Conditions: Non-Small Cell Lung Cancer
Keywords: BGB324 Bemcentinib Erlotinib NSCLC
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 40
Healthy volunteers: no

Brief summary:
A Phase 1/2 multi-center open-label study of BGB324 (bemcentinib) as a single agent (Run-in Cohort) and in combination with erlotinib (Arms A, B, and C) in participants with Stage IIIb or Stage IV non-small cell lung cancer (NSCLC). Bemcentinib is a potent selective small molecule inhibitor of AXL, a surface membrane protein kinase receptor which is connected with poor prognosis and acquired resistance to therapy.

Detailed description:
This is a multi-center, multi-arm open-label Phase 1/2 study that was conducted at 10 clinical sites in the United States and in Europe.

Total 40 participants with histologically- or cytologically-confirmed Stage IIIb or Stage IV NSCLC received bemcentinib (BGB324) as a single agent (Run-in Cohort) or in combination with erlotinib (Arms A, B, and C).

Run-in Arm to establish the safety and tolerability of bemcentinib (BGB324) administered as a single agent; bemcentinib was administered at a loading dose of 600 mg on Day 1 and Day 2 of Cycle 1, followed by 200 mg daily thereafter. After 6 participants have been dosed and safety established; Arm A (dose escalation arm) was opened to confirm the bemcentinib dose to be used in combination with erlotinib.

In Arm A the dose of bemcentinib (BGB324) was escalated in a standard 3+3 fashion until a maximum tolerated dose (MTD) of the combination (bemcentinib + erlotinib) was established. The dose of bemcentinib to be investigated in Arm B and C was confirmed upon recommendation of a Safety Review Committee.

Arm B and C was open in parallel to investigate bemcentinib in combination with erlotinib.

Arms:
arm 1: Participants in this arm received bemcentinib as monotherapy. This was to determine the safety and tolerability of bemcentinib when administered alone. arm 2: Participants in this arm received erlotinib with bemcentinib. A standard 3+3 design to determine the dose of bemcentinib that could be safely administered in combination with erlotinib in participants who had received prior treatment with erlotinib. This was to determine the maximum tolerated dose of bemcentinib that could be safely administered with erlotinib. arm 3: Participants in this arm received erlotinib with bemcentinib in participants with an activating epidermal growth factor receptor (EGFR) mutation who are T790M negative and who had progressed after receiving treatment with an approved EGFR tyrosine kinase inhibitor (TKI) \[osimertinib, afatinib, or gefitinib\]. arm 4: Participants in this arm received erlotinib daily along with bemcentinib in participants with an activating EGFR mutation (including exon 19 deletion or exon 21 \[L858R\] substitution or other rearrangement of the EGFR gene mutation) who had received greater than or equal to (≥) 12 weeks of erlotinib without disease progression.

Interventions: intervention 1: Erlotinib intervention 2: Bemcentinib intervention 3: Bemcentinib intervention 4: Bemcentinib
Intervention descriptions: intervention 1: Participants received erlotinib 150 mg for the 21-day cycle. intervention 2: Participants received bemcentinib 600 mg on Days 1 and 2 as loading dose and bemcentinib 200 mg as daily maintenance dose for the 21-day cycle. intervention 3: Participants received starting loading dose of bemcentinib 600 mg (200 mg on Days 1, 2 and 3) and bemcentinib 100 mg as daily maintenance dose for the 21-day cycle.

Depending on tolerability and DLT, the loading dose of bemcentinib was escalated to 800mg (400 mg on Days 1 and 2) and bemcentinib 100 mg as daily maintenance for the 21- day cycle and to 1200 mg daily (600 mg on Days 1 and 2, or 400 mg on Days 1, 2 and 3) and bemcentinib 200 mg as daily maintenance for the 21- day cycle). intervention 4: Participants received bemcentinib 400 mg on Days 1, 2 and 3 as loading dose and bemcentinib 200 mg as daily maintenance dose for the 21-day cycle.

