 2 schedule for pamiparib combined with RT  
Arm B (pamiparib + RT + TMZ): Patients with first-line unmethylated GBM  
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• To assess safety and tolerability of pamiparib combined with RT and TMZ  
• To identify DLTs and determine the MTD or MAD for TMZ when combined with RT 
and the length of pamiparib treatment in combination with RT as determined in arm A  
• To select the recommended phase 2 dose (RP2D) for TMZ when combined with RT and 
the length of pamiparib treatment as determined in arm A  
Arm C (pamiparib + TMZ): Patient with recurrent/refractory GBM  
• To assess safety and tolerability of pamiparib combined with TMZ  
• To identify DLTs and determine the MTD or MAD for TMZ combined with pamiparib  
• To select the RP2D for TMZ combined with pamiparib  
3.1.2 Phase 2  
Arm A, Expansion (pamiparib + RT): Patients with first-line unmethylated GBM  
• To make a preliminary assessment of efficacy of pamiparib combined with RT followed 
by maintenance treatment of pamiparib + TMZ for those patients continuing onto 
maintenance treatment 
Arm C, Expansion (pamiparib + TMZ): Patients with recurrent/refractory unmethylated or  
methylated GBM  
• To make a preliminary assessment of efficacy of pamiparib combined with TMZ  
3.2 
SECONDARY OBJECTIVES  
 Phase 1b, all Arms  
• Characterize the PK of pamiparib in combination with RT and/or TMZ  
• To make a preliminary assessment of pamiparib efficacy in combination with RT and/or 
TMZ  
Phase 2, Arm A and C 
• To further characterize the efficacy, safety and tolerability of pamiparib in combination 
with RT and/or TMZ  
• To further characterize the PK of pamiparib in combination with RT and/or TMZ  
4 
STUDY ENDPOINTS 
4.1 
PRIMARY ENDPOINTS 
Phase 1b, all Arms  
• Incidence and nature of DLTs  
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• Incidence, nature, and severity of AEs, graded according to the NCI-CTCAE, v4.03 
• Number of cycles (arm C and maintenance phase for arm A&B) and the dose intensity of 
each component of the treatment regimens, and changes in vital signs and clinical 
laboratory test results during and following study treatment  
Phase 2, ArmA (pamiparib + RT)   
• Modified disease control rate (mDCR) as assessed using the Response Assessment in 
Neuro-Oncology (RANO) criteria  
Phase 2, Arm C (pamiparib + TMZ)  
• Overall response rate (ORR) as assessed using RANO criteria  
4.2 
SECONDARY ENDPOINTS 
Phase 1b, all Arms  
• PK parameters of pamiparib: trough plasma concentration (Ctrough)  
• Modified DCR (Arms A and B), DCR (Arm C), ORR and clinical benefit rate (CBR)  
• Time-to-event endpoints: duration of response (DOR), progression-free survival (PFS) and 
overall survival (OS)  
Phase 2, Arm A (pamiparib + RT)  
• ORR and CBR as assessed using RANO  
• Time-to-event endpoints: DOR, PFS and OS  
• Incidence, nature, and severity of AEs, graded according to NCI-CTCAE, v4.03  
• The dose intensity of each component of the treatment regimens, and changes in vital 
signs and clinical laboratory test results during and following study treatment  
• PK parameters of pamiparib: Ctrough  
Phase 2, Arm C (pamiparib + TMZ)  
• DCR and CBR as assessed using RANO criteria  
• Time-to-event endpoints: DOR, PFS and OS  
• Incidence, nature, and severity of AEs, graded according to NCI-CTCAE, v4.03  
• Number of cycles and the dose intensity of each component of the treatment regimens, 
and changes in vital signs and clinical laboratory test results during and following study 
treatment 
• PK parameters of pamiparib: Ctrough  
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5 
SAMPLE SIZE CONSIDERATIONS 
Approximately 300 patients (60 in Phase 1b and 240 in Phase 2) were originally planned for 
enrollment. The actual sample size in Phase 1b depended on the number of Cohorts enrolled per 
arm and was 46 patients. The overall sample size was reduced during the study since the 
expansion cohorts were considered too large for this nonrandomized and nonregistrational study. 
The sample size in arm A expansion cohort is 40 and the sample size in arm C expansion cohort 
is 30. Overall the total number of patients enrolled in this study was 116.   
 
