Clinical trial NCT03184558
Conditions: Triple Negative Breast Cancer Inflammatory Breast Cancer Stage IV
Keywords: bemcentinib TNBC pembrolizumab Keytruda BGB324
Sponsor: BerGenBio ASA
Start date: 2017-07-26; Completion date: 2018-08-20
Enrollment: 29 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open label, single arm, multi-centre phase II study to assess the anti-tumour activity and safety of bemcentinib (BGB324) in combination with pembrolizumab in participants with previously treated, locally advanced and unresectable, or metastatic TNBC or TN-IBC. The primary objective is objective response rate.

Detailed description:

Arms: arm 1: Participants received Bemcentinib (BGB324) capsules orally once daily as a loading dose of 400 milligram (mg) on Days 1, 2, and 3. A dose of 200 mg pembrolizumab was given by intravenous infusion over 30 minutes every 3 weeks in all participants. Dosing of both drugs commenced on Day 1. On days when both BGB324 and pembrolizumab were given, pembrolizumab was given first and participants were observed for 1 hour after the end of infusion before BGB324 was administered. From Day 4 onward, participants received a daily maintenance dose of 200 mg along with Pembrolizumab 200 mg intravenous (IV) infusion over 30 minutes every 3 weeks until disease progression, until an unacceptable toxicity occurred that required treatment withdrawal or withdrawal of consent or until 106 weeks had passed.
Interventions: intervention 1: Bemcentinib; pembrolizumab
Intervention descriptions: intervention 1: Bemcentinib is a selective Axl kinase inhibitor; pembrolizumab is a programmed death receptor-1 (PD-1) inhibitor.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
Investigational Products: 
BGB324; Pembrolizumab 
Sponsor:  
BerGenBio ASA 
Jonas Lies vei 91 
5009 Bergen, Norway 
Protocol Number: 
BerGenBio ASA: BGBC007 
Merck & Co: 
MK-3475 PN-530 
Phase: 
Phase II 
Protocol Title: 
A Phase II, Multi Center Study of BGB324 in 
combination with Pembrolizumab in Patients with 
Previously 
Treated, 
Locally 
Advanced 
and 
Unresectable or Metastatic Triple Negative Breast 
Cancer (TNBC) or Triple Negative Inflammatory 
Breast Cancer (TN-IBC)  
IND Number: 
134381 
EudraCT Number: 
 
2016-003608-30 
Version and Date: 
Version 4.0 (USA) / 13 June 2017 
Previous Version Table: 
Final, Version 1.0  
02 November 2016 
Version (USA 2.0) Amendment 1 
22 March 2017 
Version (USA 3.0) Amendment 2 
22 May 2017 
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CONFIDENTIAL STATEMENT: 
Information in this protocol is confidential and should not be disclosed, other than to those 
directly involved in the execution or the ethical/regulatory review of the study, without written 
authorization from BerGenBio ASA 
 
 
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Protocol Approval Signatures 
 
Sponsor’s Approval: 
This study will be conducted in compliance with International Conference on Harmonisation 
(ICH) guidelines on Good Clinical Practice (GCP), the Declaration of Helsinki (with 
amendments), and in accordance with local legal and regulatory requirements. 
 
This protocol has been approved by BerGenBio ASA. 
 
 
 
Signature:  
           Date:  27 June 2017 
 
 
 
BerGenBio ASA 
Jonas Lies vei 91 
5009 Bergen 
Norway 
 
Email: medical_monitoring@bergenbio.com 
 
Pharmacovigilance global fax number: +1-877-464-7787 
 
 
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Investigator’s Approval: 
I have read this protocol and agree that it contains all the necessary details for carrying out this 
study. I will conduct the study as described and will complete the study within the time 
designated. I verify that I am suitably qualified by education, scientific and medical training and 
experience to conduct the study. Documentation of my qualifications and professional 
affiliations are contained in my up-to-date curriculum vitae. 
I will provide the supplied copies of the protocol, including future protocol amendments, and all 
information relating to non-clinical, and clinical experience when available e.g. in updated 
editions of the Investigator’s Brochure (IB), to all staff in my unit involved in the conduct of this 
study. I will discuss this material with them to ensure that they are fully conversant with medical 
treatment and study design, and that they will handle the data and information generated in the 
study confidentially. 
I will conduct the study in accordance with Good Clinical Practice (GCP), the Declaration of 
Helsinki, and the moral, ethical and scientific principles that justify medical research. The study 
will be conducted in accordance with the relevant laws and regulations relating to clinical studies 
and the protection of patients. All patients will be informed comprehensively about the nature of 
the study and will give their written consent to participate before entry into the study. They will 
be informed that they may withdraw from the study at any time. I will use only the consent and 
information form approved by BerGenBio ASA (BerGenBio) and the Ethics Committee (EC) for 
this study. I will supply BerGenBio with any material written by myself e.g. summary of study, 
which is given to the EC in support of the application. 
Where applicable, the patient information contained in clinic records, reports and manuscripts 
will be transcribed to the case report forms (the case report form may be the original source 
document for specified items). Either I or an appointed person will attest to the authenticity of 
the data and accuracy and completeness of the transcription by signing the case report form. I 
agree to the audit and monitoring procedures that involve verification of such study records 
against original records. Should it be requested by government regulatory agencies, I will make 
available additional background data from my records, and where allowed, from the hospital or 
institution where the study was conducted.  
I understand that the case report forms and other data pertinent to this study are the property of 
BerGenBio and are confidential. I will supply BerGenBio (or their delegates) with the study data 
in such a way that the patient cannot be personally identified. 
 
Investigator:_________________________________ 
_____________________________ 
Signature 
 
 
 
 
 
Date 
 
Print Name:__________________________________________________________________ 
 
Institution Name:______________________________________________________________ 
 
Institution Address:____________________________________________________________ 
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OTHER CONTACT INFORMATION 
Full contact details for each Investigational site, the Sponsor (including medical out-of-hours 
contact number), and key coordinating and operational personnel will be maintained in the Trial 
Master File (TMF) and in each Site Study File. 
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PROTOCOL SYNOPSIS 
Protocol No:  BGB324 BGBC007 / MK-3475 PN-530 
Study Title:  A Phase II Multi Center Study of BGB324 in combination with Pembrolizumab in 
Patients with Previously Treated, Locally Advanced and Unresectable or Metastatic Triple 
Negative Breast Cancer (TNBC) or Triple Negative Inflammatory Breast Cancer (TN-IBC)  
Investigational Products: 
• BGB324: a potent selective small molecule inhibitor of Axl, a surface membrane protein 
kinase receptor. 
• Pembrolizumab: humanized monoclonal antibody against the programmed death receptor-
1 (PD-1) protein. 
Phase of Development: Phase II 
Number of Sites: Up to approximately 20 sites. Additional sites may be added as required to 
meet the enrolment needs of the clinical trial. 
Number of Patients:  
Up to 56 evaluable patients will be enrolled into the study. Approximately 75 patients will be 
screened in order to identify up to 56 patients who meet all the inclusion and exclusion criteria 
and are evaluable for response. This assumes a 25% screen failure rate, given the need for 
patients to provide a fresh tissue biopsy sample.  
Study Objectives and Endpoints 
Table 1: Study Objectives and Endpoint (Assessment) 
Objective 
       Endpoint (Assessment) 
Primary: 
 
• To assess anti-tumor activity of the 
combination of BGB324 and pembrolizumab  
• 
Objective response rate (complete response 
and partial response) 
Secondary: 
 
• 
To assess the safety of BGB324 and 
pembrolizumab 
when 
given 
in 
combination  
• 
To further assess the anti-tumor activity 
of the combination of BGB324 and 
pembrolizumab 
• 
The number and frequency of adverse events; 
assessment of safety laboratory parameters, 
vital signs and ECGs 
• 
To include Disease Control Rate, Duration of 
Response; Progression-free Survival; 12-month 
Overall Survival 
• 
To evaluate the pharmacokinetic profile of 
BGB324 when given with pembrolizumab. 
• 
Assessment 
of 
pharmacokinetic 
variables 
including Cmax, AUC, t½  
Exploratory: 
 
• To assess relevant biomarkers 
• 
To assess PD-L1 and Axl expression in patients 
with TNBC and TN-IBC 
• 
To assess any correlation or association 
between expression level of PD-L1 and Axl and 
anti-tumor outcomes such as ORR 
• 
Assessment of relevant biomarkers in tumor 
and blood which support immune modulation 
and Axl signalling 
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Study Design 
This is an open-label, single arm, multi-center phase II study to assess the anti-tumor activity and 
safety of BGB324 in combination with pembrolizumab in patients with previously treated, 
locally advanced and unresectable, or metastatic TNBC or TN-IBC. 
Pembrolizumab has not previously been combined with BGB324 in patients (in any indication) 
and therefore, a safety run-in will include a total of 12 patients. The internal Data Review 
Committee (DRC) will conduct a review of the safety data from the first 6 patients who have had 
the potential to be followed for at least 6 weeks (minimum 2 cycles), and then again after a 
further 6 patients (12 patients in total) have had the potential to be followed for at least 6 weeks. 
The DRC will consider the emerging safety profile, together with the number of patients 
requiring a BGB324 dose reduction and the number of patients requiring either BGB324 or 
pembrolizumab or both to be permanently discontinued. The DRC will consider whether a 
revised BGB324 dose (dose level -1) is appropriate for new patients entering the study. 
The study will utilize a 2-stage, single arm, extension of Simon’s 2-stage design1 with one 
(efficacy) interim and a final analysis. The interim analysis will be conducted when 28 patients 
are evaluable for Objective Response Rate (ORR). If 5 or fewer responses are observed in up to 
28 patients, the trial will be terminated in favor of the null for futility. If 11 or more responses 
are observed, then the trial will be stopped in favor of the alternative for demonstration of 
activity. Where 6 to 10 patients have an observed response at the interim analysis, up to a further 
28 patients may be evaluated, for a total of 56 patients (Section 8.1) taking the overall risk: 
benefit of the combination into consideration. A schematic diagram of the study design is 
provided in Figure 1. 
Recruitment to the study will be halted once 28 evaluable patients have been entered and whilst 
the Stage 1 interim analysis is conducted. Recruitment will recommence if the decision is made 
to continue to the maximum of 56 evaluable patients. 
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Figure 1: Schematic diagram of the study design 
 
BGB324 will be administered orally once daily. On the first 3 days of administration, the 
BGB324 dose will be a ‘loading’ dose of 400 mg on Days 1, 2 and 3. From Day 4 onwards, 
patients will receive a dose of 200 mg daily. If the DRC recommend dose level -1 for new 
patients (after or during the safety run-in), the dose of BGB324 will reduce to a loading dose of 
200 mg on Days 1, 2 and 3 and to 100 mg from Day 4 onwards. 
A fixed dose of 200 mg pembrolizumab will be given by intravenous (i.v.) infusion over 30 
minutes every 3 weeks in all patients. The 3-weekly pembrolizumab dosing schedule will be 
used to define 3-week treatment cycles throughout the treatment period of the study. 
The BGB324 and pembrolizumab dose levels selected for this study are summarized in Table 2. 
 
 
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Table 2: BGB324 and pembrolizumab dosing 
BGB324: 
Loading Dose: 
Days 1, 2 & 3 
Daily Dose:  
Day 4 onwards 
Frequency 
Route of 
administration 
Dose level 
400 mg 
200 mg 
Daily 
Oral 
Dose level -1 
200 mg 
100 mg 
Daily 
Oral 
Pembrolizumab 
Dose 
Regimen 
Frequency 
Route of 
administration 
200 mg 
Day 1 of each cycle 
Every  
3 weeks 
IV 
Dosing of both drugs will commence on Day 1. On days when both BGB324 and 
pembrolizumab are given, pembrolizumab will be given first and patients will be observed for 1 
hour for infusion and other adverse events (AEs). BGB324 may then be administered.  
BGB324 and pembrolizumab will be given until disease progression (note that in the absence of 
clinical deterioration, treatment can continue and clinical progression should be confirmed after 
4 weeks) or until an unacceptable toxicity has occurred which necessitates treatment withdrawal 
(Section 6.6), or until 106 weeks (35 cycles), equivalent to 24 calendar months. 
Patients who discontinue BGB324 treatment (for reasons other than disease progression) may be 
able to continue with (monotherapy) pembrolizumab until 106 weeks (that is, 35 completed 
cycles of pembrolizumab, equivalent to 24 calendar months).  
Patients who discontinue pembrolizumab (for reasons other than disease progression) may be 
able to continue with BGB324 for up to 106 weeks (equivalent of 24 calendar months). 
If a tumor imaging assessment is suggestive of progressive disease, but the patient has an 
absence of clinical deterioration, a confirmatory scan after 4 weeks (this may be an unscheduled 
scan) will be made in order to rule out a pseudo or false progression caused by an inflammatory 
immune response. In the absence of clinical deterioration, treatment with both BGB324 and 
pembrolizumab can continue until disease progression is confirmed. 
As per RECIST 1.12, all patients who are considered to have a complete or partial response must 
have this response confirmed by a confirmatory scan at least 4 weeks later. 
A DRC, consisting of Principal Investigators, the Sponsor’s Medical Monitor, at least one 
representative from both the Sponsor and Merck, and invited experts as required, will review all 
patient safety data after 6 patients have been enrolled and followed up for 6 weeks (2 cycles), 
and then again after an additional 6 patients (total 12 patients) have had the potential to be 
followed for 6 weeks. At each of these safety reviews, the DRC will consider the rate of 
BGB324 dose reductions and the rate of permanent discontinuation from BGB324 and 
pembrolizumab. The DRC will consider if a revised dose (dose level -1) for BGB324 is 
appropriate. 
Additionally, a review of emerging safety data from the whole BGB324 program will be made 6-
monthly. 
The Sponsor may request ad-hoc DRC meetings at any time during the study to assess interim 
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safety data and review the need for dose modifications. For more details on the dose 
modification rules for BGB324 and pembrolizumab, please refer to Section 6.6.1 and Section 
6.6.2. 
Study Procedures and Assessments 
Please refer to Schedule of Study Assessment Table 4 and Table 5 for full details of all study 
assessments. For patients who have stopped BGB324, but continue with monotherapy 
pembrolizumab, there will be an adjusted list of study assessments. 
The study will consist of a Screening period, Treatment period (made up of consecutive, 3-week 
cycles), a Post Treatment Visit, and Follow-up Assessments. Patients must provide informed 
consent prior to commencing the study screening procedures. All patients are required to have a 
fresh (newly acquired) tumor biopsy taken at Screening, and are required to provide sufficient 
tumor specimens to enable both Axl kinase and PD-L1 expression to be measured.  
Tumor specimens are therefore to be submitted in sufficient quantity to allow for PD-L1 
immunohistochemistry (IHC) and Axl IHC analysis (see the Pathology Manual). Samples with 
limited tumor content (<100 viable tumor cells), cytology, cell block, decalcified or formalin 
fixed but previously frozen, frozen sample, plastic embedded, bone, bone marrow, clot and fine 
needle aspirates are inadequate for defining tumor PD-L1 and Axl status. 
Axl expression can only be obtained from a fresh (newly acquired) tumor tissue sample. PD-L1 
expression can be determined from either a fresh (newly acquired) or archival sample. In all 
cases, the tumor tissue must not have been previously irradiated. 
Different testing laboratories will be used for Axl kinase and PD-L1 expression. 
The fresh (newly acquired) tumor tissue sample will be either newly obtained core needle biopsy 
(minimum gauge 18) or a newly obtained excisional biopsy. 
The following tumor tissue options are available (all options require fresh tumor tissue sample, 
however, if there’s insufficient fresh tumor tissue available, the 3rd option below allows the 
submission of archival tissue in addition to the fresh tissue sample):  
• Where only a core needle biopsy is used, a minimum of 4 core biopsy samples are 
required. These should be placed in formalin and processed into 2 single paraffin 
embedded (FFPE) blocks (2 cores in one block and 2 cores in the other block) within 24-
48 hours. 
• Alternatively, where only a newly obtained excisional biopsy sample is used, this biopsy 
should be processed into 2 paraffin embedded (FFPE) blocks within 24-48 hours. 
• Alternatively, 2 core needle (fresh tumor) biopsies or a single newly obtained excisional 
biopsy sample can be submitted (processed into one FFPE block), together with either an 
archival (FFPE) tumor tissue block or a minimum of 10 unstained slides each 5µm cut 
from the archival tumor sample block. The unstained slides must arrive at the testing 
laboratory within 14 days. In this option, an archival FFPE block is strongly preferred 
over unstained slides cut from an archival FFPE block. 
Archival blocks must be clearly labelled as archival. 
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Slides cut from an archival tissue block must be clearly marked as having come from an archival 
block. 
Finally, where patients also have (additional) archived biopsy material which is suitable for 
additional (such as exploratory) biomarker assessment a sample of this material (either as an 
archival FFPE block or slides cut (and paraffin dipped) from the archival block) can also be 
prepared for study biomarker assessment. The patient will be offered a separate optional patient 
consent to enable this ‘archival biomarker tumor sample’ to be submitted. 
The first dose of study drug must be administered within 4 weeks of commencing the Screening 
assessments. Tumor imaging by computed tomography (CT) or magnetic resonance imaging 
(MRI) of the chest, abdomen and pelvis is required during the Screening period. X-ray scans can 
be used where appropriate (for example, for symptomatic sites that are negative on a bone scan). 
All patients should undergo a bone scan and a brain scan in the 6 weeks prior to starting 
treatment. 
Recording of AEs and concomitant medications, plus laboratory screens including 
electrocardiographs (ECGs) will be performed at each study visit. During Cycle 1, patients will 
have study visits on Days 1, 2, 3 and 4, then on Days 8 and 15. From Cycle 2, Day 1, study visits 
will be reduced to every 3 weeks. 
ECG assessments will be performed in triplicate at pre-dose and 6 hours after the BGB324 dose 
on Day 1, Cycle 1 and then repeated pre-BGB324 dose on Days 2, 3 and 4 (Cycle 1) and then at 
every visit thereafter. 
Further tumor imaging will be performed in all patients every 9 weeks for the first 46 weeks and 
then 12-weekly thereafter until progression (which may be confirmed). On each occasion, tumor 
assessments will include imaging of the chest, abdomen and pelvis. Additional anatomy, 
including brain and bone, should be imaged based on signs and symptoms of individual patients. 
Disease response will be evaluated at these time points according to RECIST 1.12. If either or 
both of the study treatments are stopped for any reason other than confirmed progression, tumor 
imaging will continue every 12 weeks until confirmed progression. 
Patients who are suspected of having a complete or partial response will have their response 
confirmed at the next scheduled assessment or no earlier than 4 weeks (28 days) later. 
Blood sampling for PBMC and Axl signaling and inhibition biomarker analysis will be 
performed at Screening, Cycle 1, Days 4 and 8 and every study visit thereafter until Cycle 9, Day 
1. 
Blood sampling for BGB324 pharmacokinetic (PK) analysis will be performed on blood samples 
taken on:  
• 
Cycle 1, Days 1 and 3 as follows: pre-dose and at 2, 4, 6 and 8 hours post dose;  
• 
Cycle 1, pre-dose on Days 2, 4, 8 and 15;  
• 
Cycles 2 and 3, pre-dose (study days 22 and 43 respectively). 
Blood sampling for future pembrolizumab PK analysis will be performed on blood samples 
taken pre-dose on Cycle 1, Days 1 to 4, 8 and 15 and then pre-dose at Cycles 2 and 3 (study days 
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22 and 43 respectively). These samples will be frozen and stored centrally for future reference 
and analysis. 
Patients with tumor amenable to repeat sampling may have additional fresh biopsies taken on up 
to 2 occasions post-dose at time points agreed between the Investigator and the patient. Where 
possible, efforts will be made to obtain follow up biopsy material where a patient has responded 
to treatment or has progressed on treatment. 
Further details on sample collection and handling for all PK and biomarker assessments are 
described in the Laboratory Manual. 
Patients who discontinue BGB324 treatment (for reasons other than disease progression) may be 
able to continue with (monotherapy) pembrolizumab until 106 weeks (that is, 35 completed 
cycles of pembrolizumab). These patients will no longer be required to have the following 
assessments from 6 weeks after the discontinuation of BGB324 (unless clinically indicated): 
• 
ECG; 
• 
Echocardiogram (or Multi Gated Acquisition Scan (MUGA)); 
• 
Optional tumor biopsy (for example at subsequent progression); 
• 
Biomarker sampling. 
The Post Treatment Visit will occur 30 days after the patient has discontinued both treatments on 
study. Patients who withdraw from either or both study treatments prior to disease progression 
will continue to have tumor imaging assessments every 12 weeks until disease progression is 
documented (and confirmed, if necessary). The date of disease progression will be captured. 
Subsequent to disease progression (confirmed if necessary), patients will continue to have their 
survival status checked every 12 weeks until death or the Last Patient Last Visit (LPLV) date 
(see Section 8.6), whichever is earlier. Survival status can be checked via telephone. 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
A patient will be suitable to proceed to treatment on study if they meet all of the following 
criteria: 
1. 
Provision of signed informed consent. 
2. 
Male and non-pregnant females who are aged 18 years or older at the time of 
provision of informed consent. 
3. 
Histopathologically or cytologically documented TNBC or TN-IBC. Tumors must 
have been confirmed negative for ER and PR by IHC (<1% positive tumor nuclei, as 
per ASCO-CAP guideline recommendations3) and negative for HER2 by IHC or 
fluorescent or chromogenic in situ hybridization (FISH or CISH). Patients with 
equivocal HER2 results by IHC should have their negativity status confirmed by 
FISH. 
4. 
Locally advanced and unresectable or metastatic TNBC or triple negative 
inflammatory breast cancer. 
5. 
Received one or more prior therapies for TNBC or inflammatory breast cancer in the 
metastatic setting, and prior treatment (metastatic or (neo) adjuvant) must have 
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included a prior taxane and/or anthracycline-based therapy  
6. 
Has measurable disease as defined by RECIST 1.12 on computed tomography (CT) 
or magnetic resonance imaging (MRI) and as determined by the site study team. 
Tumor lesions situated in a previously irradiated area are considered measurable if 
progression has been demonstrated in such lesions. 
7. 
Provision of suitable tumor tissue for the analysis of Axl kinase expression and PD-
L1 expression. Suitable tumor tissue must consist of a minimum of newly acquired 
(fresh) tumor tissue sample (as a FFPE block), together with either further newly 
acquired tumor tissue (i.e. further FFPE block) or an archival tumor tissue sample (as 
a further FFPE block or further 10 unstained slides). See Section 5.3.13 for further 
details. 
8. 
Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1 [Appendix 
A]. 
9. 
Life expectancy of at least 3 months. 
10. 
Adequate organ function confirmed at Screening and within 10 days of initiating 
treatment, as evidenced by: 
a. 
Platelet count ≥100,000 /mm3; 
b. 
Hemoglobin ≥9.0 g/dL (≥5.6 mmol/L); 
c. 
Absolute neutrophil count (ANC) >1,500 /mm3; 
d. 
Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤2.5 
times the upper limit of normal (ULN), or ≤5 times the ULN for patients with 
liver metastases; 
e. 
Total bilirubin ≤1.5 times the ULN, or direct bilirubin <ULN for patients with 
total bilirubin levels >1.5xULN; 
f. 
Creatinine ≤1.5 times the ULN and calculated creatinine clearance >60 mL/min 
(by Cockcroft Gault formula; see Appendix B);  
g. 
International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 times the 
ULN and Activated Partial Thromboplastin Time (aPTT) ≤1.5 times the ULN. 
Note: If patient is receiving anticoagulant therapy, then PT or PTT must be 
within therapeutic range of intended use of anticoagulants; 
h. 
LDH ≤2.5 times the ULN. 
11. 
Female patients of childbearing potential must have a negative pregnancy test (either 
urine or serum pregnancy test) within 72 hours prior to the first dose of study 
treatment. If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required. 
12. 
Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or less (except alopecia). If the patient received major surgery or radiation therapy of 
>30 Gy, they must have recovered from the toxicity and/or complications from the 
intervention. 
13. 
Patients of reproductive potential must be willing to practice highly effective 
methods of contraception (such as those described in Section 6.14) throughout the 
study and for 120 days after the last dose of study medication. Abstinence is 
acceptable if this is the usual lifestyle of the patient. Female patients are considered 
NOT of childbearing potential if they have a history of surgical sterility or evidence 
of post-menopausal status defined as any of the following: 
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a. 
≥45 years of age and has not had menses for more than 1 year; 
b. 
Amenorrheic for >2 years without a hysterectomy and oophorectomy and a 
follicle stimulating hormone (FSH) value in the postmenopausal range upon 
Screening evaluation and oestradiol <30 pg/mL; 
c. 
Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy 
or oophorectomy must be confirmed with medical records of the actual 
procedure or confirmed by an ultrasound. Tubal ligation must be confirmed 
with medical records of the actual procedure. 
 
Exclusion Criteria 
A patient will not be suitable to proceed to treatment on study if they meet any of the following 
criteria: 
1. 
Has disease that is suitable for local therapy administered with curative intent. 
2. 
More than 3 previous lines of therapy in the metastatic setting. 
3. 
Has received prior therapy with an immunomodulatory agent. 
4. 
Has a known additional malignancy that is progressing or requires active treatment. 
Note: Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma 
of the skin that has undergone potentially curative therapy or in situ cervical cancer. 
5. 
Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Note: Patients with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging (using the 
identical imaging modality for each assessment, either MRI or CT scan) for at least 4 
weeks prior to the first dose of trial treatment and any neurological symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and 
are not using steroids for at least 7 days prior to trial treatment. 
6. 
History of the following cardiac conditions: 
a. 
Congestive cardiac failure of >Grade II severity according to the 
NYHA (Appendix C: defined as symptomatic at less than ordinary levels of 
activity); 
b. 
Ischemic cardiac event including myocardial infarction within 3 months prior 
to first dose; 
c. 
Uncontrolled cardiac disease, including unstable angina, uncontrolled 
hypertension (i.e. sustained systolic BP >160 mmHg or diastolic BP >90 
mmHg), or need to change medication due to lack of disease control within 6 
weeks prior to the provision of consent; 
d. 
History or presence of sustained bradycardia (≤55 BPM), left bundle branch 
block, cardiac pacemaker or ventricular arrhythmia. Note: Patients with a 
supraventricular arrhythmia requiring medical treatment, but with a normal 
ventricular rate are eligible; 
e. 
Family history of long QTc syndrome; personal history of long QTc syndrome 
or previous drug-induced QTc prolongation of at least Grade 3 (QTc >500 ms). 
7. 
Abnormal left ventricular ejection fraction on echocardiography or MUGA (less than 
the lower limit of normal for a patient of that age at the treating institution or <45%, 
whichever is lower). 
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8. 
Current treatment with any agent known to cause Torsades de Pointes which cannot 
be discontinued at least five half-lives or two weeks prior to the first dose of study 
treatment. 
9. 
Screening 12-lead ECG with a measurable QTc interval according to Fridericia’s 
correction >450 ms. 
10. 
Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of study treatment. 
11. 
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤Grade 1 or at 
baseline) from AEs due to a previously administered agent. Note: Patients with 
≤Grade 2 alopecia are an exception to this criterion and may qualify for the study. 
12. 
Received an anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the first 
dose of study treatment or who has not recovered (i.e. ≤Grade 1 or baseline) from 
AEs due to agents administered more than 4 weeks earlier. 
13. 
Major surgery within 28 days prior to start of study treatment and failure to have 
recovered adequately from the toxicity and/or complications from the intervention 
prior to the first dose of study treatment. Note: Major surgery does not include 
procedures for insertion of venous catheters or biopsies. 
14. 
Received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including G-CSF, GM-CSF or 
recombinant erythropoetin) within 4 weeks prior to the first dose of study treatment. 
Note: Patients receiving stable dose of growth factors with a hemaglobin value that 
meets Inclusion Criterion 10b may be included. 
15. 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of 
study treatment.  
16. 
Active autoimmune disease that has required systemic treatment in past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment. 
17. 
Known history of human immunodeficiency virus (HIV 1/2 antibodies) 
18. 
Has known active infection with Hepatitis B (e.g., HBsAg reactive) or Hepatitis C 
(e.g., HCV RNA (qualitative) is detected). Note: i) Patients with a history of 
hepatitis B infection are eligible provided they are hepatitis B surface antigen 
negative ii) Patients with a history of hepatitis C infection are eligible provided they 
have no evidence of hepatitis C RNA using a qPCR at least 6 months after 
completing treatment for hepatitis C infection. 
19. 
Has received a live-virus vaccination within 30 days of planned treatment start. Note: 
Seasonal flu vaccines that do not contain live virus are permitted. 
20. 
Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
21. 
Has a history of interstitial lung disease. 
22. 
Inability to swallow or tolerate oral medication. 
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23. 
Existing gastrointestinal disease affecting drug absorption such as celiac disease or 
Crohn’s disease, or previous bowel resection which is considered to be clinically 
significant or could interfere with absorption. 
24. 
Known lactose intolerance. 
25. 
Requires vitamin K antagonists. Note: Patients receiving low doses prescribed to 
maintain the patency of venous access devices may be included. Factor Xa 
antagonists are permitted. 
26. 
Treatment with any of the following: histamine receptor 2 inhibitors, proton pump 
inhibitors or antacids within 7 days of start of study treatment. 
27. 
Treatment with any medication which is predominantly metabolized by CYP3A4 and 
has a narrow therapeutic index. 
28. 
Known severe hypersensitivity (≥Grade 3) to BGB324, pembrolizumab, and/or any 
of their excipients. 
29. 
Has an active infection requiring systemic therapy (apart from cutaneous infections). 
30. 
Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that, in the opinion of the Investigator, might confound the results of the 
trial, interfere with the patient’s participation and compliance in the trial, or means it 
is not in the best interests of the patient to participate. 
31. 
Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting from Screening through to 120 days after the 
last dose of study treatment. 
32. 
Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
Statistical Methods and Sample Size 
The trial will follow a k-stage single arm design with k=2, being an extension of Simon’s 2-stage 
design1. In this design with k=2, there are two analyses: a single interim and a final analysis. At 
the interim, the response rate is evaluated in a fixed number (m) of patients using a predefined 
decision rule to determine if the study should stop for futility (in the situation where the null is 
confirmed) or for efficacy (in the situation where the alternative hypothesis is confirmed). If 
neither hypothesis is confirmed, a further fixed number of patients (l) are assessed for response 
and a final analysis is performed on all (m+l) patients. In both interim and final analyses, the 
response rate will be presented together with the associated exact 90% confidence interval (CI). 
The rationale for a null hypothesis of p0=0.20 is based on previously published10 analysis from a 
clinical trial with pembrolizumab (KEYNOTE-012) in 32 patients with metastatic TNBC (27 
patients were evaluable), where an ORR of 18.5% has been observed for pembrolizumab 
monotherapy. These patients were relatively heavily pre-treated PD-L1 positive patients, with 
over 50% having received 3 or more lines of therapy. 
The ORR of pembrolizumab in combination with BGB324 is expected to be at least as high as 
this in patients unselected for PD-L1 positive disease. 
With p0=0.20 and p1=0.35, the interim will be conducted with m=28 evaluable patients who have 
the potential for at least 24 weeks (that is, at least 2 on treatment scans) of follow-up. If 5 or 
fewer responses are observed in up to 28 patients, the trial will be terminated in favor of the null 
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for futility; however, if 11 or more responses are observed, then the trial will be stopped in favor 
of the alternative for demonstration of activity. Otherwise, up to a further 28 patients may be 
evaluated, for a maximum total of 56 evaluable patients. The full study population will have the 
potential for at least 24 weeks of follow-up. If a total of 17 or more responses are seen in up to 
56 patients, then the null will have been rejected in favor of the alternative; otherwise the null 
will not have been rejected. 
Up to 56 evaluable patients may therefore be enrolled to this clinical trial. It is expected that 
approximately 75 patients will be screened in order to identify 56 patients who meet all the 
inclusion and exclusion criteria and who are evaluable for response. 
An evaluable patient is defined as one who has received at least one dose of pembrolizumab and 
BGB324, and has measurable disease, as determined by the investigator site at baseline. 
Demographic and clinical characteristics at entry will be summarized using appropriate 
descriptive statistics. PD-L1 and Axl expression will be summarized. 
Further details on the statistical methods and sample size can be found in Section 8.1. 
Schedules of Assessment and Pembrolizumab Administration Timing 
Table 3 summarizes the timing of pembrolizumab administration up to cycle 35 (approximately 
24 months of treatment) in relation to the timing of disease assessment.  
Table 4 summarizes the schedule of assessments in Year 1 and Table 5 summarizes the schedule 
of assessments in Year 2. 
Table 3: Pembrolizumab 3 weekly schedule and disease assessment timings 
Year 1, First 6 months* 
Week Number: 
1 
4 
7 
10 
13 
16 
19 
22 
25 
Start of month: 
1 
 
 
 
4 
 
 
 
7 
Pembrolizumab cycle: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Disease Assessment / Scan 
(+/- 7 days): 
Scanned at 
screening 
 
 
X 
 
 
X 
 
 
Year 1, Second 6 months*  
Week Number: 
28 
31 
34 
37 
40 
43 
46 
49 
52 
Start of month: 
 
 
 
10 
 
 
 
13 
 
Pembrolizumab cycle: 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Disease Assessment / Scan 
(+/- 7 days): 
X 
 
 
X 
 
 
X 
 
 
Year 2, First 6 months*  
Week Number: 
55 
58 
61 
64 
67 
70 
73 
76 
79 
Start of month: 
 
 
16 
 
 
 
19 
 
 
Pembrolizumab cycle: 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Disease Assessment / Scan 
(+/- 7 days): 
 
X 
 
 
 
X 
 
 
 
Year 2, Second 6 months*  
Week Number: 
82 
85 
88 
91 
94 
97 
100 
103 
106 
Start of month: 
 
22 
 
 
 
25 
 
 
 
Pembrolizumab cycle: 
28 
29 
30 
31 
32 
33 
34 
35 
Stop 
Disease Assessment / Scan 
X 
 
 
 
X 
 
 
 
X 
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(+/- 7 days): 
*A month is 4 weeks (not a calendar month). 
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Table 4: Schedule of Study Assessments – Year 1 
 
 
Screening 
Cycle 1 (21-d cycle) 
Cycle Number – Year 1 
Post 
Treatmen
t Visit14 
Follow 
Up15 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Day 
Up to -28 
1 
2 
3 
4 
8 
15 
22 
43 
64 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
+30 from 
last dose 
Start of Week # (+/- 3 days) 
-4 weeks to 
0 
1 
2 
3 
4 
7 
10 
13 
16 
19 
22 
25 
28 
31 
34 
37 
40 
43 
46 
49 
  
  
Demographics17 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/exclusion checks 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy or FSH test1 
X 
  
  
  
  
  
  
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
ECOG PS 
X 
  
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Physical examination3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Clinical chemistry18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Hematology18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Coagulation4 
X 
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Urinalysis 
X 
X 
  
  
  
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Thyroid function tests5 
X 
  
  
  
  
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
  
Echocardiogram (or MUGA)16 
X 
  
  
  
  
  
  
  
  
  
X 
X 
  
  
ECG6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Tumor imaging7 
X 
  
  
  
  
  
  
  
X 
X 
X 
X 
X 
(X) 
(X) 
Disease Assessment7 
 X 
  
  
  
  
  
  
  
X 
  
X 
  
  
X 
  
  
X 
  
  
X 
(X) 
(X) 
Tumor (fresh tissue) biopsy8 
X 
(X: up to 2 optional post treatment biopsies) 
  
  
  
Tumor (archival)8 
(X) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Biomarkers9 
X 
(X
) 
  
  
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
Pembrolizumab dosing10 
  
X 
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
BGB324 dosing11 
  
X – consecutive daily dosing in 21-d cycles  
  
  
PK sampling (BGB324)12 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PK sampling (pembrolizumab )12 
  
X 
X 
X 
X 
X 
X 
 X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse events 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
X 
(X) 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
X 
(X) 
Subsequent anti-cancer 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Survival Follow Up15 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
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Table 5: Schedule of Study Assessments - Year 2 
 
Cycle Number – Year 2 
Post Treatment 
Visit14 
Follow 
Up15 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
Day 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
+30 from last 
dose 
Week Number (+/- 3 days) 
52 
55 
58 
61 
64 
67 
70 
73 
76 
79 
82 
85 
88 
91 
94 
97 
100 
103 
  
  
Pregnancy test1 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Physical examination3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Clinical chemistry18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Hematology18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Coagulation4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Urinalysis 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
X 
  
Thyroid function tests5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Echocardiogram (or MUGA)16 
  
  
  
X 
X 
 
  
  
ECG6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Tumor imaging7 
  
X 
  
  
X 
X 
X 
 
(X) 
(X) 
Disease Assessment7 
  
  
X 
  
X 
  
  
 X 
  
 X 
 
(X) 
(X) 
Tumor (fresh tissue) biopsy8 
(X: up to 2 optional post treatment biopsies) 
 
 
Pembrolizumab dosing10 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
BGB324 dosing 11 
X – consecutive daily dosing in 21-d cycles 
 
 
Adverse events 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
X 
X 
(X) 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
X 
X 
(X) 
Subsequent anti-cancer treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Survival Follow Up15 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
X 
 