Protocol document:
Prot_000.pdf: 
 
BerGenBio ASA  
Jonas Lies vei 91 
5009 Bergen, Norway  
 
 
BGBC004 V5 16 May 2017 
CONFIDENTIAL 
Page 1 of 80 
 
           
 
CLINICAL STUDY PROTOCOL 
 
 
 
Investigational Product: 
BGB324 
 
Protocol Number: 
BGBC004 
 
Phase: 
Phase 1/2 
 
Protocol Title: 
A Multi-Center Open-Label Phase 1/2 Study of 
BGB324 in Combination with Erlotinib in Patients with 
Stage IIIb or Stage IV Non-Small Cell Lung Cancer 
 
Version and Date: 
 
5.0 (16th May 2017) 
 
IND Number: 
 
124645 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study will be conducted in compliance with International Conference on 
Harmonization (ICH) guidelines on Good Clinical Practice (GCP), the 
Declaration of Helsinki (with amendments), and in accordance with local legal 
and regulatory requirements 


 
BerGenBio ASA  
Jonas Lies vei 91 
5009 Bergen, Norway  
 
 
BGBC004 V5 16 May 2017 
CONFIDENTIAL 
Page 2 of 80 
 
SUMMARY OF CHANGES SINCE THE PREVIOUS VERSION 
 
Administrative 
• 
Version and date updated. 
• 
Update of sponsor name to BerGenBio ASA 
• 
Table of Contents updated. 
• 
Confirmation that at the time of this Amendment the Run-in Cohort and Arm A have 
completed recruitment.  
• 
Additional preclinical data added on BGB324 and high dose steroids in mice (New Section 
6.1.5) 
• 
Section referencing updated in Table 9. 
• 
SAE reporting fax and email address has been updated (previous contacts are still 
operational). 
• 
Renumbering of inclusion criteria.  
• 
Formatting and typographical errors updated.  
• 
Table 5 Schedule of Assessments updated to reflect changes. 
• 
Table 6 updated to reflect the revised pharmacokinetic (PK) schedule. 
• 
Synopsis text has been updated to reflect changes in the body of the protocol. 
 
Study Design and Methodology 
 
Arm B and C, General 
• 
Clarification that the erlotinib dose for Arms B and C may be reduced from 150mg in 
accordance with the prescribing information (Sections 11.3.2; 8.3.1). 
• 
Epidermal Growth Factor Receptor (EGFR) mutation status expanded to include “other 
rearrangements of the EGFR gene” (Section 9.1.4 Arm B Incl. 12, and Arm C Section 
9.1.5 Incl.20). 
• 
CTs scan frequency: Patients who remain on treatment for 12 months or longer will require 
scans at a frequency of 6 months, or earlier if progression of disease is suspected 
(Section 10.2.10). 
• 
Patients who remain on BGB324 for 12 months or more will be able to reduce the 
frequency and number of assessments required at each visit. Patients will return to clinic 
every 6 weeks (every 2 cycles) (New Section 10.1.7). 
• 
The End of Study (EOS) is defined as when all patients have completed or withdrawn and 
the EOS visit has been completed (Section 8.11).  
• 
Inclusion of 15% boundary from the prescribed dose (Section 13.4.8). 
• 
Post dose 30-hour ECG collection time point has been removed (Section 10 and Table 5). 
• 
New Section 10.1.8 Visit schedule while on corticosteroids 
Additional weekly monitoring (physical exam, vital signs, hematology / chemistry 
analysis) while patients are receiving prednisolone (or equivalent) at 10mg to 40 mg 
daily  
 
• 
New Section 11.3.1.4 
BGB324 dose modification for steroids doses over 40mg daily (prednisolone equivalent) 


BGBC004 V5 16 May 2017  
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If a patient requires prednisolone (or equivalent) at daily doses above 40mg then 
BGB324 should be interrupted until the steroid dose is equivalent to or less than 40mg 
prednisolone daily, at which time weekly monitoring will be undertaken until the steroid 
dose is equivalent or less than 10mg (Section 10.1.8)  
For those patients who experience a BGB324 dose delay of ≥7 days, the BGB324 
loading dose assigned should be repeated. If the patient was unable to tolerate the 
loading dose in Cycle 1 the repeat loading dose can be omitted. The requirement to 
reintroduce the loading dose should be discussed with the Medical Monitor. 
Steroid restrictions do not apply to topical/ inhaled/ eye or nasal drops. If required, 
additional advice on the concomitant use of steroids with BGB324 should be obtained 
from the BerGenBio Medical Monitor. 
 