Due to the reduction in sample size of the arm C expansion cohort, the analysis will not separate 
patients by MGMT status. 
 
In Phase 2, the original sample size calculation was carried out using modified DCR in Arms A 
and B and ORR in each expansion cohort of arm C. 
1) Assuming modified DCR of 60% in Arms A and B vs. 40% in historical control, the 
study is powered at ~82% to show 20% difference in modified DCR using a one-sided 
alpha of 0.025 when n = 60 per expansion cohort. Due to the reduction in actual sample 
size to 40 patients, assuming an observed modified DCR of 60%, the lower bound of the 
80% exact confidence interval (CI) for the estimated modified DCR will exclude values 
less than 48%. The minimum observed modified DCR that has an 80% exact CI 
excluding 40% will be 53% (21 out of 40).  
2) Assuming ORR of 25% in arm C vs. 10% in historical control, the study is powered at 
~85% to show an 15% difference in ORR using a one-sided alpha of 0.025 when n=60 
per expansion cohort. Due to the reduction in actual sample size to 30 patients, assuming 
an observed ORR of 25%, the lower bound of the 80% exact CI for the estimated ORR 
will exclude values less than 16%. The minimum observed ORR that has an 80% exact 
CI excluding 10% will be 20% (6 out of 30).  
6 
STATISTICAL METHODS 
6.1 
ANALYSIS POPULATIONS 
Safety Analysis Set: includes all patients who received any dose of any of the study treatments 
(pamiparib, RT and/or TMZ). The Safety Analysis Set will be used for efficacy and safety 
analyses.  
Efficacy Analysis Set: includes all patients in the Safety Analysis Set who: 
Arms A & B:  had a tumor assessment at baseline and at End of Treatment unless discontinued 
treatment or study early due to disease progression or death prior to tumor assessment. 
Arm C:  had measurable disease at baseline and at least one postbaseline tumor assessment unless 
discontinued treatment or study early due to disease progression or death prior to tumor 
assessment. 
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DLT-Evaluable Analysis Set: includes patients from  escalation cohorts only in the Safety Analysis 
Set who received ≥ 42 Gy of RT (Arms A and B) and ≥ 70% of scheduled pamiparib (Arms A, B 
and C) and TMZ (Arms B and C) during the DLT assessment window.  All patients who had a 
DLT event will be considered DLT-evaluable regardless of study treatment intensity.  
PK Analysis Set: includes all patients for whom valid pamiparib PK parameters can be estimated.  
6.2 
DATA ANALYSIS GENERAL CONSIDERATIONS 
6.2.1 Definitions and Computations 
Study day: Study day will be calculated in reference to the first dose date of study drug. First 
dose date of study drug is defined as the earliest date of the first dose of any study drug. For 
maintenance phase, C1D1 is the first dose date. For assessments conducted on or after the first 
dose date, study day will be calculated as (assessment date – first dose date of study drug + 1).  
For assessments conducted before the first dose date, study day is calculated as (assessment date 
– first dose date of study drug). There is no study day 0.  
 
In the situation where the event date is partial or missing, the date will appear partial or missing in 
the listings. Study day and any corresponding durations will be presented based on the imputations 
specified in Appendix 1. 
Baseline: Unless otherwise specified, a baseline value is defined as the last non-missing value 
collected before the time of first dose. 
 