 
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General instructions: 
• 
Informed Consent must be obtained using the current version of the PIS/ICF prior to commencing Screening. 
• 
From C2 onwards a tolerance window of +/-3 days is permitted. Other tolerance windows for specific study assessments are described in the footnotes below. 
• 
On dosing days, assessments should be performed prior to dosing unless specified otherwise. 
• 
(X) denotes an optional sample; or a sample which is not taken at every cycle; or the particular assessment is ‘if applicable’; X denotes a study visit with multiple samples. 
Please refer to Footnotes. 
• 
Additional assessments may be carried out at any point in the study where clinically indicated. 
Footnotes: 
1 A pregnancy test is required within 3 days prior to C1D1. A negative pregnancy test may be confirmed by urine or blood test. Where a urine test is positive or equivocal, a 
blood test must be performed to confirm the result. Patients requiring confirmation of post-menopausal status will have FSH and oestradiol levels assessed at Screening. 
Where applicable, and in accordance with local regulations, a pregnancy test should be conducted at each cycle (or monthly). 
2 Vital signs will include temperature, systolic blood pressure, diastolic blood pressure, heart rate and respiratory rate. On pembrolizumab dosing days, vital signs will be taken 
both pre-dose and at the end of infusion. 
3 Physical examination includes height at Screening and weight at Screening and the start of each cycle. After Screening, further assessments may be symptom-directed. 
4 Coagulation parameters may be assessed from the Hematology sample. 
5 Thyroid function testing may be assessed from the Clinical chemistry sample. 
6 For each ECG assessment, triplicate 12-lead ECGs must be taken less than 5 minutes apart, with the patient having rested for at least 10 minutes in the supine position prior 
to assessment. Time points are relative to BGB324 dosing: C1 D1 pre-dose and 6 hours after dose; D2 pre-dose; D3 pre-dose; D4 pre-dose. All other time-points are pre-dose 
unless clinically indicated. If a patient permanently discontinues BGB324 (but continues pembrolizumab), the last ECG will be performed at the next pembrolizumab 
administration. If a patient has BGB324 interrupted for 14 days for toxicity or QTC prolongation, an ECG will be conducted twice weekly for the following 2 weeks once a 
patient restarts BGB324 daily dosing. 
7 Tumor imaging will be performed at Screening, then every 9 weeks for the first 46 weeks, and then every 12 weeks thereafter (+/- 7 days). A tumor response or disease 
progression should be confirmed no less than 28 days after the initial finding. If treatment administration is misaligned with weeks (e.g. because of treatment delay), the 
tumor imaging schedule should be maintained by week number and continue if necessary. The schedule of disease assessments is every 12 weeks once a patient has 
stopped (one or both study treatments) or completed their treatment in the absence of progression. These may continue into Follow Up. 
8 Fresh tumor tissue from all patients at Screening is mandatory, and optional at up to 2 time points during participation in the clinical trial (‘on-study’ biopsy). Where possible, 
these optional samples should be taken at the point of tumor response or progression. Suitable archival biopsy material may also be obtained at Screening. Please refer to 
protocol Section 5.3.13, the Laboratory or Pathology Manual for full details on biopsy sample collection, time-points, processing, storage and shipment. If a patient 
discontinues BGB324 (but continues pembrolizumab), there is no requirement for the optional ‘on study’ biopsy. 
9 Blood samples will be collected at Screening (or D1 pre-dose), D4, D8, then at every study visit up to and including C9 D1 to prepare PBMC and serum samples for Axl 
signaling and inhibition biomarker assessment. Please refer to the Laboratory Manual for full details on biomarker sample collection, time-points, processing, storage and 
shipment. If a patient discontinues BGB324 (but continues pembrolizumab), there is no requirement for biomarker blood samples. 
10 Pembrolizumab dose of 200 mg will be administered every 3 weeks (timing window +/- 3 days). Each dose will be infused over 30 minutes (timing window -5/+10 minutes) 
11 BGB324 will be taken orally once daily. On visits when pembrolizumab and BGB324 are given on the same day, pembrolizumab must be given first and the patient observed 
for 1 h prior to administration of BGB324. 
12 a) The maximum PK sampling time points for the measurement of BGB324 in blood will be: C1 D1 pre-dose, 2, 4, 6, 8 hours ; D2 pre-dose; D3 pre-dose, 2, 4, 6, 8 hours; D4 
pre-dose; and then pre-dose at C1D8, C1D15, C2D1 and then C3D1. Samples should be taken contemporaneously with the ECG assessments on C1 D1-4. All sample times are 
approximate but every effort must be made to take PK samples at specified times.  
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b) The maximum PK sampling time points for the measurement of pembrolizumab in blood will be: C1 D1 pre-dose; D2; D3; D4; and then at C1D8, C1D15; C2D1 pre-pembro 
dose and then C3D1 pre-pembro dose. All sample times are approximate but every effort must be made to take PK samples at specified times 
c) All sample times are approximate and every effort must be made to take PK samples at specified times. Actual sampling times must be recorded in order to assess result 
relative to BGB324 or pembrolizumab dose. Please refer to the local Laboratory Manual for full details on PK sample collection, time-points, processing, storage and 
shipment. 
13 D1 of next cycle would be “D22” of the previous cycle. 
14 A Post Treatment Visit is to be conducted up to 30 days (+/-3 days) from last dose of study drugs. Adverse events and concomitant medications must be assessed to 30 days. 
Some AEs must be assessed for longer (see Section 7.4.3 and Section 7.5). Other assessments may be carried out between 7-30 days from last dose. Tumor imaging and 
disease assessment is only required where is part of next scheduled assessment (where patient has not yet progressed) or to confirm response or progression.  
15 Tumor imaging and disease assessment will continue every 12 weeks from the last dose of study drug where the patient has not yet progressed or to confirm response or 
progression. An assessment of disease status, survival status and details of any anti-cancer therapies received after last dose of study drug will also be collected. Survival 
status (every 12 weeks) can be collected by telephone. 
16 Echocardiogram (or MUGA) will be conducted every 6 months whilst a patient receives BGB324. If a patient discontinues BGB324 (but continues pembrolizumab), a final 
echocardiogram (or MUGA) will be conducted only if one is scheduled in the following 6 weeks. 
17 Demography – race, ethnicity, gender, age (birth month and year). 
18 Hematology and Clinical Chemistry to be assessed at a suitable time prior to administration of study treatment(s). 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ..................................................................................................................................... 6 
1 
INTRODUCTION .......................................................................................................................................... 30 
1.1 
TRIPLE NEGATIVE BREAST CANCER AND INFLAMMATORY BREAST CANCER ................................................................ 30 
1.2 
RATIONALE FOR STUDY BGBC007 ................................................................................................................... 30 
1.3 
NON-CLINICAL STUDIES WITH BGB324 ............................................................................................................. 32 
1.3.1 
Non-clinical pharmacology of BGB324 ................................................................................................ 32 
1.3.2 
Non-clinical toxicology of BGB324 ....................................................................................................... 33 
1.3.3 
Pharmacokinetics and metabolism of BGB324 .................................................................................... 34 
1.4 
CLINICAL STUDIES WITH BGB324 ..................................................................................................................... 34 
1.4.1 
Safety summary and reference safety information ............................................................................. 34 
1.5 
RATIONALE FOR BGB324 DOSE AND SCHEDULE SELECTION .................................................................................. 35 
1.6 
PEMBROLIZUMAB BACKGROUND AND CLINICAL TRIALS ......................................................................................... 37 
1.6.1 
Rationale for pembrolizumab dose selection ....................................................................................... 38 
2 
STUDY OBJECTIVES AND ENDPOINTS .......................................................................................................... 40 
3 
SELECTION CRITERIA ................................................................................................................................... 41 
3.1 
INCLUSION CRITERIA ....................................................................................................................................... 41 
3.2 
EXCLUSION CRITERIA ...................................................................................................................................... 42 
3.3 
PATIENT WITHDRAWAL OF CONSENT AND DISCONTINUATION OF TREATMENT........................................................... 45 
3.4 
PERMITTED CESSATION OF PEMBROLIZUMAB TREATMENT ON STUDY ...................................................................... 46 
3.5 
DEFINITION OF EVALUABLE PATIENT, ACCEPTABLE TREATMENT COMPLIANCE AND REPLACEMENT OF PATIENTS ............... 46 
3.6 
PROCEDURES FOR PATIENT CESSATION OF STUDY TREATMENT ............................................................................... 46 
3.7 
STUDY OR SITE TERMINATION .......................................................................................................................... 47 
4 
STUDY DESIGN ............................................................................................................................................ 48 
4.1 
SAFETY RUN-IN ............................................................................................................................................. 48 
4.2 
DURATION OF TREATMENT .............................................................................................................................. 50 
5 
STUDY SCHEDULE ....................................................................................................................................... 52 
5.1 
SCHEDULE OF STUDY ASSESSMENTS .................................................................................................................. 52 
5.1.1 
Schedule of Study Assessment – Year 1 and Year 2 ............................................................................. 52 
5.2 
VOLUME OF BLOOD SAMPLING ........................................................................................................................ 56 
5.3 
DESCRIPTION OF STUDY INTERVENTIONS AND ASSESSMENTS .................................................................................. 56 
5.3.1 
Demography and medical history ........................................................................................................ 56 
5.3.2 
Pregnancy, FSH and oestradiol test ..................................................................................................... 56 
5.3.3 
ECOG performance score ..................................................................................................................... 57 
5.3.4 
Vital signs ............................................................................................................................................. 57 
5.3.5 
Physical exam....................................................................................................................................... 57 
5.3.6 
Clinical chemistry, hematology, coagulation and urinalysis ................................................................ 57 
5.3.7 
Thyroid function test ............................................................................................................................ 58 
5.3.8 
Echocardiography or MUGA ................................................................................................................ 58 
5.3.9 
Electrocardiogram ............................................................................................................................... 58 
5.3.10 
Tumor imaging ................................................................................................................................ 59 
5.3.11 
Disease assessment ......................................................................................................................... 60 
5.3.12 
Biomarkers ...................................................................................................................................... 60 
5.3.13 
Tumor Sample Requirements .......................................................................................................... 60 
5.3.14 
Pharmacokinetics ............................................................................................................................ 61 
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6 
STUDY MEDICATION AND ADMINISTRATION .............................................................................................. 63 
6.1 
PREPARATION AND DOSING OF STUDY TREATMENTS ............................................................................................ 63 
6.1.1 
BGB324 ................................................................................................................................................ 63 
6.1.2 
Pembrolizumab .................................................................................................................................... 63 
6.2 
TREATMENT COMPLIANCE ............................................................................................................................... 63 
6.3 
STORAGE OF STUDY TREATMENTS ..................................................................................................................... 64 
6.3.1 
BGB324 ................................................................................................................................................ 64 
6.3.2 
Pembrolizumab .................................................................................................................................... 64 
6.4 
DRUG ACCOUNTABILITY .................................................................................................................................. 64 
6.5 
METHOD OF ENROLLING PATIENT TO STUDY TREATMENT ...................................................................................... 65 
6.6 
DOSE MODIFICATIONS .................................................................................................................................... 65 
6.6.1 
BGB324 dose modification for toxicity ................................................................................................. 65 
6.6.2 
BGB324 dose modification for QTc ...................................................................................................... 66 
6.6.3 
Pembrolizumab dose modifications ..................................................................................................... 67 
6.6.4 
Dose modifications for BGB324 and pembrolizumab for overlapping toxicities .................................. 70 
6.7 
BLINDING AND PROCEDURES FOR UN-BLINDING THE STUDY ................................................................................... 71 
6.8 
PERMITTED AND RESTRICTED CONCOMITANT MEDICATIONS .................................................................................. 72 
6.9 
ACCEPTABLE CONCOMITANT MEDICATIONS ........................................................................................................ 72 
6.10 
PROHIBITED CONCOMITANT MEDICATIONS WHILST RECEIVING PEMBROLIZUMAB ..................................................... 72 
6.11 
SUPPORTIVE CARE GUIDELINES FOR PEMBROLIZUMAB .......................................................................................... 73 
6.12 
INFUSION GUIDELINES FOR PEMBROLIZUMAB ...................................................................................................... 75 
6.13 
DIET, ACTIVITY AND OTHER CONSIDERATIONS ..................................................................................................... 77 
6.13.1 
Diet .................................................................................................................................................. 77 
6.14 
CONTRACEPTION ........................................................................................................................................... 77 
6.14.1 
Use in pregnancy ............................................................................................................................. 78 
6.14.2 
Use in nursing women ..................................................................................................................... 78 
7 
ADVERSE EVENTS AND REPORTING REQUIREMENT .................................................................................... 79 
7.1 
ASSESSMENT OF SAFETY .................................................................................................................................. 79 
7.2 
ADVERSE EVENT DEFINITION ............................................................................................................................ 79 
7.3 
IMPORTANCE OF ADVERSE EVENT REPORTING ..................................................................................................... 80 
7.4 
EVALUATING ADVERSE EVENTS ......................................................................................................................... 81 
7.4.1 
Assessment of severity ......................................................................................................................... 81 
7.4.2 
Assessment of relationship .................................................................................................................. 81 
7.4.3 
Immediate reporting of adverse events and events of clinical interest to the Sponsor ....................... 82 
7.5 
REPORTING SAES AND ECIS ............................................................................................................................ 84 
7.6 
ASSESSMENT OF EXPECTED ADVERSE EVENTS ...................................................................................................... 85 
7.7 
REPORTING OF PREGNANCY OR LACTATION ........................................................................................................ 85 
7.8 
DEFINITION OF MISUSE AND OVERDOSE ............................................................................................................. 85 
7.9 
INVESTIGATIONAL PRODUCT COMPLAINTS .......................................................................................................... 86 
7.10 
REPORTING SAES TO THE IRB OR IEC ............................................................................................................... 86 
7.11 
FOLLOW UP INFORMATION ON AN SAE ............................................................................................................. 86 
7.12 
SPONSOR REPORTING OF SAES ........................................................................................................................ 87 
7.12.1 
Expedited reporting ......................................................................................................................... 87 
7.12.2 
Non-expedited reporting ................................................................................................................. 87 
8 
DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES ............................................................... 88 
8.1 
STATISTICAL CONSIDERATIONS, INTERIM ANALYSIS AND SAMPLE SIZE ...................................................................... 88 
8.2 
DATA REVIEW COMMITTEE ............................................................................................................................. 88 
8.2.1 
Safety Run-In ........................................................................................................................................ 88 
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8.2.2 
End of Stage 1 – Efficacy Analysis ........................................................................................................ 89 
8.3 
STATISTICAL ANALYSIS PLAN ............................................................................................................................ 89 
8.4 
POPULATION ................................................................................................................................................ 90 
8.5 
RECIST 1.1 AND DISEASE ASSESSMENT ............................................................................................................. 90 
8.5.1 
Immune-related RECIST 1.1 and confirmation of progression ............................................................. 92 
8.6 
COMPLETION AND CLOSURE OF THE STUDY ......................................................................................................... 93 
8.7 
DEMOGRAPHIC, MEDICAL HISTORY, PRIOR MEDICATION AND OTHER BASELINE CHARACTERISTICS ................................ 94 
8.8 
STUDY TREATMENT ........................................................................................................................................ 94 
8.9 
CONCOMITANT MEDICATION ........................................................................................................................... 95 
8.10 
REASONS FOR DISCONTINUATION FROM STUDY TREATMENT .................................................................................. 95 
8.11 
PRIMARY OBJECTIVES ..................................................................................................................................... 95 
8.12 
SECONDARY OBJECTIVES ................................................................................................................................. 96 
8.12.1 
Safety .............................................................................................................................................. 96 
8.12.2 
Efficacy ............................................................................................................................................ 96 
8.12.3 
Pharmacokinetics ............................................................................................................................ 97 
8.13 
EXPLORATORY OBJECTIVES .............................................................................................................................. 98 
8.13.1 
Biomarker analysis .......................................................................................................................... 98 
9 
QUALITY ASSURANCE ................................................................................................................................. 99 
9.1 
DATA RECORDING ......................................................................................................................................... 99 
9.2 
STUDY MONITORING ...................................................................................................................................... 99 
9.3 
CLINICAL STUDY AUDIT ................................................................................................................................... 99 
9.4 
CLINICAL STUDY REPORT ................................................................................................................................. 99 
9.5 
DATA RETENTION AND AVAILABILITY ................................................................................................................. 99 
9.6 
CURRICULA VITAE AND FINANCIAL DISCLOSURE OF INVESTIGATORS ....................................................................... 100 
9.7 
PROTOCOL MODIFICATIONS........................................................................................................................... 100 
10 
ETHICS REVIEW AND INFORMED CONSENT AND COMPETENT REGULATORY AUTHORITY APPROVAL ...... 101 
10.1 
ETHICAL CONDUCT OF THE STUDY ................................................................................................................... 101 
10.2 
INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE APPROVAL AND COMPETENT REGULATORY 
AUTHORITY APPROVALS .............................................................................................................................................. 101 
10.3 
INFORMED CONSENT .................................................................................................................................... 101 
10.4 
PATIENT PARTICIPATION CARD ....................................................................................................................... 102 
10.5 
INSURANCE................................................................................................................................................. 103 
10.6 
PATIENT PRIVACY ........................................................................................................................................ 103 
11 
PUBLICATION POLICY ................................................................................................................................ 104 
APPENDIX A: EASTER COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS ............................................ 105 
APPENDIX B: CREATININE CLEARANCE ALGORITHM .......................................................................................... 106 
APPENDIX C: THE NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL CLASSIFICATION IN A PATIENT WITH 
HEART DISEASE .................................................................................................................................................. 107 
APPENDIX D: DRUGS ASSOCIATED WITH TORSADES DE POINTES ...................................................................... 108 
APPENDIX E: LOCAL LABORATORY PARAMETERS ............................................................................................... 110 
REFERENCES ....................................................................................................................................................... 111 
 
 
 
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List of Tables 
Table 1: Study Objectives and Endpoint (Assessment) ............................................................. 6 
Table 2: BGB324 and pembrolizumab dosing ........................................................................... 9 
Table 3: Pembrolizumab 3 weekly schedule and disease assessment timings ....................... 17 
Table 4: Schedule of Study Assessments – Year 1 ................................................................... 19 
Table 5: Schedule of Study Assessments - Year 2 .................................................................... 20 
Table 6: BGB324 kinase selectivity profile .................................................................................. 32 
Table 7: Preliminary PK Data Available from Studies BGBC003 and BGBC004 ...................... 37 
Table 8: Preliminary PK Data from BGB324 Studies in Patients ................................................ 37 
Table 9: Study Objectives and Endpoint (assessment) ................................................................. 40 
Table 11: Product Descriptions ................................................................................................. 63 
Table 12: Dose Modification for BGB324-related Toxicity .................................................... 65 
Table 13: Dose modification of BGB324 for QTc Prolongation ............................................. 66 
Table 14: Dose modification guidelines for pembrolizumab drug-related adverse events .......... 68 
Table 15: Pembrolizumab and BGB324 Dose Modification for Diarrhea ................................... 70 
Table 16: Pembrolizumab and BGB324 Dose Modification for Rash ................................... 71 
Table 17: Pembrolizumab and BGB324 Dose Modification for Renal Toxicity ................... 71 
Table 18: Management of pembrolizumab-associated infusion-related reactions ....................... 75 
Table 19: Contact Details for SAE, ECI, New Cancer and Pregnancy/Lactation Reporting ....... 85 
Table 20: RECIST 1.1 evaluation and definitions of disease response ........................................ 91 
Table 21: Overall visit response algorithm ................................................................................... 92 
Table 22: Pharmacokinetic parameters ......................................................................................... 97 
 
List of Figures 
Figure 1: Schematic diagram of the study design ...................................................................... 8 
Figure 2: BGB324 in combination with anti mCTLA4 and anti mPD-1 ...................................... 33 
Figure 3: Stimulated Plasma Concentrations of BGB324 for 600 mg Loading Dose on Days 1 
and 2 and Daily Dose of 200 mg from Day 3 (fasted) .................................................................. 36 
Figure 4: Predicted Plasma Concentrations of BGB324 after 1200 mg Loading Dose Given as 
600 mg on Days 1 and 2 or 400 mg on Days, 1, 2 and 3, followed by Daily Dose of 200 mg 
(fasted) .......................................................................................................................................... 36 
Figure 5: Flow Chart ..................................................................................................................... 50 
Figure 6: Sample Patient Participation Card ............................................................................... 103 
 
 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
ALK 
anaplastic lymphoma kinase 
ALT 
Alanine aminotransferase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
AUC0- ∞ 
AUC from time zero to infinity 
AUC0-24h 
AUC from time zero to 24 hours 
AUC0-48h 
AUC from time zero to 48 hours 
AUC0-T 
AUC from time zero to time t 
BP 
Blood pressure 
BPM 
Beats per minute 
Cav 
average concentration 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
Cmax 
Maximum concentration achieved 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Cardiovascular 
DCR 
Disease control rate 
DLT 
Dose limiting toxicity 
DoR 
Duration of response 
DSUR 
Development Safety Update Report 
EC 
European Community 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECI 
Events of clinical interest 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EGFR 
Epidermal growth factor receptor 
EMT 
Epithelial-to-mesenchymal transition 
EU 
European Union 
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FDA 
Food and Drug Administration 
FPI 
First patient in 
FPPE 
Formalin fixed paraffin embedded 
FSH 
Follicle-stimulating hormone 
FT3 
Free Triidothyromine 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte-colony stimulating factor 
GM-CSF 
Granulocyte-macrophage colony-stimulating factor 
GMP 
Good Manufacturing Practice 
HCV 
Hepatitis C virus 
hERG 
Human ether-à-go-go related gene  
HIV 
Human immunodeficiency virus 
HPMC 
Hydroxypropyl methylcellulose 
hr 
Hour 
i.v. 
Intravenous(ly) 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH  
International Conference on Harmonization 
IEC 
Institutional Ethics Committee 
IHC 
Immunohistochemistry 
IMP 
Investigational medicinal product 
IND 
Investigational new drug 
INR 
International normalization ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
LPLV 
Last patient, last visit 
mAb 
Monoclonal antibody 
MDS 
Myelodysplastic syndrome 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multi Gated Acquisition Scan 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NYHA 
New York Heart Association 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cell(s) 
PD 
Pharmacodynamic(s) 
PFS 
Progression-free survival 
PIS 
Patient information sheet 
PK 
Pharmacokinetic 
PT 
Prothrombin time 
PTT 
Partial Thromboplastin Time 
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Q2W 
(dose) every 2 weeks 
Q3W 
(dose) every 3 weeks 
Qd 
(dose) daily 
qPCR 
quantitative polymerase chain reaction 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval utilizing Fridericia’s correction 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase 2 dose 
RTK 
receptor tyrosine kinases 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SmPC 
summary of product characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
t½ 
Elimination half-life 
T3 
Triiodothyromine 
TL 
Target lesion 
tmax 
Time to maximum concentration 
TMF 
Trial Master File 
TPS 
tumor proportion score 
TSH 
Thyroid stimulating hormone 
ULN 
Upper limit of normal 
US 
United States (of America) 
DRC 
Data Review Committee 
TNBC 
Triple negative breast cancer 
TN-IBC 
Triple negative inflammatory breast cancer 
FISH 
Fluorescent in situ hybridization 
CISH 
Chromogenic in situ hybridization 
LDH 
Lactate Dehydrogenase 
EDC 
Electronic Data collection 
PD 
Progression of disease 
CrCl 
Creatinine clearance 
 
 
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1 
INTRODUCTION 
This is an open-label, Multi-Center, Phase II, Simon 2-stage design1 study of the anti-tumor 
activity and safety of BGB324, an Axl kinase inhibitor, when given in combination with 
pembrolizumab, the humanized monoclonal antibody (mAb) which targets the programmed 
death receptor-1 (PD-1) protein in patients with advanced or metastatic triple negative breast 
cancer (TNBC) or triple negative Inflammatory Breast Cancer (TN-IBC). 
1.1 
Triple Negative Breast Cancer and Inflammatory Breast Cancer 
TNBC is a disease of exclusion describing any breast cancer that does not express estrogen or 
progesterone receptors or overexpress Her2. In total TNBC represents 15 to 25% of cases of 
breast cancer. As such the term represents a heterogeneous population although most cases in 
younger women are “basal – like” defined by the presence of cytokeratin 5/6 and epithelial 
growth factor expression on histology4. TNBC is more common in younger women, Africans, 
Hispanics and women with germline mutations of BRCA 1. Following initial therapy patients 
with TNBC have a much higher risk of recurrence during the first 3–5 years but this risk of 
recurrence drops sharply thereafter. The pattern of disease spread within the body is also 
different from other types of breast cancer with a much higher rate of intracerebral metastases. 
Current treatment is currently limited to cytotoxic chemotherapy and radiotherapy. TNBC is 
particularly sensitive to taxanes and anthracyclines, and because of the high risk of early relapse, 
patients often receive a combination of these drugs in the (neo)adjuvant setting. This limits the 
utility of the same drugs in the metastatic setting when many tumors have already become 
resistant. Although initial response rates to non- or partially cross resistant chemotherapy 
regimens are high chemosensitivity correlates poorly with overall survival and median survival 
for patients from the appearance of metastatic disease is 13 months5. As such there remains a 
significant unmet medical need for new approaches to the treatment of metastatic disease 
especially therapies that do not exhibit cross-resistance to existing cytotoxics. 
Inflammatory breast cancer is a rare and very aggressive disease in which cancer cells block 
lymph vessels in the skin of the breast. Inflammatory breast cancer accounts for 1 to 5% of all 
breast cancers in the USA6. Most are invasive ductal carcinomas7. The disease progresses 
rapidly, and usually, at diagnosis, the disease is already stage III or IV. Like TNBC, 
inflammatory breast cancer is more common in younger women and women of African origin. It 
is also more often seen in obese women. Inflammatory breast cancers are often hormonal 
negative and therefore current treatment is limited to cytotoxic chemotherapy, surgery and 
radiotherapy. As with TNBC, taxanes and anthracyclines are the mainstay of the chemotherapy. 
1.2 
Rationale for Study BGBC007 
There is a strong scientific/pre-clinical rationale for the use of BGB324 in TNBC and TN-IBC. 
There is no clinical data available from patients with these diseases. 
BGB324 is a highly selective inhibitor of Axl kinase, a receptor tyrosine kinase enzyme 
associated with the epithelial-mesenchymal transition. TNBC reflects a heterogenous population 
of molecular subtypes. Typically, TNBC subtypes can be assigned to 3 intrinsic molecular 
subtypes: basal like, mesenchymal like and luminal like8. In TN-IBC, high tumoral expression of 
TIG1, a functionally undefined membrane protein confers shorter survival in patients with IBC. 
Axl kinase is a TIG1 binding protein – which regulates invasion of IBC cells by supporting the 
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Axl signaling pathway in IBC cells. TIG1 and Axl are highly expressed in patients with TNBC 
and IBC in particular9. 
Pembrolizumab has demonstrated initial clinical efficacy in single arm monotherapy trials in 
subjects with non-small cell lung cancer, head and neck squamous cell carcinoma, urothelial 
cancer, gastric cancer, triple negative breast cancer and Hodgkin’s Lymphoma as determined 
by response rate (KEYNOTE-012). Keynote-012 was a multicenter, non-randomised phase 1b 
trial of single agent pembrolizumab given intravenously at 10 mg/kg every 2 weeks to patients 
with advanced PD-L1 positive (expression in stroma or ≥1% of tumor cells by IHC) TNBC, 
gastric cancer, urothelial cancer and head and neck cancer. Thirty-two women with TNBC were 
enrolled, of which, 27 were evaluable for anti-tumor activity and the overall response rate was 
18.5%10. Further ongoing clinical trials in TNBC are being conducted - including a phase II 
clinical trial (KEYNOTE-86) and a phase III clinical trial (KEYNOTE-119). Ongoing clinical 
trials are also ongoing in other tumor types as well as a number of other advanced solid tumor 
indications and hematologic malignancies. For study details please refer to the pembrolizumab 
Investigator’s Brochure. 
The rationale to assess the safety and anti-tumor effect of BGB324 and pembrolizumab when 
given in combination, is based on the following: 
• Dysregulation of the AXL receptor tyrosine kinase (RTK) enzyme has been associated 
with many types of cancer. AXL is one of 58 RTKs, and belongs to the TAM (tyro3, 
AXL, MER) subfamily. High levels of AXL expression have been associated with: 
 Poor prognosis in different cancers such as glioblastoma multiforma11, breast 
(including inflammatory breast cancer)9 and lung cancer12, osteosarcoma13, and 
acute myeloid leukemia14; 
 Epithelial-mesenchymal transition (EMT)15; 
 Developed drug resistance to targeted therapies16,17,18 and chemotherapy19,20. 
 EMT is the process consisting of multiple biochemical changes by which 
polarised epithelial cells gain a mesenchymal cell phenotype, leading to increased 
migration and invasive properties. In cancer, EMT is a hallmark of invading cells 
and consequently cancer/metastases.  
 BGB324 is a highly selective AXL kinase inhibitor. 
• It is increasingly understood that cancers are recognized by the immune system and, 
under some circumstances, the immune system may control or even eliminate tumors21. 
However, if elimination is incomplete, the tumor may evolve mechanisms to avoid or 
attenuate the immune system. In the tumor microenvironment, PD-L1 expressed on 
tumor cells binds with PD-1 on activated T-cells reaching the tumor. This delivers an 
inhibitory signal to those T-cells, preventing them from killing the tumor cells, and thus, 
protecting the tumor from immune elimination22. Pembrolizumab is a PD-1 inhibitor 
(Section 1.6). 
• A strong association between EMT status and an inflammatory tumor micro-environment 
with elevation of multiple targetable immune checkpoint molecules, including PD-L1, 
PD-1, PD-L2, BTLA, CTLA-4 etc. has been shown. Multiple agents, including 
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pembrolizumab, that target these checkpoint molecules, are in development for a range of 
cancers that are considered to have highly immunogenic microenvironments.  
• Pre-clinically, BGB324 has been combined with PD-1 and PD-L1 inhibitors, and has 
been shown to potentiate the effect of PD-1/PD-L1 inhibition and to enhance tumor 
leukocyte infiltration in a TNBC orthotopic xenograft model and lung cancer syngeneic 
model in C57B1/6 mice (Section 1.3.1). 
• There is therefore, a strong scientific rationale for combination of BGB324 with 
pembrolizumab in TNBC and IBC breast cancer. The proposed population will have 
advanced disease and therefore, the combination of BGB324 with pembrolizumab is 
expected to increase the response rate and prolong the duration of response. 
1.3 
Non-Clinical Studies with BGB324 
Please refer to the current version of the Investigator’s Brochure for further details of the non-
clinical studies with BGB324. 
1.3.1 Non-clinical pharmacology of BGB324 
BGB324 demonstrates potent inhibition of Axl in biochemical and cell-based kinase inhibition 
assays. The selectivity of BGB324 for Axl is illustrated in Table 6. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
n/a = not applicable 
BGB324 inhibits the growth and survival of tumor cell lines derived from a range of solid and 
leukemic tumors. 
The anti-tumor activity of BGB324 in combination with anti-mPD-1 and anti-mCTLA-4 was 
evaluated in a syngeneic 4T1 mammary adenocarcinoma model in Balb/c mice. In this poorly 
immunogenic 4T1–BalbC model, BGB324 potentiated the effect of anti-mCTLA-4 and anti-
mCTLA-4+anti-mPD-1 antibodies and resulted in significantly increased median survival, more 
complete responders and reduced primary tumor growth. Responding mice were immune against 
re-challenge with 4T1 cells. 
See the Investigator Brochure for details. 
BGB324 in combination with PD-1 and CTLA-4 inhibitors potentially promotes survival in 
syngeneic mammary adenocarcinoma model (Figure 2): 
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Figure 2: BGB324 in combination with anti mCTLA4 and anti mPD-1 
 
1.3.2 Non-clinical toxicology of BGB324 
To support clinical studies with BGB324 a series of animal toxicology and safety studies, 
including 28-day repeat dosing studies in rodents and monkeys and a single dose telemetered 
cardiovascular (CV) safety study in monkeys, have been conducted. Comparisons of the data 
reported in the rodent and monkey studies indicate that primates are more sensitive to BGB324 
on a per body weight basis. 
The results of the repeat dose 28-day study in monkeys identified the liver, reticuloendothelial 
system and hematopoietic system as target organs. These events were largely thought to be due 
to macrophage accumulation, and were only partially reversible across the planned 16-day 
recovery period, although this was anticipated to be due to the slow elimination of the 
compound. Similar findings were identified in mice treated across a range of dose levels with 
partial recovery noted 16 days later. 
In the CV safety study, single oral administration of BGB324 (7.5 mg/kg – 60 mg/kg) was 
associated with recoverable, non-adverse decreases in heart rate and corresponding increases in 
the RR interval durations. Dose-dependent increase in QTc interval was noted at all dose levels; 
the magnitude of the QTc effect at the highest dose level was 17%, whilst at 7.5 mg/kg and 15 
mg/kg, the change generally fell below 10% compared to vehicle control and pre-dose values. 
These observations were consistent with the previously identified IC50 for human ether-à-go-go 
related gene (hERG) channel inhibition of 0.53 µM BGB324. 
In an academic model of osteoporosis, BGB324 was administered in combination with high dose 
corticosteroids (12.5 mg/kg per day of prednisolone). In this research study, 6 out of 7 mice 
experienced severe toxicity after five continuous days of combination therapy.  Four of the 6 
animals (that developed severe toxicity) died and the other 2 were euthanized for humane 
reasons. The exact mechanism of this effect is currently under investigation.  The mice received 
very high levels of corticosteroids to induce rapid onset of osteoporosis – on a mg/kg basis, the 
corticosteroid dose was 20 fold higher than a typical high dose commonly used in clinical 
practice. Additionally, the dose of BGB324 used in this model was 50mg/kg which is 6 fold 
higher than the maximum exposure observed in human clinical studies. 
 
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BGB324 was negative in the Ames bacterial mutation assay, suggesting that BGB324 is not 
mutagenic. BGB324 was also negative in an in vitro mammalian cell cytogenetic study in human 
lymphocytes suggesting that BGB324 is not clastogenic. 
1.3.3 Pharmacokinetics and metabolism of BGB324 
BGB324 had moderate to high plasma clearance (33.7, 18.7 and 43.3 mL/min/kg in rats, dogs 
and monkeys, respectively) i.e. plasma clearance approached hepatic blood flow in these species. 
Since BGB324 is sequestered into blood cells, blood clearance will be lower than plasma 
clearance at least in monkeys (monkeys are currently the only species tested). However, 
BGB324 was metabolically stable in vitro suggesting that liver metabolism was unlikely to 
contribute significantly to the elimination of BGB324 in vivo. 
There was an inhibitory effect of BGB324 on cytochrome P450 (CYP) 3A4 IC50 1 to 5 
micromolar; therefore, there is at least a moderate risk of interactions with co-administered drugs 
that are CYP3A4 substrates. 
1.4 
Clinical studies with BGB324 
Please refer to the current version of the BGB324 Investigator’s Brochure for further details of 
the clinical studies with BGB324. 
A phase I, first-in-human study in healthy male subjects (Study BGBC001) has been completed. 
Two phase 1b/2 clinical studies are currently underway in patients with advanced cancers: Study 
BGBC003 in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), 
and Study BGBC004 in patients with NSCLC. Study BGBC003 will define a recommended 
Phase 2 dose (RP2D) of single agent BGB324 in patients with advanced hematologic 
malignancy, then further evaluate the RP2D in an expansion phase. This expansion phase will 
also explore BGB324 given in combination with standard treatments for AML. Study BGBC004 
will identify the RP2D for BGB324 given in combination with erlotinib in patients with NSCLC. 
The study will then continue to enroll to an expansion phase to further evaluate the effectiveness 
of BGB324 in combination with erlotinib. 
1.4.1 Safety summary and reference safety information 
The reference safety information below is based on a data cut of active trials on 31 March 2016 
(8 April 2016 for serious adverse events (SAEs)) as presented in the IB V9.0 dated 28 July 2016. 
At the time of cut-off, 24 and 10 patients (including two who received BGB324 in combination 
with erlotinib) had received BGB324 in Studies BGBC003 and BGBC004, respectively. Please 
refer to the latest edition of the IB for the most up-to-date safety information during the conduct 
of this clinical study. 
AEs to date assessed to be study treatment related following repeat oral doses of BGB324 in 
Studies BGBC003 and BGBC004 indicate that gastrointestinal disorders are the most commonly 
observed events (National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) Grade 1 to 3) and were observed in approximately one half of patients treated 
in both repeat dose studies. In most cases these events responded well to symptomatic treatment 
and did not lead to treatment discontinuation or dose reduction. As expected the incidence of 
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infections was higher in the relapsed/refractory AML/MDS patient group whilst reversible 
increases in serum creatinine were more frequent in patients with NSCLC. 
At the data cut-off date of 08 April 2016, valid SAEs had only been reported from patients 
treated in Study BGBC003. A total of 26 SAEs reports (with 36 events) in 16 patients have been 
recorded. The majority of SAEs are cardiovascular disorders and infections, including multiple 
cardiovascular disorders in one patient with MDS who had pre-existing ischemic heart disease 
who experienced two distinct episodes of myocardial infarction whilst receiving BGB324 which 
were considered unrelated to treatment with BGB324. The majority of the remaining reports are 
due to episodes of sepsis most commonly pneumonia which are common events in patients with 
myeloid malignancies. Three SAEs in two patients were study treatment-related. One 85-year old 
male patient with AML had an SAE of Grade 3 diarrhea, which was considered definitely related 
to study treatment. The intensity decreased to Grade 1 in response to adequate anti-diarrheal 
treatment. A 68-year old male patient with AML had two SAEs of myocardial ischemia and 
increased Troponin T which were considered probably related to study treatment. These events 
were recovering/resolving eight days later at the time of the patient’s death from Grade 3 sepsis 
and upper gastrointestinal hemorrhage which were considered to be unrelated to treatment with 
BGB324. 
To date there is limited clinical experience with BGB324, and therefore all related SAEs should 
be considered unexpected and require expedited reporting to the regulatory authorities as 
SUSARs (see current IB, together with any relevant addendum for further details). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.6 
Pembrolizumab Background and Clinical Trials 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 
(PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
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Keytruda™ (pembrolizumab) is indicated for the treatment of patients across a number of 
indications.  For more details on specific indications refer to the Investigator brochure. 
 
1.6.1 Rationale for pembrolizumab dose selection 
The dose of pembrolizumab planned to be studied in this trial is 200 mg, administered every 3 
weeks (Q3W). The dose recently approved in the US and several other countries for treatment of 
melanoma and NSCLC subjects is 2 mg/kg Q3W. Information on the rationale for selecting 200 
mg Q3W is summarized below. 
In KEYNOTE-001, an open-label Phase I study conducted to evaluate the safety, tolerability, PK 
and pharmacodynamics (PD), and anti-tumor activity of pembrolizumab when administered as 
monotherapy. The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 
mg/kg and 10 mg/kg, administered every 2 weeks (Q2W) and dose expansion cohorts evaluated 
2 mg/kg Q3W and 10 mg/kg Q3W in subjects with advanced solid tumors. All dose levels were 
well tolerated and no dose-limiting toxicities (DLTs) were observed. This first-in-human study 
of pembrolizumab showed evidence of target engagement and objective evidence of tumor size 
reduction at all dose levels. No maximum tolerated dose (MTD) has been identified. In addition, 
two randomized cohort evaluations of melanoma subjects receiving pembrolizumab at a dose of 
2 mg/kg versus 10 mg/kg Q3W have been completed, and one randomized cohort evaluating 10 
mg/kg Q3W versus 10 mg/kg Q2W has also been completed. The clinical efficacy and safety 
data demonstrate a lack of important differences in efficacy or safety profile across doses. 
An integrated body of evidence suggests that 200 mg every 3 weeks (Q3W) is expected to 
provide similar response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W. Previously, a 
flat pembrolizumab exposure-response relationship for efficacy and safety has been found in 
subjects with melanoma in the range of doses between 2 mg/kg and 10 mg/kg. Exposures for 200 
mg Q3W are expected to lie within this range and will be close to those obtained with 2 mg/kg 
Q3W dose. 
A population pharmacokinetic (PK) model, which characterized the influence of body weight 
and other patient covariates on exposure, has been developed. The PK profile of pembrolizumab 
is consistent with that of other humanized monoclonal antibodies, which typically have a low 
clearance and a limited volume of distribution. The distribution of exposures from the 200 mg 
fixed dose are predicted to considerably overlap those obtained with the 2 mg/kg dose and 
importantly will maintain individual patient exposures within the exposure range established in 
melanoma as associated with maximal clinical response. PK properties of pembrolizumab, and 
specifically the weight-dependency in clearance and volume of distribution are consistent with 
no meaningful advantage to weight-based dosing relative to fixed dosing. 
In translating to other tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in subjects with melanoma can be expected, as the anti-tumor 
effect of pembrolizumab is driven through immune system activation rather than through a direct 
interaction with tumor cells, rendering it independent of the specific tumor type. In addition, 
available PK results in subjects with melanoma, NSCLC, and other tumor types support a lack of 
meaningful difference in PK exposures obtained at tested doses among tumor types. Thus, the 
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200 mg Q3W fixed-dose regimen is considered an appropriate fixed dose for other tumor 
indications as well. 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and 
to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. The existing data suggest 200 mg 
Q3W as the appropriate dose for pembrolizumab for the treatment of patients with TNBC and 
TN-IBC. 
 