• 
Section 11.5 – Concomitant Medications and Procedures (New Text) 
Patients receiving BGB324 who require the support of prednisolone (or equivalent) at 
10mg daily or above should be monitored at weekly intervals whilst receiving treatment. If 
a patient requires prednisolone (or equivalent) at daily doses above 40mg then BGB324 
should be interrupted until the steroid dose is equivalent to or less than 40mg daily, at 
which time weekly monitoring will be undertaken until the steroid dose is equivalent to or 
less than 10mg. 
 
Steroid restrictions do not apply to topical/ inhaled/ eye or nasal drops. If required, 
additional advice on the concomitant use of steroids with BGB324 should be obtained from 
the BerGenBio Medical Monitor 
. 
 
Arm B 
• 
The requirement for collection of and analysis of circulating tumor cell (CTC) samples in 
has been removed. Pharmacodynamic (PD) endpoints associated with analysis of CTC 
have been removed (Sections 10.2.9.1. 7.8). 
• 
As a 3-day loading dose has been confirmed in Arm A, reference to pharmacokinetic (PK) 
schedules associated with a 2-day loading dose have been removed (Table 6 updated). 
• 
Requirement for starting erlotinib 1 week prior to the first dose of BG324 has been removed 
(Section 9; Arm B). 
• 
PK sampling will be limited to BGB324 and pre-dose PK sampling will stop at Cycle 3 
(Table 6 updated).  
• 
Cycle 1 –Day 1 assessments have been removed (Section 10.1.2.). 
• 
Clarification that only BGB324 PK samples will be required in Arm B (Section 10). 
• 
Clarification on the requirements for T790M testing - patients who have progressed on 
osimertinib will not require retesting (New Section 10.2.11). 
• 
The 28-day screening window may be extended to allow for T790M testing, all other 
assessments are to be conducted in the 28-day window (Section 9.1.4; Arm B Incl.12). 
• 
Expansion of the inclusion criteria to allow patients who have progressed on an approved 
EGFR inhibitor to be considered for inclusion into the study (Section 9.1.4; Arm B 
Incl.14). 
• 
Clarification that toxicities associated with other EGFR inhibitors must be <Grade 2 in 
severity at the time of first dose of BGB324 (Section 9.1.4; Arm B Incl.15). 
• 
Confirmation that afatinib or gefitinib treatment must complete 1 week before the first dose 
of BGB324 (Section 9.1.4; Arm B Incl.16). 
• 
Expansion to allow up to 4 previous treatments in the advanced setting (Section 9.1.4; 
Arm B Incl 18). 
• 
Secondary objectives looking at BGB324 and erlotinib PK have been revised to reflect that 
only BGB324 PK samples will be collected (Section 7.3.2). 


BGBC004 V5 16 May 2017  
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• 
PK population revised to reflect that no erlotinib PK will be collected in Arm B 
(Section 14.4.1). 
 
Arm C 
• 
This arm may be closed if Arm B stops or completes recruitment before Arm C reaches 
the 14patient target. Patients already enrolled into Arm C will be able to continue in 
accordance with the protocol (Section 8.5). 
• 
Clarification of the exclusion criteria to facilitate those patients who may have received 
alternative treatment while awaiting confirmation of EGFR status (Section 9.1.5; Arm C 
Incl.24). 
 
--------------------------------------------------------------------------------------------------------------------------- 
Safety Justifications 
 
The protocol has been changed to include patients who experienced disease progression 
whilst receiving an approved EGFR inhibitor such as afatinib or gefitinib as an alternative to 
erlotinib. This has been done as the biological mechanisms of resistance to all 3 agents are 
similar and may be reversed following exposure to BGB324. 
 
Pharmacokinetic data collected and analyzed to date supports that there is no interaction 
between erlotinib and BGB324, therefore no requirement to collect additional erlotinib PK or 
long term pre-dose BGB324 PK. BGB324 PK will be collected as per schedule up to Cycle 3 
and EOS. 
 