Treatment Duration:  
 
Arm A&B regular treatment period (with RT) is defined as date of the last non-zero dose of 
latest treatment – first dose date of earliest treatment +1; treatment duration 
 
Arm A&B maintenance period is defined as last non-zero dose of latest treatment in maintenance 
phase – date of C1D1 of maintenance phase +1   
 
Arm C is defined as date of last non-zero dose of latest treatment – first dose date of earliest 
treatment +1. 
 
RANO assessments: 
 
ORR (objective response rate) is defined as proportion of patients with best overall response of 
CR or PR per RANO criteria (confirmed by a subsequent tumor assessment at least four weeks 
apart). Best overall response will be assessed from the start of study treatment until data cut-off 
date, disease progression or start of new anti-cancer therapy. Patients without postbaseline tumor 
assessment are considered non-responders. 
Modified DCR (disease control rate) is defined as the proportion of patients with CR, PR or 
SD per RANO criteria as the response assessment at the end-of-treatment (EOT) visit, as 
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scheduled per protocol. Patients with no EOT tumor assessment, as scheduled per protocol (due 
to any reason), will be considered non-responders for modified DCR. 
DCR (disease control rate) is defined as the proportion of patients with best overall response of 
CR, PR or SD per RANO criteria. CR or PR will be confirmed by a subsequent tumor assessment 
at least four weeks apart. 
CBR (clinical benefit rate) is defined as the proportion of patients with best overall response of CR, 
PR or SD ≥ 24 weeks per RANO criteria. CR or PR will be confirmed by a subsequent tumor 
assessment at least four weeks apart. 
BOR (best of response) is defined as the best response recorded from the start of study treatment 
until data cutoff, or start of new anti-cancer therapy. Computation of BOR will consider 
timepoints prior to PD when determining BOR. 
Time to event data 
 
OS (overall survival) is defined as the time from the first dose date to date of death for any cause. 
Patients that are still alive at the time of analysis will be censored at the last contact date that is 
known to be alive. 
PFS (progression free survival) is defined as the time from the first dose date to disease progression 
per RANO criteria or death, whichever occurs first. Censoring rules for PFS are described in Table 
1 in section 6.4.2. 
DOR (duration of response) is defined as the time from the date of the earliest documented response 
to disease progression or death for any cause whichever occurs earlier. 
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 
significant digit. 
• 1 month = 30.4375 days. Number of months is calculated as (days / 30.4375) rounded up 
to 1 significant digit. 
• Age will be calculated as the integer part of (first dose date – date of birth + 1)/3                                        
65.25 
• 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. 
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• 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), unless otherwise specified. 
• For discrete endpoints, summary statistics will include frequencies and percentages. 
6.2.3 Handling of Missing Data 
Missing data will not be imputed unless otherwise specified elsewhere in the SAP. Missing dates 
or partially missing dates will be imputed conservatively for adverse events and prior/concomitant 
medications/procedures. Specific rules for handling of missing or partially missing dates for 
adverse events and prior/concomitant medications/procedures are provided in Appendix 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. 
6.2.4 Handling of Treatment Cycles 
In arm C, patients will be treated in a 28 days cycle. The schedule of each cycle will not change 
for dose delays or dose holds. 
During maintenance treatment in Arms A and B, patients will be treated in a 28 days cycle. The 
schedule of each cycle will not change for dose delays or dose holds. 
6.2.5 Adjustment for Covariates 
No covariates will be adjusted in primary analyses. 
6.2.6 Data Integrity 
Before the final statistical analysis begins, the integrity of the data should be reviewed to assure 
fit-for-purpose.  The data set for analysis should be an accurate and complete representation of the 
patients' relevant outcomes from the clinical database.  All data should be complete and reviewed 
up to a pre-specified cutoff date.  Consistency checks and appropriate source data verification 
should be complete. 
6.3 
PATIENT CHARACTERISTICS 
6.3.1 Patient Disposition 
The number (percentage) of subjects treated, discontinued from study treatment, entered efficacy 
and survival follow-up phase, discontinued from study and duration of follow-up will be 
summarized. The primary reason for treatment and study discontinuation will be summarized 
according to the categories in the eCRF.  
6.3.2 Protocol Deviations 
Major protocol deviation criteria will be established and patients with major protocol deviations 
will be identified and documented before the database lock. Major protocol deviations will be 
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summarized for all patients in the Safety Analysis Set. They will also be presented in a listing by 
each category. 
6.3.3 Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized using descriptive statistics in 
the Safety Analysis Set.  
Continuous variables include:  
• Age (years) 
• Time (weeks) from initial diagnosis of glioblastoma to first dose date 
• Time (weeks) from initial surgical resection 
Categorical variables include: 
• Age group (< 65, ≥65 years) 
• Gender (Male, Female) 
• Race (Asian, Black or African American, White, others) 
• ECOG performance status (0, 1) 
• Surgical status for initial diagnosis of glioblastoma (biopsy, partial resection, complete 
resection and no prior surgery) 
• Baseline corticosteroids use (yes, no)  
• Relapse status (arm C only) 
• MGMT promoter status (arm C only) 
• Prior use of temozolomide (arm C only) 
• WHO grade at initial diagnosis (arm C only) 
 