 
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2 
STUDY OBJECTIVES AND ENDPOINTS 
The objective of this study is to assess the anti-tumor activity of the combination treatment of 
BGB324 and pembrolizumab in patients with previously treated locally advanced and un-
resectable or metastatic triple negative breast cancer (TNBC) or inflammatory breast cancer 
(IBC). Table 9 presents the study objectives. 
Table 9: Study Objectives and Endpoint (assessment) 
 
Objective 
    Endpoint (Assessment) 
Primary: 
 
• To assess anti-tumor activity of the combination 
of BGB324 and pembrolizumab  
• 
Objective response rate (complete response 
and partial response) 
Secondary: 
 
• To 
assess 
the 
safety 
of 
BGB324 
and 
pembrolizumab when given in combination  
 
• To further assess the anti-tumor activity of the 
combination of BGB324 and pembrolizumab 
• 
The number and frequency of adverse events; 
assessment of safety laboratory parameters, 
vital signs and ECGs 
• 
To include Disease Control Rate, Duration of 
Response; Progression-free Survival; 12-month 
Overall Survival 
• To evaluate the pharmacokinetic profile of 
BGB324 when given with pembrolizumab. 
• 
Assessment 
of 
pharmacokinetic 
variables 
including Cmax, AUC, t½  
Exploratory: 
 
• To assess relevant biomarkers 
• 
To assess PD-L1 and Axl expression in patients 
with TNBC and TN-IBC 
• 
To assess any correlation or association 
between expression level of PD-L1 and Axl and 
anti-tumor outcomes such as ORR 
• 
Assessment of relevant biomarkers in tumor 
and blood which support immune modulation 
and Axl signaling 
 
 
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3 
SELECTION CRITERIA 
The study will enroll adult patients with pre-treated, advanced or metastatic TNBC. 
3.1 
Inclusion Criteria 
A patient will be suitable to proceed to treatment on study if they meet all of the following 
criteria: 
1. 
Provision of signed informed consent. 
2. 
Male and non-pregnant females who are aged 18 years or older at the time of 
provision of informed consent. 
3. 
Histopathologically or cytologically documented TNBC or TN-IBC. Tumors must 
have been confirmed negative for ER and PR by IHC (<1% positive tumor nuclei, as 
per ASCO-CAP guideline recommendations3) and negative for HER2 by IHC or 
fluorescent or chromogenic in situ hybridization (FISH or CISH). Patients with 
equivocal HER2 results by IHC should have their negativity status confirmed by 
FISH. 
4. 
Locally advanced and unresectable or metastatic TNBC or triple negative 
inflammatory breast cancer. 
5. 
Received one or more prior therapies for TNBC or inflammatory breast cancer in the 
metastatic setting, and prior treatment (metastatic or (neo) adjuvant) must have 
included a prior taxane and/or anthracycline-based therapy  
6. 
Has measurable disease as defined by RECIST 1.12 on computed tomography (CT) 
or magnetic resonance imaging (MRI) and as determined by the site study team. 
Tumor lesions situated in a previously irradiated area are considered measurable if 
progression has been demonstrated in such lesions. 
7. 
Provision of suitable tumor tissue for the analysis of Axl kinase expression and PD-
L1 expression. Suitable tumor tissue must consist of a minimum of newly acquired 
(fresh) tumor tissue sample (as a FFPE block), together with either further newly 
acquired tumor tissue (i.e. further FFPE block) or an archival tumor tissue sample (as 
a further FFPE block or further 10 unstained slides). See Section 5.3.13 for an 
explanation. 
8. 
Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1 (Appendix 
A). 
9. 
Life expectancy of at least 3 months. 
10. 
Adequate organ function confirmed at Screening and within 10 days of initiating 
treatment, as evidenced by: 
a. 
Platelet count ≥100,000 /mm3; 
b. 
Hemoglobin ≥9.0 g/dL (≥5.6 mmol/L); 
c. 
Absolute neutrophil count (ANC) >1,500 /mm3; 
d. 
Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤2.5 
times the upper limit of normal (ULN), or ≤5 times the ULN for patients with 
liver metastases; 
e. 
Total bilirubin ≤1.5 times the ULN, or direct bilirubin <ULN for patients with 
total bilirubin levels >1.5xULN.  
f. 
Creatinine ≤1.5 times the ULN or calculated creatinine clearance >60 mL/min 
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(by Cockcroft Gault formula; see Appendix B)  
g. 
International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 times the 
ULN and Activated Partial Thromboplastin Time (aPTT) ≤1.5 times the ULN. 
Note: If patient is receiving anticoagulant therapy, then PT or PTT must be 
within therapeutic range of intended use of anticoagulants; 
h. 
LDH ≤2.5 times the ULN 
11. 
Female patients of childbearing potential must have a negative pregnancy test (either 
urine or serum pregnancy test) within 3 days prior to the first dose of study treatment. 
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy 
test will be required. 
12. 
Have resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or less (except alopecia). If the patient received major surgery or radiation therapy of 
>30 Gy, they must have recovered from the toxicity and/or complications from the 
intervention. 
13. 
Patients of reproductive potential must be willing to practice highly effective 
methods of contraception (such as those described in Section 6.14) throughout the 
study and for 120 days after the last dose of study medication. Abstinence is 
acceptable if this is the usual lifestyle of the patient. Female patients are considered 
NOT of childbearing potential if they have a history of surgical sterility or evidence 
of post-menopausal status defined as any of the following: 
a. 
≥45 years of age and has not had menses for more than 1 year; 
b. 
Amenorrheic for <2 years without a hysterectomy and oophorectomy and a 
follicle stimulating hormone (FSH) value in the postmenopausal range upon 
Screening evaluation and oestradiol <30pg/mL. 
c. 
Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy 
or oophorectomy must be confirmed with medical records of the actual 
procedure or confirmed by an ultrasound. Tubal ligation must be confirmed 
with medical records of the actual procedure. 
3.2 
Exclusion Criteria 
A patient will not be suitable to proceed to treatment on study if they meet any of the following 
criteria: 
1. 
Has disease that is suitable for local therapy administered with curative intent. 
2. 
More than 3 previous lines of therapy in the metastatic setting. 
3. 
Has received prior therapy with an immunomodulatory agent. 
4. 
Has a known additional malignancy that is progressing or requires active treatment. 
Note: Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma 
of the skin that has undergone potentially curative therapy or in situ cervical cancer. 
5. 
Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Note: Patients with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging (using the 
identical imaging modality for each assessment, either MRI or CT scan) for at least 4 
weeks prior to the first dose of trial treatment and any neurological symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and 
are not using steroids for at least 7 days prior to trial treatment. 
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6. 
History of the following cardiac conditions: 
a. 
Congestive cardiac failure of >Grade II severity according to the 
NYHA (Appendix C: defined as symptomatic at less than ordinary levels of 
activity). 
b. 
Ischemic cardiac event including myocardial infarction within 3 months prior 
to first dose. 
c. 
Uncontrolled cardiac disease, including unstable angina, uncontrolled 
hypertension (i.e. sustained systolic BP >160 mmHg or diastolic BP >90 
mmHg), or need to change medication due to lack of disease control within 6 
weeks prior to the provision of consent.  
d. 
History or presence of sustained bradycardia (≤55 BPM), left bundle branch 
block, cardiac pacemaker or ventricular arrhythmia. Note: Patients with a 
supraventricular arrhythmia requiring medical treatment, but with a normal 
ventricular rate are eligible. 
e. 
Family history of long QTc syndrome; personal history of long QTc syndrome 
or previous drug-induced QTc prolongation of at least Grade 3 (QTc >500ms). 
7. 
Abnormal left ventricular ejection fraction on echocardiography or MUGA (less than 
the lower limit of normal for a patient of that age at the treating institution or <45%, 
whichever is lower). 
8. 
Current treatment with any agent known to cause Torsade de Points which cannot be 
discontinued at least five half-lifes or two weeks prior to the first dose of study 
treatment. 
9. 
Screening 12-lead ECG with a measurable QTc interval according to Fridericia’s 
correction >450 ms. 
10. 
Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of study treatment. 
11. 
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from AEs due to a previously administered agent. Note: Subjects with ≤ 
Grade 2 alopecia are an exception to this criterion and may qualify for the study. 
12. 
Received an anti-cancer monoclonal antibody (mAb) within 4 weeks prior to the first 
dose of study treatment or who has not recovered (i.e. ≤Grade 1 or baseline) from 
AEs due to agents administered more than 4 weeks earlier. 
13. 
Major surgery within 28 days prior to start of study treatment and failure to have 
recovered adequately from the toxicity and/or complications from the intervention 
prior to the first dose of study treatment. Note: Major surgery does not include 
procedures for insertion of venous catheters or biopsies. 
14. 
Received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including G-CSF, GM-CSF or 
recombinant erythropoetin) within 4 weeks prior to the first dose of study treatment. 
Note: Patients receiving stable dose of growth factors with a hemoglobin value that 
meets Inclusion Criterion 10b may be included. 
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15. 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of 
study treatment.  
16. 
Active autoimmune disease that has required systemic treatment in past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment. 
17. 
Known history of human immunodeficiency virus (HIV 1/2 antibodies). 
18. 
Has known active infection with Hepatitis B (e.g., HBsAg reactive) or Hepatitis C 
(e.g., HCV RNA [qualitative] is detected). Note: i) Patients with a history of 
hepatitis B infection are eligible provided they are hepatitis B surface antigen 
negative ii) Patients with a history of hepatitis C infection are eligible provided they 
have no evidence of hepatitis C RNA using a qPCR at least 6 months after 
completing treatment for hepatitis C infection. 
19. 
Has received a live-virus vaccination within 30 days of planned treatment start. Note: 
Seasonal flu vaccines that do not contain live virus are permitted. 
20. 
Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis 
21. 
Has a history of interstitial lung disease. 
22. 
Inability to swallow or tolerate oral medication. 
23. 
Existing gastrointestinal disease affecting drug absorption such as celiac disease or 
Crohn’s disease, or previous bowel resection which is considered to be clinically 
significant or could interfere with absorption. 
24. 
Known lactose intolerance. 
25. 
Requires vitamin K antagonists. Note: Patients receiving low doses prescribed to 
maintain the patency of venous access devices may be included. Note: Factor Xa 
antagonists are permitted. 
26. 
Treatment with any of the following: histamine receptor 2 inhibitors, proton pump 
inhibitors or antacids within 7 days of start of study treatment. 
27. 
Treatment with any medication which is predominantly metabolized by CYP3A4 and 
has a narrow therapeutic index. 
28. 
Known severe (≥Grade 3) hypersensitivity to BGB324, pembrolizumab, and/or any 
of their excipients. 
29. 
Has an active infection requiring systemic therapy (apart from cutaneous infections). 
30. 
Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that, in the opinion of the Investigator, might confound the results of the 
trial, interfere with the patient’s participation and compliance in the trial, or means it 
is not in the best interests of the patient to participate. 
31. 
Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting from Screening through to 120 days after the 
last dose of study treatment. 
32. 
Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
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3.3 
Patient Withdrawal of Consent and Discontinuation of Treatment 
Patients may withdraw their consent to further treatment on study or withdraw their consent to 
any further participation in any further assessments at any time without stating a reason and 
without prejudice to further treatment. 
Patients who have withdrawn their consent to receive further treatment, but not 
withdrawn their consent to further participation in the study, are expected to continue in 
follow-up to enable assessment of the duration of their response and other endpoints until 
confirmed progression and then survival status. 
Patients who discontinue BGB324 treatment (for reasons other than disease progression) may be 
able to continue with (monotherapy) pembrolizumab until 106 weeks (that is, 35 completed 
cycles of pembrolizumab, equivalent to 24 calendar months). 
Patients who discontinue pembrolizumab (for reasons other than disease progression) may be 
able to continue with BGB324 for up to 106 weeks (equivalent of 24 calendar months). 
A Post Treatment Visit should be performed 30 +/-3 days after the last dose of study treatment 
(BGB324 and/or pembrolizumab), to enable follow up safety assessments and further tumor 
assessment where required. 
The Investigator may discontinue study treatment at any time. Example reasons for discontinuing 
study treatment are: 
• 
Patient withdrawal of consent to further treatment and/or further participation in the 
study. 
• 
Disease progression (note that treatment can continue if progression is suspected in 
the absence of clinical deterioration – progression is to be confirmed no less than 4 
weeks after the initial observation). 
• 
The patient experiences a toxicity, considered related to BGB324, including those 
necessitating a BGB324 dose delay of >14 days (Section 6.6), and where the re-
introduction of BGB324 (including a dose reduction of BGB324), is not considered 
suitable.  
• 
The patient experiences a toxicity, considered to be related to treatment with 
pembrolizumab which necessitates pembrolizumab treatment withdrawal (Section 
6.6.3). 
• 
Other toxicities or events, unrelated to BGB324 or pembrolizumab, that would, in the 
Investigator’s opinion, prevent the patient from continuing on study treatment(s).  
• 
Treatment non-compliance. (All documentation concerning the patient must be as 
complete as possible. Withdrawals due to non-attendance of study visits must be 
followed-up by the Investigator to obtain the reason for where possible. For further 
information on treatment non-compliance, please see also Section 3.5). 
• 
Pregnancy. 
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A patient is defined as ‘lost to follow-up’ only if every effort has been made to contact the 
patient and determine the patient’s willingness to continue with all or some of the study 
assessments (irrespective of whether the patient is still receiving study treatment). 
Patients who are unwilling to continue to receive further treatment are expected to 
continue in follow-up to enable assessment of the duration of their response and other 
endpoints until confirmed progression and then survival status. 
The Sponsor reserves the right to request the withdrawal of study treatment from a patient due to 
protocol violation or other significant reason. 
3.4 
Permitted Cessation of Pembrolizumab Treatment on Study 
Note that Investigators may wish to stop pembrolizumab treatment per local treatment practice 
for patients who have attained a confirmed complete response (CR) that have been treated for at 
least 24 weeks with pembrolizumab and had at least 2 treatments with pembrolizumab beyond 
the date when the initial CR was declared. Patients will remain on study and continue to receive 
BGB324 treatment and continue disease assessments. 
Once pembrolizumab treatment has been stopped for this reason, it cannot be restarted on study. 
3.5 
Definition of Evaluable Patient, Acceptable Treatment Compliance and Replacement 
of Patients 
Patients will be replaced if they are considered to be non-evaluable. An evaluable patient is one 
that has received at least one combination dose and has measureable disease according to the 
Investigator site assessment. 
Patients who have failed screening (usually because they have failed one or more of the inclusion 
or exclusion criteria) will not receive study treatments and are considered not to be evaluable. 
Treatment non-compliance for this study will be defined as follows: 
• 
For BGB324: missing more than 7 doses in any 21-day period (other than a dose 
delay for toxicity management (see Section 6.6.1 and Section 6.6.2) or an 
interruption for corticosteroid administration (Section 6.8)).  
• 
For pembrolizumab: Dosing interruptions are permitted in the case of medical / 
surgical events or logistical reasons not related to study therapy (for example, 
elective surgery, unrelated medical events, patient vacation etc). Patients should be 
placed back on study therapy within 3 weeks of the scheduled interruption. The 
reason for the interruption should be documented in the patient’s study notes. 
3.6 
Procedures for Patient Cessation of Study Treatment 
When a patient stops or discontinues one or both of their study treatments, the reason for 
cessation will be recorded in the patient file and the Case Report Form (CRF). Patients must 
complete a post treatment visit, and continue with their scans and assessments of disease (if the 
patient has not already progressed) and/or survival status. 
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3.7 
Study or Site Termination 
If the Sponsor or their representatives, Investigator, or Competent Authority officials discover 
conditions during the study that indicate that the study or site involvement should be terminated, 
this action may be taken after appropriate consultation with the Sponsor and the Investigator. 
Conditions that may warrant termination of the study or involvement of a study site include, but 
are not limited to: 
• 
The discovery of an unexpected, serious, or unacceptable risk to patients enrolled in 
the study. 
• 
The decision on the part of the Sponsor to suspend or discontinue testing, evaluation, 
or development of the study drug. 
• 
Failure of the Investigator(s) to comply with pertinent clinical trial regulations. 
• 
Submission of knowingly false information from the research facility to the Sponsor, 
study monitor, or Competent Authority. 
• 
Insufficient adherence to protocol requirements. 
Study termination and follow-up will be performed in accordance with applicable local 
regulations. 
 
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4 
STUDY DESIGN 
This is an open-label, multi-center, single arm, phase II study to assess the anti-tumor activity 
and safety of BGB324 in combination with pembrolizumab in patients with previously treated 
locally advanced and unresectable disease or metastatic TNBC or TN-IBC. 
The study will utilize a 2-stage, single arm, extension of Simon’s 2-stage design1 with one 
interim and a final analysis. The interim analysis will be conducted when 28 patients are 
evaluable for ORR. If 5 or fewer responses are observed in up to 28 patients, the trial will be 
terminated in favor of the null for futility. If 11 or more responses are observed, then the trial 
will be stopped in favor of the alternative for demonstration of activity. Where 6 to 10 patients 
have an observed response at the interim analysis, up to a further 28 patients may be evaluated, 
for a total of 56 patients (see Section 8.1), taking the overall risk: benefit of the combination into 
consideration. 
BGB324 will be administered orally once daily. On the first 3 days of administration, the 
BGB324 dose will be a ‘loading’ dose of 400 mg on Days 1, 2 and 3. From Day 4 onwards, 
patients will receive a daily dose of 200 mg. A fixed dose of 200 mg pembrolizumab will be 
given by intravenous (i.v.) infusion over 30 minutes every 3 weeks in all patients. The 3-weekly 
pembrolizumab dosing schedule will be used to define 3-week treatment cycles throughout the 
treatment period of the study. 
The BGB324 and pembrolizumab dose levels selected for this study are summarized in Table 10. 
Table 10: BGB324 and pembrolizumab dosing 
 
BGB324: 
Loading Dose:  
Days 1, 2 & 3 
Daily Dose:  
Day 4 onwards 
Frequency 
Route of 
administration 
Dose level 
400 mg 
200 mg 
Daily 
Oral 
Dose level -1 
200 mg 
100 mg 
Daily 
Oral 
Pembrolizumab 
Dose 
Regimen 
Frequency 
Route of 
administration 
200 mg 
Day 1 of each cycle 
Every 3 weeks 
i.v. 
Dosing of both drugs will commence on Day 1. On days when both BGB324 and 
pembrolizumab are given, pembrolizumab will be given first and patients will be observed for 1 
hour for infusion and other AEs. BGB324 may then be administered. 
4.1 
Safety Run-In 
Pembrolizumab has not previously been combined with BGB324 in patients (in any indication) 
and therefore, a safety run-in will include a total of 12 patients. The internal DRC will conduct a 
review of the safety data from the first 6 patients who have had the potential to be followed for at 
least 6 weeks (min 2 cycles), and then again after a further 6 patients (12 patients in total) have 
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had the potential to be followed for at least 6 weeks. At each of these safety reviews, the DRC 
will consider the rate of BGB324 dose reductions and the rate of permanent discontinuation from 
BGB324 and pembrolizumab. 
The DRC will consider whether to recommend a lower dose of BGB324 (dose level -1) for new 
patients. Dose level -1 is defined as 200 mg BGB324 on Days 1, 2 and 3, followed by 100 mg 
from day 4 onwards. 
For the safety run-in reviews, each patient will have had the potential to receive (as a minimum): 
• 2 cycles of pembrolizumab; 
• BGB324 at 400 mg for 3 days, followed by 200 mg daily for ~ 6 weeks. 
The DRC, consisting of Principal Investigators, the Sponsors’ (BerGenBio and Merck) Medical 
Monitors, and invited experts as required, will review all patient safety data, including SAEs, 
AEs, laboratory and ECG results, dosing information, including dose reductions and permanent 
discontinuations. 
Where there is a suggestion of an immune response leading to a false categorization of disease 
progression, results from later tumor imaging time points may be used for the objective response 
assessment following the 2-stage single arm design. The Sponsor may request ad-hoc DRC 
meetings at any time during the study to assess interim safety data and review the need for dose 
modifications. For more details on the dose modification rules for BGB324 and pembrolizumab, 
please refer to Section 6.6. 
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Figure 5: Flow Chart 
 
4.2 
Duration of Treatment 
BGB324 and pembrolizumab will be given until disease progression (in the absence of clinical 
deterioration, treatment can continue and disease progression should be confirmed after 4 weeks) 
or until an unacceptable toxicity has occurred which necessitates treatment withdrawal (Section 
6.6), or until 106 weeks (35 cycles), equivalent to 24 calendar months. Patients participating in 
clinical trials with pembrolizumab receive treatment for a maximum duration of 2 years (35 
cycles of therapy). This is consistent across the whole pembrolizumab development program. 
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Responses to pembrolizumab are expected to be durable, and the duration of response after 
stopping pembrolizumab continues to be evaluated and monitored across the pembrolizumab 
program. 
Patients who discontinue BGB324 treatment (for reasons other than disease progression) may be 
able to continue with (monotherapy) pembrolizumab until 106 weeks (that is, 35 completed 
cycles of pembrolizumab, equivalent to 24 calendar months). 
Patients who discontinue pembrolizumab (for reasons other than disease progression) may be 
able to continue with BGB324 for up to 106 weeks (equivalent of 24 calendar months). 
Otherwise, in the absence of progression, toxicity, or other reason for stopping treatment, 
pembrolizumab in combination with BGB324 will be given until the end of cycle 35 (this cycle 
ends at approximately week 106, 24 months). 
 
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5 
STUDY SCHEDULE 
The study consists of a Screening period, Treatment period, Post Treatment Visit and Follow-up 
period. Patients will attend the clinic for Screening period assessments up to 28 days before 
receiving the first dose of study treatment. The Post Treatment Visit will occur 30 days after the 
patient has discontinued both study treatments. All patients will continue in follow-up visits and 
continue to have their disease assessed and scanned (unless progression of disease has already 
been confirmed) and for survival status. 
The study schedule will continue in keeping with the Study Assessment calendar. Patients will 
be required to visit the study sites for each study visit (which includes each pembrolizumab 
dose). From Cycle 2 onwards, a tolerance window of +/- 3 days is permitted. Pembrolizumab 
that cannot be given within these tolerance windows will be treated as a missed dose, although it 
is acceptable to have a pembrolizumab dose interruption for up to 3 weeks (for reasons other 
than toxicity). See Section 6.6.3 for full details on pembrolizumab dose interruptions, including 
the duration of interruption for toxicity. 
It is important that the calendar schedule for tumor assessment relative to Cycle 1, Day 1 is 
maintained (subject to permitted tolerance windows). If treatment administration is misaligned 
with weeks (e.g. because of treatment delay), the tumor assessment schedule should be 
maintained by week number (Table 3, Table 4 and Table 5). The schedule of disease 
assessment is every 12 weeks once a patient has stopped one or both or completed their 
(combination) treatment in the absence of progression. 
Assessments requiring specific timing relative to the BGB324 or pembrolizumab dose are 
described in the footnotes to Schedule of Study Assessment Table 4 and Table 5. 
5.1 
Schedule of Study Assessments 
This section provides a list of study assessments described by visit. All procedures and 
assessments should be conducted pre-dose unless otherwise specified. A summary of this 
information is also provided in the Schedule of Study Assessment Table 4 and Table 5 and the 
associated footnotes. Additional assessments may be conducted as clinically indicated. 
5.1.1 Schedule of Study Assessment – Year 1 and Year 2 
Screening (up to 28 days prior to Day 1) 
∼ 
Demographics – gender, ethnicity, race, age (birth month and year) 
∼ 
Medical history 
∼ 
Inclusion/exclusion checks 
∼ 
Pregnancy or FSH and oestradiol levels (as appropriate) 
∼ 
ECOG PS 
∼ 
Vital signs 
∼ 
Physical examination 
∼ 
Clinical chemistry 
∼ 
Hematology 
∼ 
Coagulation 
∼ 
Urinalysis 
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∼ 
Thyroid function tests 
∼ 
Echocardiogram (or MUGA) 
∼ 
ECG (triplicate tests) 
∼ 
Tumor imaging 
∼ 
Disease Assessment 
∼ 
Tumor biopsy (fresh tissue mandatory; archival optional) 
∼ 
Biomarkers 
∼ 
Concomitant medication 
 
Cycle 1, Day 1 (21 day cycle) 
∼ 
Vital signs 
∼ 
Physical examination 
∼ 
Clinical chemistry 
∼ 
Hematology 
∼ 
Coagulation 
∼ 
Urinalysis 
∼ 
ECG (triplicate tests; pre-dose and at 6 hours post dose) 
∼ 
Biomarkers (if not collected at Screening) 
∼ 
Pembrolizumab 200 mg fixed dose - infusion 
∼ 
BGB324 oral dosing 400 mg  
∼ 
PK sampling - BGB324 pre-dose, 2, 4, 6 and 8 hours post dose 
∼ 
PK sampling for storage - pembrolizumab (pre-dose) 
∼ 
Adverse events 
∼ 
Concomitant medication 
 
Cycle 1, Day 2 
∼ Vital signs 
∼ Physical examination 
∼ Clinical chemistry 
∼ Hematology 
∼ ECG (triplicate test; pre-dose) 
∼ BGB324 oral dosing 400 mg 
∼ PK sampling - BGB324 (pre-dose) 
∼ PK sampling for storage - pembrolizumab (pre-dose) 
∼ Adverse events 
∼ Concomitant medication 
 
Cycle 1, Day 3 
∼ 
Vital signs 
∼ 
Physical examination 
∼ 
Clinical chemistry 
∼ 
Hematology 
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∼ 
ECG (triplicate test pre-dose) 
∼ 
BGB324 oral dosing 400 mg 
∼ 
PK sampling - BGB324 pre-dose, 2, 4, 6, 8 hours post dose. 
∼ 
PK sampling for storage – pembrolizumab (pre-dose) 
∼ 
Adverse events 
∼ 
Concomitant medication 
 
Cycle 1, Day 4 
∼ 
Vital signs 
∼ 
Physical examination 
∼ 
Clinical chemistry 
∼ 
Hematology 
∼ 
ECG (triplicate test; pre-dose) 
∼ 
Biomarkers  
∼ 
BGB324 oral dosing 200 mg (consecutive daily dosing 21 day cycle) 
∼ 
PK sampling - BGB324 (pre-dose) 
∼ 
PK sampling for storage – pembrolizumab (pre-dose) 
∼ 
Adverse events 
∼ 
Concomitant medication 
 
Cycle 1, Day 8 
∼ 
Vital signs 
∼ 
Physical examination 
∼ 
Clinical chemistry 
∼ 
Hematology 
 
∼ 
Coagulation 
∼ 
Urinalysis 
∼ 
ECG (triplicate test; pre-dose) 
∼ 
Biomarkers  
∼ 
BGB324 oral dosing 200 mg (consecutive daily dosing 21 day cycle) 
∼ 
PK sampling - BGB324 (pre dose) 
∼ 
PK sampling for storage (pre-dose) - pembrolizumab 
∼ 
Adverse events 
∼ 
Concomitant medication 
 
Cycle 1, Day 15 
∼ 
Vital signs 
∼ 
Physical examination 
∼ 
Clinical chemistry 
 
∼ 
Hematology 
 
∼ 
Coagulation 
∼ 
Urinalysis 
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∼ 
ECG (triplicate test; pre-dose) 
∼ 
BGB324 oral dosing 200 mg (consecutive daily dosing 21 day cycle) 
∼ 
PK sampling BGB324 (pre-dose) 
∼ 
PK sampling for storage (pre-dose) - pembrolizumab 
∼ 
Adverse events 
∼ 
Concomitant medication 
 
 
Cycle 2-35 (every 3 weeks), Day 1 
∼ 
ECOG PS 
∼ 
Vital signs 
∼ 
Physical examination 
∼ 
Clinical chemistry 
∼ 
Hematology 
∼ 
Coagulation 
∼ 
Urinalysis (performed on Cycle 2 Day 1 only) 
∼ 
Pregnancy test (if applicable) 
∼ 
Thyroid function tests (performed at Cycles 3, 5, 7, 9, 11, 13, 15, 17 only in Year 1 and 
then Cycles 19, 21, 23, 25, 27, 29, 31, 33, 35 in Year 2) 
∼ 
Echocardiogram (or MUGA) (performed at Cycles 9 and 17 in Year 1 and then Cycles 25 
and 33 in Year 2) 
∼ 
ECG (triplicate test; pre-dose) 
∼ 
Tumor imaging (performed at Cycles 4, 7, 10, 13, 16, 20, 24, 28, 32 or Weeks 10, 19, 28, 
37, 46, 58, 70, 82, 94, 106, and then every 12 weeks until progression) 
∼ 
Disease assessment (performed at Cycles 4, 7, 10, 13, 16, 20, 24, 28, 32 or Weeks 10, 19, 
28, 37, 46, 58, 70, 82, 94, 106, and then every 12 weeks until progression)  
∼ 
Tumor biopsy (up to 2 optional post treatment biopsies) 
∼ 
Biomarkers (performed only at Cycles 2-9) 
∼ 
Pembrolizumab 200 mg fixed dose (infusion) 
∼ 
BGB324 dosing 200 mg (daily oral dosing 21 day cycle) 
∼ 
PK sampling BGB324 (pre-dose Cycles 2 and 3 only) 
∼ 
PK sampling - pembrolizumab (pre-dose Cycles 2 and 3 only) 
∼ 
Adverse events 
∼ 
Concomitant medication 
 
Post Treatment Visit (only after both treatments are discontinued in either Year 1 or Year 2) 
+30 days from last dose of study treatment(s) 
∼ 
ECOG PS 
∼ 
Vital signs 
∼ 
Physical examination 
∼ 
Clinical chemistry 
∼ 
Hematology 
∼ 
Coagulation 
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∼ 
Urinalysis 
∼ 
Thyroid function tests 
∼ 
ECG (triplicate test) 
∼ 
Adverse events 
∼ 
Concomitant medication 
∼ 
Tumor imaging (where applicable – for example, to confirm progression) 
∼ 
Disease assessment (where applicable – for example, to confirm progression) 
∼ 
Tumor biopsy (optional) at progression 
 
Follow-Up (if the patient has had a Post Treatment visit in Year 1 or Year 2) - every 12 weeks 
∼ 
Concomitant medication (where applicable) 
∼ 
Tumor imaging (where applicable; every 12 weeks until disease progression) 
∼ 
Disease assessment (where applicable; every 12 weeks until disease progression) 
∼ 
Subsequent anti-cancer treatment 
∼ 
Adverse events (where applicable, see Section 7.4 and Section 7.5) 
∼ 
Survival status – this can be done by telephone. 
 
5.2 
Volume of Blood Sampling 
Total blood volumes required during study participation will be provided in Informed Consent 
form provided to each patient. The Laboratory Manual will also describe unit and total blood 
volumes and provide examples based on various durations on study. Efforts will be made to limit 
PK and PD blood-letting during the study where on-going data analysis during the study suggests 
redundancy in sampling. Any such reductions in requirements for PK and PD blood sampling 
will be described and maintained in the Laboratory Manual. 
5.3 
Description of Study Interventions and Assessments 
Details of the procedures to be followed for specified study assessments are provided. Additional 
assessments may be carried out as clinically indicated. 
5.3.1 Demography and medical history 
There will be a baseline assessment of demography (gender, race, ethnicity age (birth month and 
year) and medical history conducted at Screening to confirm eligibility and to record significant 
medical history and concurrent illnesses in the CRF. Concurrent illnesses recorded at Screening 
(excluding the primary disease under evaluation), that worsen in severity or frequency from the 
time of signing the consent form, but before treatment allocation need to be reported as an AE if 
the event causes the patient to be excluded from the trial or is a result of a protocol specific 
intervention (Section 7.1). 
5.3.2 Pregnancy, FSH and oestradiol test 
Female patients of reproductive potential will have a pregnancy test carried out at Screening. 
This test must be carried out within 3 days prior to first study drug administration. A urine test is 
acceptable; however, a positive or equivocal urine test must be confirmed by a blood test. 
Patients confirmed as pregnant will be excluded from participation in the clinical study. 
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Female patients of reproductive potential will continue to have a pregnancy test before each 
cycle of pembrolizumab, or monthly. 
Female patients who require documented confirmation of post-menopausal status will have their 
FSH and oestradiol levels assessed at Screening. Where post-menopausal status is not confirmed, 
patients will be required to undergo pregnancy testing per protocol to confirm suitability to 
proceed to dosing. 
5.3.3 ECOG performance score 
ECOG performance score (PS) will be assessed at the times given in Schedule of Study 
Assessment Table 4 and Table 5. Details of the ECOG PS categories are presented in Appendix 
A. Patients must be confirmed as ECOG PS 0 or 1 at Screening in order to be eligible for study 
participation. 
5.3.4 Vital signs 
Vital sign parameters will be taken at the times given in Schedule of Study Assessment Table 4 
and Table 5. The date and time of collection will be recorded in the source data and on the CRF. 
Vital sign parameters will consist of measurements of temperature, resting heart rate, seated 
blood pressure and respiratory rate. 
If any clinically significant findings are identified during the assessment of vital signs, the 
Investigator will record it as part of the medical history prior to start of dosing and as an AE post 
dose, where the finding represents a change from baseline. Findings identified prior to start of 
dosing must be checked against the study exclusion criteria (Section 3.2). 
5.3.5 Physical exam 
A physical examination, including measurement of weight, will be taken at the times given in 
Schedule of Study Assessment Table 4 and Table 5. The patient’s height will be measured at 
Screening. The patient’s weight will also be assessed at Screening and at the start of every cycle. 
Height and body weight will be obtained while the patient is wearing light clothing (without 
shoes). 
A full physical examination will include assessment of the following categories: head, eyes, ears, 
nose, throat, heart, lungs, abdomen, skin, musculoskeletal, extremities, neurological, lymph 
nodes, and ‘other’. After the Screening assessment, the physical examination may be reduced to 
a symptom-directed assessment. 
If any clinically significant findings are identified during the physical examination, the 
Investigator will record it as part of the medical history prior to start of dosing and as an AE post 
dose, where the finding represents a change from baseline. 
5.3.6 Clinical chemistry, hematology, coagulation and urinalysis 
Blood and urine samples for determination of clinical chemistry, hematology, coagulation and 
urinalysis parameters will be taken at the times given in Schedule of Study Assessment Table 4 
and Table 5 and prior to administration of study treatment. The date and time of collection will 
be recorded in the source data and on the CRF. 
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All testing will be performed at each site’s local laboratory. Coagulation parameters may be 
assessed from the hematology sample. 
Copies of laboratory accreditation certificates and reference ranges will be obtained from each 
study site prior to the analysis of their first patient sample. 
The laboratory variables to be measured are described in Appendix E. 
If any clinically significant findings are identified from the safety lab assessments, the 
Investigator will record it as part of the medical history prior to start of dosing and as an AE post 
dose, where the finding represents a change from baseline. Findings identified prior to start of 
dosing must be checked against the study inclusion and exclusion criteria (Section 3.1 and 
Section 3.2). 
5.3.7 Thyroid function test 
Blood samples for thyroid function testing will be taken at the times given in Schedule of Study 
Assessment Table 4 and Table 5. The date and time of collection will be recorded in the source 
data and on the CRF. 
The thyroid assessment panel should include: 
• 
Triiodothyronine (T3) or Free Triiodothyronine (FT3) 
• 
Free thyroxine (FT4) 
• 
Thyroid stimulating hormone (TSH) 
All testing will be performed at each site’s local laboratory. This assessment may be performed 
from the clinical chemistry sample (Section 5.3.6). Copies of laboratory accreditation certificates 
and reference ranges will be obtained from each study site prior to the analysis of their first 
patient sample. Laboratory variables to be measured are described in Appendix E. 
If any clinically significant findings are identified, the Investigator will record it as part of the 
medical history prior to start of dosing and as an AE post dose, where the finding represents a 
change from baseline. Findings identified prior to start of dosing must be checked against the 
study inclusion criteria (Sections 3.1). 
5.3.8 Echocardiography or MUGA 
An echocardiography or MUGA assessment will be performed at Screening, and after every 6 
months (every 8 cycles thereafter i.e. Cycle 9, Day 1, Cycle 17, Day 1, Cycle 25, Day 1, Cycle 
33 Day 1). 
Clinically significant findings identified prior to start of dosing must be checked against the 
study exclusion criteria (Section 3.2). 
Patients who discontinue BGB324, but continue with monotherapy pembrolizumab, will stop 
undergoing an echocardiogram or MUGA assessment. Their final echocardiogram / MUGA 
assessment will occur if their next scheduled assessment is within the next 6 weeks (of 
discontinuing BGB324). 
5.3.9 Electrocardiogram 
A resting 12-lead ECG will be performed at the times given Schedule of Study Assessment 
Table 4 and Table 5. Each assessment time point must be performed in triplicate. 
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All 12-lead ECGs should be recorded while the patient is in the supine position. ECGs will be 
recorded at 25 mm/sec. All efforts should be made to ensure that an identical ECG machine is 
used to collect traces for individual patients. The Investigator or designated physician will review 
the ECG results. 
If any clinically significant findings are observed on the ECG, the Investigator will record it as 
part of the medical history prior to the start of dosing, and as an AE post dose where the finding 
represents a change from baseline. Clinically significant findings identified prior to start of 
dosing must be checked against the study exclusion criteria (Section 3.2). Note that the average 
value of the three assessments performed at each time point should be applied, except at 
Screening, where both the Screening and pre-dose Cycle 1 Day 1 assessments should be 
combined. Patients may be excluded based on the initial triplicate assessment at Screening. 
Patients who discontinue BGB324, but continue with monotherapy pembrolizumab will stop 
undergoing an ECG. 
Patients who have a BGB324 interruption of 14 days for toxicity (see Table 12 and Table 13) 
will require an ECG twice weekly for the 2 weeks following recommencement of BGB324 daily 
dosing. This is to ensure cardiac safety monitoring whilst BGB324 returns to steady state. 
5.3.10 Tumor imaging 
Efficacy endpoints in this study, including ORR, DoR, PFS will all be based on tumor imaging 
evaluation by RECIST 1.12. 
RECIST assessments will be performed at the times given in Schedule of Study Assessment 
Table 4 and Table 5 using contrast-enhanced CT (preferred method) or MRI assessments of 
chest, abdomen, and pelvis. X-ray scans can be used where appropriate.  Bone scans and brain 
scans should be conducted in the 6 weeks prior to study entry. Subsequently, x-ray, bone scans 
and brain scans will be used as appropriate. Additional anatomy should be imaged based on signs 
and symptoms of individual patients at baseline and follow-up. 
Baseline assessments should be performed no more than 28 days before start of study treatment 
(6 weeks for brain and bone scans), and ideally should be performed as close as possible to the 
start of study treatment. The Screening imaging assessments must confirm the patient has 
measurable disease per RECIST 1.12 (see Section 3.1). 
For each patient, the same modality used at Screening must be used serially throughout the 
duration of study participation. All imaging procedures will be performed according to standard 
local imaging protocols to ensure consistency across study assessments. 
All radiological and non-radiological (e.g. MRI) scans will be reviewed by the local site 
investigator; and if possible, stored electronically (de-identified with the patient’s notes) at site. 
A maximum of 5 target lesions (TLs) must be selected at baseline. All target lesions are 
measurable. Target lesions should be selected on the basis of their size (longest diameter for non-
nodal lesions or short axis for nodal lesions), but in addition should be those that lend themselves 
to reproducible repeated measurements. All remaining lesions present at baseline are considered 
non-target, irrespective of whether they are measurable. 
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Disease assessments will be performed as per the schedule described in Table 3, Table 4 and 
Table 5 – that is, every 9 weeks ±7 days for the first 46 weeks relative to the date of first 
treatment administration and then every 12 weeks ±7 days thereafter until confirmed objective 
disease progression as defined by RECIST 1.12 (irrespective of a delay to treatment, or the 
reason for stopping treatment or subsequent therapy). 
Any other sites at which new disease is suspected should also be adequately imaged at a 
follow-up visit. 
If an unscheduled assessment is performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits. 
In addition to performing further scans where clinically indicated, scans also should be 
performed, as appropriate, to confirm response or disease progression. 
5.3.11 Disease assessment 
A disease assessment according to RECIST 1.12 will be performed and all measurements of 
existing target lesions and new or existing non target lesions will be recorded in the CRF 
whenever a tumor imaging assessment is made during the Treatment period, Post Treatment 
Visit or during Follow Up Visits. 
For more information on data evaluation by RECIST 1.12 for studies with checkpoint inhibitors, 
please refer to Section 8.5. 
5.3.12 Biomarkers 
Evaluation of biomarkers will be performed at the time points described in Schedule of Study 
Assessment Table 4 and Table 5. 
Blood samples will be collected at these time points to prepare PMBC and blood samples for 
assessment of Axl inhibition and other relevant markers including sAxl such as MAPK signaling 
pathway intermediates (ERK/pERK), pAxl expression and T-cell populations, Akt, pAkt, 
SLFN11, Bcl2, and Puma. 
Patients who discontinue BGB324, but continue with pembrolizumab monotherapy are not 
required to provide further blood samples for biomarker evaluation. 
Full details of the blood volumes required, plus requirements for sample collection, handling and 
shipment to the assigned central laboratory, will be described in Laboratory Manual for the 
study. 
5.3.13 Tumor Sample Requirements 
All patients are required to provide a fresh (newly acquired) tumor biopsy at Screening. Tumor 
specimens are to be submitted in sufficient quantity to allow for PD-L1 IHC and Axl IHC 
analysis (see the Pathology Manual). 
Samples with limited tumor content (<100 viable tumor cells), cytology, cell block, decalcified 
or formalin fixed but previously frozen, frozen sample, plastic embedded, bone, bone marrow, 
clot and fine needle aspirates are inadequate for defining tumor PD-L1 and Axl status. 
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Axl expression can only be obtained from a fresh (newly acquired) tumor tissue sample. PD-L1 
expression can be determined from either a fresh (newly acquired) or archival sample. In all 
cases, the tumor tissue must not have been previously irradiated. 
Different testing laboratories will be used for Axl kinase and PD-L1 expression. 
The fresh (newly acquired) tumor tissue sample will be either newly obtained core needle biopsy 
(minimum gauge 18) or newly obtained excisional biopsy. 
The following tumor tissue options are available (all options require fresh tumor tissue sample, 
however, if there’s insufficient fresh tumor tissue available, the 3rd option below allows the 
submission of archival tissue in addition to the fresh tissue sample): 
• Where only a core needle biopsy is used, a minimum of 4 core biopsy samples are 
required. These should be placed in formalin and processed into 2 single paraffin 
embedded (FFPE) blocks (2 cores in one block and 2 cores in the other block) within 24-
48 hours.  
• Alternatively, where only a newly obtained excisional biopsy sample is used, this biopsy 
should be processed into 2 paraffin embedded (FFPE) blocks within 24-48 hours. 
• Alternatively, 2 core needle (fresh tumor) biopsies or a single newly obtained excisional 
biopsy sample can be submitted (processed into one FFPE block), together with either an 
archival (FFPE) tumor tissue block or a minimum of 10 unstained slides each 5µm cut 
from the archival tumor sample block. The unstained slides must arrive at the testing 
laboratory within 14 days. In this option, an archival FFPE block is strongly preferred 
over unstained slides. 
Archival blocks must be clearly labelled as archival. 
Slides cut from an archival tissue block must be clearly marked as having come from an archival 
block. 
Finally, where patients also have (additional) archived biopsy material which is suitable for 
additional (such as exploratory) biomarker assessment a sample of this material (either as an 
archival FFPE block or slides cut (and paraffin dipped) from the archival block) can also be 
prepared for study biomarker assessment. The patient will be offered a separate optional patient 
consent to enable this ‘archival biomarker tumor sample’ to be submitted. 
Optional ‘on study’ tumor tissue (fresh tissue) biopsies can be conducted on up to 2 separate 
occasions on suitable lesions (for example, lesions that have progressed). Separate patient 
consent is required for these ‘on study’ biopsies. 
Full details of the requirements for both fresh and archival biopsy sample collection, handling 
and shipment to the assigned (central) laboratories, will be described in the Pathology and 
Laboratory Manuals for the study. 
5.3.14 Pharmacokinetics 
Blood samples will be collected for the evaluation of the levels of BGB324 and pembrolizumab 
in plasma at the time points described in Schedule of Study Assessment Table 4 and Table 5. 
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Nominal PK blood sampling times should be adhered to as closely as possible. It is essential that 
the actual time and date of collection of each blood sample be recorded in the patient’s records 
and in the CRF. 
Full details of sample collection and handling for these samples will be described in Laboratory 
Manual for the study. 
Full details of the blood volumes required, plus requirements for sample collection, handling and 
shipment to the assigned central laboratory, will be described in Laboratory Manual for the 
study. 
 