30hr ECG removed. ECGs are already being collected pre-dose on Days 1,2, and 3. The 
change is not considered to have any impact on safety. 
 
Arm B: Inclusion 18 - revised in response to Investigator eligibility request. The change is 
not considered to have any impact on patient safety or study integrity. 
 
Arm B: Inclusion.14/15- The Sponsor has seen an increase in the use of EGFR inhibitors 
other than erlotinib as standard of care. Additional criteria have been implemented that 
restricts use to 1 week before the first dose of BGB324 and requires the patient to have Grade 
2 or less toxicities at the time of BGB324 dosing. 
 
Only erlotinib will be administered in combination with BGB324 thus the change is not 
anticipated to have any effect on the safety of the patients. 
 
Revised visit schedule after 12 month: This has been expanded from a visit each cycle to 
a visit to every 2 cycles. This change in frequency is not anticipated to have any effect on 
patient safety as it only applies to patients who have received treatment with BGB324 for one 
year, and reduces the visit burden for the patient.  
 
Oral Corticosteroid use with BGB324 
Following advice from the FDA on preclinical data in mice with high dose steroids and 
BGB324, additional weekly monitoring has been introduced for those patients who require 
treatment with 10mg or above daily prednisolone (or equivalent) and guidance that  at doses 
above 40mg daily BGB324 should be interrupted until the  steroid  dose is 40mg or less daily. 
 


 
BerGenBio ASA  
Jonas Lies vei 91 
5009 Bergen, Norway  
 
 
BGBC004 V5 16 May 2017 
CONFIDENTIAL 
Page 5 of 80 
 
 
 
PROTOCOL SIGNATURES 
Protocol BGBC004 Version 5, 16 May 2017 
 
 
Sponsor’s Approval 
This protocol has been approved by BerGenBio ASA. 
 
 
 
Signature _____________________________  
 
 
 
Date ___________________ 
M.D., Ph.D. 
 
 
 
 
Investigator’s Acknowledgment 
 
I, the undersigned, have reviewed the protocol and appendices and I will conduct the 
BGBC004 clinical study as described and in accordance with International Conference on 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and all the ethical and 
regulatory considerations stated. I have read and understood the contents of the BGB324 
Investigator’s Brochure. 
 
 
 
Signature _____________________________  
 
 
 
Date ___________________ 
 
Printed Name __________________________  
 
 
 
 


BGBC004 V5 16 May 2017  
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Page 6 of 80 
 
STUDY PERSONNEL 
 
Sponsor’s Representative 
M.D., Ph.D. 
Sponsor’s Medical Contact 
M.D., Ph.D. 
Sponsor Site 
BerGenBio ASA 
Jonas Lies vei 91 
5009 Bergen 
Norway 
Clinical Research Organization 
 
Chiltern International Inc 
4000 CentreGreen Way 
Suite 300 
Cary NC, 27513 
United States of America 
Telephone: +1 919 462 8867 
Pharmacovigilance 
SAE Reporting 
Pregnancy Reporting 
Chiltern International 
GlobalSAEInbox@Chiltern.com  
Fax: +1 888-726-8416 
 
Note: Laboratory details and contact information are provided in the laboratory manual. 
 
 


BGBC004 V5 16 May 2017  
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TABLE OF CONTENTS 
 
SUMMARY OF CHANGES SINCE THE PREVIOUS VERSION ........................................... 2 
 
PROTOCOL SIGNATURES ......................................................................................... 5 
 
STUDY PERSONNEL .................................................................................................. 6 
 
TABLE OF CONTENTS ............................................................................................... 7 
LIST OF TABLES ................................................................................................................ 12 
LIST OF FIGURES ............................................................................................................. 12 
 