6.3.4 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) code. 
The number (percentage) of patients reporting prior and concomitant medications will be 
summarized by ATC medication class and WHO DD preferred term by phase in the Safety 
Analysis Set. Prior medications are defined as medications that started 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 or 
initiation of a new anti-cancer therapy. A listing of prior and concomitant medications will be 
provided. 
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6.3.5 Prior GBM Related Therapy (arm C only) 
The number (percentage) of prior GBM related anti-cancer systemic therapies, surgical history and 
radiation therapy will be summarized in the Safety Analysis Set.  
6.3.6 Medical History 
Medical History will be coded using MedDRA (version currently in effect at BeiGene at the time 
of database lock). The number (percentage) of patients reporting a history of any medical 
condition, as recorded on the CRF, will be summarized by system organ class and preferred term 
in the Safety Analysis Set. A listing of medical history will be provided. 
6.4 
EFFICACY ANALYSIS 
The primary efficacy analysis will be conducted when mature response data have been observed, 
which will be determined by the Sponsor.  
An independent read of the tumor scans by Independent Review Committee (IRC) was planned at 
the beginning stage of the study. Following sample size reduction and due to the nonrandomized 
and nonregistrational nature of the study, the decision was made that independent reads would not 
be requested and investigator-evaluated assessments would be used to calculate ORR, DCR, CBR, 
DOR and PFS. 
6.4.1 Primary Efficacy Endpoints 
Efficacy analysis will be performed on all patients for all arms.  For Arm A and Arm C, phase 1b and 
phase 2 are presented in different table columns. 
Arm A and Arm B 
Modified Disease Control Rate is the primary efficacy endpoint in Arms A and B. It is defined as 
the proportion of patients with CR, PR or SD per RANO criteria as the response assessment at the 
end-of-treatment (EOT) visit, as scheduled per protocol. Patients with no EOT tumor assessment, 
as scheduled per protocol (due to any reason), will be considered non-responders for modified 
DCR.  Modified DCR of Pamiparib combination therapy is assumed as 60% in the study 
population. The historical rate in a similar population is estimated as 40% (Rivera et al., 2010). No 
formal hypothesis testing will be performed. Two-sided binomial exact 80% and 95% CI of 
modified DCR will be constructed to assess the precision of the rate estimate.    
Arm C 
Objective Response Rate (ORR) is the primary efficacy endpoint in arm C. The analysis will be 
performed for the efficacy analysis set. It is defined as proportion of patients with best overall 
response of CR or PR per RANO criteria (confirmed by a subsequent tumor assessment at least 
four weeks apart). Best overall response will be assessed from the start of study treatment until 
data cut-off date, disease progression or start of new anti-cancer therapy. Patients without 
postbaseline tumor assessment is considered nonresponders. ORR of Pamiparib combination 
therapy is assumed as 25% in the study population. The historical rate in a similar population is 
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estimated as 10% (Chen et al, 2013). Two-sided binomial exact 80%  and 95% CI of ORR will be 
constructed to assess the precision of the rate estimate.  
In addition, the number (%) of the best overall response categories (CR, PR, SD, PD) will be 
presented.  
6.4.2 Secondary Efficacy Endpoints 
 