 
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6 
STUDY MEDICATION AND ADMINISTRATION 
Investigational Medicinal Product (IMP) will be provided by the Sponsor as summarized in 
Table 11 Both BGB324 and pembrolizumab will be labelled in compliance with GMP Annex 13 
requirements or other applicable local regulatory guidelines. 
Table 11: Product Descriptions 
Product Name & Potency 
Dosage Form 
BGB324 100 mg 
HPMC capsule 
MK-3475 10 mL, 100 mg/vial (Liquid) 
(4 mL fill volume, 25 mg/mL potency) 
Solution for Injection 
6.1 
Preparation and Dosing of Study Treatments 
Further details on preparation and administration of both BGB324 and pembrolizumab are 
provided in the Pharmacy Manuals. 
6.1.1 BGB324 
BGB324 is provided in bottles containing a specified number of capsules per bottle to dispense 
to the patients. Patients will be asked to take the specified number of capsules for their 
prescribed dose on an empty stomach at a regular time each day with water. On 
pembrolizumab dosing days, patients will be asked not to take their BGB324 dose before coming 
into the clinic. On these days, pembrolizumab will be administered first, and the patient observed 
for 1 hour after the end of infusion (for infusion and other AEs), prior to taking their BGB324 
dose (on an empty stomach and with water). Patients should not eat for at least one hour after 
taking BGB324. 
6.1.2 Pembrolizumab 
Pembrolizumab will be administered at a dose of 200 mg (two vials) given as a 30 minute i.v. 
infusion through an intravenous line containing a sterile, non-pyrogenic, low-protein-binding 
0.2-5 micron in-line or add-on filter. Dosing will be on Day 1 of each 3-week treatment cycle.  
Trial treatment of pembrolizumab may be administered up to 3 days before or after the scheduled 
Day 1 of each cycle due to administrative reasons.  
Sites should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window between -5 minutes 
and +10 minutes is permitted i.e. infusion time may be 30 minutes -5 min/+10 min. 
6.2 
Treatment Compliance 
The patient will be asked to bring all bottles, including the empty ones, with them to each study 
visit to check compliance and for the Drug Accountability to be completed in the eCRF.   
At each visit the Investigator or study staff will question the patient about the proper intake. 
Proper intake, missed doses or failures in compliance will be recorded in the patient’s file. The 
patient will be instructed as to the importance of taking their BGB324 in accordance with 
instructions. 
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6.3 
Storage of Study Treatments 
6.3.1 BGB324 
BGB324 will be shipped to the site and must be stored at the site in a secure location under 
controlled, ambient temperature conditions (<25 °C or <77 °F). Instructions for the storage of 
dispensed BGB324 at home will be provided to every patient enrolled in the clinical study. 
6.3.2 Pembrolizumab 
Pembrolizumab (in 10 mL glass vials) will be shipped to the site and must be stored as follows: 
• 
Cold storage (2 to 8 oC; 36 to 46 oF); 
• 
Protect from light (a maximum of 24 hours exposure to light is permitted); 
• 
Do not freeze; 
• 
Do not shake.  
6.4 
Drug Accountability 
The Investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations. 
The Investigator may assign some or all of the Investigator’s duties for drug accountability to an 
appropriate pharmacist. Roles and responsibilities of site staff will be recorded in the TMF. 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
the sponsor or designee, the amount dispensed to and returned by the patients and the amount 
remaining at the conclusion of the trial. For all trial sites, the local country sponsor personnel or 
designee will provide appropriate documentation that must be completed for drug accountability 
and return, or local discard and destruction, if appropriate. Where local discard and destruction is 
appropriate, the investigator is responsible for ensuring that a local discard/ destruction 
procedure is documented. 
Certificates of delivery and return must be signed by the responsible pharmacist, and copies 
retained in the Pharmacy File. 
The medication provided for this study is for use only as directed in the protocol. It is the 
Investigator and their institution’s responsibility to establish a system for handling study drug to 
ensure that: 
• 
deliveries of BGB324 and pembrolizumab are correctly received by a responsible 
person; 
• 
such deliveries are recorded; 
• 
study treatments are handled and stored safely and properly as stated on the label; 
• 
study drug is only dispensed to study patients in accordance with the protocol; and 
• 
any unused study drug is destroyed locally or returned for destruction in liaison with 
the study monitor. 
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6.5 
Method of Enrolling Patient to Study Treatment 
During Screening, patients will be allocated a unique patient number from the RAVE, once 
written informed consent has been obtained. Patients will continue to be identified by this 
number throughout the study. Once a Subject Number has been assigned, it cannot be used again. 
6.6 
Dose Modifications 
Note: Three toxicities have been identified as potentially overlapping with both BGB324 
and pembrolizumab – diarrhea, rash and renal toxicity. Please see Section 6.6.4 for the 
management of these toxicities. 
Other toxicities can be managed as described in Section 6.6.1, Section 6.6.2 and Section 6.6.3.  
6.6.1 BGB324 dose modification for toxicity 
If a patient experiences drug related toxicity that requires treatment with BGB324 to be 
interrupted, a delay of up to 14 days is permitted to allow for resolution of toxicity. In the 
absence of recovery, treatment with BGB324 should be discontinued. See Table 12. 
If treatment with BGB324 is interrupted, the relevant toxicity must have resolved to ≤Grade 1 or 
tolerable Grade 2 or baseline for treatment to recommence.  
Only one dose reduction from 200 mg to 100 mg daily dose is possible. 
Table 12: Dose Modification for BGB324-related Toxicity 
Grade (CTCAE) 
Recommended Dose Modification 
Grade 1 and Grade 2 (tolerable) 
Any occurrence 
Maintain dose of 200 mg if toxicity is tolerated by the patient 
Grade 2 (intolerable) 
1st or 2nd occurrence of same 
adverse event  
Interrupt treatment until toxicity returns to baseline, Grade 1 or tolerable 
Grade 2 
Resume dosing at 200 mg 
3rd occurrence of same adverse 
event  
Interrupt treatment until toxicity returns to baseline, Grade 1 or tolerable 
Grade 2 
Dose reduce to 100 mg 
4th occurrence of same adverse 
event  
Discontinue permanently 
Grade 3 
1st occurrence 
Interrupt treatment until toxicity returns to baseline, Grade 1 or tolerable 
Grade 2 
Dose reduce to 100 mg or 
Discontinue permanently if dose has already been reduced  
2nd occurrence of same adverse 
event at G3 
Discontinue permanently 
Grade 4  
1st occurrence 
Discontinue permanently 
Notes: 
• Treatment interruption for BGB324-related toxicity should be limited to 14 days  
• Dose reduction below 100 mg daily is not possible (a single capsule contains 100 mg BGB324) 
• Patients being considered for dose reduction or permanent discontinuation of BGB324, may be discussed with 
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Grade (CTCAE) 
Recommended Dose Modification 
the Medical Monitor 
• Patients require an ECG twice weekly for the first 2 weeks after recommencing BGB324 following an interruption 
(see Section 5.3.9) 
6.6.2 BGB324 dose modification for QTc 
Treatment with BGB324 produces QTc prolongation. In order to reduce the risk of QTc 
prolongation, all efforts should be made to maintain the patient’s serum potassium levels at 
>4 mmol/L during treatment with BGB324 and for 2 weeks following completion of therapy (at 
an unscheduled visit, if required). Serum calcium and magnesium should be measured and 
reasonable efforts made to maintain at normal levels throughout treatment. Patients with an 
average QTc of >480 ms should be closely monitored until the QTc falls below 480 ms; 
electrolytes should be measured and corrected as necessary.  
If a patient experiences QTc prolongation, BGB324 dosing should be reduced as outlined in 
Table 13. Treatment with BGB324 should be permanently discontinued in the presence of 
ventricular arrhythmia. 
Table 13: Dose modification of BGB324 for QTc Prolongation 
QTcF 
Recommended BGB324 Dose Modification 
Grade 1 (450-480 ms) 
Any occurrence 
No dose modification required 
Grade 2 (481-500 ms) - on two consecutive occasions per protocol assessments or investigator’s judgement   
1st occurrence 
  
Interrupt treatment with BGB324: 
i) if QTcF reduces to ≤Grade 1 by 14 days from initial recording, restart BGB324 at a 
reduced dose of 100mg or discontinue if no further dose reduction is possible. 
ii) if QTcF does not reduce to ≤Grade 1 by 14 days from initial recording, 
discontinue BGB324 permanently.  
≥2nd occurrence (following a 
previous dose reduction for 
QTcF) 
Discontinue BGB324 permanently. 
 
≥Grade 3 (>501 ms)  
1st occurrence 
Interrupt treatment with BGB324: 
- if QTcF reduces to ≤Grade 1 by 14 days from initial recording, restart BGB324 
at a reduced dose of 100mg or discontinue treatment if dose reduction is not 
possible 
- if QTcF does not reduce to ≤Grade 1, discontinue BGB324 permanently. 
2nd occurrence  
Discontinue BGB324 permanently 
Ventricular arrhythmia 
1st occurrence 
Discontinue BGB324 permanently 
Notes: 
• Serum calcium, magnesium and potassium should be measured regularly whilst receiving BGB324; all abnormal 
results should be corrected 
• The mean QTcF value from triplicate ECG readings should be used when considering dose modification 
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QTcF 
Recommended BGB324 Dose Modification 
• Treatment interruption for BGB324-related toxicity should be limited to 14 days 
• Dose reduction below 100 mg daily is not possible (a single capsule contains 100 mg BGB324) 
• Patients being considered for dose reduction or permanent discontinuation of BGB324 may be discussed with 
the Medical Monitor 
• Patients require an ECG twice weekly for the first 2 weeks after recommencing BGB324 following an interruption 
(see Section 5.3.9) 
 
6.6.3 Pembrolizumab dose modifications 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology. These AEs may occur shortly after the first dose or several 
months after the last dose of treatment. Pembrolizumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as per Table 14 below. See Section 6.11 for 
supportive 
care 
guidelines, 
including 
use 
of 
corticosteroids.
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Table 14: Dose modification guidelines for pembrolizumab drug-related adverse events 
Toxicity 
Hold 
Treatment For 
Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes mellitus 
(if new onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 
1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence 
of beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate 
premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 or 
Recurrent 2 
Permanently discontinue 
Permanently discontinue 
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Toxicity 
Hold 
Treatment For 
Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-Related 
Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for pneumonitis) drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate (e.g., from 100 mL/hr to 50 
mL/hr). Otherwise dosing will be held until symptoms resolve and the subject should be premedicated for the next scheduled dose; Refer to Section 6.12, 
Table 18 – Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
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Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Patients should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for interruption 
should be documented in the patient's study record. 
6.6.4 Dose modifications for BGB324 and pembrolizumab for overlapping toxicities 
Three toxicities are identified as potentially overlapping with both BGB324 and pembrolizumab: 
diarrhea, rash (including dermatitis, pruritus) and renal toxicity (renal failure, serum creatinine 
elevation, nephritis). 
See also, Supportive Care Guidelines for Pembrolizumab – Section 6.11. 
6.6.4.1 
Dose modifications for diarrhea 
Patients may continue with baseline anti-diarrheal medications throughout treatment with 
pembrolizumab. If a patient experiences an increase in diarrheal symptoms after starting 
BGB324 they may increase the dose of anti-diarrheal medication such as loperamide during the 
first week of treatment only. Starting treatment with loperamide is also acceptable during this 
period. Thereafter any increased diarrheal symptoms should be reported to the investigator 
immediately and further medication should not be given. See Table 15. 
Table 15: Pembrolizumab and BGB324 Dose Modification for Diarrhea 
Diarrhea with onset in the 2nd cycle 
or later cycle 
Pembrolizumab 
BGB324 
Grade 2-3 
Withhold for up to 12 weeks of last 
dose 
• If resolved to Grade 0 or 1, 
restart pembrolizumab 
• Permanently discontinue if not 
resolved to grade 0 or 1, or, 
there is an inability to reduce 
corticosteroid to ≤10 mg 
(prednisone or equivalent) per 
day 
Withhold for up to 14 days 
• If resolved to grade 0 or 1, 
restart BGB324 at 100 mg qd 
• Permanently discontinue if not 
resolved to grade 0 or 1 
Grade 4 
Permanently discontinue 
Permanently discontinue 
 
 
 
 
 
 
 
 
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6.6.4.2 
Dose modifications for rash (including dermatitis, pruritus) – Table 16 
Table 16: Pembrolizumab and BGB324 Dose Modification for Rash 
Rash – onset during any cycle 
Pembrolizumab 
BGB324 
Grade 2  
Pembrolizumab can continue as 
scheduled 
BGB324 can continue as scheduled 
Grade 3 or severe 
Withhold for up to 12 weeks of last 
dose 
• If resolved to grade 0 or 1, 
restart pembrolizumab 
• Permanently discontinue if not 
resolved to grade 0 or 1, or, 
there is an inability to reduce 
corticosteroid to ≤10 mg 
(prednisone or equivalent) per 
day 
Withhold for up to 14 days. 
• If resolved to grade 0, 1 or 
tolerable grade 2, restart at 100 
mg qd 
• Permanently discontinue if not 
resolved to grade 0, 1 or 
tolerable grade 2 
 
Grade 4 
Permanently discontinue 
Permanently discontinue 
6.6.4.3 
Dose modifications for renal toxicity (renal failure, serum creatinine elevation, 
nephritis) – Table 17 
Table 17: Pembrolizumab and BGB324 Dose Modification for Renal Toxicity 
Renal failure, serum creatinine 
elevation, nephritis  
– onset during any cycle 
Pembrolizumab 
BGB324 
Grade 2 
Withhold for up to 12 weeks of last 
dose 
• If resolved to grade 0 or 1, 
restart pembrolizumab 
• Permanently discontinue if not 
resolved to grade 0 or 1, or, 
there is an inability to reduce 
corticosteroid to ≤10 mg 
(prednisone or equivalent) per 
day 
Withhold for up to 14 days 
• If resolved to grade 0 or 1, 
restart at 100 mg qd 
• Permanently discontinue if not 
resolved to grade 0 or 1  
Grade 3 
Permanently discontinue 
Withhold for up to 14 days 
• 
If resolved to grade 0, 1 or 
tolerable grade 2, restart at 100 
mg qd 
• 
Permanently discontinue If not 
resolved to grade 0, 1 or 
tolerable grade 2 
Grade 4 
Permanently discontinue 
Permanently discontinue 
6.7 
Blinding and Procedures for Un-Blinding the Study 
This is an open-label study, and there are no blinding/un-blinding procedures. 
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6.8 
Permitted and Restricted Concomitant Medications 
In general, medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial. Treatment with antacids, proton pump inhibitors and histamine 
receptor 2 inhibitors can be initiated as rescue therapy after patients have been receiving 
BGB324 for one week, provided they are taken in the evening. 
If there is a clinical indication for any medication or vaccination specifically prohibited during 
the trial, discontinuation from trial therapy or vaccination may be required. The investigator 
should discuss any questions regarding this with the Sponsor Clinical Director. The final 
decision on any supportive therapy or vaccination rests with the investigator and/or the patient's 
primary physician. However, the decision to continue the patient on trial therapy or vaccination 
schedule (see Section 6.10) requires the mutual agreement of the investigator, the Sponsor and 
the patient. 
Patients should not receive BGB324 during periods of systemic corticosteroid treatment. If a 
patient requires treatment with systemic corticosteroids, BGB324 should be interrupted 
immediately. Treatment with BGB324 may be restarted upon completion of systemic 
corticosteroid therapy. BGB324 may be continued at the appropriate dosage during periods of 
topical and inhaled corticosteroid therapy. 
Hormonal contraception for female breast cancer patients is contraindicated. 
 
6.9 
Acceptable Concomitant Medications 
All treatments that the Investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the CRF including all prescription, 
over-the-counter, herbal supplements, and i.v. medications and fluids. If changes occur during 
the trial period, documentation of drug dosage, frequency, route, and date may also be included 
on the CRF. 
All concomitant medications received within 30 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
Events of Clinical Interest (ECIs) as defined in Section 7.4.3.2. 
6.10 Prohibited Concomitant Medications Whilst Receiving Pembrolizumab 
Patients are prohibited from receiving the following therapies during the Screening and 
Treatment period (including retreatment for post-complete response relapse) of this trial: 
• 
Antineoplastic systemic chemotherapy or biological therapy  
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than BGB324 and pembrolizumab 
• 
Radiation therapy  
o Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on an exceptional case by case basis after consultation with Sponsor. 
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The patient must have clear measurable disease outside the radiated field. 
Administration of palliative radiation therapy will be considered clinical 
progression for the purposes of determining PFS. Note: Treatment with 
pembrolizumab and BGB324 must have been discontinued at least one week prior 
to radiotherapy and should not be restarted within one week of completing 
radiotherapy.  
• 
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed. However, intranasal influenza vaccines (e.g. Flu - 
Mist®) are live attenuated vaccines, and are not allowed. 
• 
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. If a patient requires 
physiologic doses of corticosteroids, they must discontinue their BGB324. 
o Note: Inhaled steroids are allowed for management of asthma. 
Patients who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the trial. Patients may receive other 
medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications that are prohibited in this trial. 
There are no prohibited therapies during the Follow Up period once the patient has discontinued 
both treatments. 
6.11 Supportive Care Guidelines for Pembrolizumab 
Patients should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined below. Where appropriate, these guidelines include the use of 
oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory agents 
if symptoms do not improve with administration of corticosteroids. Patients receiving oral or 
intravenous corticosteroids must interrupt treatment with BGB324 throughout the duration of 
therapy. 
Note that several courses of steroid tapering may be necessary as symptoms may worsen when 
the steroid dose is decreased. For each disorder, attempts should be made to rule out other causes 
such as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the investigator 
determines the events to be related to pembrolizumab. 
Note: If after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 6.6 for dose 
modification. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event. 
• 
Pneumonitis:  
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o 
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o 
For Grade 3-4 events, immediately treat with i.v. steroids. Administer 
additional anti-inflammatory measures, as needed. 
o 
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
• 
Diarrhea/Colitis:  
Patients should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).  
o 
All patients who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via i.v. infusion. For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o 
For Grade 2 diarrhea/colitis administer oral corticosteroids.  
o 
For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids.  
o 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
o 
For T1DM or Grade 3-4 hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  
 
Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
• 
Hypophysitis: 
o 
For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o 
For Grade 3-4 events, treat with an initial dose of i.v. corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
• 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
o 
Grade 2 hyperthyroidism events and Grade 2-4 hypothyroidism: 
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 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o 
Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of i.v. corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
 
• 
Hepatic: 
o 
For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 
Treat with IV or oral corticosteroids 
o 
For Grade 3-4 events, treat with i.v. corticosteroids for 24 to 48 hours.  
o 
When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
• 
Renal Failure or Nephritis: 
o 
For Grade 2 events, treat with corticosteroids. 
o 
For Grade 3-4 events, treat with systemic corticosteroids. 
o 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
 
6.12 Infusion Guidelines for Pembrolizumab 
Signs and symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion.  
Table 18 shows treatment guidelines for patients who experience an infusion reaction associated 
with administration of pembrolizumab (MK-3475). 
Table 18: Management of pembrolizumab-associated infusion-related reactions 
NCI CTCAE Grade 
Treatment 
Premedication  
at subsequent dosing 
Grade 1: Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as 
medically indicated until the patient 
is deemed medically stable in the 
opinion of the Investigator. 
None 
Grade 2: Requires infusion 
interruption but responds promptly 
to symptomatic treatment (e.g., 
antihistamines, NSAIDS, narcotics, IV 
fluids); prophylactic medications 
Stop Infusion and monitor 
symptoms. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
Patient may be pre-medicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
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NCI CTCAE Grade 
Treatment 
Premedication  
at subsequent dosing 
indicated for <=24 hrs 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the patient 
is deemed medically stable in the 
opinion of the Investigator. 
If symptoms resolve within one hour 
of stopping drug infusion, the 
infusion may be restarted at 50% of 
the original infusion rate (e.g., from 
100 mL/hr to 50 mL/hr). Otherwise 
dosing will be held until symptoms 
resolve and the patient should be 
pre-medicated for the next 
scheduled dose. 
 
Patients who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grade 3: Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
 
Grade 4: Life-threatening; pressor or 
ventilatory support indicated 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
• 
IV fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Pressors 
• 
Corticosteroids 
• 
Epinephrine 
Increase monitoring of vital signs as 
medically indicated until the patient 
is deemed medically stable in the 
opinion of the Investigator. 
Hospitalization may be indicated. 
Patient is permanently discontinued 
from further trial treatment 
administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
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6.13 Diet, Activity and Other Considerations 
6.13.1 Diet 
Patients should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
6.14 Contraception 
Pembrolizumab and BGB324 may have adverse effects on a fetus in utero. Furthermore, it is not 
known if pembrolizumab has transient AEs on the composition of sperm. 
For this trial, male patients will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition). 
Female patients will be considered of non-reproductive potential if they are either:  
• 
postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age a high FSH level in the postmenopausal 
range may be used to confirm a post-menopausal state in women not using hormonal 
contraception or hormonal replacement therapy. In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.);  
OR  
• 
have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
• 
has a congenital or acquired condition that prevents childbearing. 
Female and male patients of reproductive potential must agree use highly effective methods of 
contraception while receiving study drug and for 120 days after the last dose of study drug by 
complying with one of the following highly effective methods‡: 
• 
intrauterine device (IUD); 
• 
intrauterine hormone-releasing system (IUS); 
• 
bilateral tubal occlusion; 
• 
vasectomized partner; 
• 
practice abstinence from heterosexual activity† 
 
Note: hormonal contraceptives are normally contraindicated in female patients with breast 
cancer.  
 
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if 
it is consistently employed as the patient’s preferred and usual lifestyle and if considered 
acceptable by local regulatory agencies and Institutional Review Board (IRB)/Institutional Ethics 
Committee (IECs). Periodic abstinence e.g. calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc. and withdrawal are not acceptable methods of contraception. 
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‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does 
not qualify as an acceptable method of contraception for patients participating at sites in this 
country/region. 
Patients should be informed that taking the study medication may involve unknown risks to the 
foetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the 
study, patients of childbearing potential must adhere to the contraception requirement (described 
above) from the day of study medication initiation (or 14 days prior to the initiation of study 
medication for oral contraception) throughout the study period up to 120 days after the last dose 
of trial therapy. If there is any question that a patient of childbearing potential will not reliably 
comply with the requirements for contraception, that patient should not be entered into the study. 
6.14.1 Use in pregnancy 
If a patient inadvertently becomes pregnant while on treatment with study medication, the patient 
will immediately be removed from the study. The site will contact the patient at least monthly 
and document the patient’s status until the pregnancy has been completed or terminated. The 
outcome of the pregnancy will be reported to the Sponsor without delay and within 24 hours if 
the outcome is a serious adverse experience e.g. death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn. The study Investigator will 
make every effort to obtain permission to follow the outcome of the pregnancy and report the 
condition of the fetus or newborn to the Sponsor. 
6.14.2 Use in nursing women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
patients who are breast-feeding are not eligible for enrolment. 
 
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7 
ADVERSE EVENTS AND REPORTING REQUIREMENT 
7.1 
Assessment of Safety 
Progression of the cancer under study is not considered an AE unless it is considered to be drug-
related by the investigator. 
All AEs that occur after the consent form is signed but before treatment allocation must be 
reported by the investigator if they cause the patient to be excluded from the trial, or are the 
result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment allocation through 30 days following cessation of treatment, all 
AEs must be reported by the investigator. Such events will be recorded at each examination 
on the Adverse Event case report forms/worksheets. 
The reporting timeframe for AEs meeting any serious criteria is described in Section 7.4.3. The 
investigator will make every attempt to follow all patients with non-serious adverse events for 
outcome. From the time of treatment allocation through 90 days following cessation of 
treatment, all SAEs (including serious events of special interest) must be reported by the 
investigator. Where a patient has initiated a new cancer treatment, the time period is 30 days 
after cessation of treatment. See Section 7.4.3.1 and Section 7.4.3.2. 
The reporting timeframe for a new pregnancy is described in Section 7.5. 
7.2 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical study subject administered a 
pharmaceutical product and which does not necessarily have a causal relationship with the 
product. An AE can therefore be any unfavorable or unintended sign, symptom or disease 
temporally associated with the use of the IMP whether or not considered related to the IMP. This 
includes any occurrence that is new, an exacerbation of an existing disease (a worsening of the 
character, frequency or severity of a known condition) or abnormal results of diagnostic 
procedures, including clinically significant laboratory test abnormalities. 
Suggested criteria for the assessment of clinical significance for laboratory abnormalities are as 
follows. 
The laboratory abnormality: 
• 
is clearly consistent with the pattern of the patient’s underlying disease or disease 
progression; 
• 
is accompanied by clinical symptoms; 
• 
requires study drug dose modification or interruption or permanent discontinuation of 
study treatment; 
• 
requires more frequent follow-up assessments, further diagnostic investigation, etc.; 
• 
requires a change in concomitant medication, therapy, or treatment. 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g. 
alkaline phosphatase and bilirubin 5X ULN associated with cholecystitis), only the diagnosis 
(e.g. cholecystitis) needs to be recorded on the AE CRF. If the clinically significant laboratory 
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abnormality is not a sign of a disease or syndrome, the abnormality itself should be recorded as 
an AE or SAE on the CRF. If the laboratory abnormality can be characterized by a precise 
clinical term, the clinical term should be recorded as the AE or SAE. For example, an elevated 
serum potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.” Observations of the 
same clinically significant laboratory abnormality from visit to visit should not be repeatedly 
recorded as AEs or SAEs on the CRF, unless their severity, seriousness, or etiology changes. 
For all AEs, a diagnosis should be recorded on the CRF rather than individual signs and 
symptoms (e.g. record only liver failure or hepatitis rather than jaundice, asterixis, and elevated 
transaminases) wherever possible. However, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single syndrome at the time of reporting, each individual sign 
and/or symptom should be recorded as an AE or SAE on the CRF. If a diagnosis is subsequently 
established, the reported event term should be updated to reflect the medical diagnosis. 
Note that AEs occurring secondary to an initiating event that are separated in time or medically 
significant should be recorded as independent events on the CRF. For example, if a severe 
gastrointestinal hemorrhage leads to a renal failure, both events should be recorded separately on 
the CRF. 
A pre-existing medical condition which is present at the start of the study and described in the 
Medical History CRF, should only be recorded as an AE or SAE if the frequency, severity, or 
character of the condition worsens during the study. When recording such events on the AE 
CRF, it is important to convey the concept that the pre-existing condition has changed by 
including applicable descriptors (e.g. “more frequent headaches”). 
Surgical procedures or other therapeutic interventions themselves are not AEs, but the condition 
for which the surgery/intervention is required is an AE and should be documented accordingly. 
Planned surgical measures and the condition(s) leading to these measures are not AEs, if the 
condition(s) was (were) known before the period of observation and did not worsen during study. 
In the latter case, the condition should be reported as medical history. 
During clinical trials, AEs can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a patient. To prevent reporting bias, patients should 
not be questioned regarding the specific occurrence of one or more AEs. 
Symptoms and signs of exacerbation or worsening of the patient’s primary disease will not be 
captured as AEs. Progression of the disease under study (i.e. TNBC) will not be captured as an 
AE unless it is considered to be drug-related by the Investigator. 
7.3 
Importance of Adverse Event Reporting 
Timely and complete reporting of safety information assists BerGenBio in identifying any 
untoward medical occurrence, thereby allowing: 
• 
safety of study patients;  
• 
a greater understanding of the overall safety profile of the investigational drug;  
• 
recognition of dose-related investigational drug toxicity;  
• 
appropriate modification of study protocols;  
• 
improvements in study design or procedures; and  
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• 
adherence to worldwide regulatory requirements. 
7.4 
Evaluating Adverse Events 
Following the patient’s written consent to participate in the study, AEs occurring after consent, 
but before treatment, and during treatment and within 30 days after cessation of treatment are 
collected in accordance with Section 7.1, Section 7.4.3 and Section 7.5. 
All identified AEs must be accurately recorded and described on the appropriate AE page of the 
electronic Case Report Form (eCRF). If known, the diagnosis of the underlying illness or 
disorder should be recorded, rather than its individual symptoms. The following information 
should be captured for all AEs: date of onset and resolution, severity of the event (see definitions 
in Section 7.4.1), Investigator's opinion of the relationship to IMP (see definitions in Section 
7.4.2), and assessment whether the event was serious or non-serious (see definitions in Section 
7.4.3). In addition, treatment required for the AE, action taken with IMP, information regarding 
resolution/outcome. 
7.4.1 Assessment of severity 
All AEs (including SAEs) are to be accurately recorded on the AE page of the patient’s eCRF. 
Each event will be graded for severity using the classifications of National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. For events not 
addressed in the NCI CTCAE v4.03, classifications the following grading will apply: 
• 
Mild (Grade 1) - Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.  
• 
Moderate (Grade 2) - Moderate; minimal, local or non-invasive intervention 
indicated; limiting age-appropriate instrumental activity of daily living. 
• 
Severe (Grade 3) - Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activity of daily living. 
• 
Life-threatening (Grade 4) - Life-threatening consequences; urgent intervention 
indicated. 
• 
Death (Grade 5) - Related to adverse event. 
7.4.2 Assessment of relationship 
All AEs (including SAEs) will be assessed for the relationship of the AE to both pembrolizumab 
and BGB324 study drug using the following definitions: 
• 
Not/unlikely related - The AE is not related if exposure to the investigational 
product has not occurred, OR the occurrence of the AE is not reasonably related in 
time, OR the AE is considered unlikely to be related to use of the investigational 
product because there are no facts (evidence) or arguments to suggest a causal 
relationship AND there is a possible alternative explanation.  
• 
Possibly related - The administration of the investigational product and AE are 
considered reasonably related in time AND the AE could be explained by causes 
other than exposure to the investigational product. 
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• 
Probably related - Exposure to the investigational product and AE are reasonably 
related in time AND the investigational product is more likely than other causes to be 
responsible for the AE OR is the most likely cause of the AE. 
• 
Definitely related - There is a reasonable temporal sequence between exposure to 
the investigational product and the AE, OR the event follows a known or expected 
response pattern to the investigational product, AND is confirmed by improvement 
on stopping the dosage of the investigational product. It may also be confirmed by 
reappearance upon repeated exposure where this is medically and ethically 
acceptable. 
The relationship of the study treatment to an AE will be determined by the Investigator and 
subsequently reviewed by the Medical Monitor. 
For reporting and data analysis purposes, AEs reported with a causality assessment of 
“Definitely”, “Probably”, and “Possibly” are to be considered as “having a reasonable causal 
relationship” to study drug. In case of disagreement between the Investigator and the Sponsor’s 
Medical Monitor, the more conservative assessment will determine the reportability of the case. 
7.4.3 Immediate reporting of adverse events and events of clinical interest to the Sponsor 
7.4.3.1 Serious adverse events  
An SAE is any untoward medical occurrence that at any dose (including overdose): 
• 
Results in death. 
• 
Is life-threatening: 
o 
“Life-threatening” means that the patient was at immediate risk of death at the 
time of the SAE; it does not refer to an SAE that hypothetically might have 
caused death if it were more severe. 
• 
Requires hospitalization or prolongation of existing hospitalization: 
o 
This means that hospital inpatient admission or prolongation of hospital stay 
were required for the treatment of the SAE or that they occurred as a 
consequence of the event. 
o 
Visits to a hospital by ambulance or to the emergency room without admission 
will not be regarded as hospitalization unless the event fulfils any other of the 
serious criteria. 
• 
Results in persistent or significant disability or incapacity: 
o 
“Persistent or significant disability or incapacity” means a permanent or 
significant and substantial disruption of a person’s ability to carry out normal 
life functions. 
• 
Is a congenital anomaly or birth defect. 
• 
Is an important medical event: 
o 
Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in situations where none of the outcomes 
listed above occurred. Important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require intervention to prevent one of the other outcomes listed 
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in the definition above should also usually be considered serious. Examples of 
such events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias, or convulsions that do not result 
in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
Note: In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per International Conference Harmonisation (ICH) definition, are reportable to the 
Sponsor in the same timeframe as SAEs to meet certain local requirements. 
Therefore, these events are considered serious by the Sponsor for collection purposes. 
• 
Is a new cancer (that is not a condition of the study); 
• 
Is associated with an overdose. 
For the time period beginning when the consent form is signed until treatment allocation, 
any SAEs, or follow up to a SAE, including death due to any cause other than progression 
of the cancer under study, that occurs to any patient must be reported within 24 hours to 
the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation through 90 days following cessation 
of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any SAE, or follow up to a SAE, including death 
due to any cause other than progression of the cancer under study, whether or not related 
to the Sponsor's product, must be reported within 24 hours to the Sponsor either by 
electronic media or paper. Electronic reporting procedures can be found in the electronic data 
capture (EDC) data entry guidelines. Paper reporting procedures can be found in the Investigator 
Trial File Binder (or equivalent). 
Additionally, any SAE, considered by an investigator who is a qualified physician to be related 
to the Sponsor's product that is brought to the attention of the investigator at any time following 
consent through the end of the specified safety follow-up period specified in the paragraph 
above, or at any time outside of the time period specified in the previous paragraph also must be 
reported immediately to the Sponsor. 
All patients with SAE must be followed up for outcome. 
7.4.3.2 Events of clinical interest 
Selected non-serious and serious AEs are also known as Events of Clinical Interest (ECI) and 
must be reported to the Sponsor. 
For the time period beginning when the consent form is signed until treatment allocation, 
any ECI, or follow up to an ECI, that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of 
a protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
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For the time period beginning at treatment allocation through 30 days following cessation 
of treatment, any ECI, or follow up to an ECI, whether or not related to the Sponsor’s 
product, must be reported within 24 hours to the Sponsor, either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent). 
ECIs for this trial include: 
• 
an overdose of Sponsor's product (either pembrolizumab or BGB324), as defined in 
Section 7.8, that is not associated with clinical symptoms or abnormal laboratory 
results.  
• 
an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value 
that is less than 2X the upper limit of normal, as determined by way of protocol-
specified laboratory testing or unscheduled laboratory testing* 
*Note: These criteria are based upon available regulatory guidance documents. The purpose of 
the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. The trial site guidance for assessment and follow up of 
these criteria can be found in the Guidance for Potential Drug-Induced Liver Injury (DILI) Cases 
Meeting Hy’s Law Criteria held in the Investigator Trial File Binder (or equivalent). 
7.5 
Reporting SAEs and ECIs 
Adverse events classified as SAEs or ECIs must be recorded on the designated eCRF page and 
require expeditious handling and reporting to the Drug Safety group at INC to comply with 
regulatory requirements. 
The Principal Investigator (or designee) will notify INC within 24 hours of identifying an SAE 
or ECI, whether related or unrelated to investigational drug, by completing the SAE form and 
faxing the eCRF pages and any available supporting documentation to INC (see Table 19 below 
for contact details). 
When an overdose or drug misuse of either of the investigational products occurs with an 
adverse outcome, the Investigator should only complete the designated AE or SAE eCRF page. 
Expeditious handling and reported may be appropriate. 
In the case of pregnancy, a separate ‘pregnancy’ and ‘pregnancy outcome’ form is used. 
However, the patient should be withdrawn from study treatment and appropriate follow up 
agreed with the Sponsor. 
 