LIST OF ABBREVIATIONS ........................................................................................ 13 
 
PROTOCOL SYNOPSIS ............................................................................................ 15 
 
INTRODUCTION ....................................................................................................... 27 
6.1 
Non-clinical Studies with BGB324 ....................................................................... 27 
6.1.1 
Specificity of inhibition of Axl kinase activity ............................................. 27 
6.1.2 
Inhibition of proliferation of NSCLC cells .................................................. 27 
6.1.3 
Re-sensitization to erlotinib in a NSCLC cell line by BGB324................... 28 
6.1.4 
In vivo anti-tumor activity of BGB324 and erlotinib ................................... 29 
6.1.5 
High Dose Steroids and Mouse Model ..................................................... 30 
6.2 
Clinical Studies with BGB324 .............................................................................. 30 
6.2.1 
Summary of clinical safety to date ........................................................... 30 
6.2.2 
BGB324 pharmacokinetics ...................................................................... 31 
6.2.3 
Rationale for BGB324 starting dose ......................................................... 32 
 
OBJECTIVES AND ENDPOINTS .............................................................................. 33 
7.1 
Run-In Cohort (Phase 1) ..................................................................................... 33 
7.1.1 
Primary objective ..................................................................................... 33 
7.2 
Arm A (Phase 1) ................................................................................................. 33 
7.2.1 
Primary objective ..................................................................................... 33 
7.2.2 
Secondary objective ................................................................................ 33 
7.2.3 
Exploratory objective ............................................................................... 34 
7.3 
Arm B (Phase 2) ................................................................................................. 34 
7.3.1 
Primary objective ..................................................................................... 34 
7.3.2 
Secondary objective ................................................................................ 34 
7.3.3 
Exploratory objective ............................................................................... 34 
7.4 
Arm C (Phase 2) ................................................................................................. 34 
7.4.1 
Primary objective ..................................................................................... 34 
7.4.2 
Secondary objective ................................................................................ 34 


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7.4.3 
Exploratory objective ............................................................................... 34 
7.5 
Safety Endpoints ................................................................................................. 34 
7.6 
Clinical Efficacy Endpoints .................................................................................. 34 
7.7 
Pharmacokinetic Endpoints ................................................................................. 35 
7.8 
Pharmacodynamic Endpoints .............................................................................. 35 
 
STUDY DESIGN ........................................................................................................ 35 
8.1 
Overview ............................................................................................................. 35 
8.2 
Run-in Cohort (Phase 1) ..................................................................................... 37 
8.3 
Arm A (Phase 1) ................................................................................................. 37 
8.3.1 
BGB324 and erlotinib dose levels ............................................................ 38 
8.3.2 
Dose escalation scheme .......................................................................... 39 
8.3.3 
Assessment of DLTs ................................................................................ 40 
8.4 
Arm B (Phase 2) ................................................................................................. 40 
8.5 
Arm C (Phase 2) ................................................................................................. 41 
8.6 
Overall Study Duration and Follow-Up ................................................................ 41 
8.7 
Screening ............................................................................................................ 41 
8.8 
Treatment ........................................................................................................... 41 
8.9 
End-of-Study Visit ............................................................................................... 42 
8.10 Study Stopping Rules .......................................................................................... 42 
8.11 End of Study ....................................................................................................... 42 
 
SELECTION OF PATIENTS ...................................................................................... 43 
9.1 
Inclusion Criteria ................................................................................................. 43 
9.1.1 
General inclusion criteria ......................................................................... 43 
9.1.2 
Additional inclusion criteria for run-in cohort ............................................. 43 
9.1.3 
Inclusion criteria for Arm A ....................................................................... 43 
9.1.4 
Inclusion criteria for Arm B ....................................................................... 43 
9.1.5 
Inclusion criteria for Arm C ....................................................................... 44 
9.2 
Exclusion Criteria ................................................................................................ 44 
 
STUDY PROCEDURES AND ASSESSMENTS ......................................................... 46 
10.1 Procedures at each Visit ..................................................................................... 50 
10.1.1 
Screening and enrollment ........................................................................ 50 
10.1.2 
Cycle 1 .................................................................................................... 50 
 Day -1 (Arm A) ............................................................................. 51 
 Day 1, Day 8, Day 15 ................................................................... 51 