Disease Control Rate (DCR – for arm C) 
DCR is defined as the proportion of patients with best overall response of CR, PR or SD per RANO 
criteria. CR or PR will be confirmed by a subsequent tumor assessment at least four weeks apart. 
DCR will be performed in similar fashion as described in primary endpoint modified DCR on 
Efficacy Analysis Set.  
Objective Response Rate (ORR – for arm A&B) 
ORR for arm A&B will be performed for Efficacy Analysis Set in similar fashion as in primary 
endpoint for arm C. 
Progression-Free Survival (PFS)  
PFS is defined as the time from the first dose date to disease progression per RANO criteria or death, 
whichever occurs first. PFS analysis will be performed for all arms using Safety Analysis Set. 
PFS censoring rule will follow FDA Guidance for Industry, Clinical Trial Endpoints for 
Approval of Cancer drugs and Biologics (2007). The censoring rules are described in Table 1. If 
a patient meets the criteria for more than 1 censoring rule, PFS will be censored at the earliest 
censoring date. 
Table 1 Censoring Rules for Analysis of Progression-Free Survival  
Censoring Categories 
Date of Progression or Censoring 
Outcome 
Progression documented on scheduled 
visit or between scheduled visits 
Date of first PD assessment  
Progressed 
Death before first tumor assessment 
Date of death 
Progressed 
Death between scheduled adequate 
assessment visits 
Date of death 
Progressed 
No baseline or postbaseline tumor 
assessments 
Date of the first dose  
Censored 
No PD or death at the time of data cut-off 
or withdrawal from study 
Date of last adequate radiologic 
tumor assessment prior to or on date 
of data cut-off or withdrawal from 
study 
Censored 
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New anticancer treatment started 
Date of last adequate radiologic 
tumor assessment prior to or on date 
of new anticancer treatment 
Censored 
Death or PD immediately after two or 
more missed visits  
Date of last adequate radiologic 
tumor assessment before missed 
tumor assessments 
Censored 
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. 
Duration of Response (DOR)  
 
DOR is defined as the time from the date of the earliest documented response (confirmed or 
unconfirmed) of CR or PR to disease progression or death for any cause, whichever occurs earlier. 
Only responders will be included in the DOR analysis. Censoring rule for DOR  will follow PFS 
censoring rule.  
 