 
 
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Table 19: Contact Details for SAE, ECI, New Cancer and Pregnancy/Lactation Reporting 
Drug Safety CRO: 
INC Research  
3201 Beechleaf Court 
Suite 600 
Raleigh, NC 27604 
USA 
SAE Facsimile Transmission: 
Each country will have a dedicated specific toll free fax number. A general toll 
fax number is provided below; whilst the list of countries with the dedicated 
toll-free fax numbers will be provided on the SAE cover page. 
1-877-464-7787 (US/Canada toll free fax number and Global toll fax number) 
SAE e-Mail Contact: INC 
INCDrugsafety@INCResearch.com 
7.6 
Assessment of Expected Adverse Events 
The Sponsor will assess all SAEs whether they are expected or unexpected. An unexpected AE is 
any adverse drug event considered to be at least possibly related to BGB324 or pembrolizumab 
where the outcome, specificity, or severity of which is not consistent with those noted in the 
current IB for BGB324, or the SmPC or Prescribing Information for pembrolizumab. 
7.7 
Reporting of Pregnancy or Lactation 
Although pregnancy and lactation are not considered AEs, it is the responsibility of investigators 
or their designees to report any pregnancy or lactation in a patient (spontaneously reported to 
them) that occurs during the trial.  
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the patient to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
Pregnancies and lactations that occur from the time of first dose of study treatment 
through to 120 days following cessation of Sponsor’s product, or 30 days following 
cessation of treatment if the patient initiates new anticancer therapy, whichever is earlier, 
must be reported by the investigator. All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage 
and stillbirth must be reported as serious events (as Important Medical Events). If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 
Pregnancies are to be reported using the same procedures/transmission methods as SAEs: the 
same fax numbers/email address / same SAE cover sheet. A study specific pregnancy form will 
be provided for pregnancy reporting. 
7.8 
Definition of Misuse and Overdose 
BGB324 overdose is defined as any dose level administered which exceeds the assigned study 
dose level (including dose reductions). 
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For this trial, a pembrolizumab overdose will be defined as ≥1000 mg (5 times the dose) of 
pembrolizumab. No specific information is available on the treatment of overdose of 
pembrolizumab. In the event of overdose, the subject should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated. 
If the pharmacy discovers that an overdose has or may have been administered, they should 
contact the Study Investigator immediately. The Study Investigator will determine if the 
overdose is an Event of Clinical Interest (see Section 7.4.3.2). 
7.9 
Investigational Product Complaints 
Pharmaceutical technical complaints associated with the investigational product must be reported 
to the Sponsor immediately. The same reporting timelines as for SAEs apply. 
7.10 Reporting SAES to the IRB or IEC 
The Investigator must comply with the applicable regulatory requirements related to the 
reporting of SAEs to the IRB or IEC. All SAEs that are related and unexpected must be reported 
by the Investigator (or alternative responsible person where specified in study delegation log) to 
the IEC/IRBs responsible for the study.  
In such cases, the Drug Safety group will send the Principal Investigator a Council for 
International Organizations of Medical Sciences (CIOMS) or MedWatch form describing the 
event, for them to report to their IEC/IRB. 
Other SAEs (i.e. expected or unrelated SAEs) should be reported per the relevant institution’s 
procedures. 
The Principal Investigator should also comply with the IEC/IRB procedures for reporting any 
other safety information. Periodically (at least annually), the IB will be updated to include new 
and relevant safety information. 
Until such time that an AE becomes identified in the BGB324 IB, it should be considered 
unexpected in regard to BGB324 causality, regardless of whether the AE has been the patient of 
a previous Safety Update. 
7.11 Follow Up Information on an SAE 
Collection of complete information concerning SAEs is extremely important. Thus, follow-up 
information that becomes available as the SAE evolves, as well as supporting documentation 
(e.g. hospital discharge summaries and autopsy reports), should be collected subsequently, if not 
available at the time of the initial report, and immediately sent using the same procedure as the 
initial SAE report. The original SAE form(s) must be kept on file at the study site. The Sponsor 
will also review SAE reports for missing information and send queries to the site for resolution 
as appropriate. 
Appropriate diagnostic tests should be performed and therapeutic measures, if indicated, should 
be instituted. Appropriate consultation and follow-up evaluations should be carried out by the 
Principal Investigator (or designee). An SAE is followed until it is considered resolved, returns 
to baseline, is chronically ongoing, or is explained by the Principal Investigator. 
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7.12 Sponsor Reporting of SAEs 
The Sponsor is responsible for reporting serious, study drug–related AEs to the Competent 
Authorities of the countries participating, the Central IRBs/IECs participating in the clinical trial 
and to the study Investigators. The Sponsor has assigned the drug safety group at INC Research 
to act on their behalf for safety submissions on this clinical study. 
The Sponsor (or their delegated Medical Monitor) will determine whether expedited reporting is 
necessary for SAEs depending on the assessment of seriousness, expectedness, and relationship. 
In case of disagreement between the Investigator and the Sponsor’s Medical Monitor regarding 
causal relationship, the more conservative assessment will determine the reportability of the case. 
The Sponsor, or their delegated Clinical Research Organization (CRO), will prepare 
Development Safety Update Reports (DSUR) and send the DSUR to the European Competent 
Authority(ies) and the US Authority(ies) where the trial is approved within the regulatory 
timeframe appropriate for the outcome of their assessment (see Section 7.12.1 and Section 
7.12.2). The assigned CRO will send the DSUR to the concerned IRB/IECs. 
7.12.1 Expedited reporting 
The Sponsor (or delegate) is responsible for the ongoing safety evaluation of the IMP. The 
assigned drug safety group is responsible for ensuring that expedited reports are made to all 
concerned Investigators, to the concerned IRB/IECs (where required), and to the relevant 
regulatory authorities of all adverse drug reactions that are both serious and unexpected, and of 
findings that could adversely affect the health of patients, impact on the conduct of the trial, or 
alter the Competent Authority’s authorization to continue the trial. 
In accordance with the US Code of Federal Regulations, Title 21 CFR Part 312.32, the European 
Directive 2001/20/EC, and the ICH Guidelines for Clinical Safety Data Management Definitions 
and Standards for Expedited Reporting, the Sponsor must submit written documentation in the 
form of an Investigational new drug (IND) Safety Report or suspected unexpected serious 
adverse reaction (SUSAR) reports, respectively. The Sponsor should submit to the Regulatory 
Authority all safety updates and periodic reports, as required by applicable regulatory 
requirements. 
The drug safety group will assign a case number to be used in all future correspondence 
regarding the event. 
All events qualifying as IND Safety Reports/SUSARs will be reported to the relevant regulatory 
authorities, IRB/IECs, and Investigators by the drug safety group. IND Safety Reports/SUSARs 
are required to be reported within 7 calendar days for life-threatening events and those resulting 
in death or 15 calendar days for all others. These timeframes begin with the first notification of 
the IND Safety Reports/SUSARs to the drug safety group from the Investigator. 
7.12.2 Non-expedited reporting 
All SAEs that do not require expedited reporting will be described in the interim safety reports. 
 
 
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8 
DATA EVALUATION: CRITERIA FOR EVALUATION OF OBJECTIVES 
8.1 
Statistical Considerations, Interim Analysis and Sample Size 
The study will employ a k-stage single arm design, an approach derived from basic statistical 
theory23. If p denotes the true tumor response rate with drug, the null and alternative hypotheses 
to be assessed in this trial are: H0 : RR=p0 vs H1 : RR=p1 (p0 <p1), with p0=0.20 and p1=0.35. To 
test these hypotheses, this trial is a k-stage single arm design with k=2, being an extension of 
Simon’s 2-stage design1. In this design with k=2, there are two analyses: a single interim and a 
final analysis. At the interim, the response rate is evaluated in a fixed number (m) of patients 
using a predefined decision rule to determine if the study should stop for futility (in the situation 
where the null is confirmed) or for efficacy (in the situation where the alternative hypothesis is 
confirmed). If neither hypothesis is confirmed, a further fixed number of patients (l) are assessed 
for response and a final analysis is performed on all (m+l) patients. In both interim and final 
analyses, the response rate will be presented together with the associated exact 90% confidence 
interval (CI). 
With p0=0.20 and p1=0.35, the interim will be conducted with m=28 patients. If 5 or fewer 
responses are observed in these 28 patients, the trial will be terminated in favor of the null for 
futility; however, if 11 or more responses are observed, then the trial will be stopped in favor of 
the alternative for demonstration of activity. Otherwise a further 28 patients may be evaluated, 
for a total of 56 patients. If a total of 17 or more responses are seen in 56 patients, then the null 
will have been rejected in favor of the alternative; otherwise the null will not have been rejected. 
Based on 500,000 trial simulations, this design provides an overall power of 80.6% to test the 
stated null and alternative hypothesis with a 1-sided Type I error rate of 0.048. Under the null 
hypothesis, the probability of correctly stopping for futility at the interim is 50.2% and, under the 
alternative hypothesis, the probability of correctly stopping for activity at the interim is 38.4%. 
Consequently, the expected sample size for the design is 42-44 subjects. 
8.2 
Data Review Committee 
8.2.1 Safety Run-In 
Pembrolizumab has not previously been combined with BGB324 in patients (in any indication) 
and therefore, a safety run-in will include a total of 12 patients. 
A Data Review Committee (DRC), consisting of Principal Investigators, the Sponsors’ 
(BerGenBio and Merck) Medical Monitors, and invited experts as required, will review all 
patient safety data after 6 patients have been enrolled and had the potential to be followed for 6 
weeks (2 cycles), and then again after a further 6 patients (total 12 patients) have had the 
potential for 6 weeks follow-up. At each of these safety reviews, the DRC will consider the rate 
of BGB324 dose reductions and the rate of permanent discontinuation from BGB324 and 
pembrolizumab. 
Each patient will have had the potential to receive (as a minimum): 
• 2 cycles of pembrolizumab 
• BGB324 at 400 mg for 3 days, followed by 200 mg daily for ~6 weeks 
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At the 1st safety run-in (based on 6 patients) the DRC will evaluate the need for dose 
modification for individual patients, or BGB324 loading or daily dose modification. A rate of 
>66% (4 or more) of patients requiring treatment to be dose reduced (BGB324) or permanently 
discontinued (either BGB324 or pembrolizumab, or both) will considered as a significant rate. 
The 2nd safety run-in (based on the 12 patients) the DRC will again evaluate the need for dose 
modification for individual patients, or BGB324 loading or daily dose modification. A rate of 
>40% (5 or more) of patients requiring treatment to be dose reduced (BGB324) or permanently 
discontinued (either BGB324 or pembrolizumab, or both) will considered as a significant rate. 
During the safety run-in reviews, the DRC will have the option to recommend a lower dose of 
BGB324 (dose level -1) for new patients. Dose level -1 is defined as 200 mg BGB324 on Days 1, 
2 and 3 followed by 100 mg from Day 4 onwards. 
Additionally, a review of emerging safety data from the whole BGB324 program will be made 6-
monthly. 
8.2.2 End of Stage 1 – Efficacy Analysis 
Recruitment to the study will be halted once 28 evaluable patients have been entered, and whilst 
the Stage 1 analysis is conducted. Recruitment will recommence if the decision is made to 
continue to the maximum of 56 evaluable patients. 
The DRC will meet to review the overall risk/benefit profile of the combination, together with 
the ORR when 28 patients have had the potential to be followed for 24 weeks – and therefore 
these patients have the potential to have data from at least 2 post-treatment tumor-imaging 
assessments. The DRC will document the ORR and if it favors the null hypothesis for futility, or 
the alternative hypothesis for demonstration of activity, and recommend if the study should 
proceed to evaluate up to a further 28 patients. This recommendation will take into account the 
statistically-driven endpoint, in the context of on-going safety data review of the combination 
approach, as well as the quality of the response e.g. available data on duration of response (DoR) 
and progression-free survival (PFS), where possible. 
Appropriate representatives of the Sponsor and the coordinating personnel may also attend and 
minute DRC meetings. Recommendations of the DRC will be documented and sent to the sites. 
Further details on the composition of the DRC, as well as the process for data review, issue of 
recommendations and decision making, are described in a separate DRC charter for this study.  
8.3 
Statistical Analysis Plan 
Detailed statistical analysis information will be provided separately in the Statistical Analysis 
Plan (SAP). The SAP will detail all data handling rules e.g. full definition of patient populations 
for analysis, including the management of missing values and the handling of data for patients 
lost to follow-up or missing other important information. The SAP will also outline protocol 
deviation criteria. Any deviations to the planned analyses specified or populations defined within 
the SAP will be justified in writing and presented within the final clinical study report. It will 
also describe the rules the handling of missing data points for the primary, secondary and 
exploratory endpoints. 
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An interim analysis will be performed after 28 evaluable patients have had the potential to have 
at least 24 week follow-up (enabling each patient to have the potential for at least 2 ‘on 
treatment’ disease assessment scans). Recruitment will be halted during this period and until the 
interim analysis has been conducted. 
The SAP will fully describe the efficacy analyses and descriptive summaries that will be 
undertaken for both the interim and final analyses. All efficacy endpoints (ORR, DoR, PFS, 
DCR and OS) will be summarized and described for both the interim and final analyses. See 
Section 8.11 and Section 8.12 for further details. 
Summaries of ORR by PD-L1 and Axl expression will be provided for both the interim and final 
analyses. 
The clinical database lock for the final analysis will occur after the final patient has had the 
potential to be followed for 24 weeks and after all data are reconciled (i.e. “cleaned”) for all 
patients who participate in the study. A single clinical study report (CSR) will be generated. The 
SAP will be finalized and signed before the database lock. 
An addendum (or addenda) to the CSR will be generated to report SAEs from patients remaining 
on treatment at the time of the LPLV patients to closure of the study (defined as every patient 
completing their study combination treatment) (Section 8.6). 
The main data analyses intended for this trial are briefly described in this section and in Section 
8.11 and Section 8.12. The SAP will provide full details of all planned data analyses for the 
primary, secondary and exploratory objectives of the study. 
8.4 
Population 
The efficacy objectives will include all evaluable patients. An evaluable patient will have 
received at least one combination dose and who have measurable disease at entry according to 
the Investigator Site assessment. 
For all safety objectives, the safety set consisting of all patients that have received at least one 
dose of BGB324 and/or pembrolizumab will be used. 
For some objectives (PK and biomarker) a subgroup of patients of the safety set with respective 
baseline and post-baseline measurements will be used. 
Patients who signed a consent form and were screened but did not receive any treatment will be 
listed if they reported an AE in the time after consent and before treatment allocation (Section 
7.1). All AEs that occur after the consent form is signed but before treatment allocation must be 
reported if they cause the patient to be excluded from the trial, or are result of protocol-specific 
intervention, including but not limited to, washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure (Section 7.1). 
8.5 
RECIST 1.1 and Disease Assessment 
Efficacy endpoints in this study, including ORR, DoR, PFS will all be based on tumor imaging 
evaluation by RECIST 1.12. 
RECIST assessments will be performed using contrast-enhanced CT/MRI assessments of chest, 
abdomen, and pelvis. Additionally, x-ray, bone scans and brain scans will be used as appropriate. 
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Additional anatomy should be imaged based on signs and symptoms of individual patients at 
baseline and follow-up. Baseline assessments should be performed no more than 28 days before 
start of study treatment (although bone scans and brain scans may be done within 6 weeks), and 
ideally should be performed as close as possible to the start of study treatment. 
All radiological and non-radiological (eg, MRI) scans will be reviewed by the local site 
investigator; and if possible, stored electronically (de-identified with the patient’s notes) at site. 
A maximum of 5 target lesions must be selected at baseline. All target lesions are measurable. 
Target lesions should be selected on the basis of their size (longest diameter for non-nodal 
lesions or short axis for nodal lesions), but in addition should be those that lend themselves to 
reproducible repeated measurements. 
All remaining lesions present at baseline are considered non-target, irrespective of whether they 
are measurable. 
Disease assessments will be performed every 9 weeks ±7 days for the first 46 weeks relative to 
the date of first treatment administration and then every 12 weeks ±7 days thereafter until 
confirmed objective disease progression as defined by RECIST 1.12 (irrespective of the reason 
for stopping treatment or subsequent therapy). 
Any other sites at which new disease is suspected should also be adequately imaged at follow/up. 
If an unscheduled assessment was performed and the patient has not progressed, every attempt 
should be made to perform the subsequent assessments at their scheduled visits. This schedule is 
to be followed in order to minimize any unintentional bias caused by some patients being 
assessed at a different frequency than other patients. 
Table 20 provides the RECIST 1.12 evaluation and definitions of disease response (based on 
TLs). 
Table 20: RECIST 1.1 evaluation and definitions of disease response 
Complete Response (CR) 
Disappearance of all TLs since baseline. Any pathological lymph nodes 
selected as TLs must have a reduction in short axis to <10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of the diameters of TLs, taking as 
reference the baseline sum of diameters 
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD 
Progression of disease (PD) 
At least a 20% increase in the sum of diameters of TLs and an absolute 
increase of at least 5 mm, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on study). 
Not Evaluable (NE) 
Only relevant if any of the TLs were not assessed or not evaluable or had a 
lesion intervention at this visit. Note: if the sum of diameters meets the 
progressive disease criteria, progressive disease overrides not evaluable as 
a TL response 
All patients who are considered to have had a complete or partial response must have this 
response confirmed by a confirmatory scan at least 4 weeks later. 
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Details of any new lesions will also be recorded with the date of assessment. The presence of one 
or more new lesions is assessed as progression, however, in the absence of clinical deterioration, 
treatment can continue. The suspected disease progression should be confirmed after 28 days. 
A lesion identified at a follow up assessment in an anatomical location that was not scanned at 
baseline is considered a new lesion and will indicate disease progression. 
The finding of a new lesion should be unequivocal: i.e., not attributable to differences in 
scanning technique, change in imaging modality, or findings thought to represent something 
other than tumor. 
If a new lesion is equivocal, for example because of its small size, the treatment and tumor 
assessments should be continued until the new lesion has been confirmed. If repeat scans 
confirm there is a new lesion, then the progression date should be declared using the date of the 
initial scan. 
Disease progression requires confirmation. The confirmatory scan should occur preferably at the 
next scheduled visit and no earlier than 4 weeks after the initial assessment of progression of 
disease (PD) in the absence of clinical deterioration. 
The overall visit response will be derived using the algorithm shown in Table 21. 
Table 21: Overall visit response algorithm 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No or NE 
CR 
CR 
NA 
No or NE 
CR 
CR 
Non CR/Non PD 
No or NE 
PR 
CR 
NE 
No or NE 
PR 
PR 
Non PD or NE or NA 
No or NE 
PR 
SD 
Non PD or NE or NA 
No or NE 
SD 
NE 
Non PD or NE or NA 
No or NE 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR Complete response, PR Partial response, SD Stable disease, PD Progression of disease, NE Not evaluable, NA 
Not applicable (only relevant if there were no non-target lesions at baseline). 
8.5.1 Immune-related RECIST 1.1 and confirmation of progression 
RECIST 1.12 will be adapted to account for the unique tumor response characteristics seen with 
treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may produce 
antitumor effects by potentiating endogenous cancer-specific immune responses. The response 
patterns seen with such an approach may extend beyond the typical time course of responses 
seen with cytotoxic agents, and can manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. Standard RECIST may not provide an accurate 
response assessment of immunotherapeutic agents such as pembrolizumab. Therefore, RECIST 
1.12 will be used with the following adaptations: 
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If radiologic (or non-radiological) imaging suggest that the patient has progressive disease 
(initial PD), tumor assessment should be repeated ≥4 weeks later in order to confirm PD with the 
option of continuing treatment per below while awaiting radiologic confirmation of progression. 
• 
If repeat imaging shows <20% tumor burden compared to nadir, stable or improved 
previous new lesion (if identified as cause for initial PD), and stable/improved non-
target disease (if identified as cause for initial PD), treatment may be 
continued/resumed; 
• 
If repeat imaging confirms PD due to any of the scenarios list below, patients will be 
discontinued from study therapy. 
In determining whether or not the tumor burden has increased or decreased, site study team 
should consider all target lesions as well as non-target lesions. 
Scenarios where PD is confirmed at repeat imaging: 
• 
Tumor burden remains ≥20% and at least 5 mm absolute increase compared to nadir; 
• 
Non-target disease resulting in initial PD is worse (qualitative); 
• 
New lesion resulting in initial PD is worse (qualitative); 
• 
Additional new lesion(s) since last evaluation. 
In patients who have initial evidence of radiological PD, it is at the discretion of the treating 
physician whether to continue a patient on study treatment until repeat imaging is obtained. This 
clinical judgment decision should be based on the patient’s overall clinical condition, including 
performance status, clinical symptoms, and laboratory data. Patients may receive pembrolizumab 
treatment while waiting for confirmation of PD if they are clinically stable as defined by the 
following criteria: 
• 
Absence of signs and symptoms indicating disease progression; 
• 
No decline in ECOG PS; 
• 
Absence of rapid progression of disease; 
• 
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention. 
When feasible, patients should not be discontinued from their study treatment until progression is 
confirmed. This allowance to continue treatment despite initial radiologic progression takes into 
account the observation that some patients can have a transient tumor flare in the first few 
months after the start of immunotherapy, but with subsequent disease response. Patients that are 
deemed clinically unstable are not required to have repeat imaging for confirmation of 
progressive disease.  
8.6 
Completion and Closure of the Study 
The study will be completed when either: 
• 
The study is terminated at the interim analysis following the DRC review of the ORR 
and risk/benefit for all patients included in the interim analysis. In this (early 
termination) situation a Clinical Study Report will be written. The interim analysis 
will occur once 28 evaluable patients have had the potential to be followed for at 
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least 24 weeks. In this situation, the last patient, last visit (LPLV) will occur at this 
point. 
OR 
• 
The study will complete and the final analysis will occur once all patients (planned 
56 evaluable patients) have had the potential to be followed for at least 24 weeks. 
The last patient, last visit (LPLV) will occur at this point. All data will be reconciled 
and the database will be locked for analysis. These data will be included in the CSR. 
 
Assuming that there are patients continuing on study treatment at the date of LPLV, the study 
will be closed once all patients have completed their last dose of study drug or discontinued 
study drug and have completed their post treatment visit. 
• 
If this closure date occurs after the date of LPLV, only serious safety data will be 
collected between LPLV and the final closure date. An addendum (or addenda) to the 
CSR will be generated to report any outstanding serious safety data. 
• 
If this ‘closure date’ occurs before the date of LPLV (because every patient has 
stopped their study treatment, for example), the study will close at the same time as 
the date of LPLV. 
Study start is defined by the first patient to enter screening, however, the First Patient In (FPI) is 
when the first patient receives the first dose of study drug. 
LPLV is defined as the last visit after all evaluable patients who have had the potential to be 
followed for at least 24 weeks and includes all data for the final analysis of all evaluable patients. 
Study Completion is defined by the date of the LPLV i.e. after the planned number of evaluable 
patients have had the potential to be followed for at least 24 weeks. 
Study Closure is defined by completion of the last dose of study drug and post treatment visit i.e. 
when the last patient has completed the last dose of study drug or discontinued for any reason 
and been followed up to the Post Treatment Visit. This date will either be the same as the date of 
Study Completion or later in time. 
8.7 
Demographic, Medical History, Prior Medication and Other Baseline Characteristics 
Demographic characteristics, medical history, prior medication and other baseline data will be 
listed and summarized using descriptive statistics for continuation data and contingency tables 
for categorical data. Prior medication will be summarized by anatomical therapeutic chemical 
(ATC) terms. 
8.8 
Study Treatment 
The number of doses of BGB324 and pembrolizumab by cycle and over entire study period will 
be listed and summarized using descriptive statistics. The time on study drug until last treatment 
received will be listed and presented by descriptive statistics. 
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8.9 
Concomitant Medication 
Concomitant medication and significant non-drug therapies after the start of study treatment will 
be listed and summarized by ATC term in contingency tables. 
8.10 Reasons for Discontinuation from Study Treatment 
Reasons for discontinuation of study treatment(s) will be listed and summarized. 
8.11 Primary Objectives 
Objective response rate as defined by achieving complete response and/or partial response will 
be presented by percentage rates and 90% CIs. All response assessments will be listed. 
Note that the Disease Assessment time point used for this analysis may vary, and need not be the 
first on treatment assessment. Where there is the possibility of an immune response leading to a 
false categorization of disease progression, results from later tumor imaging time points may be 
used for the ORR assessment following the k-stage design.  
Objective response rate is defined as the percentage of patients with a CR or PR (out of the 
number evaluable), a 90% CI for the overall ORR will be calculated assuming an exact binomial 
distribution. 
A patient who has discontinued both treatments, and subsequently responds having received a 
subsequent anti-cancer treatment may be excluded (at the statistical analysis) from the subset of 
responding patients (these patients are evaluable, and will be included in the denominator). Such 
patients will contribute to the time to progression and death Kaplan Meier plots. 
All patients with a documented PR or CR are expected to have the result confirmed by repeat 
scan at least 4 weeks (28 days) later. 
The ORR will further be explored as follows: 
• 
By PD-L1 status (+ve/-ve), using a Chi square or Fishers Exact Test 
• 
By Axl status (+ve/-ve), using a Chi square or Fishers Exact Test, and 
• 
Summarized in a table of PD-L1 by Axl expression status to explore the ORR in each 
of the four quadrants (++, +-, -+, --). That is, patients will be allocated into one of the 
4 groupings: where both Axl and PD-L1 are positive; where there is one positive and 
one negative and where there are both Axl and PD-L1 negative. 
If the PD-L1 expression status is provided as a TPS or, in one of 3 categories usually <1%, 1-
49% and >50%, the patient will be regarded as PD-L1 positive if their TPS is >1%. 
A patient with Axl positive disease is defined as one with an expression level of 1+ or greater 
according to IHC staining intensity, although other cut offs may be considered. 
For each patient, the best percentage change in tumor volume will be illustrated in a ‘waterfall’ 
plot. 
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8.12 Secondary Objectives 
8.12.1 Safety 
8.12.1.1 
Adverse event 
Adverse events will be coded as described in Section 8.4. The number of AEs occurring at least 
once in a patient will be listed and summarized by contingency tables for: 
• 
primary system organ class, preferred term; 
• 
preferred term; 
• 
NCI CTCAE grade; 
• 
relationship to both study drugs; 
• 
interruption of study drug; 
• 
leading to discontinuation; 
• 
Grade 3 and higher; 
• 
SAEs; 
• 
AEs leading to death; 
• 
standard medical queries. 
8.12.1.2 
Safety laboratory 
Laboratory values will be graded by NCI CTCAE version 4.03; if no grading exists values will 
be classified into low/normal/high based on laboratory normal ranges. Each parameter will be 
presented by descriptive statistics at each visit and change from baseline values at each visit. 
Shift tables for CTCAE grades and normal ranges will be presented. All laboratory values will be 
listed. A separate listing for abnormal lab values (Grade 3 and higher, and low/high values) will 
be presented. 
8.12.1.3 
Vital signs 
Vital signs will be summarized by descriptive statistics at each visit, change from baseline will 
be presented and a listing will be provided. 
8.12.1.4 
Electrocardiogram 
ECG data will be listed overall and a separate listing for any clinical significant finding in ECG 
values will be provided.  
8.12.2 Efficacy 
8.12.2.1 
Duration of response 
The duration of response (DoR) will only be calculated for patients that have an objective 
response. The duration of response is calculated from the date of the first documented response 
until the date of progression or death; patients who continue to respond at the date of data cut-off 
(last patient last visit) will be censored using the same date used to censor for the progression 
free survival time. Median DoR and respective 95% CIs will be presented. 
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8.12.2.2 
Disease control rate 
Disease control rate (DCR) is defined as the percentage of patients with a PR, CR or with stable 
disease (out of number evaluable). A 95% CI for the DCR will be calculated using an exact 
binomial distribution. 
A Kaplan Meier plot of the duration of response will be presented along with the median 
duration of response. Descriptive statistics will be used as required, including 95% CIs. 
8.12.2.3 
Progression free survival and overall survival 
Kaplan Meier plots of the time to progression and death will be presented, along with the median 
progression free survival and the estimated survival at 12 months. Descriptive statistics will be 
used as required, including 95% CI. 
PFS is measured from the date of the 1st dose of the 1st cycle until the date of progression (the 
date on which the progression is initially observed) or the date of death (whichever is earlier). 
Patients who have not progressed or died before the date of data cut-off (last patient, last visit) 
will be censored at their last clinical evaluation. 
The estimated survival at 12 months will be read from the Kaplan Meier OS curve. The time to 
death is defined as the time from the date of enrolment until the date of death (from any cause 
and irrespective of any subsequent ant-cancer treatment given). Patients who remain known to be 
alive at the date of data cut-off (last patient, last visit) will be censored at their date last known to 
be alive. Patients who are lost to follow-up will be censored at the point last known to be alive; 
however, if ≥2% of patients are in this category, a sensitivity summary will be produced to 
illustrate the overall survival assuming the patient died at the date last known in the trial. If 
possible, the date of death may be recovered from publically available sources such as death 
registries. 
8.12.3 Pharmacokinetics 
The analysis plan for PK assessment for BGB324 in the study will be part of the SAP. PK 
parameters (see Table 22) will be estimated for each patient using a fully validated version of 
WinNonlin Pro (Version 6.3 PhoenixTM, Pharsight®), or later version as appropriate. The 
following parameters will be derived for BGB324, where appropriate, from the individual 
plasma concentration versus time profiles from all patients. 
Blood samples taken for the purpose of PK assessment of pembrolizumab will be frozen and 
stored in case they are required in the future (for example, at the request of a regulatory 
authority). 
Table 22: Pharmacokinetic parameters 
Parameter 
Definition 
Cmax 
The maximum observed concentration. 
tmax 
The time at Cmax  
AUC0-24h 
The area under the concentration versus time curve from time zero to 24 h post-dose; that is, 
within a dosing interval 
Cav 
Average concentration calculated as AUC0-24h /24 
t1/2 
The elimination half-life 
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Blood samples taken for the purpose of PK assessment of pembrolizumab will be frozen and 
stored in case they are required in the future (for example, at the request of a regulatory 
authority). 
8.13 Exploratory Objectives 
8.13.1 Biomarker analysis 
The PD-L1 and Axl expression status will be available at the time of the database lock and will 
be utilized in the analysis of the study, as described in Section 8.11. 
However, results from other biomarkers (for example, for the assessment of Axl inhibition and 
signaling) may not be available at the time of the interim analysis clinical database lock, but are 
intended to be completed before the closure of the study or before the clinical study report is 
written at study completion (whichever is later) – see Section 8.6. A separate analysis plan and 
report (addendum to the CSR) for biomarker analysis will be written. All samples will be 
destroyed within 5 years of the last patient being entered to Stage 1. 
 
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9 
QUALITY ASSURANCE 
9.1 
Data Recording 
The Investigator will be responsible for the recording of all data on the CRFs provided, as 
certified by the Investigator’s signature and date on the designated pages. All study data will be 
collected using an eCRF within a fully validated and CFR 21 Part 11-compliant electronic data 
capture system. All data will be entered into the eCRF by the site staff. These data will then be 
source-data verified and reviewed by the study monitor (or Clinical Research Associate) before 
data cleaning by Data Management is performed. All queries will be raised and resolved within 
the electronic data capture system. During entry, programmatic checking of the data will be 
performed and, once saved into the database, more complex programmatic checks will also be 
performed. During the conduct of the study, all system users will have real-time access to the 
data. The level of access to the data and study privileges will be determined by their user role.  
After all queries have been resolved, the SAP approved and signed, and any summary/analysis 
populations approved, the database will be locked and the data released for summary and 
analysis. All summary and analysis of the data will be performed using SAS® version 9.3 and/or 
WinNonLin Pro (Version 6.3 PhoenixTM, Pharsight®), or later. 
9.2 
Study Monitoring 
Study monitors will be responsible for the monitoring of the study. 
The study monitor will review the progress of the study on a regular basis to ensure adequate and 
accurate data collections. Monitoring site visits to review the eCRF(s), patient case notes, 
administrative documentation, including the Investigator Site File, and to perform drug 
accountability will be performed throughout the study at appropriate intervals. 
At each study monitoring visit, the Investigator will make available all records pertaining to the 
study. To allow sufficient time to assemble documentation for the Study Monitor, monitoring 
visits will be confirmed in advance of planned visits. 
9.3 
Clinical Study Audit 
The Sponsor, Sponsor representative, or external regulatory agency may at any time during or 
after completion of the study conduct a GCP audit at any trial site. Prior notice will be given to 
each site selected for audit in advance of a planned audit. 
9.4 
Clinical Study Report 
The results of the study will be presented in an integrated Clinical Study Report according to 
ICH guidelines. 
9.5 
Data Retention and Availability 
The Investigator is required to maintain copies of all essential study documentation, including 
the Site Study File, a disc containing all eCRF data (including the full audit trail and all data 
queries), signed informed consent forms, and records for the receipt and disposition of study 
medications, for a specified period required by ICH GCP, or longer if required by local or 
regulatory authorities. 
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US Federal laws require that an Investigator maintain all study records for the indication under 
investigation for two years following the date a Product Licensing Application is approved or, if 
no application is to be filed or if the application is not approved for such indication, until two 
years after the investigation is discontinued and the FDA is notified. 
European laws require that the Investigator maintain all study records (excluding the patients’ 
medical files) for at least 15 years after completion or discontinuation of the trial, or for at least 
two years after the granting of the last marketing authorization in the European Community (EC) 
and where there are no pending or contemplated marketing applications in the EC, or for at least 
two years after the formal discontinuation of clinical development of the investigational product. 
During the study, the Investigator must make study data accessible to the study monitor(s), the 
Sponsor (or a third-party auditor assigned by the Sponsor), and relevant IEC/IRBs and regulatory 
agencies. The Investigator must ensure the availability of source documents from which the 
information in the eCRF was derived. 
9.6 
Curricula Vitae and Financial Disclosure of Investigators 
All Principal Investigators will be required to provide a current signed and dated curriculum 
vitae, a completed FDA Form 1572 (required in the US; in the EU, if applicable) and a financial 
disclosure statement (required in the US; in the EU, if applicable). Sub-investigators may also be 
required to provide a current curriculum vitae and a financial disclosure statement according to 
the regulations of the countries involved. 
9.7 
Protocol Modifications 
No modification of the protocol should be implemented without the prior written approval of the 
Sponsor or the Sponsor’s representative. Any such changes which may affect a patient’s 
treatment or informed consent, especially those increasing potential risks, must receive prior 
approval by the IRB/IEC (Section 10). The exception to this is where modifications are 
necessary to eliminate an immediate hazard to trial patients, or when the change involves only 
logistical or administrative aspects of the trial (e.g. change in monitor, change in telephone 
number). Other administrative revisions which may impact the clinical portion of a study will be 
duly reported to the IRB/IEC by the Principal Investigator. 
 
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10 ETHICS REVIEW AND INFORMED CONSENT AND COMPETENT 
REGULATORY AUTHORITY APPROVAL 
10.1 Ethical Conduct of the Study 
The study will be conducted in accordance with ICH GCP, the Declaration of Helsinki, the 
European Union Clinical Trials Directive 2001/20/EC, the GCP Directive 2005/28/EC, the 
requirements of local IEC/IRB, and the US Code of Federal Regulations, Title 21 CFR Part 50. 
10.2 Institutional Review Board or Independent Ethics Committee Approval and 
Competent Regulatory Authority Approvals 
The final study protocol and patient informed consent form will be approved by the appropriate 
IEC/IRB for each investigational site. Approval will be received in writing before initiation of 
the study. 
Changes to the protocol during the trial will be documented as amendments. Depending on the 
contents of the amendment and local legal requirements, the amendment will be submitted for 
approval to the relevant IEC/IRBs and to the relevant competent authorities prior to 
implementation. Exceptions are cases of changes made to protect patient safety, which will be 
implemented immediately. 
If an amendment substantially alters the trial design, increases the potential risk to the patients, 
affects the treatment of the patient, or might otherwise influence the willingness of the patient to 
participate in the trial, then the information sheet must be revised and submitted to the relevant 
IEC/IRB and, where necessary, to the relevant competent authorities, for review and approval. 
When a patient is currently undergoing trial procedures and is affected by the amendment, then 
the patient must be asked to consent again using the new information sheet. 
10.3 Informed Consent 
The principles of informed consent in the Declaration of Helsinki and GCP guidelines will be 
implemented before any protocol-specific procedures or interventions are carried out. 
All patients will be informed that participation is voluntary and that they can cease their study 
treatment(s) and/or their further participation to any further study assessments at any time 
without necessarily giving a reason and without any penalty or loss of benefits to which they are 
entitled. 
Patients will be provided with two consent forms prior to the commencement of any procedures 
or investigations: 
i. 
The Main Consent to participate in the study will include information about the patient’s 
disease, alternative treatment options, the study treatments and their duration, study 
design and study assessments and procedures, risks, side effects and potential benefits of 
participation. This consent will include: 
a. Consent to provide sufficient tumor tissue to enable Axl kinase and PD-L1 
expression measurement by IHC, and an explanation that this includes the 
provision of a newly acquired tumor tissue sample. 
b. If possible, the electronic storage of all radiological and non-radiological scans at 
site for future reference (e.g. medical case studies, publications and training).  
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c. Information regarding the expected (maximum) blood volume to be provided. 
d. Information that treatment with checkpoint inhibitors, such as pembrolizumab, is 
occasionally associated with worsening of disease before clinical improvement is 
observed. Therefore, their treatment may continue if their doctor suspects that the 
patient is benefiting from the treatment. 
e. Information that treatment with checkpoint inhibitors, such as pembrolizumab, 
and treatment with BGB324 are associated with side effects and that the patient 
must inform the doctor of any side effects, even if the patient does not think they 
are important. 
f. An explanation that patients will continue to have 12 weekly follow-up visits (or 
in some cases, a telephone call) to assess their disease and/or well-being after the 
completion of their study treatments. Follow-up visits or telephone contact will 
continue until the end of the study. 
g. Information to explain that on-study blood samples will be collected for the 
purpose of assessing biomarkers of Axl signaling and inhibition. 
ii. 
A separate Optional Consent for the provision of a baseline archival tumor tissue sample 
for the purpose of exploratory biomarker analysis will be presented to the patient. 
During the trial, patients may be offered a further consent to provide an optional newly acquired 
tumor tissue sample for exploratory biomarker assessment. 
The patient must give consent (the Main Consent form) to participate prior to enrolment in the 
trial. This consent must be given in writing. The Investigator who conducts the informed consent 
discussion must also sign. The Investigator may delegate this responsibility to a suitably 
qualified member of the study team (e.g. Sub-Investigator) if permitted by local regulations. This 
delegation of responsibility must be recorded in the Site Study File. By giving signed consent, 
the patient will confirm that his or her participation is voluntary and that he or she will follow the 
instructions of the Investigator and answer the questions asked. Signatures must be personally 
dated. 
The signed and dated consent form(s) will be kept by the Investigator. Prior to participation in 
the trial, the patient should receive a copy of the signed and dated written informed consent 
form(s). 
The consent forms must include all elements required by law, local regulations, GCP and ICH 
guidelines including consent to allow the Sponsor, Sponsor representative, or external regulatory 
auditor to review the patient’s medical records. This gives permission to examine, analyse, 
verify, and reproduce any records and reports that are important to the evaluation of the trial. 
10.4 Patient Participation Card 
A study participation card will be provided to each patient on the trial. The card will indicate that 
he or she is participating in a clinical trial and give the name and contact details of the Sponsor 
and the Investigator/study site. The patient will be asked to retain this card while participating in 
the trial and show it to any other medical practitioners consulted during this time. Patients will be 
advised to contact the Investigator/study site if there are any questions.  
A sample patient participation card is shown in Figure 6 below: 
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Figure 6: Sample Patient Participation Card 
Dear Patient, 
Please inform any physician you are going to 
visit during the course of the study that you are 
participating in a clinical trial by presenting this 
contact card. 
Please carry this card with you at all times until 
the end of the study. 
INSERT NAME is participating in an open-label 
trial of an experimental drug called BGB324 in 
combination with pembrolizumab in patients with 
triple negative breast cancer. 
Subject No.: (optional) 
Study Contact Card 
Clinical Trial BGBC007/ MK-3475 PN 530 
Eudract Number: 2016-003608-30  
Dear Doctor, 
In the case that additional medications must be 
prescribed to this patient, or you need more 
information about the clinical trial they are 
participating in, or you need to notify the study 
physician about the patient’s worsening 
condition, please contact: 
INSERT NAME, ADDRESS & CONTACT NO. 
10.5 Insurance 
Appropriate insurance for this clinical trial will be arranged by the Sponsor in accordance with 
the regulatory requirements of the countries involved. A copy of the country-specific insurance 
certificate will be held in the TMF and in the Investigator Site File.  
10.6 Patient Privacy 
Any party with direct access to patient records or any material which identifies the patient must 
take all reasonable precautions within the constraints of the applicable regulatory requirement(s) 
to maintain the confidentiality of the patients’ identities and Sponsor’s proprietary information. 
In order to maintain patient confidentiality, all CRFs, study reports and communications relating 
to the study will only identify patients by their assigned study number; patients should not be 
identified by name. Depending on the countries involved in the clinical trial, use of patient 
initials, and full date of birth may be prohibited. 
 