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 Day 2, Day 3, Day 4 ..................................................................... 51 
 Day 9 ............................................................................................ 51 
 Days 5-7, 10-14, 16-21 ................................................................. 51 
10.1.3 
Cycle 2 .................................................................................................... 52 
 Day 1, Day 8, Day 15 ................................................................... 52 
 Days 2-7, 9-14, 16-20 ................................................................... 52 
10.1.4 
Cycles ≥3-C17 ......................................................................................... 52 
 Day 1 ............................................................................................ 52 
 Days 2-20 ..................................................................................... 52 
10.1.5 
End-of-study visit ..................................................................................... 52 
10.1.6 
Assessments at disease progression ....................................................... 53 
10.1.7 
Visit schedule after 12 months of treatment ............................................. 53 
10.1.8 
Visit schedule while on corticosteroids ..................................................... 53 
10.2 Details of Study Procedures ................................................................................ 54 
 Clinical Laboratory Assessments .................................................. 54 
10.2.2 
Pregnancy test ......................................................................................... 54 
10.2.3 
Vital signs ................................................................................................ 54 
10.2.4 
Triplicate 12-lead ECG............................................................................. 54 
10.2.5 
Echocardiogram/MUGA ........................................................................... 55 
10.2.6 
Physical examination ............................................................................... 55 
10.2.7 
Performance status .................................................................................. 55 
10.2.8 
Pharmacokinetic assessments ................................................................. 55 
10.2.9 
Pharmacodynamic assessments (Arms A, B and C) ................................ 56 
 Pharmacodynamic tissue and blood samples ............................... 56 
10.2.10 Clinical efficacy ........................................................................................ 56 
10.2.11 T790M confirmation ................................................................................. 57 
 
STUDY TREATMENT ................................................................................................ 57 
11.1 Treatment Schedule and Administration of BGB324 ........................................... 57 
11.2 Treatment Schedule and Administration of Erlotinib ............................................ 57 
11.3 Dose Modification ............................................................................................... 58 
11.3.1 
BGB324 toxicities and dose modification ................................................. 58 
 BGB324 loading dose toxicities .................................................... 58 
 BGB324 daily dose toxicities ........................................................ 58 
 BGB324 dose modification for QTC .............................................. 59 


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 BGB324 dose modification for steroids doses over 40mg daily 
(prednisolone equivalent) ...................................................... 60 
11.3.2 
Erlotinib dose reduction ........................................................................... 60 
11.4 Prior and Concomitant Therapies ........................................................................ 60 
11.5 Concomitant Medication and Procedures ............................................................ 61 
11.6 Discontinuation of Treatment and Withdrawal ..................................................... 61 
11.7 Patient Replacement ........................................................................................... 62 
 
MANAGEMENT OF STUDY MEDICATIONS ............................................................. 62 
12.1 BGB324 .............................................................................................................. 62 
12.1.1 
BGB324 storage ...................................................................................... 62 
12.1.2 
BGB324 accountability............................................................................. 62 
12.2 Erlotinib ............................................................................................................... 62 
 
SAFETY MONITORING AND REPORTING .............................................................. 62 
13.1 Adverse Event Definitions ................................................................................... 63 
13.1.1 
Adverse event .......................................................................................... 63 
13.1.2 
Serious adverse event ............................................................................. 63 
13.2 Adverse Event Reporting Period ......................................................................... 64 
13.3 Assessment of Adverse Events ........................................................................... 64 
13.3.1 
Assessment of severity of adverse events ............................................... 64 
13.3.2 
Assessment of causality of adverse events.............................................. 65 
13.4 Recording Adverse Events .................................................................................. 65 
13.4.1 
Adverse events occurring secondary to other events ............................... 65 
13.4.2 
Persistent and recurrent adverse events .................................................. 66 
13.4.3 
Abnormal laboratory and ECG values ...................................................... 66 
13.4.4 
Abnormal vital sign values ....................................................................... 66 
13.4.5 
Abnormal liver function tests .................................................................... 67 
13.4.6 
Deaths ..................................................................................................... 67 
13.4.7 
Hospitalization or prolonged hospitalization ............................................. 67 
13.4.8 
Overdoses ............................................................................................... 68 
13.5 Reporting of Serious Adverse Events .................................................................. 68 
13.6 Immediate Reporting of Serious Adverse Events ................................................ 68 
13.7 Procedures for Handling Special Situations ........................................................ 69 
13.7.1 
Pregnancy ............................................................................................... 69 
13.7.2 
Medical emergency .................................................................................. 69 
13.8 Investigator’s Safety Responsibilities .................................................................. 70 