Overall Survival (OS) 
OS is defined as the time from the date of first study treatment to death of any cause. Patients who 
have not died by the analysis cutoff date will be censored at the last date known to be alive or the data 
cutoff date, whichever is earlier. OS will be performed for Safety Analysis Set. 
Time-to-event variables PFS, OS and DOR 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 possible 
to estimate, in each arm will be presented, along with their 2-sided 95% CIs using Brookmeyer and 
Crowley method (Brookmeyer & Crowley, 1982). The PFS-6m, PFS-12m, OS-6m, and OS-12m, 
defined as the proportion of patients in the Safety Analysis Set who remain alive and progression-
free at 6 months and 12 months (or alive at 6 month and 12 months for OS), will be estimated using 
KM method along with the corresponding 95% confidence interval constructed using Greenwood’s 
formula (Greenwood, 1926).  
6.4.3 Subgroup Analyses 
Modified DCR (Arms A & B combined) and ORR (arm C) will be summarized for following 
subgroups: 
• Age (< 65, ≥ 65) 
• Gender (Female and Male) 
• Race (white, nonwhite)  
• ECOG performance status (0, 1) 
• Prior surgery status (biopsy only, partial resection, complete resection) 
• Baseline corticosteroid use (yes, no) 
• Methylation status (arm C only) 
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• Relapse status for arm C ORR only (first relapse, second relapse) 
Forest plot will be provided for these subgroups as well. These planned subgroup analyses may 
not be explored if sufficient number of samples cannot be achieved for certain subgroups. The 
subgroup variables and the cutoff values are patient to change if warranted to better represent the 
data. 
6.5 
SAFETY ANALYSES 
All safety analyses will be performed by dose cohorts (Phase 1b and Phase 2 will be presented as 
different table columns) and arms (A, B and C). 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, and ECGs findings will also be used in determining the 
safety. Descriptive statistics (n, mean, standard deviation, median, Q1, Q3, minimum, maximum 
for continuous variables; n [%] for categorical variables) will be used to analyze all safety data in 
the safety population.  
6.5.1 Extent of Exposure 
Descriptive summaries will be provided by cohort and each arms for following variables: 
• Number of cycles received (in arm C and in Arms A and B for maintenance patients) 
• Treatment duration (days) for all arms (see section 6.2.1 for definitions) 
• Number of patients require dose interruptions and reductions 
• Total dose received per patient (mg for pamiparib and TMZ, and Gy for RT) 
• Dose intensity (mg/day for pamiparib and TMZ) and relative dose intensity. Dose intensity 
per patient is defined as sum of actual dose received divided by planned duration of 
treatment. Relative dose intensity is defined as total actual dose received divided by total 
planned dose. Total planned dose is the total dose that would be delivered, if there were 
no modification to dose or schedule. 
Patients with dose reductions and interruptions and the reasons for reductions and interruptions 
will be listed. 
6.5.2 Dose Limiting Toxicity 
Dose-limiting toxicity in the DLT evaluation period will be assessed to determine the dose and 
schedule in phase 2. DLT events from the adverse event eCRF will be summarized descriptively 
for each dose cohort and arm in phase 1b in the DLT evaluable population. 
6.5.3 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 22.0 or higher), lower level term closest to the 
verbatim term. The linked MedDRA preferred term (PT) and primary system organ class (SOC) 
are also captured in the database. 
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A treatment-emergent adverse event (TEAE) is defined as an AE that had an onset date on or 
after first dose of study treatment or was worsening in severity from baseline (pretreatment) up 
to 30 days following permanent study treatment discontinuation or initiation of new anti-cancer 
therapy, whichever occurs first. All AEs, treatment emergent or otherwise, will be presented in 
patient data listings. TEAEs will be summarized and presented for all cohorts and all arms.  
An overview table, including the number and percentage of patients with any TEAEs, any 
treatment-related TEAEs,  treatment-emergent serious adverse events (SAEs), TEAEs with grade 
3 or above, treatment-related SAEs, TEAEs that led to death, and TEAEs that led to treatment 
discontinuation, dose reduction or dose interruption will be provided. Treatment-related AEs 
include those events considered by the investigator to be unlikely, possibly or probably or 
definitely related to study drug or with missing assessment of the causal relationship. The overview 
table will be completed for each study Arm.  
The following TEAEs will also be tabulated in summary tables for all arms and cohorts: 
• TEAE 
• SAE 
• TEAEs with grade 3 or above 
• Treatment-related TEAEs 
• Treatment-related SAEs 
• TEAEs that led to death 
• TEAEs leads to treatment discontinuation 
• TEAEs leads to dose reduction or dose interruption of either Pamiparib or RT or TMZ  
A patient will be counted only once by the highest severity grade according to CTCAE v.4.03 
within an SOC and PT, even if the patient experienced more than 1 TEAE within a specific SOC 
and PT. TEAEs with grade 3 or above will also be summarized by PT in descending order.  
In addition, the following listings will be provided: 
• Listing of all AEs, 
• Listing of all SAEs 
• Treatment-related AEs 
• Grade 3 or above AEs  
• AEs leading to death  
• AEs leading to treatment discontinuation  
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6.5.4 Laboratory Values 
Clinical laboratory values will be evaluated for selected parameters described in table 2.   
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 
Lymphocyte (Absolute) 
Blood Urea Nitrogen 
 