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11 PUBLICATION POLICY 
The original eCRFs and all data generated during the clinical study using the given protocol will 
become the property of the Sponsor. 
Any proposed publication or presentation (including a manuscript, abstract, or poster) for 
submission to a journal or scientific meeting should be sent to the Sponsor for review at least 1 
month prior to submission. No single center or groups of centers may publish individually. 
Publications arising from this clinical study will include all Investigators as authors. The 
Sponsor's comments on the proposed publication shall be considered in good faith by the 
authors. Sponsor may delay such submission by a maximum of 90 (ninety) days if it reasonably 
believes that publication of results may compromise its intellectual property rights or else insist 
that such information or data are removed from the proposed publication. Publication of the 
results will not include confidential information without the permission of the Sponsor. 
The Sponsor may announce quality assured summary data in order to comply with Financial 
Regulatory Authorities, while ensuring, so far as possible, that such announcements will not 
compromise the Investigators ability to publish the data in appropriate scientific forums. 
 
 
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APPENDIX A: Easter Cooperative Oncology Group Performance Status 
Grade 
ECOG Performance status24 
0 
Fully active. Able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature (e.g. light 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. 
 
 
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APPENDIX B: Creatinine Clearance Algorithm 
 
Creatinine clearance should be calculated using the Cockroft-Gault Formula25, which is given 
below: 
 
 
US calculation formula: 
 
CrCl = (140 - Age) x Mass (kilograms) x (0.85 if Female) 
 
 
 
 
 
 
 
 
 
 
 
72 x serum Creatinine (mg/dL) 
 
 
European calculation formula: 
 
                1.25 x (140 – age) x weight (kg) 
Males:  ____________________________ 
 
         Serum creatinine (µmol/l) 
 
 
 
 
    1.05 x (140 – age) x weight (kg) 
 
Females: ____________________________ 
 
        Serum creatinine (µmol/l) 
 
 
 
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APPENDIX C: The New York Heart Association (NYHA) Functional Classification in a 
Patient with Heart Disease 
 
Overview: The NYHA developed a functional classification for patients with heart disease.  
 
Patients: Heart disease must be present.  
 
Parameters:  
• Limitations on physical activity  
• Symptoms (undue fatigue palpitations dyspnoea and/or anginal pain) with ordinary 
physical activity  
• Status at rest 
 
Limitations on  
Physical Activity 
Symptoms with Ordinary 
Physical Activity 
Status at Rest 
Class 
none  
none  
comfortable 
I 
slight  
symptomatic with ordinary 
activities  
comfortable 
II 
marked  
symptomatic at less than 
ordinary levels of activity  
comfortable 
III 
unable to perform any 
activity  
discomfort with any activity  
symptomatic at rest 
IV 
 
From The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. (1994). (9th ed.). Boston: Little, Brown & 
Co. 253 – 256 
 
 
 
 
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APPENDIX D: Drugs Associated with Torsades de Pointes 
See example list below. The following website for an updated list of drugs that may cause 
Torsades de Pointes www.AZCERT.org 
Generic Name 
Brand Name 
Amiodarone 
Coradone/Pacerone 
Anagrelide 
Agrylin®, Xagrid® 
Arsenic trioxide 
Trisenox 
Astemizole 
Hismanal 
Azithromycin 
Zithromax®, Zmax® 
Bepridil 
Vascor 
Chlorquine 
Arelan 
Chlorpromazine 
Thorazine 
Cisapride 
Propulsid 
Citalopram 
Celexa®, Cipramil® 
Clarithromycin 
Biaxin 
Cocaine 
Cocaine 
Disopyramide 
Norpace 
Dofetilide 
Tikosyn 
Domperidone 
Motilium 
Dronedarone 
Multaq® 
Droperidol 
Inapsine 
Erythromycin 
Erythrocin/E.E.S. 
Escitalopram 
Cipralex®, Lexapro® 
Flecainide 
Tambocor®, Almarytm® 
Halofantrine 
Halfan 
Haloperidol 
Haldol 
Ibutilide 
Covert 
Levomethadyl 
Orlaam 
Mesoridazine 
Serentil 
Methadone 
Methadose/Dolophine 
Moxifloxacin 
Avelox 
Ondansetron 
Zofran®, Anset® 
Petamidine 
NebuPent/Pentam 
Pimozide 
Orap 
Probucol 
Lorelco 
Procainamide 
Pronestyl/Procan 
Quinidine 
Cardioquin/Quinaglute 
Sevoflurane 
Ulane®, Sojourn® 
Sotalol 
Betapace 
Sparfloxacin 
Zagam 
Sulpiride 
Dogmatil®, Dolmatil® 
Terfenadine 
Seldane 
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Thioridazine 
Mellaril 
Vandetanib 
Zactima 
 
 
 
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APPENDIX E: Local Laboratory Parameters 
 
Clinical Chemistry 
Hematology, including Coagulation 
Calcium 
Red cell count, mean corpuscular volume 
Total protein 
Hemaglobin, free hemaglobin 
Albumin 
Absolute reticulocyte count 
Total bilirubin 
Platelet count 
Alanine transaminase (ALT, SGPT) 
White blood cells 
Aspartate transaminase (AST, SGOT) 
Leucocyte differential count (% & absolute) 
Lactate dehydrogenase (LDH) 
International normalized ratio or prothrombin time 
Alkaline phosphatase 
Activated partial thromboplastin time  
Glucose (random) 
Urinalysis 
Sodium 
Glucose 
Potassium 
Protein 
Bicarbonate 
Bilirubin 
Chloride 
Ketones 
Magnesium 
Blood 
Urea = Blood urea nitrogen 
pH 
Creatinine 
Specific gravity 
Phosphate 
Microscopic examination when indicated 
Amylase 
FSH (female menopausal patients; at Screening 
TSH, Free T4, T3, Free T3 
HCG (female pre-menopausal patients; at Screening) 
 
 
 
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Hammond  EM, Hayes, DF, Dowsett D, et al. American Society of Clinical 
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Hutterer, M. et al; Axl and growth arrest-specific gene 6 are frequently overexpressed in 
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Niederst, M.J.; Engelman, J.A. Bypass mechanisms of resistance to receptor tyrosine 
inhibition in lung cancer. Sci. Signaling 2013, 6, re6 
13  
Han, J. et al; Gas6/Axl mediates tumor cell apopyosis, migration and invasion and predicts 
the clinical outcome of osteosarcoma patients. Biochem. Biophys. Res. Commun. 2013, 
435, 493-500 
14  
Ben-Batalla, I.; et al; Axl, a prognostic snd therapeutic target in acute myeloid leukemia 
mediates paracrine crosstalk of leukemia cells with bone marrow stroma. Blood 2013 122, 
2443-2452 
15  
Byers, L. et al; An epithelial –mesenchymal transition gene signature predicts resistance to 
EGFR and PI3K inhibitors and identifies Axl as a thereuptic target for overcoming EGFR 
inhibitor resistance. Clin. Cancer Res. 2013, 19, 279-290 
16  
Cichon, M.A. et al; The receptor tyrosine kinase Axl regulates cell-cell adhesion and 
stemness in cutaneous squamous cell carcinoma. Oncogene 2014, 33, 4185-4192 
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17  
Zhang, Z.; et al; Activation of the Axl kinase causes resistance to EGFR-targeted therapy 
in lung cancer. Nat. Genet. 2012, 44, 852-860 
18  
Brand, T.M; et al;Axl mediates resistance to cetumximab therapy. Cancer Res. 2014, 74, 
5152-5164 
19  
Hong, J.; et al; ABL regulation by AXL promotes cisplatin resistance in oesophageal 
cancer. Cancer Res. 2013, 73, 331-340 
20  
Hong, C.C; et al; Receptor tyrosine kinase AXL confers drug resistance in acute myeloid 
leukemia. Cancer Lett. 2008, 268, 314-324 
21  
Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev 
Immunol 2004, 22, 329-60 
22  
Zou W, Chen L. Inhibitory B7-family molecules in the tumor microenvironment. Nat Rev 
Immunol 2008 Jun; 8(6), 467-77 
23  
Tan and Xiong. A flexible multi-stage design for phase II oncology trials. Pharm Stat, 
2011. 10(4):369-73. 
24  
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. 
25  
Cockcroft D, Gault MD. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976. 16:31-41. 
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SAP_001.pdf: 
Statistical Analysis Plan
This document is proprietary and confidential to INC Research LLC. 
03.007A.03 
  INC Research © LLC 
Page 1 of 69 
Sponsor Name: 
BerGenBio ASA 
Protocol Number and Title: 
BGBC007 
Merck & Co: MK-3475 PN-530 
A Phase II Multi Center Study of BGB324 in 
Combination with Pembrolizumab in Patients 
with Previously Treated, Locally Advanced 
and Unresectable or Metastatic Triple 
Negative Breast Cancer (TNBC) or Triple 
Negative Inflammatory Breast Cancer (TN-
IBC) 
Protocol Version and Date: 
Final Version 1.0, dated 02 Nov 2016 
Version 2.0, dated 13 Apr 2017 
Version 3.0, dated 22 May 2017 
Version 4.0, dated 13 Jun 2017 
INC Research Project Code: 
1007823 
Author(s): 
Manager, Biostatistics 
SAP Version: 
Final Version 1.0 
SAP Version Date: 
17 November 2017 
Notice of Confidential and Proprietary Information: 
The information contained in this document is confidential belonging to BerGenBio. Acceptance 
of this document constitutes agreement by the recipient that no information contained herein 
will be published or disclosed without prior written authorization from an official of BerGenBio. 
However, this document may be disclosed to appropriate Institutional Review Board and Ethics 
Committees or duly authorized representatives of a national regulatory authority under the 
condition that they are requested to keep it confidential. In the event of an actual or suspected 
breach of this obligation, INC Research should be notified promptly. 
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NCT03184558


Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007823 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 2 of 69 
Revision History 
 
Version # 
Date (dd-mmm-yyyy) 
Document Owner 
Revision Summary 
Draft Version 0.1 
24 Aug 2017 
 
Initial Release Version –draft 
version 01 
Draft Version 0.2 
17 Nov 2017 
 
Updated draft Version 02 
Final Version 1.0 
14 Dec 2017 
 
Final Version 1.0 
 
 
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S'atl•U~•l An•l~f. Plan 
ritt&t v~~l\' 1.-0 
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Clinical Study Report version: final 1.0
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007823 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 4 of 69 
TABLE OF CONTENTS 
Contents 
1. 
GLOSSARY OF ABBREVIATIONS ........................................................................... 8 
2. 
PURPOSE ............................................................................................................... 10 
2.1. 
Responsibilities ................................................................................................................. 10 
2.2. 
Timings of Analyses .......................................................................................................... 10 
2.2.1. 
Safety Run-In .............................................................................................................. 10 
2.2.2. 
End of Stage 1 – Efficacy Analysis ............................................................................. 10 
3. 
STUDY OBJECTIVES ............................................................................................. 12 
3.1. 
Primary Objective .............................................................................................................. 12 
3.2. 
Secondary Objectives ....................................................................................................... 12 
3.3. 
Exploratory Objectives ...................................................................................................... 12 
3.4. 
Brief Description of Study ................................................................................................ 13 
3.5. 
Subject Selection ............................................................................................................... 14 
3.5.1. 
Inclusion Criteria ......................................................................................................... 14 
3.5.2. 
Exclusion Criteria ........................................................................................................ 14 
3.6. 
Determination of Sample Size .......................................................................................... 14 
3.7. 
Treatment Assignment & Blinding ................................................................................... 15 
3.8. 
Administration of Study Medication ................................................................................ 15 
3.8.1. 
Duration of Treatment ................................................................................................. 16 
3.9. 
Study Procedures and Flowchart ..................................................................................... 17 
4. 
ENDPOINTS ............................................................................................................ 25 
4.1. 
Primary Endpoint ............................................................................................................... 25 
4.2. 
Secondary Endpoints ........................................................................................................ 25 
4.3. 
Exploratory Endpoints ...................................................................................................... 25 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007823 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
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5. 
ANALYSIS SETS ..................................................................................................... 26 
5.1. 
Screened Set ...................................................................................................................... 26 
5.2. 
Safety Set ............................................................................................................................ 26 
5.3. 
Evaluable Analysis Set ...................................................................................................... 26 
5.4. 
Protocol Deviations ........................................................................................................... 26 
6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS ........................................... 29 
6.1. 
General Methods ................................................................................................................ 29 
6.2. 
Key Definitions ................................................................................................................... 29 
6.3. 
Missing Data ....................................................................................................................... 30 
6.4. 
Visit Windows ..................................................................................................................... 31 
6.5. 
Pooling of Centers ............................................................................................................. 31 
6.6. 
Subgroups .......................................................................................................................... 31 
7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND MEDICATION .. 32 
7.1. 
Subject Disposition and Withdrawals .............................................................................. 32 
7.2. 
Demographic and Other Baseline Characteristics ......................................................... 32 
7.3. 
Medical / Surgical History ................................................................................................. 32 
7.4. 
Other Baseline Characteristics ........................................................................................ 33 
7.4.1. 
Cancer Diagnosis ........................................................................................................ 33 
7.5. 
Medication .......................................................................................................................... 33 
7.5.1. 
Prior Medication .......................................................................................................... 34 
7.5.2. 
Concomitant Medication .............................................................................................. 34 
7.6. 
Other Therapies ................................................................................................................. 34 
7.6.1. 
Prior Radiotherapy ...................................................................................................... 34 
7.6.2. 
Prior Anticancer Therapy for Study Disease ............................................................... 35 
8. 
EFFICACY ............................................................................................................... 36 
8.1. 
Primary Efficacy Endpoint and Analysis ......................................................................... 36 
8.2. 
Secondary Efficacy Endpoints and Analyses ................................................................. 37 
8.2.1. 
Duration of Response ................................................................................................. 37 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007823 
 
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03.007A.03     
  INC Research © LLC 
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8.2.2. 
Disease Control Rate .................................................................................................. 38 
8.2.3. 
Progression Free Survival ........................................................................................... 38 
8.2.4. 
Overall Survival ........................................................................................................... 39 
9. 
ANALYSIS OF PHARMACOKINETICS ................................................................... 40 
9.1. 
Presentation of Concentration Data ................................................................................ 40 
10. EXPLORATORY OBJECTIVES .............................................................................. 43 
10.1.1. 
Biomarker Analysis ..................................................................................................... 43 
11. SAFETY ................................................................................................................... 44 
11.1. 
Extent of Exposure ............................................................................................................ 44 
11.2. 
Treatment Compliance ...................................................................................................... 45 
11.3. 
Adverse Events .................................................................................................................. 45 
11.4. 
Laboratory Evaluations ..................................................................................................... 47 
11.5. 
Vital Signs ........................................................................................................................... 50 
11.6. 
12-Lead Electrocardiogram (ECG) ................................................................................... 51 
11.7. 
Physical Examination ........................................................................................................ 52 
11.8. 
Eastern Cooperative Oncology Group (ECOG) Performance Status ........................... 52 
11.9. 
Echocardiography (or MUGA) .......................................................................................... 52 
12. INTERIM ANALYSES .............................................................................................. 54 
12.1. 
Data Review Committee .................................................................................................... 54 
12.2. 
Interim Analysis ................................................................................................................. 54 
13. CHANGE FROM ANALYSIS PLANNED IN PROTOCOL ........................................ 56 
14. REFERENCE LIST .................................................................................................. 57 
15. PROGRAMMING CONSIDERATIONS .................................................................... 58 
15.1. 
General Considerations .................................................................................................... 58 
15.2. 
Table, Listing and Figure Format ..................................................................................... 58 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007823 
 
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03.007A.03     
  INC Research © LLC 
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15.2.1. 
General ........................................................................................................................ 58 
15.2.2. 
Headers ....................................................................................................................... 59 
15.2.3. 
Display Titles ............................................................................................................... 59 
15.2.4. 
Column Headers ......................................................................................................... 59 
15.2.5. 
Body of the Data Display ............................................................................................. 59 
15.2.6. 
Footnotes .................................................................................................................... 62 
16. QUALITY CONTROL ............................................................................................... 63 
17. INDEX OF TABLES AND FIGURES ........................................................................ 64 
18. INDEX OF LISTINGS ............................................................................................... 67 
19. APPENDICES .......................................................................................................... 69 
 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007823 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 8 of 69 
1. 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Description 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
CI 
Confidence Interval 
CM(s) 
Concomitant medication(s) 
Cmax 
Maximum concentration achieved 
CR 
Complete Response 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of Variation 
DCR 
Disease Control Rate 
DoR 
Duration of Response 
DRC 
Data Review Committee 
DY 
Relative Day 
ECG 
Electrocardiogram 
ECI 
Events of Clinical Interest 
eCRF 
Electronic Case Report Form 
Gmean 
Geometric Mean 
IV 
Intravenous(ly) 
K-M 
Kaplan-Meier 
LLOQ 
Lower Limit of Quantification 
LPLV 
Last patient, last visit 
Max 
Maximum 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Minimum 
MUGA 
MULTI Gated Acquisition Scan 
N 
Number 
N/A 
Not Applicable 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007823 
 
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03.007A.03     
  INC Research © LLC 
Page 9 of 69 
Abbreviation 
Description 
NA 
Not Applicable 
NC 
Not Calculable 
NCI 
National Cancer Institute 
NQ 
Not Quantifiable 
ORR 
Objective Response Rate 
OS 
Overall Survival 
PFS 
Progression Free Survival 
PK 
Pharmacokinetic(s) 
PR 
Partial Response 
PT 
Preferred Term 
RECIST 
Response Evaluation Criteria In Solid Tumors 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SI 
Standard International System of Units 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
StD 
Standard Deviation 
t1/2 
Elimination half-life 
TEAE 
Treatment Emergent Adverse Event 
TLF(s) 
Table(s), Listing(s) and Figure(s) 
tmax 
Time of maximum concentration 
TN-IBC 
Triple Negative Breast Cancer 
 
TNBC 
Triple Negative Inflammatory Breast Cancer 
WHO-DD 
World Health Organization Drug Dictionary 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007823 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 10 of 69 
2. 
PURPOSE 
The purpose of this statistical analysis plan (SAP) is to ensure that the data listings, 
summary tables, and figures which will be produced, and the statistical methodologies 
that will be used, are complete and appropriate to allow valid conclusions regarding the 
study objectives.   
2.1. 
RESPONSIBILITIES 
INC Research will perform the overall safety and efficacy statistical analyses and is 
responsible for the production and quality control of all tables, listings and figures 
(TLFs). 
Pharmacokinetic (PK) analyses will be performed by Charlie Brindley (labs based in 
Scotland). Pharmacokinetic parameters will be estimated for each subject using a fully 
validated version of WinNonlin Pro (Version 6.3 PhoenixTM, Pharsight®), or later version 
as appropriate and the PK TLF outputs will be produced by INC Research. 
2.2. 
TIMINGS OF ANALYSES 
2.2.1. 
Safety Run-In  
Pembrolizumab has not previously been combined with BGB324 in patients (in any 
indication) and therefore, a safety run-in will include a total of 12 subjects.  
A Data Review Committee (DRC), consisting of Principal Investigators, the Sponsor’s 
(BerGenBio and Merck) Medical Monitors, and invited experts as required, will review all 
patient safety data after 6 patients have been enrolled and had the potential to be 
followed for 6 weeks (2 cycles), and then again after a further 6 patients (total 12 
patients) have had the potential for 6 weeks follow-up. At each of these safety reviews, 
the DRC will consider the rate of BGB324 dose reductions and the rate of permanent 
discontinuation from BGB324 and pembrolizumab. During the safety run-in reviews, the 
DRC will have the option to recommend a lower dose of BGB324 (dose level -1) for new 
patients. Dose level -1 is defined as 200 mg BGB324 on Days 1, 2 and 3 followed by 100 
mg from Day 4 onwards.  
 
2.2.2. 
End of Stage 1 – Efficacy Analysis  
The DRC will meet to review the overall risk/benefit profile of the combination, 
together with the ORR after 28 subjects have had the potential for at least 24 weeks of 
follow-up. The DRC will document the ORR and if it favors the null hypothesis for 
futility, or the alternative hypothesis for demonstration of activity, and recommend if 
the study should proceed to evaluate up to a further 28 subjects. Recruitment to the 
study will be halted whilst the Stage 1 interim analysis is conducted. Recruitment will 
recommence if the decision is made to continue to the maximum of 56 evaluable 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007823 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 11 of 69 
subjects, which is when the final analysis will be performed. A full analysis will be 
performed at the end of stage 1. 
The Sponsor may request ad-hoc DRC meetings at any time during the study to assess 
interim safety data and review the need for dose modifications.  
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007823 
 
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03.007A.03     
  INC Research © LLC 
Page 12 of 69 
3. 
STUDY OBJECTIVES 
3.1. 
PRIMARY OBJECTIVE 
The primary objective of this study is to assess the anti-tumor activity of the 
combination treatment of BGB324 and Pembrolizumab in patients with previously 
treated locally advanced and unresectable or metastatic TNBC or TN-IBC. 
 
3.2. 
SECONDARY OBJECTIVES 
The secondary objectives of this study are:  
 
To assess the safety of BGB324 and Pembrolizumab when given in combination in 
patients with previously treated locally advanced and unresectable or metastatic 
TNBC or TN-IBC. 
 
To further assess the anti-tumor activity of the combination of BGB324 and 
Pembrolizumab. 
 
To evaluate the pharmacokinetic profile of BGB324 when given with 
Pembrolizumab. 
3.3. 
EXPLORATORY OBJECTIVES 
The exploratory objective of this study is: 
 
To assess relevant biomarkers  
Note:  
The PD-L1 and Axl expression status will be available at the time of the database lock 
and will be utilized in the analysis of the study, as described in Section 8.11 of the 
protocol.  
However, results from other biomarkers (for example, for the assessment of Axl 
signaling and inhibition) might not be available at the time of the interim analysis 
clinical database lock, but are intended to be completed before the closure of the 
study, or before the clinical study report is written at study completion (whichever is 
later) – see Section 8.6 of the protocol. INC Research will receive the biomarker results 
and merge with patient demographic and other baseline and outcome data, and  
produce a separate analysis plan and report (addendum to the CSR) for biomarker 
analysis. All samples will be destroyed within 5 years of the last subject being entered 
to Stage 1.  
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007823 
 
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03.007A.03     
  INC Research © LLC 
Page 13 of 69 
 
3.4. 
BRIEF DESCRIPTION OF STUDY 
This is an open-label, multi-center, single arm, phase II study to assess the anti-tumor 
activity and safety of BGB324 when given in combination with Pembrolizumab in 
patients with previously treated, locally advanced and unresectable or metastatic TNBC 
or TN-IBC.Pembrolizumab has not previously been combined with BGB324 in patients (in 
any indication) and therefore, a safety run-in will include a total of 12 patients. The 
internal DRC will conduct a review of the safety data from the first 6 subjects who have 
had the potential to be followed for at least  6 weeks (minimum 2 cycles), and again 
when a further 6 subjects (12 subjects in total) have had the potential to be followed 
for at least 6 weeks. The DRC will consider the emerging safety profile, together with 
the number of patients requiring a BGB324 dose reduction and the number of patients 
requiring either BGB324 or pembrolizumab or both to be permanently discontinued. The 
DRC will consider whether a revised BGB324 dose (dose level -1) is appropriate for new 
patients entering the study.The study will utilise a 2-stage, single arm, extension of 
Simon’s 2-stage design1 with one (efficacy) interim and a final analysis. The interim 
analysis will be conducted when 28 subjects are evaluable for Objective Response Rate 
(ORR). If 5 or fewer responses are observed in up to 28 subjects, the trial will be 
terminated in favor of the null for futility. If 11or more responses are observed, then 
the trial will be stopped in favor of the alternative for demonstration of activity. Where 
6 to 10 subjects have an observed response at the interim analysis, up to a further 
28subjects may be evaluated, for a total of 56 subjects (see Section 8.1 of the 
protocol), taking the overall risk: benefit of the combination into consideration.  
Recruitment to the study will be halted after 28 evaluable subjects have been entered 
and whilst the Stage 1 interim analysis is conducted. Recruitment will recommence if 
the decision is made to continue to the maximum of 56 evaluable subjects. If a total of 
17 or more responses are seen in 56 patients, then the null will have been rejected in 
favour of the alternative; otherwise the null will not have been rejected. 
The following figure (Figure 1) summarizes the study design in a form of a diagram. 
 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007823 
 
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03.007A.03     
  INC Research © LLC 
Page 14 of 69 
 
Figure 1: Schematic Diagram of the Study Design 
 
3.5. 
SUBJECT SELECTION 
Adult patients with pre-treated, advanced or metastatic TNBC  will be enrolled in the 
study. 
3.5.1. 
Inclusion Criteria 
The inclusion criteria are defined in the protocol Section 3.1. 
3.5.2. 
Exclusion Criteria 
The exclusion criteria are defined in the protocol Section 3.2. 
3.6. 
DETERMINATION OF SAMPLE SIZE 
Up to 56 evaluable subjects will be enrolled in this study. Approximately 7564 patients 
will be screened in order to identify up to 5648 subjects who meet all of the inclusion 
1
BGBC007 - Phase II 2 stage study of BGB324 in combination with pembrolizumab
Triple Negative Breast Cancer (TNBC) and TN-Inflammatory Breast Cancer (TN-IBC)
Previously treated, 
locally advanced un-
resectable or advanced 
TNBC or TN-IBC
•
Previous treatment 
with a taxane and/or 
anthracycline
•
Locally advanced, 
unresectable or 
metastatic
•
Measurable disease
•
Fresh tissue biopsy
•
PD-L1 +ve and -ve
•
Axl +ve and -ve
Stage 1 – interim analysis.
N=28 patients – each patient has 
the potential for at least 24 weeks 
follow-up
Stop at this stage for:
Futility (Ho:20% if <5 responses ) 
or
Efficacy (H1:35% if >11 responses) 
or 
unfavourable risk/benefit
Efficacy:
10 endpoint: 
• Objective Response Rate
20 endpoints:
•
Duration of Response
•
Disease Control Rate
•
Time to progression
•
Survival at 12 months
•
Response by Biomarker expression
Safety
Pk
Stage 2 – Final 
analysis.
N=56 patients –
each patient has the 
potential for at least 
24 weeks follow-up
Endpoints as at 
Stage 1
•
Pembro 200mg fixed
•
BGB324 400mg loading 
dose on days1-3, then 
200mg daily
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007823 
 
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03.007A.03     
  INC Research © LLC 
Page 15 of 69 
and exclusion criteria and who are evaluable for response. This assumes a 25% screen 
failure rate, given the need for subjects to provide a fresh tissue biopsy sample. 
The study will employ a k-stage single arm design, an approach derived from basic 
statistical theory2. If p denotes the true tumor response rate with drug, the null and 
alternative hypotheses to be assessed in this trial are:  
H0 : RR=p0 vs H1 : RR=p1 (p0 <p1), with p0=0. 20 and p1=0.35 
To test these hypotheses, this trial is a k-stage single arm design with k=2, being an 
extension of Simon’s 2-stage design1. In this design with k=2, there are two analyses: a 
single interim and a final analysis. At the interim, the response rate is evaluated in a 
fixed number (m) of subjects using a predefined decision rule to determine if the study 
should stop for futility (in the situation where the null is confirmed) or for efficacy (in 
the situation where the alternative hypothesis is confirmed). If neither hypothesis is 
confirmed, a further fixed number of subjects (l) are assessed for response and a final 
analysis is performed on all (m+l) subjects. In both interim and final analyses, the 
response rate will be presented together with the associated exact 90% confidence 
interval (CI). 
With p0=0.20 and p1=0.35, the interim will be conducted with m =28 subjects. If 5 or 
fewer responses are observed in these 28 subjects, the trial will be terminated in favor 
of the null for futility; however, if 11 or more responses are observed, then the trial 
will be stopped in favor of the alternative for demonstration of activity. Otherwise a 
further 28 subjects may be evaluated, for a total of 56 subjects. If a total of 17 or more 
responses are seen in 56 subjects, then the null will have been rejected in favor of the 
alternative; otherwise the null will not have been rejected. 
Based on 500,000 trial simulations, this design provides an overall power of 80.6 % to 
test the stated null and alternative hypothesis with a 1-sided Type I error rate of 0.048. 
Under the null the probability of correctly stopping for futility at the interim is 50.2% 
and, under the alternative, the probability of correctly stopping for activity at the 
interim is 38.4%. Consequently, the expected sample size for the design is 42-
44subjects. 
3.7. 
TREATMENT ASSIGNMENT & BLINDING 
This is an open-label study, and there are no blinding/un-blinding procedures. 
 
3.8. 
ADMINISTRATION OF STUDY MEDICATION 
BGB324 will be administered orally once daily. On the first 3 days of administration, the 
BGB324 dose will be a ‘loading’ dose of 400 mg Days 1, 2 and 3. From Day 4 onwards, 
subjects will receive a daily dose of 200 mg daily. If the DRC recommend dose level -1 
for new subjects (after or during the safety run-in), the dose of BGB324 will reduce to a 
loading dose of 200mg on Days 1, 2 and 3 and to 100mg from Day 4 onwards.  
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Clinical Study Report version: final 1.0
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
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BGBC007 / Merck & Co: MK-3475 PN-530  
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03.007A.03     
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Page 16 of 69 
A fixed dose of 200mg Pembrolizumab will be given by intravenous (IV) infusion over 30 
minutes every 3 weeks in all subjects. The 3-weekly dosing Pembrolizumab dosing 
schedule will be used to define 3-week treatment cycles throughout the treatment 
period of the study.  
The BGB324 and Pembrolizumab dose levels selected for this study are summarized in 
Table 1.  
Table 1: BGB324 and Pembrolizumab Dosing 
BGB324: 
Loading Dose:  
Days 1, 2 & 3 
Daily Dose:  
Day 4 onwards 
Frequency 
Route of 
administration 
Dose level 
400 mg 
200 mg 
Daily 
Oral 
Dose level -1 
200 mg 
100 mg 
Daily 
Oral 
Pembrolizumab 
Dose 
Regimen 
Frequency 
Route of 
administration 
200 mg 
Day 1 of each cycle  
Every  
3 weeks 
IV 
 
Dosing of both drugs will commence on Day 1. On days when both BGB324 and 
Pembrolizumab are given, Pembrolizumab will be given first and subjects will be 
observed for 1 hour for infusion or other adverse events (AEs). BGB324 may then be 
administered. 
3.8.1. 
Duration of Treatment 
BGB324 and Pembrolizumab will be given until disease progression (note that in the 
absence of clinical deterioration, treatment can continue and clinical progression 
should be confirmed after 4 weeks) or until an unacceptable toxicity has occurred which 
necessitates treatment withdrawal (see Section 66. of the protocol), or until 106 weeks 
(35 cycles), equivalent to 24 calendar months. 
Patients who discontinue BGB324 treatment (for reasons other than disease progression) 
may be able to continue with (monotherapy) Pembrolizumab until 106 weeks (that is, 35 
completed cycles of Pembrolizumab, equivalent to 24 calendar months). 
Patients who discontinue Pembrolizumab (for reasons other than disease progression) 
may be able to continue with BGB324 for up to 106 weeks (equivalent of 24 calendar 
months). 
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Clinical Study Report version: final 1.0
Page 17 of 127


Statistical Analysis Plan  
Final Version 1.0 
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BGBC007 / Merck & Co: MK-3475 PN-530  
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03.007A.03     
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Otherwise, in the absence of progression, toxicity, or other reason for stopping 
treatment, Pembrolizumab in combination with BGB324 will be given until the end of 
cycle 35 (this cycle ends at approximately week 106, 24 months). 
3.9. 
STUDY PROCEDURES AND FLOWCHART 
The study will consist of a Screening period, Treatment period (made up of consecutive, 
3-week cycles), a Post Treatment Visit, and Follow-up Assessments. Subjects must 
provide informed consent prior to commencing the study screening procedures. All 
subjects are required to have a fresh (newly acquired) tumor biopsy taken at Screening, 
and are required to provide sufficient tumor specimens to enable both Axl kinase and 
PD-L1 expression to be measured. Subjects will attend the clinic for Screening period 
assessments up to 28 days before receiving the first dose of study treatment. The Post 
Treatment Visit will occur 30 days (+/- 3 days) after the subject has discontinued both 
study treatments. All subjects will continue in Follow-up visits and continue to have 
their disease assessed and scanned (unless progression of disease has already been 
confirmed) and for survival status (see Figure 2).  
The study schedule will continue in keeping with the Study Assessment calendar. 
Subjects will be required to visit the study sites for each study visit (which includes 
each Pembrolizumab dose). From Cycle 2 onwards, a tolerance window of +/- 3 days is 
permitted relative to Day 1. Pembrolizumab that cannot be given within these tolerance 
windows will be treated as a missed dose, although it is acceptable to have a 
Pembrolizumab dose interruption for up to 3 weeks for reasons other than toxicity. See 
Section 6.5.3 of the protocol for details on Pembrolizumab related toxicity dose 
interruption, including the duration of dose interruption. 
 
 
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Clinical Study Report version: final 1.0
Page 18 of 127


Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
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03.007A.03     
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Page 18 of 69 
 
Figure 2: Study Flow Chart 
   
 
Please refer to Schedule of Study Assessments (Table 3 and Table 4) for full details of 
all study assessments. Table 2 summarizes the timing of Pembrolizumab administration 
up to Cycle 35 (approximately 24 months of treatment) in relation to the timing of 
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Clinical Study Report version: final 1.0
Page 19 of 127


Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007823 
 
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03.007A.03     
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Page 19 of 69 
disease assessment. Table 3 summarizes the schedule of assessments in Year 1 and 
Table 4 summarizes the schedule of assessments in Year 2.  Assessments requiring 
specific timing relative to the BGB324 or Pembrolizumab dose are described in the 
footnotes to Schedule of Study Assessments – Table 3 and Table 4.  
Subjects who discontinue BGB324 treatment (for reasons other than disease progression) 
may be able to continue with (monotherapy) Pembrolizumab until 106 weeks (that is, 35 
completed cycles of Pembrolizumab). These subjects will no longer be required to have 
the following assessments from 6 weeks after the discontinuation of BGB324 (unless 
clinically indicated):  
• 
ECG;  
• 
Echocardiogram (or MULTI Gated Acquisition Scan [MUGA]);  
• 
Optional tumor biopsy (for example at subsequent progression);  
• 
Biomarker sampling.  
Subjects who withdraw from either or both study treatments prior to disease 
progression will continue to have tumor imaging assessments on study every 12 weeks 
until disease progression is documented (and confirmed, if necessary). The date of 
disease progression will be captured.  
Subjects will continue to have their survival status checked every 12 weeks until either 
the subject dies or the study ends. 
 
 
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Clinical Study Report version: final 1.0
Page 20 of 127


Statistical Analysis Plan  
Final Version 1.0 
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BGBC007 / Merck & Co: MK-3475 PN-530  
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Table 2: Pembrolizumab 3-Weekly Schedule and Disease Assessment Timings 
Year 1, First 6 months* 
Week: 
1 
4 
7 
10 
13 
16 
19 
22 
25 
Start of month: 
1 
 
 
 
4 
 
 
 
7 
Pembrolizumab cycle: 
1 
2 
3 
4 
5 
6 
7 
8 
9 
Disease Assessment / Scan  
(+/- 7 days): 
Scanned at Screening 
 
 
X 
 
 
X 
 
 
Year 1, Second 6 months* 
Week: 
28 
31 
34 
37 
40 
43 
46 
49 
52 
Start of month: 
 
 
 
10 
 
 
 
13 
 
Pembrolizumab cycle: 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Disease Assessment / Scan 
(+/- 7 days): 
X 
 
 
X 
 
 
X 
 
 
Year 2, First 6 months* 
Week: 
55 
58 
61 
64 
67 
70 
73 
76 
79 
Start of month: 
 
 
16 
 
 
 
19 
 
 
Pembrolizumab cycle: 
19 
20 
21 
22 
23 
24 
25 
26 
27 
Disease Assessment / Scan  
(+/- 7 days): 
 
X 
 
 
 
X 
 
 
 
Year 2, Second 6 months* 
Week: 
82 
85 
88 
91 
94 
97 
100 
103 
106 
Start of month: 
 
22 
 
 
 
25 
 
 
 
Pembrolizumab cycle: 
28 
29 
30 
31 
32 
33 
34 
35 
Stop 
Disease Assessment / Scan  
(+/- 7 days): 
X 
 
 
 
X 
 
 
 
X 
*A month is 4 weeks (not a calendar month). 
 
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BerGenBio, BGBC007
Clinical Study Report version: final 1.0
Page 21 of 127


Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
BGBC007 / Merck & Co: MK-3475 PN-530  
INC Research 1007828 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
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Page 21 of 69 
Table 3: Schedule of Study Assessments – Year 1 
 
Screening 
Cycle 1 (21-d cycle) 
Cycle Number – Year 1 
Post 
Treatmen
t Visit14 
Follow 
Up15 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
Day 
Up to -28 
1 
2 
3 
4 
8 
15 
22 
43 
64 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
+30 from 
last dose 
Start of Week # (+/- 3 days) 
-4 weeks to 
0 
1 
2 
3 
4 
7 
10 
13 
16 
19 
22 
25 
28 
31 
34 
37 
40 
43 
46 
49 
  
  
Demographics17 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion/exclusion checks 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy or FSH test1 
X 
  
  
  
  
  
  
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
ECOG PS 
X 
  
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Physical examination3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Clinical chemistry18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Hematology18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Coagulation4 
X 
X 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Urinalysis 
X 
X 
  
  
  
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Thyroid function tests5 
X 
  
  
  
  
  
  
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
  
X 
X 
  
Echocardiogram (or MUGA)16 
X 
  
  
  
  
  
  
  
  
  
X 
X 
  
  
ECG6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Tumor imaging7 
X 
  
  
  
  
  
  
  
X 
X 
X 
X 
X 
(X) 
(X) 
Disease Assessment7 
 X 
  
  
  
  
  
  
  
X 
  
X 
  
  
X 
  
  
X 
  
  
X 
(X) 
(X) 
Tumor (fresh tissue) biopsy8 
X 
(X: up to 2 optional post treatment biopsies) 
  
  
  
Tumor (archival)8 
(X) 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Biomarkers9 
X 
(X) 
  
  
X 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
Pembrolizumab dosing10 
  
X 
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
BGB324 dosing11 
  
X – consecutive daily dosing in 21-d cycles  
  
  
PK sampling (BGB324)12 
  
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PK sampling (pembrolizumab )12 
  
X 
X 
X 
X 
X 
X 
 X 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Adverse events 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
X 
(X) 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
X 
(X) 
Subsequent anti-cancer 
treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Survival Follow Up15 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
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BerGenBio, BGBC007
Clinical Study Report version: final 1.0
Page 22 of 127


Statistical Analysis Plan  
Final Version 1.0 
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BGBC007 / Merck & Co: MK-3475 PN-530  
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Table 4: Schedule of Study Assessments – Year 2 
 
Cycle Number – Year 2 
Post Treatment 
Visit14 
Follow 
Up15 
18 
19 
20 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
32 
33 
34 
35 
Day 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
113 
+30 from last 
dose 
Week Number (+/- 3 days) 
52 
55 
58 
61 
64 
67 
70 
73 
76 
79 
82 
85 
88 
91 
94 
97 
100 
103 
  
  
Pregnancy test1 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
ECOG PS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Vital signs2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Physical examination3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Clinical chemistry18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Hematology18 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Coagulation4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Urinalysis 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
X 
  
Thyroid function tests5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Echocardiogram (or MUGA)16 
  
  
  
X 
X 
 
  
  
ECG6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Tumor imaging7 
  
X 
  
  
X 
X 
X 
 
(X) 
(X) 
Disease Assessment7 
  
  
X 
  
X 
  
  
 X 
  
 X 
 
(X) 
(X) 
Tumor (fresh tissue) biopsy8 
(X: up to 2 optional post treatment biopsies) 
 
 
Pembrolizumab dosing10 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
BGB324 dosing 11 
X – consecutive daily dosing in 21-d cycles 
 
 
Adverse events 
 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
X 
X 
(X) 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
X 
X 
(X) 
Subsequent anti-cancer treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Survival Follow Up15 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
X 
General instructions: 
 
Informed Consent must be obtained using the current version of the PIS/ICF prior to commencing Screening. 
 