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13.9 Sponsor’s Safety Responsibilities ....................................................................... 70 
 
STATISTICAL CONSIDERATIONS ........................................................................... 70 
14.1 Patient Disposition, Demography and Baseline Disease Characteristics ............. 70 
14.2 Safety.................................................................................................................. 70 
14.2.1 
Safety analysis population ....................................................................... 70 
14.2.2 
Methods of analysis ................................................................................. 70 
14.3 Efficacy ............................................................................................................... 71 
14.3.1 
Efficacy analysis population ..................................................................... 71 
14.3.2 
Methods of analysis ................................................................................. 71 
14.4 Pharmacokinetics ................................................................................................ 71 
14.4.1 
Pharmacokinetic analysis population ....................................................... 71 
14.4.2 
Methods of analysis ................................................................................. 71 
14.5 Pharmacodynamics ............................................................................................. 71 
14.5.1 
Pharmacodynamic analysis population .................................................... 71 
14.5.2 
Methods of analysis ................................................................................. 72 
14.6 Sample Size Considerations ............................................................................... 72 
14.7 Clinical Study Report ........................................................................................... 72 
 
ETHICAL CONSIDERATIONS ................................................................................... 73 
15.1 Good Clinical Practice Statement ........................................................................ 73 
15.2 Institutional Review Board ................................................................................... 73 
15.3 Patient Information and Consent ......................................................................... 73 
15.4 Subject Data Protection ...................................................................................... 73 
 
ADMINISTRATIVE PROCEDURES ........................................................................... 73 
16.1 Quality Assurance ............................................................................................... 73 
16.2 Case Report Form and Source Document Verification ........................................ 73 
16.3 Study Monitoring ................................................................................................. 74 
16.4 Retention of Study Data ...................................................................................... 74 
16.5 Use of Information and Publication Policy ........................................................... 74 
16.5.1 
Clinical research organizations ................................................................ 74 
16.5.2 
Changes to the final study protocol .......................................................... 75 
16.5.3 
Investigator responsibilities ...................................................................... 75 
 
REFERENCES .......................................................................................................... 76 
 
APPENDICES ............................................................................................................ 77 
Appendix 1 ECOG Performance Status Scale .............................................................. 77 


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Appendix 2 The NYHA Functional Classification in a Subject with Heart Disease ......... 78 
Appendix 3 Drugs that are Generally Accepted to Have a Risk of Causing Torsades de 
Pointes ....................................................................................................... 79 
Appendix 4 NCI CTCAE, Version 4.03 .......................................................................... 80 
LIST OF TABLES 
Table 1 
BGB324 Kinase Selectivity Profile.............................................................. 27 
Table 2 
Effect of BGB324 on Proliferation of Human NSCLC Cell Lines ................. 28 
Table 3 
BGB324-Related AEs Reported Following a Single Oral Administration of 
BGB324 to Healthy Male Subjects ............................................................. 31 
Table 4 
Possible BGB324 Dosing Levels Involving A Loading Dose and Daily Dose .. 
 
 .................................................................................................................. 38 
Table 5 
Schedule of Events .................................................................................... 47 
Table 6 
Time points for Pharmacokinetic Sample Collection (Run-in Cohort, Arms A 
and B Only) ................................................................................................ 55 
Table 7 
Daily Dose Modification of BGB324 for Toxicity ......................................... 58 
Table 8 
Daily Dose Modification of BGB324 for QTc Prolongation .......................... 59 
Table 9 
Guidelines for Assessment of Severity for Adverse Events not Listed in 
CTCAE ....................................................................................................... 64 
Table 10 
BGB324 Pharmacokinetic Parameters to be Evaluated ............................. 71 
Table 11 
Operating Characteristics of the 3+3 Study Design .................................... 72 
 