Creatinine 
Chloride 
 
Phosphate 
 
Glucose 
 
Lactate dehydrogenase 
 
Total Protein 
 
Potassium 
 
Sodium 
 
ALP = alkaline phosphatase, ALT = alanine aminotransferase, AST = aspartate aminotransferases, WBC = white 
blood cell 
For all quantitative parameters listed in Table 2, the actual value and the change from baseline to 
each postbaseline visit and to the end of treatment will be summarized by visit using descriptive 
summary statistics (n, mean, standard deviation, median, minimum, maximum for continuous 
variables).  Qualitative parameters listed in Table 2 will be summarized using frequencies 
(number and percentage of patients), and changes from baseline to each postbaseline visit and to 
end of treatment will be reported using shift tables.  Percentages will be based on the number of 
patients with non-missing baseline and relevant postbaseline results. 
Laboratory parameters will be categorized according to NCI CTCAE version 4.03 grades and 
shifts from baseline CTCAE grades to maximum and the last postbaseline grades will be 
assessed. Laboratory parameters will be summarized by worst postbaseline CTCAE grade as 
well. For the lab tests with both high and low abnormality, separate records of worst CTCAE 
grade (for high and low) will be generated. 
Patient data listings of selected hematology and serum chemistry parameters, urinalysis and 
coagulation will be provided. 
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6.5.5 Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, pulse rate, 
temperature, height and weight) and changes from baseline will be presented by visit. Vital signs 
will be listed by patients and visits. 
6.5.6 Electrocardiograms (ECG) 
Single 12-lead ECGs will be collected at screening and end of treatment. Additional ECGs will 
be performed if clinically indicated. The percentage of patients with abnormal and clinical 
significant ECGs at EOT will be presented. 
6.5.7 Eastern Cooperative Oncology Group (ECOG) 
ECOG scores and change from baseline will be summarized by visit using Safety Analysis Set. 
6.6 
PHARMACOKINETIC ANALYSES 
6.6.1 Plasma Concentrations 
Pharmacokinetic samples will be collected from patients in all cohorts at the following time 
points: predose (within 30 min prior to dose) and 2 hours (± 30 min) post-dose on both Day 1 
and Day 15 (collection takes place in Cycle 1 for arm C). If pamiparib treatment is administered 
only for a 2-week (14-day) time period, PK samples will be collected on Day 1 and Day 14 
instead. The time of study drug administration on the day prior to Day 15 (Day 14 for patients 
receiving only 2 weeks of pamiparib) must be recorded on the eCRF. Details concerning 
collection, handling, and processing of the PK plasma samples will be provided in the laboratory 
manual. 
Plasma pamiparib concentration-time data will be summarized and displayed in both tabular and 
graphical form. Concentration-time data will be analyzed with standard noncompartmental 
and/or compartmental methods. Pharmacokinetic concentration data for pamiparib will be listed 
including the dose level, relative time to dosing, actual sample collection time. The concentration 
data will also be summarized with descriptive statistics for each time point by dose level. The 
number of patients with non-missing plasma concentration, mean, standard deviation, minimum, 
median, maximum, geometric coefficient of variation and geometric mean will be included in the 
summary.  
7 
INTERIM ANALYSIS 
No interim analysis is planned.  
8 
CHANGES IN THE PROTOCOL PLANNED ANALYSIS 
1. Sample size reduction: The overall sample size was reduced during the study since the 
expansion cohorts were considered too large for this non-randomized and non-registrational 
study.  
2. All arm B expansion cohort related analysis and language are removed since it was decided 
not to enroll expansion cohort for arm B 
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3. Primary analysis will be performed on efficacy analysis set, not safety analysis set. No 
sensitivity analysis will be performed. 
4. Exploratory objectives and endpoints in the protocol will not be explored in this SAP  
9 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time, Biometrics 1982; 38(1): 29-
41. 
Chen C, Xu T, Lu Y, Chen J, Wu S. The efficacy of temozolomide for recurrent glioblastoma 
multiforme. Eur J Neurol. 2013 Feb;20(2):223-30.  
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 Patients (London: 
Her Majesty’s Stationery Office). 1926; 33:1-26. 
Rivera AL, Pelloski CE, Gilbert MR, Colman H, De La Cruz C, Sulman EP, et al. MGMT promoter 
methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant 
alkylating chemotherapy for glioblastoma. Neuro Oncol. 2010 Feb;12(2):116-21. 
 