From C2 onwards a tolerance window of +/-3 days is permitted. Other tolerance windows for specific study assessments are described in the footnotes below. 
 
On dosing days, assessments should be performed prior to dosing unless specified otherwise. 
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Clinical Study Report version: final 1.0
Page 23 of 127


Statistical Analysis Plan  
Final Version 1.0 
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 
(X) denotes an optional sample; or a sample which is not taken at every cycle; or the particular assessment is ‘if applicable’; X denotes a study visit with multiple 
samples. Please refer to Footnotes. 
 
Additional assessments may be carried out at any point in the study where clinically indicated. 
Footnotes: 
1 A pregnancy test is required within 3 days prior to C1D1. A negative pregnancy test may be confirmed by urine or blood test. Where a urine test is positive or equivocal, 
a blood test must be performed to confirm the result. Patients requiring confirmation of post-menopausal status will have FSH and oestradiol levels assessed at 
Screening. Where applicable, and in accordance with local regulations, a pregnancy test should be conducted at each cycle (or monthly). 
2 Vital signs will include temperature, systolic blood pressure, diastolic blood pressure, heart rate and respiratory rate. On pembrolizumab dosing days, vital signs will be 
taken both pre-dose and at the end of infusion. 
3 Physical examination includes height at Screening and weight at Screening and the start of each cycle. After Screening, further assessments may be symptom-directed. 
4 Coagulation parameters may be assessed from the Hematology sample. 
5 Thyroid function testing may be assessed from the Clinical chemistry sample. 
6 For each ECG assessment, triplicate 12-lead ECGs must be taken less than 5 minutes apart, with the patient having rested for at least 10 minutes in the supine position 
prior to assessment. Time points are relative to BGB324 dosing: C1 D1 pre-dose and 6 hours after dose; D2 pre-dose; D3 pre-dose; D4 pre-dose. All other time-points 
are pre-dose unless clinically indicated. If a patient permanently discontinues BGB324 (but continues pembrolizumab), the last ECG will be performed at the next 
pembrolizumab administration. If a patient has BGB324 interrupted for 14 days for toxicity or QTC prolongation, an ECG will be conducted twice weekly for the 
following 2 weeks once a patient restarts BGB324 daily dosing. 
7 Tumor imaging will be performed at Screening, then every 9 weeks for the first 46 weeks, and then every 12 weeks thereafter (+/- 7 days). A tumor response or disease 
progression should be confirmed no less than 28 days after the initial finding. If treatment administration is misaligned with weeks (e.g. because of treatment delay), 
the tumor imaging schedule should be maintained by week number and continue if necessary. The schedule of disease assessments is every 12 weeks once a patient 
has stopped (one or both study treatments) or completed their treatment in the absence of progression. These may continue into Follow Up. 
8 Fresh tumor tissue from all patients at Screening is mandatory, and optional at up to 2 time points during participation in the clinical trial (‘on-study’ biopsy). Where 
possible, these optional samples should be taken at the point of tumor response or progression. Suitable archival biopsy material may also be obtained at Screening. 
Please refer to protocol Section 5.3.13, the Laboratory or Pathology Manual for full details on biopsy sample collection, time-points, processing, storage and shipment. 
If a patient discontinues BGB324 (but continues pembrolizumab), there is no requirement for the optional ‘on study’ biopsy. 
9 Blood samples will be collected at Screening (or D1 pre-dose), D4, D8, then at every study visit up to and including C9 D1 to prepare PBMC and serum samples for Axl 
signaling and inhibition biomarker assessment. Please refer to the Laboratory Manual for full details on biomarker sample collection, time-points, processing, storage 
and shipment. If a patient discontinues BGB324 (but continues pembrolizumab), there is no requirement for biomarker blood samples. 
10 Pembrolizumab dose of 200 mg will be administered every 3 weeks (timing window +/- 3 days). Each dose will be infused over 30 minutes (timing window -5/+10 
minutes) 
11 BGB324 will be taken orally once daily. On visits when pembrolizumab and BGB324 are given on the same day, pembrolizumab must be given first and the patient 
observed for 1 h prior to administration of BGB324. 
12 a) The maximum PK sampling time points for the measurement of BGB324 in blood will be: C1 D1 pre-dose, 2, 4, 6, 8 hours ; D2 pre-dose; D3 pre-dose, 2, 4, 6, 8 hours; 
D4 pre-dose; and then pre-dose at C1D8, C1D15, C2D1 and then C3D1. Samples should be taken contemporaneously with the ECG assessments on C1 D1-4. All sample 
times are approximate but every effort must be made to take PK samples at specified times.  
________________________________________________________
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Clinical Study Report version: final 1.0
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Statistical Analysis Plan  
Final Version 1.0 
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03.007A.03     
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Page 24 of 69 
b) The maximum PK sampling time points for the measurement of pembrolizumab in blood will be: C1 D1 pre-dose; D2; D3; D4; and then at C1D8, C1D15; C2D1 pre-
pembro dose and then C3D1 pre-pembro dose. All sample times are approximate but every effort must be made to take PK samples at specified times 
c) All sample times are approximate and every effort must be made to take PK samples at specified times. Actual sampling times must be recorded in order to assess 
result relative to BGB324 or pembrolizumab dose. Please refer to the local Laboratory Manual for full details on PK sample collection, time-points, processing, storage 
and shipment. 
13 D1 of next cycle would be “D22” of the previous cycle. 
14 A Post Treatment Visit is to be conducted up to 30 days (+/-3 days) from last dose of study drug. Adverse events and concomitant medications must be assessed to 30 
days. Some AEs must be assessed for longer (see Section 7.4.3 and Section 7.5 of the protocol). Other assessments may be carried out between 7-30 days from last 
dose. Tumor imaging and disease assessment is only required where is part of next scheduled assessment (where patient has not yet progressed) or to confirm 
response or progression.  
15 Tumor imaging and disease assessment will continue every 12 weeks from the last dose of study drug where the patient has not yet progressed or to confirm response 
or progression. An assessment of disease status, survival status and details of any anti-cancer therapies received after last dose of study drug will also be collected. 
Survival status (every 12 weeks) can be collected by telephone. 
16 Echocardiogram (or MUGA) will be conducted every 6 months whilst a patient receives BGB324. If a patient discontinues BGB324 (but continues pembrolizumab), a 
final echocardiogram (or MUGA) will be conducted only if one is scheduled in the following 6 weeks. 
17 Demography – race, ethnicity, gender, age (birth month and year). 
18 Hematology and Clinical Chemistry to be assessed at a suitable time prior to administration of study treatment(s). 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
BerGenBio ASA 
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4. 
ENDPOINTS 
4.1. 
PRIMARY ENDPOINT 
The primary endpoint for this study is the Objective Response Rate (complete response 
and partial response). 
4.2. 
SECONDARY ENDPOINTS 
The secondary endpoints of this study will consist of: 
 
The number and frequency of adverse events; 
 
Safety laboratory parameters; 
 
Vital signs; 
 
12-Lead Electrocardiograms (ECGs); 
 
Disease Control Rate (DCR); 
 
Duration of Response (DoR);  
 
Progression-Free Survival (PFS);  
 
12-month Overall Survival (OS); 
 
Pharmacokinetic parameters including Cmax, AUC, t1/2. 
4.3. 
EXPLORATORY ENDPOINTS  
The exploratory endpoints of this study will consist of: 
 
PD-L1 and Axl expression in patients with TNBC and TN-IBC; 
 
Any correlation or association between expression level of PD-L1 and Axl; 
 
Anti-tumor outcomes, such as ORR;  
 
Assessment of relevant biomarkers in tumor and blood which support immune 
modulation and Axl signaling. 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
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     INC Research 1007823 
 
 
 
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5. 
ANALYSIS SETS 
5.1. 
SCREENED SET 
The Screened Set will include all subjects who are enrolled in the study or are screening 
failures. The Screened Set will be used for the listing and summaries of subject 
disposition and for the listing of Adverse Events and protocol deviations. 
5.2. 
SAFETY SET 
The Safety Set will include all subjects who are enrolled in the study and who have 
received at least one dose of study product (BGB324 and/or Pembrolizumab). The 
Safety Set will be used for all analyses of safety endpoints and for the presentation of 
subjects in all subject listings, with the exception of subject disposition, protocol 
deviations, efficacy and AE listings. 
For some objectives (pharmacokinetics and biomarker) a subgroup of subjects of the 
safety set with respective baseline and post-baseline measurements will be used. 
5.3. 
EVALUABLE ANALYSIS SET 
The Evaluable analysis set will include all evaluable subjects; subjects that have 
received at least one combination dose of Pembrolizumab and BGB324 and who have 
measurable disease at entry, as determined by the Investigator Site assessment. The 
Evaluable analysis set will be used for summarizing and listing the efficacy objectives. 
5.4. 
PROTOCOL DEVIATIONS 
Protocol deviations will be addressed by monitoring on an ongoing basis. All protocol 
deviations are to be recorded in RAVE (Table 5) with the indication of whether they are 
major or minor as determined by the Study Management Team, in cooperation with 
Data Management, Medical Monitoring, and the Sponsor.  
All protocol deviations will be listed only for all subjects in the Screened Set, including 
their assignment of minor or major, the date the deviation occurred and the action 
taken. 
 
Table 5: List of protocol deviations that are recorded in Rave 
 
Protocol Deviation Category 
Important 
Non-Important 
Inclusion/Exclusion Criteria: I/E not met 
x 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
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     INC Research 1007823 
 
 
 
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Protocol Deviation Category 
Important 
Non-Important 
Informed Consent: ICF not signed or signed 
late 
x 
 
Informed Consent: ICF used was not current 
approved version 
x 
 
Informed Consent: Other 
x 
 
Randomization: Treated and not Enrolled 
x 
 
Randomization: Multiple Enrolments of the 
same patient 
x 
 
Randomization: Other 
x 
 
Investigation 
Product/Dosing: 
IP 
Storage 
issues, IP provided to subject 
x 
 
Investigation 
Product/Dosing: 
IP 
Storage 
issues, IP NOT provided to subject 
 
x 
Investigation Product/Dosing: IP Dosing – 
patient did not receive dose per protocol 
x 
 
Investigation Product/Dosing: IP Dosing – site 
did not adhere to dose reduction guidelines 
x 
 
Investigation Product/Dosing: other 
x 
 
Study Procedures: Prohibited Concomitant 
Treatment 
 
x 
Study Procedures: PK samples not collected or 
not collected per protocol 
x 
 
Study Procedures: Biopsy not collected as per 
protocol/lab manual 
x 
 
Study Procedures: SAE or ECI reported late 
x 
 
Study Procedures: Visit not performed within 
visit window 
 
x 
Study Procedures: ECGs not performed 
x 
 
Study 
Procedure: 
Other 
Procedure 
not 
performed 
 
x 
Study Procedure:  
Site Staff Authorization, Delegation, Training 
 
x 
Study Procedures: Patient Met withdrawal 
criteria but not withdrawn 
x 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
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     INC Research 1007823 
 
 
 
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Protocol Deviation Category 
Important 
Non-Important 
Study Procedures: Imaging not performed per 
protocol, including the scheduled CT scans for 
PD confirmation 
x 
 
Study Procedure: Other 
 
x 
 
 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
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     INC Research 1007823 
 
 
 
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6. 
GENERAL ASPECTS FOR STATISTICAL ANALYSIS 
6.1. 
GENERAL METHODS 
This section describes analytical analysis issues that relate to all or some of the analytic 
analysis sections that follow. It describes general guidelines for analysis as well as the 
following items:  
 
SAS version 9.3 or higher will be used. 
 
 INC Research will be responsible for reporting the demographic, safety and 
efficacy data, including the listings and tables of PK data. However, INC 
Research is not responsible for the derivation of the PK parameters. 
 
Unless otherwise specified, summaries will be presented by dose level (if needed 
based on the DRC recommendation) and overall. 
 
The total number of subjects in the treatment group will be used as the 
denominator for percentage calculations, unless stated otherwise in the table 
shell.  
 
Continuous variables will be summarized using the number of observations (n), 
mean, standard deviation (SD), median, minimum, and maximum. Categorical 
variables will be summarized using number of observations (n), frequency and 
percentages of subjects. 
 
All subjects who provide informed consent will be accounted for in this study. 
 
In general, the listings will be sorted by subject number and assessment date 
(and time), if applicable.  
 
Multiple assessments at a given time point (planned, repeat, and unscheduled) 
will not be included in summary tables unless specified otherwise, but will be 
included in the listings. For example if there are multiple laboratory results at a 
given visit, the closest value to the scheduled visit date will be used, or the 
earlier, in the event the values are equidistant from the nominal visit date. The 
listings will highlight the value for the subject that contributed to the summary 
table, wherever feasible. 
 
See Section 15 for INC standard programming conventions. 
6.2. 
KEY DEFINITIONS 
Study Day is the day relative to the date of first dose of study drug, where Day -1 is the 
day before the first dose of study drug and Day 1 is the day of study drug. Note that 
‘study drug’ refers to BGB324 and/or Pembrolizumab. 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
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The first dose date is defined as the first non-missing date where a non-zero dose of 
study drug was recorded. 
The last dose date is defined as the last non-missing date where a non-zero dose of 
study drug was recorded. For subjects ongoing at time of analysis, last dose date will be 
considered the date of the most recent study visit in the database for that subject 
where a non-zero dose of study drug was recorded. 
Unless otherwise specified, baseline is the last non-missing observation before the start 
of study drug, which is expected to be the on Day 1 of Cycle 1 (pre-dose) or Screening if 
the Day 1 data are not available. 
For interim analysis if a subject is ongoing in the study at the time of data cut off then 
the day of the data cut off will be used as the last dose date. 
6.3. 
MISSING DATA 
Missing data (other than presented here) will not be imputed. Analyses will be 
performed considering all data observed for the respective analysis sets. 
For the purpose of assigning adverse events (AEs) and concomitant medications, the 
followings rules will be applied for partial start and end dates: 
 
Partial/missing start date:  
 
Should the day be missing, impute the first day of the given month unless the 
month and year are the same as the month and year of the first dose of study 
drug, then impute the first dose date. 
 
Should the day and month be missing, impute the date as 1st January unless the 
year is the same as the year of the first dose of study drug, then impute the first 
dose date. 
 
Should the full date be missing, impute the first dose date unless the end date 
suggests the event/medication could have started prior to this, in which case 
impute the 1st January of the same year as the end date.  
 
When imputing a start date, ensure that the newly imputed date is sensible i.e. 
prior to the end date of the AE or medication.  
Partial/missing end date: 
 
Should the day be missing, impute the last day of the given month unless the 
month and year are the same as the month and year of the last dose of study 
drug, then impute the last dose date. 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
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 
Should the day and month be missing, impute the date as 31st December unless 
the year is the same as the year of the last dose of study drug, then impute the 
last dose date. 
 
Should the full date be missing, the ongoing status of the AE/medication and the 
start date in relation to the study drug should first be considered. If it is 
unknown whether or not the AE/medication is ongoing, assume that the AE is 
still present/medication is still being taken (i.e. do not impute a date). If, 
however, the AE/medication has stopped and the start date is prior to the first 
dose date, then impute the first dose date, unless it started on or after the first 
dose date, then impute a date that is after the first dose date.  
In case date of diagnosis is partial missing, please impute:  
 
Should the day be missing, impute the first day of the given month. 
 
Should the day and month be missing, impute the date as 1st January. 
 
6.4. 
VISIT WINDOWS 
There are no plans to derive visit windows, visits will be used in the analyses as 
reported on the eCRF. 
6.5. 
POOLING OF CENTERS 
The data from the individual centres will be pooled. The analyses will be based on the 
pooled data.  
6.6. 
SUBGROUPS 
No subgroup analysis is planned.  
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
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     INC Research 1007823 
 
 
 
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7. 
DEMOGRAPHIC, OTHER BASELINE CHARACTERISTICS AND 
MEDICATION 
7.1. 
SUBJECT DISPOSITION AND WITHDRAWALS 
Subject disposition at the end of Screening will be summarized for all subjects in the 
Screened Set. The summary table will show the frequency and percentage of subjects 
who either completed the Screening period and entered the treatment phase or failed 
Screening, along with the primary reasons for failure and whether or not the subject has 
measurable disease.  
Subject disposition at the end of treatment and the end of study will also be 
summarized in the same table for all subjects in the Safety Set, with the frequency and 
percentage of subjects who completed both or either one of the two treatments 
(BGB324 and/or Pembrolizumab) and who discontinued early, along with the primary 
reasons for discontinuation of study treatment, and the frequency and percentage of 
subjects who terminated the study early, along with the primary reasons for 
termination, respectively.  
The number and percentage of subjects included, and reasons for exclusion, from each 
of the analysis sets will also be tabulated. 
Informed consent and eligibility criteria met/not met will be listed only. 
7.2. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
All demographic and baseline characteristic data will be summarized for all subjects in 
the Safety Set.  
Gender and child-bearing potential (female subjects only), ethnicity and race will be 
summarized by the number and percentage of subjects in each category. 
Age (years), height (cm) and weight (kg) captured at Screening will be summarized as 
continuous variables. 
Unless otherwise stated, percentages will be calculated out of the number of subjects 
in the Safety Set. 
All demography data will be listed.  
7.3. 
MEDICAL / SURGICAL HISTORY 
Descriptions of medical/surgical history findings will be coded using Medical Dictionary 
for Regulatory Activities (MedDRA) Version 18.0 or later. Medical/surgical history, as 
recorded at Screening, will be summarized for the Safety Set by the number and 
percent of subjects within each system organ class (SOC) and preferred term (PT). 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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Conditions that are reported more than once for a given SOC and PT will be counted 
only once per subject on the PT level for each SOC. Medical/surgical history will be 
sorted by descending overall frequency, by SOC and PT in the summary table. 
Medical/surgical history shall also be listed for all subjects in the Safety Set. 
Medical history data listings will be sorted by subject number, onset date, SOC, and PT. 
7.4. 
OTHER BASELINE CHARACTERISTICS 
7.4.1. 
Cancer Diagnosis 
Cancer diagnosis, as recorded at Screening, shall be summarised by the number and 
percentage of subjects within each category for the following: 
 
Current stage of disease (I-IV); 
 
If the subjects have any known mutations (yes/no); 
 
Mutation type (EGFR, ALK, Kras and other). 
The time from initial diagnosis and time from advanced or metastatic disease to 
informed consent (years) shall be summarized as continuous variables using descriptive 
statistics where: 
Time from Initial Diagnosis to 
Informed Consent (years) = 
(Date of Informed Consent – Date of Initial Diagnosis + 
1)/365.25 
Time from Advanced or 
Metastatic Disease to Informed 
Consent (years) = 
(Date of Informed Consent – Date of Initial Diagnosis + 
1)/365.25 
All cancer diagnosis data shall also be listed for all subjects in the Safety Set. 
7.5. 
MEDICATION 
Prior and concomitant medications will be coded by the Anatomical Therapeutic 
Chemical (ATC) classification system according to the World Health Organization Drug 
Dictionary (WHO-DD). Medications will be classified as concomitant or prior, as defined 
in the Sections 7.5.1 and 7.5.2 respectively, and summarized by ATC class (level 2) and 
sub-class (PT) for all subjects in the Safety Set. 
Any concomitant medication will be recorded at each visit, including the medication 
name, indication, dose, unit, route of administration, frequency and medication start 
and end dates. 
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Statistical Analysis Plan  
Final Version 1.0 
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Prior and concomitant medications will be summarized separately. All prior and 
concomitant medications will also be listed including the derived study day (for both 
start and stop dates), with a flag identifying prior medications. 
The summary tables will show the frequency and percentage of subjects with at least 
one usage of medication on the sub-class level within each ATC class, sorted 
alphabetically.  
Percentages will be calculated out of the number of subjects in the Safety Set. 
7.5.1. 
Prior Medication 
Prior medications are those medications that were stopped prior to first study drug 
administration.  
7.5.2. 
Concomitant Medication 
Concomitant medications (CMs) are medications that are ongoing at or began after the 
start of study drug. Medications without an onset date will be defined as concomitant, 
except if an incomplete date (e.g. month and year) clearly indicates that the 
medication was started prior to the start of study drug or if the medication stop-date 
indicates that the medication was started and stopped prior to the start of study drug. 
Partial medication dates will be imputed as detailed in Section 6.3. 
All concomitant medications received within 30 days before the first dose of trial 
treatment and 30 days after the last dose of study treatment should be recorded. 
Concomitant medications administered after 30 days after the last dose of trial 
treatment should be recorded for Serious Adverse Events (SAEs) and Events of Clinical 
Interest (ECIs). 
Sections 6.7 and 6.8 of the protocol detail permitted and restricted concomitant 
medications and acceptable concomitant medications, respectively, along with 
prohibited concomitant medications whilst receiving Pembrolizumab in Section 6.9 of 
the protocol. 
7.6. 
OTHER THERAPIES 
7.6.1. 
Prior Radiotherapy 
Summary tables for prior radiotherapy shall display the number and percentage of 
subjects with at least one prior radiotherapy, as well as for each site and administration 
setting recorded. 
The time since the last dose (years) shall be summarized as a continuous variable using 
descriptive statistics where: 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
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     INC Research 1007823 
 
 
 
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Time Since Last Dose (years) = (Date of Informed Consent – Date of Last Dose + 
1)/365.25 
All prior radiotherapy data shall also be listed for all subjects in the Safety Set. 
7.6.2. 
Prior Anticancer Therapy for Study Disease 
Prior anticancer therapy for the study disease shall be summarized for all subjects in 
the Safety Set, considering the number of regimens through the number and percentage 
of subjects for each category (categorised as 0, 1, 2, 3, 4, 5 and >5) and using 
descriptive statistics, as well as the number and percentage of subjects with 
immunomodulatory agents (yes/no). 
All prior anticancer therapy for the study disease data, including regimen number, 
agent, immunomodulatory agent, route, setting, start and stop dates, best response and 
progression date as recorded at Screening shall be also listed. 
 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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Page 36 of 69 
8. 
EFFICACY 
The efficacy analysis will be performed using the Evaluable analysis set.  
The following efficacy endpoints will be summarized by time-point where disease 
assessments are performed, and analysed for both the interim and final analyses: 
 
Objective Response Rate (ORR);  
 
Duration of Response (DoR); 
 
Disease Control Rate (DCR); 
 
Progression Free Survival (PFS); 
 
Overall Survival (OS). 
Efficacy endpoints will be based on tumor imaging evaluations performed by RECIST 1.1.  
8.1. 
PRIMARY EFFICACY ENDPOINT AND ANALYSIS 
Each subject will be assigned one of the following categories for modified RECIST 
response: CR (Complete response), PR (Partial response), SD (Stable disease), PD 
(Progression of disease), NE (Not evaluable). The applicable overall response category 
for each visit that includes tumor assessment will be recorded in the eCRF. 
The primary efficacy endpoint is the Objective Response Rate (ORR), defined as the 
percentage of evaluable subjects who have at least one (confirmed) overall response of 
complete response (CR) or partial response (PR). Data obtained up until progression, or 
the last evaluable assessment in the absence of progression, will be included in the 
assessment of ORR. A subject who has discontinued both treatments, and subsequently 
responds having received a subsequent anti-cancer treatment will be excluded from the 
subset of responding subjects; however these subjects are evaluable and will be 
included in the denominator. ORR will be presented by percentage rates and 90% CIs, 
where the 90% CI will be calculated assuming an exact binomial distribution.   
All response assessments will be listed. A summary of overall response at each visit will 
also be included. 
A sensitivity ORR analysis, defined as the percentage of evaluable subjects who have at least one 
overall response (irrespective of confirmation) of complete response (CR) or partial response 
(PR) will be conducted.  
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
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Note: The Disease Assessment time point used for this analysis may vary, and need not 
be the first on treatment assessment. Where there is the possibility of an immune 
response leading to a false categorization of disease progression, results from later 
tumor imaging time points may be used for the ORR assessment.  
The target lesions, non-target lesions, new lesions, and overall tumor response data 
recorded will be listed. The best overall response will also be summarized. A patient 
will be counted only once and the order from best to worse is CR>PR>SD>PD>NE (note 
NE = Not Evaluable). The sum of the longest diameters, the change from baseline in 
sum of diameters as well as the percent change from baseline will be also listed. 
Evaluations at Screening will serve as baseline values.  
Additionally, a waterfall plot for RECIST best percentage change from baseline in the 
sum of target lesion longest diameters will be provided. The Y axis will be percent 
change from baseline and subject number on the X axis. A positive result indicates an 
increase in tumor volume from baseline; a negative result indicates a decrease 
(shrinkage).  
Best percent change from baseline (%) in the target lesion= 
([the minimum sum of the longest diameters at all post-baseline measurement time 
points − the sum of the longest diameters at baseline] / [the sum of the longest 
diameters at baseline]) x 100. 
8.2. 
SECONDARY EFFICACY ENDPOINTS AND ANALYSES 
8.2.1. 
Duration of Response 
The Duration of Response (DoR) will only be calculated for subjects that have an 
objective response. The DoR is defined as the time from the date of first documented 
response until date of documented progression or death in the absence of disease 
progression; the end of response should coincide with the date of progression or death 
from any cause. Subjects who continue to respond at the date of data cut-off (last 
subject, last visit) will be censored at their last clinical evaluation. Subjects who are 
lost to follow-up will be censored at their last clinical evaluation.  
Duration of Response will be calculated for all subjects that experience documented CR 
or PR during the study in weeks as follows: 
Duration of Response (weeks) =  ([Date of Progression/Death/Censoring – Date of First 
Recorded CR or PR] + 1)/7 
The Duration of Response will be presented as a swimmer plot with Duration of 
Response on the Y axis and patient number on the X axis. The swimmer plot will present 
all subject time-to-event data such as Complete Response Start, Partial Response Start, 
Stable Disease, time of progression or time of ongoing response at last visit, time of 
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Statistical Analysis Plan  
Final Version 1.0 
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treatment stop, Not Evaluable or Death.  
The Duration of Response from onset of response will be analysed for all subjects 
achieving objective response during the study using a Kaplan-Meier (K-M) survival 
analysis. The K-M estimate of the median duration (with 95% CIs) of response and the 
25th and 75th percentiles will be presented. A Kaplan Meier plot of the duration of 
response will also be presented.  
8.2.2. 
Disease Control Rate 
Disease Control Rate (DCR) is defined as the percentage of subjects with a ‘Complete 
Response’, ‘Partial Response’, or ‘Stable Disease (out of number evaluable). Data 
obtained up until progression, or the last evaluable assessment in the absence of 
progression, will be included in the assessment of DCR. 
Disease control is determined by the overall lesion response collected on the eCRF. If 
any response of ‘Complete Response’, ‘Partial Response’, or ‘Stable Disease’ is 
obtained, then Disease Control = ‘Yes’ (even if a subject has a disease progression 
later).  If only response of ‘Progressive Disease’ or ‘Not evaluable for a response’ is 
obtained, then Disease Control = ‘No’.  Subjects with missing overall lesion responses 
(but who do have a post first dose record for target lesion assessment) will be treated 
as Disease Control = ‘No’, i.e. they will be included in the denominator when 
calculating the percentage. DCR will be analysed by computing the estimate of disease 
control and the exact binomial 95% confidence intervals (CIs).  
8.2.3. 
Progression Free Survival  
Progression Free Survival (PFS) is defined as the duration from start of the treatment 
(Cycle 1 Day 1) until the date of disease progression (the date on which the confirmed 
progression is initially observed) or the date of death (regardless of cause of death), 
whichever is earlier.  Subjects who have not progressed or died before the date of data 
cut-off (last subject, last visit) will be censored at their last clinical evaluation (last 
evaluable RECIST assessment). Subjects who are lost to follow-up will be censored at 
their last adequate assessment to be alive. 
PFS (weeks) =  ([Date of Progression/Death/Censoring – Date of First Dose] + 1)/7 
PFS analyses will be performed using investigator lesion assessments (for RECIST v1.1 
criteria) collected in the eCRF. 
PFS will be analysed for all subjects in the evaluable analysis set using a K-M survival 
analysis. The number of events, percentiles for the PFS (25%, 50% (median and 95% CIs), 
and 75% percentiles), and the proportion of subjects who are progression-free at 12 
months will be summarized. Kaplan Meier plots of the time to progression and death 
will also be presented. 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
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     BGBC007 / Merck & Co: MK-3475 PN-530  
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A sensitivity summary of PFS using the first date that a progression is considered 
(irrespective of whether confirmed) will additionally be conducted.  
8.2.4. 
Overall Survival 
Overall survival (OS) is defined as the time from the first dose of study treatment  until 
the date of death (from any cause and irrespective of any subsequent anti-cancer 
treatment given). 
Subjects who remain known to be alive at the date of data cut-off (last subject, last 
visit) will be censored at their date last known to be alive. Subjects who are lost to 
follow-up will be censored at the point last known to be alive; however, if ≥2% of 
subjects is in this category, a sensitivity summary will be produced to illustrate the 
overall survival assuming the subject died at the date last known in the trial 
OS (weeks) =  ([Date of Death/Censoring – Date of First Dose]  + 1)/7 
Overall survival will be summarised by survival status. The number of events and 
estimates for the 25%, 50% (median and 95% CIs), and 75% percentiles for OS will be 
presented. The proportion of subjects who are surviving at 12 months will also be 
summarized. Kaplan Meier curves will be plotted. 
Data collected at the survival follow-up visit (i.e. subject status (dead, alive, lost to 
follow up and previously documented disease progression)) will be listed. 
 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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03.007A.03     
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9. 
ANALYSIS OF PHARMACOKINETICS 
PK parameters will be estimated for each subject using a fully validated version of 
WinNonlin Pro (Version 6.3 PhoenixTM, Pharsight®), or later version as appropriate. The 
following parameters (Table 5) will be derived for BGB324, where appropriate, from the 
individual plasma concentration versus time profiles from all subjects. 
Actual blood sampling times post dosing will be used in calculation of PK parameters. If 
actual sampling time is missing, nominal time may be used with sponsor approval. 
Concentrations will be used as supplied by the analytical laboratory for PK analysis. The 
units of concentration and resulting PK parameters, with the amount or concentration in 
the unit, will be presented as they are received from the analytical laboratory. 
Table 6: Pharmacokinetic parameters 
Parameter 
Definition 
Cmax 
The maximum observed concentration 
tmax 
The time at Cmax  
AUC(0-24) 
The area under the concentration versus time curve from time zero to 24h 
post-dose; that is, within a dosing interval 
Cav 
Average concentration calculated as AUC(0-24) /24 
t1/2 
The elimination half-life 
 
The maximum plasma concentration (Cmax), the time of maximum concentration (tmax) 
will be determined by inspection of the concentration-time profiles.  
The area under the plasma concentration-time curve up to 24 hours (AUC(0-24)) will be 
calculated using the linear up/ log down trapezoidal rule. 
Blood samples taken for the purpose of PK assessment of Pembrolizumab will be frozen 
and stored in case they are required in the future (for example, at the request of a 
regulatory authority). 
The sections below will present the pharmacokinetic analysis in details. 
9.1. 
PRESENTATION OF CONCENTRATION DATA 
PK data will be summarised using the safety analysis subset. Plasma concentrations of 
BGB324 and metabolite will be summarised by nominal sample time. 
Plasma concentrations and derived PK parameters will also be presented by the 
following summary statistics: 
For AUC(0-24) and Cmax: 
 
Number of observations 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
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 
Minimum 
 
Maximum 
 
Geometric mean, calculated as exp[μ], where μ is the mean of the data on a 
logarithmic scale 
 
CV, calculated as 100 √ [exp(s2)-1], where s is the standard deviation of the data 
on a log scale 
 
Standard deviation of geometric mean 
 
Arithmetic mean calculated using untransformed data 
 
Standard deviation calculated using untransformed data 
 
Median 
For tmax: 
 
Number of observations 
 
Minimum 
 
Maximum 
 
Median 
For t½: 
 
Number of observation 
 
Arithmetic mean 
 
Standard deviation 
 
Median 
 
Minimum 
 
Maximum 
Plasma concentrations below LLOQ will be reported as not quantifiable (NQ) with the 
LLOQ defined in the TFLs.  
For calculation of summary statistics for plasma concentrations: 
 
If, at a given time point, 50% or less of the plasma concentrations are NQ, the 
gmean, CV, gmean ± standard deviation, arithmetic mean and standard deviation 
will be calculated by substituting the limit of quantification (LOQ) for values 
which are NQ. 
 
If more than 50%, but not all, of the concentrations are NQ, the gmean, CV, 
gmean ± standard deviation, arithmetic mean and standard deviation will be 
reported as not calculable (NC). The maximum value will be reported from the 
individual data, and the minimum and median will be set as NQ. 
 