10 APPENDIX 
Appendix 1. Imputation of Missing/Partially Missing Dates 
Missing data will not be imputed unless otherwise specified. 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 partial dates for adverse 
events: 
Adverse Events 
If start date of an adverse event is partially missing, impute as follows: 
• If both month and day are missing and year = year of treatment start date, then set to 
treatment start date. 
• If both month and day are missing and year ≠ year of treatment start date, then set to 
January 01. 
• If day is missing and month and year = month and year of treatment start date, the set to 
treatment start date. 
• If day is missing and month and year ≠ month and year of treatment start date, the set to 
first of the month. 
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• If start date is completely missing, set to treatment start date as long as adverse event end 
date is not before treatment start date. 
If end date of an adverse event is partially missing, impute as follows: 
• If both month and day are missing, then set to December 31. 
• If only day is missing, then set to last day of the month. 
• If end date is completely missing, do not impute. 
 
Prior/Concomitant Medications, Disease and Medical History, Prior Therapy  
When the start date or end date of a medication is partially missing, the date will be imputed to 
determine whether the medication is prior or concomitant. The following rules will be applied to 
impute partial dates for medications: 
If start date of a medication is partially missing, impute as follows: 
• If both month and day are missing, then set to January 01. 
• If only day is missing, then set to the first of the month. 
If end date of a medication is partially missing, impute as follows: 
• If both month and day are missing, then set to December 31. 
• If only day is missing, then set to last day of the month. 
If start date or end date of a medication is completely missing, do not impute. 
 
Death  
In case complete death dates are not recorded, impute as follows: 
•         If both month and day are missing, then the imputed month and day will be 01Jan or the 
last date of the last date of patient known to be alive + 1, whichever is later. 
•         If only day is missing: If last known alive date is in same month as death date, then death 
date= last known alive date+1;If death month is after last known alive date, then use first 
day of the month as death date. 
 
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,   
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1)     impute the date as 31Dec, if the year is earlier than the year of the first PD date + 1 
or the treatment end date + 1, whichever is later. 
2)     impute the date as 01Jan, if the year is later than the year of the first PD date or the 
treatment end date + 1, whichever is later. 
3)     impute the date as the first PD date + 1 or the treatment end date + 1, whichever is 
later, if the year is the same year of first PD date + 1 or the treatment end date + 1, 
whichever is later. 
• 
If only day is missing,   
1)     impute the date as the first day of the month if year and month are available and 
partial new anticancer therapy date still could indicate it is at least one month later 
than the first PD date +1 or the treatment end date +1, whichever is later.  
2)     impute the date as the last day of the month if year and month are available and 
partial new anticancer therapy date still could indicate it is at least one month earlier 
than the first PD date +1 or the treatment end date +1, whichever is later. 
3)      impute the date as the first PD date +1 or the treatment end date +1, whichever is 
later, if the year and month are the same year and month of first PD date +1 or the 
treatment end date +1, whichever is later. 
 
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