If all the concentrations are NQ, the gmean and arithmetic mean will be 
reported as NQ and the CV, gmean ± standard deviation, and standard deviation 
as NC. 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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The number of values above LLOQ will be reported for each time point along with the 
total number of collected values. 
Three observations >LLOQ are required as a minimum for a plasma concentration or PK 
parameter to be summarised. Two values will be presented as a minimum and maximum 
with the other summary statistics as NC. 
PK parameters will be presented according to the conventions listed in the table below. 
Parameter 
Reporting in Summary Tables 
Listings 
AUC(0-24) 
gmean/CV/gmeanSD/mean/SD/med = 4 s.f. 
min/max = 3 s.f. 
3 s.f. 
Cmax 
gmean/CV/gmeanStD/mean/SD/med = 4 s.f. 
min/max = 3 s.f. 
same s.f. as supplied 
from bioanalysis 
t1/2 
mean/SD/med = 4 s.f. 
min/max = 3 s.f. 
3 s.f. 
tmax 
med = 2 d.p. 
min/max = 2 d.p. 
2 d.p. 
N number included in summary table for all parameters as whole numbers. 
d.p. decimal places 
s.f. significant figures 
 
The following figure will be produced: 
 
The geometric mean concentration (+/-standard deviation) versus time. 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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10. 
EXPLORATORY OBJECTIVES 
10.1.1. 
Biomarker Analysis 
The PD-L1 and Axl expression status will be available at the time of the database lock 
and will be utilized in the analysis of the study, as described below. 
The ORR will be explored as follows: 
 
By PD-L1 status (+ve or –ve), using a Chi square or Fishers Exact Test; 
 
By Axl status (+ve or –ve), using a Chi square or Fishers Exact Test; and 
 
Summarized in a table of PD-L1 by Axl expression status to explore the ORR in 
each of the four quadrants (++, +-, -+, --). That is, subjects will be allocated into 
one of the 4 groupings: where both Axl and PD-L1 are positive; where there is 
one positive and one negative and where there are both Axl and PD-L1 negative. 
If the PD-L1 expression status is provided as a TPS or in one of 3 possible categories 
(<1%, 1-49% and ≥50%), the subject will be regarded as PD-L1 positive if their TPS is 
≥1%. 
A subject with Axl positive disease is defined as one with an expression level of 1+ or 
greater according to IHC staining intensity, although other cut offs may be considered. 
However, other biomarkers are exploratory and as such, the respective samples might 
not be available at the time of clinical database lock. A separate analysis plan and 
report for biomarker analysis will be written. 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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11. 
SAFETY 
The Safety Set shall be used for all safety analyses. Safety will be assessed on the basis 
of AE reports, clinical laboratory data, vital signs measurements, ECOG performance 
status, 12-Lead Electrocardiogram (ECG) data and physical examination findings. 
11.1. 
EXTENT OF EXPOSURE 
The number of doses of BGB324 and Pembrolizumab by cycle and over the entire study 
period will be listed and summarised using descriptive statistics for all subjects in the 
Safety Set.   
The extent of exposure to BGB324/Pembrolizumab will be examined by summarizing the 
total treatment duration using descriptive statistics.  
The total treatment duration of exposure (total time on both BGB324 and 
Pembrolizumab, total time on BGB324 as monotherapy, total time on Pembrolizumab as 
monotherapy) (in weeks) is calculated as follows: 
Total Treatment Duration (weeks) =  [(date of last dose of BGB324 – date of first dose 
BGB324) + 1] /7 
= [(date of last dose of Pembrolizumab – date of 
first dose Pembrolizumab) + 1] /7 
= [(date of last dose of BGB324 (as monotherapy) – 
date of first dose BGB324 (as monotherapy) + 1] 
/7 
= [(date of last dose of Pembrolizumab (as 
monotherapy) – date of first dose Pembrolizumab 
(as monotherapy) + 1] /7 
Dose reductions (BGB324 only) and interruptions of BGB324 and Pembrolizumab shall be 
summarized by the number and percentage of subjects in each category. This data shall 
also be listed. 
For the administration of Pembrolizumab, information on the batch number, infusion 
date and start and stop times, actual dose received (and units) and dosing action taken, 
along with reason for action, shall also be collected and listed only. 
Similarly, for BGB324, information on the batch number, date and time of 
administration, dose administered and dosing action taken, along with reason for 
action, shall also be collected and listed only. 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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Details on the IP dispensation, including whether or not the subject shall receive 
Pembrolizumab/BGB324, the BGB324 dose to be administered, if the drug shall be 
dispensed to the subject and the kit/bottle number(s), shall also be collected and listed 
only. 
11.2. 
TREATMENT COMPLIANCE  
BGB324 compliance will be calculated as a percentage, with the total number of 
capsules taken overall (assuming any capsules not returned were taken by the patient) 
as the numerator and the expected total number of capsules taken as the 
denominator, i.e. 
Percentage of Compliance (%) =  
(Total Capsules Taken / Expected Total Capsules 
Taken) x 100 
The expected total number of capsules taken will be calculated by summing the 
number of days between study visits and multiplying by the number of capsules taken 
per day for the prescribed dose. 
The percent compliance will be summarized with quantitative descriptive statistics and 
also with frequency and percentages of subjects with <80%, 80-<90%, and 90-100% 
compliance.  
11.3. 
ADVERSE EVENTS 
Adverse events (AEs) will be collected throughout the study, from time of consent until 
at least 30 days following cessation of treatment. Serious adverse events will be 
collected until 90 days following cessation of treatment or 30 days following cessation 
of treatment if the subject initiates new anticancer therapy, whichever is earlier, whilst 
pregnancies will be reported for up to 120 days after cessation of treatment.  
Subjects who signed a consent form and were screened but did not receive any 
treatment will be listed only if they reported an AE in the time after consent and before 
treatment allocation (see Section 7.1 of the Protocol). 
Adverse events will be summarized by the System Organ Class (SOC) and Preferred Term 
(PT) based on the MedDRA dictionary version 18.0 or later.  
Treatment-emergent adverse events (TEAEs) are defined as any adverse events that 
commence on or after the first dose of study drug, or increased in severity if present 
prior to first dose, until exit from the study. Partial AE dates will be imputed (Section 
6.3). 
All AEs (including Serious Adverse Events [SAEs]) will be graded for severity using the 
National Cancer Institute (NCI) CTCAE version 4.03 (details of classifications are in 
Section 7.4.1 of the Protocol). 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
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Page 46 of 69 
All AEs (including SAEs) will be assessed for the relationship of the AE to both 
Pembrolizumab and BGB324 study drug. The relationship of the study treatment to an 
AE will be determined by the Investigator and subsequently reviewed by the Medical 
Monitor. Relationships of ‘definitely’, ‘probably’ and ‘possibly’ are to be considered as 
related to study drug for the summary tables. Relationships of ‘Not/unlikely related’ 
are to be considered not related to study drug. If the relationship to study drug is 
missing for TEAEs then the relationship will be counted as related to both 
Pembrolizumab and BGB324 for the summary tables. Similarly, missing severity for 
TEAEs will be counted as Grade 3 (‘severe’). Note that the original relationship, as 
recorded in the eCRF, shall be presented for data listings. 
Selected non-serious and SAEs are also known as Events of Clinical Interest (ECI), and 
these will be identified on the CRF. Details of ECI are given in Section 7.4.3.2 of the 
Protocol. 
The summary tables will include the number of subjects and the number of events. 
Percentages will be based on the number of subjects. 
For summaries by SOC and PT, a subject will be counted once at the SOC level and once 
at each PT level within the SOC level. For summaries by SOC, PT, and maximum 
intensity, a subject will be counted once at the highest grade for which the event 
occurred at the SOC level and the highest grade for each unique PT level within that 
SOC level. Therefore, subjects may only contribute once to each PT and once to each 
SOC level.  
The summaries presenting frequency of AEs by SOC and PT will be ordered by overall 
descending frequency of SOC and then, within a SOC, by overall descending frequency 
of PT. 
The following AE tables will be provided: 
 
An overall summary of the number and percentage of subjects reporting AEs, 
TEAEs, serious TEAEs, Events of Clinical Interest (ECI), TEAEs related to both 
study drugs separately, TEAEs of CTCAE grade 3 or higher, TEAEs of CTCAE grade 
3 or higher and related to both study drugs, TEAEs leading to interruption of 
study drug (BGB324 and Pembrolizumab separately), TEAEs leading to 
discontinuation of study drug and fatal TEAEs;   
 
TEAEs overall and by system organ class (SOC) and preferred term (PT); 
 
TEAEs by maximum reported CTCAE grade, overall and by SOC and PT; 
 
TEAEs of CTCAE grade 3 or higher, overall and by SOC and PT; 
 
TEAEs by relationship to BGB324 overall and by SOC and PT; 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
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 
TEAEs by relationship to Pembrolizumab overall and by SOC and PT; 
 
TEAEs related to bothBGB324 and Pembrolizumab, overall and by SOC and PT; 
 
Events of Clinical Interest (ECI), overall and by SOC and PT; 
 
Events of Clinical Interest (ECI) related to both BGB324 and Pembrolizumab, 
overall and by SOC and PT; 
 
Serious TEAEs, overall and by SOC and PT; 
 
Serious TEAEs related to both BGB324 and Pembrolizumab, overall and by SOC 
and PT; 
 
TEAEs leading to interruption of BGB324, overall and by SOC and PT; 
 
TEAEs leading to interruption of Pembrolizumab, overall and by SOC and PT;  
 
TEAEs leading to interruption of both BGB324 and Pembrolizumab, overall and by 
SOC and PT;   
 
TEAEs leading to discontinuation of BGB324, overall and by SOC and PT; 
 
TEAEs leading to discontinuation of Pembrolizumab, overall and by SOC and 
PT;TEAEs with an outcome of death, overall and by SOC and PT.  
With the exception of the overall summary AE table and the ECI summaries, only the 
TEAEs will be included in the summary tables; however, all AEs will be included in the 
listings. TEAEs will be flagged in the listings. Any AE occurring before the first dose of 
investigational product (i.e. before Cycle 1 Day 1) will be included in the data listings 
but will not be included in the summary tables of AEs. Any AE occurring within the 
defined 30 day Follow-up period after the discontinuation of study drugs will be 
included in the AE summaries.  
Additional listings will be provided for deaths, AEs with an outcome of death, SAEs, 
ECIs, AEs leading to the discontinuation of study drug and AEs leading to the 
interruption of study drug. TEAEs will be flagged in the listings.  
11.4. 
LABORATORY EVALUATIONS 
All subjects in the Safety Set will be included in the safety laboratory analysis. 
The collection times of the blood and urine samples for safety assessment are recorded 
in the protocol.  
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
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Page 48 of 69 
Samples for the following laboratory tests will be sent to the study site's local 
laboratory for analysis:  
Clinical Chemistry:  
Calcium, total protein, albumin, total bilirubin, alanine 
transaminase (ALT, SGPT), aspartate transaminase (AST, 
SGOT), lactate hydrogenase (LDH), alkaline phosphatase, 
glucose 
(random), 
sodium, 
potassium, 
bicarbonate, 
chloride, magnesium, urea, creatinine, phosphate and 
amylase. 
Hematology: 
Including coagulation. Red cell count, mean corpuscular 
volume, 
hemoglobin, 
free 
hemoglobin, 
absolute 
reticulocyte count, platelet count, white blood cells, 
leucocyte differential count [% and absolute (neutrophils, 
lymphocytes, monocytes, eosinophils and basophils)], 
international normalized ratio or prothrombin time and 
activated partial thromboplastin time. 
Urinalysis:  
Glucose, protein, bilirubin, ketones, blood, pH, specific 
gravity, FSH (female menopausal subjects; at Screening) 
and HCG (female pre-menopausal subjects; at Screening).  
Thyroid Function Test: 
Thyroid Stimulating Hormone (TSH), Triiodothyronine (T3) 
or Free Triiodothyronine (FT3) and Free thyroxine (FT4).  
Laboratory data will be recorded at the following visits and time points: 
 
Hematology and Clinical Chemistry: at every visit, taken at a suitable time prior 
to the administration of study treatments. 
 
Coagulation (assessed from Hematology sample): Screening, Cycle 1 at Days 1, 8 
and 15 only, then at each study cycle and at the Post-treatment visit. 
 
Urinalysis: Screening, Cycle 1 at Days 1, 8 and 15, Cycle 2 and at the Post-
treatment visit. 
 
Thyroid Function Test (assessed from the Clinical Chemistry sample): Screening 
and then at every other cycle, starting at Cycle 3 (i.e., Cycle 3, Cycle 5, …, 
Cycle 35). 
 
Pregnancy and FSH Test: Screening (required within 3 days of Cycle 1 Day 1) and 
at each study cycle excluding the Post Treatment Visits for female subjects of 
reproductive potential. 
Laboratory data (absolute values and absolute changes from baseline) will be 
summarized by visit for each parameter. Baseline is defined as the last non-missing pre-
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
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Page 49 of 69 
dose value (pre both BGB324 and Pembrolizumab All summaries will be based on results 
in the International System of Units (SI units); conversion will be performed prior to the 
transfer to INC Biostatistics. Summaries will include data from scheduled assessments 
only, and all data will be reported according to the nominal visit date for which it was 
recorded (i.e., no visit windows will be applied). 
Laboratory values will be graded following the NCI CTCAE grades version 4.03 where 
applicable. If no grading exists, values will be classified as ‘low’/’normal’/’high’ based 
on laboratory normal ranges, where normal ranges exist. Shift tables for CTCAE grades 
and normal ranges will be presented. 
Summary statistics (mean, median, standard deviation, minimum, maximum and 
number of observations) will be presented for all continuous assessments.  For urinalysis 
parameters, any quantitative assessments will be summarized for all subjects using the 
number of subjects with results of negative, trace or positive. In general, any 
quantitative assessments will be summarized for all subjects using the number and 
percentage of subjects with the given result. Percentages will be calculated out of the 
number of subjects with non-missing data. 
Shift tables for hematology and clinical chemistry from baseline CTCAE grade to the 
maximum grade on treatment for each test will be provided. Subjects with both a non-
missing baseline and at least one non-missing post-baseline grade will be included. 
Unscheduled data will be included in “worst post-baseline” summaries which will 
capture a worst case across all scheduled and unscheduled visits after the first dose of 
study treatment. This means that if there are CTCAE grades derived from both 
unscheduled and scheduled visits data per test per subject then the highest grade will 
be summarized. 
For non-CTCAE gradable haematology and biochemistry tests, a shift table will be 
provided showing shifts relative to the normal ranges. This summary of normal range 
category changes illustrates the number and percentage of subjects who fall into 
specified categories (Decrease to Low, Change to Normal or No Change, Increase to 
High) by comparing the baseline normal range category to the planned time normal 
range category and the worst-case on-therapy normal range category. Only laboratory 
tests which cannot be graded per CTCAE v4.03 specified criteria will be included.  
Subjects with missing baseline value are to be assumed to have normal baseline value 
since worst-case can be either ‘High’ or ‘Low’. If a subject has a ‘Decrease to Low’ and 
an ‘Increase to High’ during the same time interval, then the subject is counted in both 
the ‘Decrease to Low’ and ‘Increase to High’ categories. If a subject was ‘High’ at 
baseline and decreases to ‘Low’ during the time interval, the subject is counted in the 
‘Decrease to Low’ category. Likewise, if a subject was ‘Low’ at baseline and increases 
to ‘High’ during the time interval, the subject is counted in the ‘Increase to High’ 
category. Subjects are only counted in the ‘Change to Normal or No Change’ category if 
they are: 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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Page 50 of 69 
 
Normal at baseline and have no normal range ‘High’ and no normal range ‘Low’ 
values during the time interval; 
 
‘High’ at baseline and do not change to ‘Low’ during the time interval; 
 
‘Low’ at baseline and do not change to ‘High’ during the time interval. 
If any clinically significant findings are identified from the safety lab assessments or 
thyroid function tests, the Investigator will record it as part of the medical history 
prior to start of dosing and as an AE post dose, where the finding represents a change 
from baseline. Findings identified prior to the start of dosing must be checked against 
the study inclusion and exclusion (safety lab assessments only) criteria (see Section 3.1 
and Section 3.2 of the Protocol). 
All laboratory results in original and SI units will be included in data listings. Tests will 
be listed in alphabetical order. A separate listing for abnormal lab values (Grade 3 and 
higher and low/high values) will be presented. 
Pregnancy test data, including the date/time of collection and the result, will be 
displayed separately, and listed only. 
11.5. 
VITAL SIGNS  
All subjects in the Safety Set will be included in the vital signs analysis. 
Vital signs will be captured at each visit and will include measurement of resting heart 
rate (beats/min), seated systolic and diastolic blood pressure (mmHg), body 
temperature (°C) and respiratory rate (breaths/minute). On Pembrolizumab dosing days 
(Cycle 1 Day 1 and Cycles 2-35), vital signs will be taken both pre-dose and at the end 
of infusion. 
If any clinically significant findings are identified during the assessment of vital signs, 
the Investigator will record it as part of the medical history prior to start of dosing and 
as an AE post dose, where the finding represents a change from baseline. Findings 
identified prior to start of dosing must be checked against the study exclusion criteria 
(see Protocol Section 3.2). 
Vital signs data (absolute values and changes from baseline) will be summarized using 
descriptive statistics by visit and time point for each vital sign parameter.  
Baseline for vital signs will be the result prior to the first dose of study treatment.  
Absolute change from baseline will be calculated for the post dose time points. Absolute 
change from baseline is calculated as the result at visit minus the baseline result. 
All vital signs data will be listed chronologically and summarized by parameter, visit and 
time point.  
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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11.6. 
12-LEAD ELECTROCARDIOGRAM (ECG) 
ECG assessments will be performed in triplicate at pre-dose and 6 hours after the 
BGB324 dose on Day 1, Cycle 1 and then repeated pre-BGB324 dose on Days 2, 3 and 4 
(Cycle 1) and then at every visit thereafter. All 12-lead ECGs will be obtained after the 
subject has been resting in the supine position for at least 10 minutes prior to 
assessment. For each time point triplicate ECG recordings must be taken less than 5 
minutes apart. 
If any clinically significant findings are observed on the ECG, the Investigator will record 
it as part of the medical history prior to the start of dosing, and as an AE post dose 
where the finding represents a change from baseline. Clinically significant findings 
identified prior to start of dosing must be checked against the study exclusion criteria 
(see Section 3.2 of the Protocol). 
If a subject permanently discontinues BGB324 but continues with monotherapy 
Pembrolizumab), the last ECG assessment will be performed at the next Pembrolizumab 
administration. 
Patients who have a BGB324 interruption of 14 days for toxicity will require an ECG 
twice weekly for the 2 weeks following recommencement of BGB324 daily dosing to 
ensure cardiac safety monitoring whilst BGB324 returns to steady state. 
ECG data will be listed overall for all patients in the Safety Set, and a separate listing 
for any clinically significant findings in ECG values will be provided.  
The overall evaluation of the ECG data shall be recorded as ‘Normal’, ’Abnormal, not 
Clinically Significant (NCS)’ or ‘Abnormal, Clinically Significant (CS)’ and will be 
summarized by visit. Shifts in the overall results of ECG from baseline to worst on-
treatment result will be summarized overall. Also a Categorical analysis of QT interval 
correction will be presented. 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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11.7. 
PHYSICAL EXAMINATION 
Physical examination includes height (cm) taken at Screening (summarized with subject 
demographics) and body weight (kg) at Screening and at the start of each cycle. A full 
physical examination will be performed at Screening and Day 1 at each cycle, as well as 
at the final study visit.  
A full physical examination will include assessment of the following body systems: 
general appearance, head, eyes, ears, nose, throat, neck (HEENTN), abdomen, heart, 
lungs, extremities, neurological, lymph nodes, skin, musculoskeletal and ‘other’. After 
the Screening assessment, the physical examination may be reduced to a symptom-
directed assessment. 
Body systems will be classified as “Normal”, “Abnormal Clinically Significant” and 
“Abnormal Not Clinically Significant”, and abnormalities are described.  
If any clinically significant findings are identified during the physical examination, the 
Investigator will record it as part of the medical history prior to start of dosing and as 
an AE post dose, where the finding represents a change from baseline. 
Physical examination findings will be fully summarized using descriptive statistics for 
weight, and using the frequency and percentage of subjects under each classification 
for each body system. Summary tables will be sorted by parameter and visit. 
Physical examination data will also be listed for all subjects in the Safety Set. 
11.8. 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE 
STATUS 
ECOG performance status will be assessed at Screening, Cycles 2-35 and at the post-
treatment visit. Patients must be confirmed as having an ECOG performance status of 0 
or 1 at Screening in order to be eligible for study participation. 
A summary table will be provided with the number and percentages of patients with 
each ECOG score (0 to 5) at each study visit. 
All ECOG data shall also be listed for all patients in the Safety Set. 
11.9. 
ECHOCARDIOGRAPHY (OR MUGA) 
An echocardiography (or MUGA) assessment will be performed at Screening, and after 
every 6 months (i.e., every 8 cycles thereafter: Cycle 9, Day 1; Cycle 17, Day 1; Cycle 
25, Day 1; Cycle 33, Day 1) whilst a patient receives BGB324. 
Clinically significant findings identified prior to start of dosing must be checked against 
the study exclusion criteria (Protocol Section 3.2).  
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
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     INC Research 1007823 
 
 
 
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Patients who discontinue BGB324, but continue with monotherapy Pembrolizumab, will 
stop undergoing an echocardiogram (or MUGA) assessment and their final 
echocardiogram/MUGA assessment will occur if their next scheduled assessment is 
within the next 6 weeks (of discontinuing BGB324). 
The following information shall be collected and listed only for all patients in the Safety 
Set: 
 
Date of assessment; 
 
Assessment method; 
 
Left ventricular ejection fraction (%); 
 
Results of assessment; 
 
Abnormality. 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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12. 
INTERIM ANALYSES 
12.1. 
DATA REVIEW COMMITTEE  
Pembrolizumab has not previously been combined with BGB324 in patients (in any 
indication) and therefore, a safety run-in will include a total of 12 subjects.  
A Data Review Committee (DRC), consisting of Principal Investigators, the Sponsors’ 
(BerGenBio and Merck) Medical Monitors, and invited experts as required, will review all 
subject safety data after 6 subjects have been enrolled and had the potential to be 
followed for 6 weeks (2 cycles), and then again after a further 6 subjects (total 12 
subjects) have had the potential for 6 weeks Follow-up. At each of these safety reviews, 
the DRC will consider the rate of BGB324 dose reductions and the rate of permanent 
discontinuation from BGB324 and Pembrolizumab.  
Each patient will have had the potential to receive (as a minimum):  
 
2 cycles of Pembrolizumab 
 
BGB324 at 400 mg for 3 days, followed by 200 mg daily for ~6 weeks  
At the 1st safety run-in (based on 6 subjects) the DRC will evaluate the need for dose 
modification for individual subjects, or BGB324 loading or daily dose modification. A 
rate of >66% (4 or more) of subjects requiring treatment to be dose reduced (BGB324) 
or permanently discontinued (either BGB324 or Pembrolizumab, or both) will considered 
as a significant rate.  
The 2nd safety run-in (based on the 12 patients) the DRC will again evaluate the need for 
dose modification for individual patients, or BGB324 loading or daily dose modification. 
A rate of >40% (5 or more) of patients requiring treatment to be dose reduced (BGB324) 
or permanently discontinued (either BGB324 or Pembrolizumab, or both) will considered 
as a significant rate.  
During the safety run-in reviews, the DRC will have the option to recommend a lower 
dose of BGB324 (dose level -1) for new patients. Dose level -1 is defined as 200 mg 
BGB324 on Days 1, 2 and 3 followed by 100 mg from Day 4 onwards.  
Additionally, a review of emerging safety data from the whole BGB324 program will be 
made 6-monthly. 
12.2. 
INTERIM ANALYSIS 
An interim analysis will be performed after 28 evaluable subjects have had the potential 
to have at least 24 week Follow-up (enabling each patient to have the potential for at 
least 2 ‘on treatment’ disease assessment scans). Recruitment will be halted during this 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
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     INC Research 1007823 
 
 
 
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Page 55 of 69 
period and until the interim analysis has been conducted. The results will constitute the 
basis for the decision on the start of stage 2. 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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13. 
CHANGE FROM ANALYSIS PLANNED IN PROTOCOL 
No changes are planned from the analysis described in the protocol. 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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14. 
REFERENCE LIST 
 
1. Simon R. Optimal Two-Stage Designs for Phase II Clinical Trials. Controlled Clinical 
Trial 1989; 10:1-10.  
2. Tan and Xiong. A flexible multi-stage design for phase II oncology trials. Pharm Stat, 
2011. 10(4):369-73. 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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03.007A.03     
  INC Research © LLC 
Page 58 of 69 
15. 
PROGRAMMING CONSIDERATIONS 
All tables, data listings, figures (TLFs), and statistical analyses will be generated using 
SAS® for Windows, Release 9.3 or later (SAS® Institute Inc., Cary, NC, USA). Computer-
generated table, listing and figure output will adhere to the following specifications.   
 
15.1. 
GENERAL CONSIDERATIONS 
 
One SAS program can create several outputs. Or a separate SAS program will be 
created for each output. 
 
Each output will be stored in a separate file. 
 
Output files will be delivered in Word rtf format. 
 
Numbering of TFLs will follow International Conference on Harmonization (ICH) E3 
guidance 
 
Naming conventions: 
o Listings:  List_16_x_x_shortname.rtf 
o Tables:  Tab_14_x_x_shortname.rtf 
o Figures: Fig_14_x_x_shortname.rtf 
 
15.2. 
TABLE, LISTING AND FIGURE FORMAT 
15.2.1. 
General 
 
All TLFs will be produced in landscape format, unless otherwise specified. 
 
All TLFs will be produced using the Courier New font, size 8. 
 
The data displays for all TLFs will have a 1.5-inch binding margin on top of a 
landscape oriented page and a minimum 1-inch margin on the other 3 sides. 
 
Headers and footers for all TLFs will be in Courier New font, size 8. 
 
Legends will be used for all figures with more than 1 variable, group, or item 
displayed. 
 
TLFs will be in black and white (no colour), unless otherwise specified. 
 
Specialized text styles, such as bolding, italics, borders, shading, and superscripted 
and subscripted text, will not be used in the TLFs, unless otherwise specified. On 
some occasions, superscripts 1, 2, or 3 may be used. 
 
Only standard keyboard characters will be used in the TLFs. Special characters, such 
as non-printable control characters, printer-specific, or font-specific characters, will 
not be used. Hexadecimal-derived characters will be used, where possible, if they 
are appropriate to help display maths symbols (e.g. μ). Certain subscripts and 
superscripts (e.g. cm2) will be employed on a case-by-case basis. 
 
Mixed case will be used for all titles, footnotes, column headers, and programmer-
supplied formats, as appropriate. 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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15.2.2. 
Headers 
 
All output should have the following header at the top left of each page: 
BerGenBio ASA BGBC007            
 
All output should have Page n of N at the top or bottom right corner of each page. 
TLFs should be internally paginated in relation to the total length (i.e., the page 
number should appear sequentially as page n of N, where N is the total number of 
pages in the corresponding TFL output). 
 
The program name and date should appear as the last footer on each page. 
 
15.2.3. 
Display Titles 
 
Each TLF should be identified by the designation and a numeral. (i.e., Table 14.1.1). 
A decimal system (x.y and x.y.z) should be used to identify TLFs with related 
contents. The title is centered. The analysis set should be identified on the line 
immediately following the title. The title and table designation are single spaced. A 
solid line spanning the margins will separate the display titles from the Column 
headers. There will be 1 blank line between the last title and the solid line. 
Table x.y.z 
First Line of Title 
Second Line of Title if Needed 
ITT Analysis Set 
 
15.2.4. 
Column Headers 
 
Column headings should be displayed immediately below the solid line described 
above in initial upper-case characters.  
 
In the case of efficacy tables, the variable (or characteristic) column will be on the 
far left followed by the treatment group columns and total column (if applicable). 
P-values may be presented under the total column or in separate p-value column (if 
applicable). Within-treatment comparisons may have p-values presented in a row 
beneath the summary statistics for that treatment. 
 
For numeric variables, include “unit” in column or row heading when appropriate. 
 
Analysis set sizes will be presented for each treatment group in the column heading 
as (N=xx) (or in the row headings if applicable). This is distinct from the ‘n’ used for 
the descriptive statistics representing the number of subjects in the analysis set. 
 
15.2.5. 
Body of the Data Display 
15.2.5.1. General Conventions 
Data in columns of a table or listing should be formatted as follows: 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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• 
Alphanumeric values are left-justified; 
• 
Whole numbers (e.g., counts) are right-justified; 
• 
Numbers containing fractional portions are decimal aligned. 
 
15.2.5.2. Table Conventions 
 
Units will be included where available. 
 
If the categories of a parameter are ordered, then all categories between the 
maximum and minimum category should be presented in the table, even if n=0 for 
all treatment groups in a given category that is between the minimum and maximum 
level for that parameter. For example, the frequency distribution for symptom 
severity would appear as: 
Severity 
Rating 
N 
severe 
0 
moderate 
8 
mild 
3 
 
Where percentages are presented in these tables, zero percentages will not be 
presented and so any counts of 0 will be presented as 0 and not as 0 (0%). 
 
If the categories are not ordered (e.g., Medical History, Reasons for Discontinuation 
from the Study, etc.), then only those categories for which there is at least 1 
subject represented in 1 or more groups should be included. 
 
An Unknown or Missing category should be added to any parameter for which 
information is not available for 1 or more subjects.  
 
Unless otherwise specified, the estimated mean and median for a set of values 
should be printed out to 1 more significant digit than the original values, and 
standard deviations should be printed out to 2 more significant digits than the 
original values. The minimum and maximum should report the same significant digits 
as the original values. For example, for systolic blood pressure: 
N 
  XX 
Mean 
XXX.X 
Std Dev 
     X.XX 
Median 
XXX.X 
Minimum 
XXX 
Maximum 
XXX 
 
P-values should be output in the format: “0.xxx”, where xxx is the value rounded to 
3 decimal places. Any p-value less than 0.001 will be presented as <0.001. If the p-
value should be less than 0.0001 then present as <0.0001. If the p-value is returned 
as >0.999 then present as >0.999 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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 
Percentage values should be printed to one decimal place, in parentheses with no 
spaces, one space after the count (e.g., 7 (12.8%), 13 (5.4%)). Pre-determine how to 
display values that round down to 0.0.  A common convention is to display as '<0.1', 
or as appropriate with additional decimal places. Unless otherwise noted, for all 
percentages, the number of subjects in the analysis set for the treatment group who 
have an observation will be the denominator. Percentages after zero counts should 
not be displayed and percentages equating to 100% should be presented as 100%, 
without any decimal places.  
 
Tabular display of data for medical history, prior / concomitant medications, and all 
tabular displays of adverse event data should be presented by the body system, 
treatment class, or SOC with the highest occurrence in the active treatment group 
in decreasing order, assuming all terms are coded. Within the body system, drug 
class and SOC, medical history (by preferred term), drugs (by ATC1 code), and 
adverse events (by preferred term) should be displayed in decreasing order. If 
incidence for more than 1 term is identical, they should then be sorted 
alphabetically. Missing descriptive statistics or p-values which cannot be estimated 
should be reported as “-”. 
 
The percentage of subjects is normally calculated as a proportion of the number of 
subjects assessed in the relevant treatment group (or overall) for the analysis set 
presented. However, careful consideration is required in many instances due to the 
complicated nature of selecting the denominator, usually the appropriate number of 
subjects exposed. Describe details of this in footnotes or programming notes. 
 
For categorical summaries (number and percentage of subjects) where a subject can 
be included in more than one category, describe in a footnote or programming note 
if the subject should be included in the summary statistics for all relevant categories 
or just 1 category and the criteria for selecting the criteria. 
 
Where a category with a subheading (such as system organ class) has to be split over 
more than one page, output the subheading followed by “(cont)” at the top of each 
subsequent page.  The overall summary statistics for the subheading should only be 
output on the first relevant page. 
 
15.2.5.3. Listing Conventions 
 
Listings will be sorted for presentation in order of treatment groups as above, 
subject number, visit/collection day, and visit/collection time. 
 
Missing data should be represented on subject listings as either a hyphen (“-”) with 
a corresponding footnote (“- = unknown or not evaluated”), or as “N/A”, with the 
footnote “N/A = not applicable”, whichever is appropriate. 
 
Dates should be printed in SAS® DATE9.format (“ddMMMyyyy”: 01JUL2000). Missing 
portions of dates should be represented on subject listings as dashes (--JUL2000). 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
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     INC Research 1007823 
 
 
 
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Dates that are missing because they are not applicable for the subject are output as 
“N/A”, unless otherwise specified. 
 
All observed time values must be presented using a 24-hour clock HH:MM or 
HH:MM:SS format (e.g., 11:26:45, or 11:26). Time will only be reported if it was 
measured as part of the study. 
 
Units will be included where available. 
 
15.2.5.4. Figure Conventions 
 
Unless otherwise specified, for all figures, study visits will be displayed on the X-axis 
and endpoint (e.g., treatment mean change from Baseline) values will be displayed 
on the Y-axis. 
15.2.6. 
Footnotes 
 
A solid line spanning the margins will separate the body of the data display from the 
footnotes.  
 
All footnotes will be left justified with single-line spacing immediately below the 
solid line underneath the data display. 
 
Footnotes should always begin with “Note:” if an informational footnote, or 1, 2, 3, 
etc. if a reference footnote. Each new footnote should start on a new line where 
possible. 
 
Subject specific footnotes should be avoided, where possible. 
 
Footnotes will be used sparingly and must add value to the table, figure, or data 
listing. If more than six lines of footnotes are planned, then a cover page may be 
used to display footnotes, and only those essential to comprehension of the data will 
be repeated on each page.  
 
The last line of the footnote section will be a standard source line that indicates the 
name of the program used to produce the data display, date the program was run, 
and the listing source (i.e., ‘Program : myprogram.sas    Listing source: 16.x.y.z’). 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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16. 
QUALITY CONTROL 
SAS programs are developed to produce clinical trial output such as analysis data sets, 
summary tables, data listings, figures or statistical analyses. INC Research SOP 
03.010.01 and 03.013.01 provide an overview of the development of such SAS programs. 
INC Research SOP 03.009.01 describes the quality control procedures that are 
performed for all SAS programs and output. Quality control is defined here as the 
operational techniques and activities undertaken to verify that the SAS programs 
produce the proper clinical trial output by checking for their logic, efficiency and 
commenting and by review of the produced output. 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
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17. 
INDEX OF TABLES AND FIGURES 
Table/Figure 
Number 
Name 
14.1.1.1 
Number of Subjects Enrolled and Study Termination 
14.1.2.1 
Protocol Deviations 
14.1.2.2 
Analysis Sets 
14.1.3.1 
Subject Demographic and Baseline Characteristics 
14.1.3.2. 
Cancer diagnosis  
14.1.3.3 
Medical/Surgical History 
14.1.4.1 
Prior Medications 
14.1.4.2 
Concomitant Medications 
14.1.4.3 
Prior Radiotherapy 
14.1.4.4 
Prior Anticancer Therapy for Study Disease 
14.1.5.1 
Treatment Compliance 
14.2.1.1.1 
Objective Response Rate 
14.2.1.1.2 
Objective Response Rate- Sensitivity analysis 
14.2.1.2 
Summary of Overall Visit Response 
14.2.1.3 
Best Overall Response 
14.2.2.1 
Duration of Response in Patients with Objective Response 
14.2.2.1.1 
Kaplan-Meier Plot for Duration of Response (DoR) 
14.2.2.1.2 
Swimmer Plot of Duration of Response 
14.2.2.2 
Summary of Disease Control Rate 
14.2.2.3 
Progression Free Survival 
14.2.2.3.1 
Kaplan Meier Plot of Progression Free Survival (PFS) by irRECIST 
14.2.2.4 
Sensitivity Summary of Progression Free Survival 
14.2.2.4.1 
Kaplan Meier Plot of Progression Free Survival (PFS) by RECIST 
(Sensitivity Summary) 
14.2.2.5 
Survival Status 
14.2.2.6 
Overall Survival 
14.2.2.6.1 
Kaplan Meier Plot of Overall Survival (OS) 
14.2.2.7 
Sensitivity Summary of Overall Survival 
14.2.2.7.1 
Kaplan Meier Plot of Overall Survival (OS) (Sensitivity Summary) 
14.2.2.8 
Objective Response Rate explored by PD-L1 and Axl expression status 
14.2.2.9 
Waterfall Plot of Best Percentage Change in Sum of Longest Diameters 
14.2.2.10 
Summary Statistics for Plasma Concentrations of BGB324 
14.2.2.10.1 
Individual Plasma Concentrations of BGB324 
14.2.2.11 
Summary Statistics for Plasma Concentrations of Pembrolizumab 
14.2.2.11.1 
Individual Plasma Concentrations of Pembrolizumab 
14.2.2.12 
Summary Statistics for Pharmacokinetic Parameters of BGB324 in Plasma 
(Non-Compartmental)  
14.2.2.13 
Summary Statistics for Pharmacokinetic Parameters of Pembrolizumab in 
Plasma (Non-Compartmental)  
14.3.1.1. 
Adverse Events (AEs) - Subject Level: Overall Summary 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
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     INC Research 1007823 
 
 
 
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Table/Figure 
Number 
Name 
14.3.1.2 
Treatment Emergent Adverse Events (TEAEs) by System Organ Class and 
Preferred Term 
11.3.1.3 
Treatment Emergent Adverse Events (TEAEs) by System Organ Class, 
Preferred Term and Maximum Reported CTCAE Grade 
14.3.1.4 
Treatment Emergent Adverse Events (TEAEs) of CTCAE Grade 3 or Higher 
by System Organ Class and Preferred Term 
14.3.1.5 
Treatment Emergent Adverse Events (TEAEs) by System Organ Class, 
Preferred Term and Relationship to BGB324 
14.3.1.6 
Treatment Emergent Adverse Events (TEAEs) by System Organ Class, 
Preferred Term and Relationship to Pembrolizumab 
14.3.1.7 
Treatment Emergent Adverse Events (TEAEs) Related to Both BGB324 and 
Pembrolizumab by System Organ Class and Preferred Term 
14.3.1.8 
Events of Clinical Interest (ECI) by System Organ Class and Preferred 
Term 
14.3.1.9 
Events of Clinical Interest (ECI) Related to Both BGB324 and 
Pembrolizumab by System Organ Class and Preferred Term 
14.3.1.10 
Serious Treatment Emergent Adverse Events (TEAEs) by System Organ 
Class and Preferred Term 
14.3.1.11 
Serious Treatment Emergent Adverse Events (TEAEs) Related to Both 
BGB324 and Pembrolizumab by System Organ Class and Preferred Term 
14.3.1.12 
Treatment Emergent Adverse Events (TEAEs) Leading to Interruption of 
BGB324 by System Organ Class and Preferred Term 
14.3.1.13 
Treatment Emergent Adverse Events (TEAEs) Leading to Interruption of 
Pembrolizumab by System Organ Class and Preferred Term 
14.3.1.14 
Treatment Emergent Adverse Events (TEAEs) Leading to Interruption of 
Both BGB324 and Pembrolizumab by System Organ Class and Preferred 
Term 
 
14.3.1.15 
Treatment Emergent Adverse Events (TEAEs) Leading to Discontinuation 
of BGB324 by System Organ Class and Preferred Term 
14.3.1.16 
Treatment Emergent Adverse Events (TEAEs) Leading to Discontinuation 
of Pembrolizumab by System Organ Class and Preferred Term 
14.3.1.17 
Treatment Emergent Adverse Events (TEAEs) with an Outcome of Death 
by System Organ Class and Preferred Term 
14.3.4.1.1.1 
Hematology: Summary by Visit, Time Point and Change from Baseline 
14.3.4.1.1.2 
Hematology: Shifts in CTCAE Grades 
14.3.4.1.1.3 
Hematology: Shifts from Baseline in Non-CTCAE Gradable Parameters 
Relative to the Normal Range 
14.3.4.1.2.1 
Clinical Chemistry: Summary by Visit, Time Point and Change from 
Baseline 
14.3.4.1.2.2 
Clinical Chemistry: Shifts in CTCAE Grades 
14.3.4.1.2.3 
Clinical Chemistry: Shifts from Baseline in Non-CTCAE Gradable 
Parameters Relative to the Normal Range 
14.3.4.1.3 
Urinalysis: Summary by Visit and Time Point 
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Statistical Analysis Plan  
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Table/Figure 
Number 
Name 
14.3.4.2 
Vital Signs: Summary by Visit, Time Point and Change from Baseline 
14.3.4.3.1 
Summary of ECG Overall Result by Study Visit and Time Point 
14.3.4.3.2  
Summary of ECG Overall Shift from Baseline 
14.3.4.3.3 
Categorical Analysis of QT Interval Correction 
14.3.4.4  
Physical Examination 
14.3.4.5 
Summary of Eastern Cooperative Oncology Group (ECOG) Performance by 
Study Visit 
14.3.4.6.1 
Duration of Exposure 
14.3.4.6.2 
Duration of Study Treatment – Number of Doses 
14.3.4.6.3 
Dose Interruptions of BGB324 
14.3.4.6.4 
Dose Reductions of BGB324 
14.3.4.6.5 
Dose Interruptions of Pembrolizumab 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
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18. 
INDEX OF LISTINGS 
Listing 
Number 
Name 
16.2.1.1 
Subject Disposition at End of Screening 
16.2.1.2 
Subject Disposition at End of Treatment 
16.2.1.3 
Subject Disposition at End of Study 
16.2.2.1 
Protocol Deviations 
16.2.3.1 
Inclusion and Exclusion Criteria 
16.2.3.2 
Informed Consent and Subject Eligibility 
16.2.3.3 
Analysis Sets 
16.2.4.1 
Demographics 
16.2.4.2 
Medical and Surgical History 
16.2.4.3.1 
Cancer Diagnosis 
16.2.4.3.2 
Prior Radiotherapy 
16.2.4.3.3 
Prior Anticancer Therapy for Study Disease 
16.2.4.4 
Prior and Concomitant Medications 
16.2.5.1 
IP Dispensation 
16.2.5.2 
Pembrolizumab Administration 
16.2.5.3.1 
BGB324 Accountability 
16.2.5.3.2 
BGB324 Compliance 
16.2.5.3.3 
BGB324 Administration 
16.2.6.1 
Overall Response to Treatment 
16.2.6.2.1 
Target Lesions 
16.2.6.2.2 
Non-Target Lesions 
16.2.6.2.3 
New Lesions 
16.2.6.3.1 
Duration of Response (DoR) 
16.2.6.3.2 
Progression Free Survival (PFS) 
16.2.6.3.3 
Progression Free Survival (PFS): Sensitivity Analysis 
16.2.6.3.4 
Overall Survival (OS) 
16.2.6.3.5 
Overall Survival (OS): Sensitivity Analysis 
16.2.6.3.6 
Survival Follow-Up 
16.2.6.3.7 
Subsequent Anticancer Treatment 
16.2.6.4.1 
Fresh Tumor Biopsy for Axl Kinase and PD-L1 Expression 
16.2.6.4.2 
Optional Fresh Tumor Biopsy for Axl Exploratory Signaling Biomarker 
Analysis 
16.2.6.4.3 
Archival Tumor Biopsy for Axl Exploratory Signaling Biomarker Analysis 
16.2.6.4.4 
Biomarkers and Peripheral Blood Mononuclear Cells (PBMC) 
16.2.6.4.5 
PD-L1 and AxL Status 
16.2.6.5.1 
Pharmacokinetics (PK) Sampling: Pembrolizumab 
16.2.6.5.2 
Pharmacokinetics (PK) Sampling: BGB324 
16.2.6.5.3 
Derived Pharmacokinetics (PK) Parameters: BGB324 
16.2.7.1 
All Adverse Events 
16.2.8.1.2.1 
Hematology 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
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Listing 
Number 
Name 
16.2.8.1.2.2 
Hematology: Abnormal Laboratory Results 
16.2.8.1.3.1 
Clinical Chemistry 
16.2.8.1.3.2 
Clinical Chemistry: Abnormal Laboratory Results 
16.2.8.1.4.1 
Urinalysis 
16.2.8.1.4.2 
Urinalysis: Abnormal Laboratory Results 
16.2.8.1.5.1 
Thyroid Function Test 
16.2.8.1.5.2 
Thyroid Function Test: Abnormal Laboratory Results 
16.2.8.1.6 
Pregnancy Test 
16.2.8.2.1. 
Vital Signs 
16.2.8.2.2.1 
Electrocardiogram (ECG) 
16.2.8.2.2.2 
Electrocardiogram (ECG): Clinically Significant Results 
16.2.8.2.3 
Physical Examination 
16.2.8.2.4 
ECOG Performance Status (PS) 
16.2.8.2.5 
Echocardiography 
 
 
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Statistical Analysis Plan  
Final Version 1.0 
14-Dec-2017 
     BerGenBio  ASA 
     BGBC007 / Merck & Co: MK-3475 PN-530  
     INC Research 1007823 
 
 
 
This document is proprietary and confidential to INC Research LLC. 
03.007A.03     
  INC Research © LLC 
Page 69 of 69 
19. 
APPENDICES 
Not applicable. 
 
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