LIST OF FIGURES 
Figure 1 
Restoration of Erlotinib Sensitivity in NSCLC Cells .................................... 28 
Figure 2 
Inhibition of NSCLC Colony Formation by BGB324 and Erlotinib ............... 29 
Figure 3 
Anti-Tumor Effect (left panel) and Tolerability (right panel) of BGB324 and 
Erlotinib in the A549 Human NSCLC Xenograft Model ............................... 29 
Figure 4 
 BGB324 Blocks Acquired Resistance to Erlotinib in the HCC827 Human 
NSCLC Xenograft Model ............................................................................ 30 
Figure 5 
Mean Plasma Concentrations of BGB324 Following a Single Oral 
Administration of BGB324 at 50, 100, 150, 200, 400, 600, 1000, and 1500 mg 
to Healthy Male Subjects ............................................................................ 32 
Figure 6 
Simulated Plasma Concentrations of BGB324 Following Repeat Once Daily 
Oral Administration of 200 mg BGB324 to Healthy Male Subjects Under 
Fasted Conditions (Loading Dose of 600 mg on Day 1 and Day 2) ............. 33 
Figure 7 
BGBC004 Study Design Outline ................................................................ 37 
Figure 8 
Operating Characteristics of the 3+3 Dose Escalation Process .................. 40 
 
 
 


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LIST OF ABBREVIATIONS 
3-D 
Three-dimensional 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC0-∞ 
Area under the curve extrapolated to infinity 
AUC0-t 
Area under the curve within a dosing interval 
BID 
Twice daily 
Cmax 
Maximum concentration achieved 
CNS 
Central nervous system 
CRO 
Clinical Research Organization 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTC 
Circulating tumor cell 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic acid 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EGFR 
EOS 
Epidermal growth factor receptor 
End of Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
H0 
Null hypothesis 
HIV 
Human immunodeficiency virus 
HPMC 
Hydroxypropyl methylcellulose 
IB 
Investigator’s Brochure 
IC50 
Half maximal inhibitory concentration 
ICF 
Informed consent form 
ICH  
International Conference on Harmonisation 
IND 
Investigational new drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
LC/MS/MS 
Liquid chromatography/tandem mass spectrometry 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
MUGA 
Multi-gated acquisition 
NCI 
National Cancer Institute 
NSCLC 
Non-small cell lung cancer 
NYHA 
PD 
New York Heart Association 
Progressive disease 
QA 
Quality assurance 
QD 
Once daily 
QTcF 
QT interval utilizing Fridericia’s correction 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
Recommended Phase 2 dose 
SAE 
Serious adverse event 
SMC 
Safety Monitoring Committee 


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SUSAR 
Suspected unexpected serious adverse reaction 
tmax 
Time to maximum concentration 
ULN 
Upper limit of normal range 
US 
United States of America 
 
 


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PROTOCOL SYNOPSIS 
PROTOCOL TITLE 
A multi-center open-label Phase 1/2 study of BGB324 in 
combination with erlotinib in patients with Stage IIIb or 
Stage IV non-small cell lung cancer. 
PROTOCOL NUMBER 
BGBC004 
SPONSOR 
BerGenBio ASA 
Jonas Lies vei 91 
5009 Bergen 
Norway 
INVESTIGATIONAL 
PRODUCT 
BGB324 
PHASE OF DEVELOPMENT 
Phase 1/2 
RATIONALE 
In patients with non-small cell lung cancer (NSCLC), there is 
a progressive decline in response to repeated lines of 
therapy, primarily due to development of biologic resistance 
within the underlying tumor and a progressive decline in 
patient performance status resulting from treatment- and 
disease-related morbidities. There is a significant need for 
development of strategies that can prolong response and 
prevent development of resistance to earlier-stage treatment 
regimens. 
 
BGB324 is a potent selective small molecule inhibitor of Axl, 
a surface membrane protein kinase receptor that is 
over-expressed in many metastatic solid tumors and has 
been identified as a marker of a poor prognosis in patients 
with NSCLC. In vitro studies indicate that signaling through 
Axl stimulates several pro-survival pathways, some of which 
are mediated by AKT phosphorylation and up-regulation of 
the epithelial receptor kinase pathway. Recent non-clinical 
data implicate Axl in development of resistance to several 
agents used in the treatment of NSCLC, especially epidermal 
growth factor receptors (EGFR) inhibitors including erlotinib. 
 
This study is designed primarily to evaluate the safety and 
tolerability of BGB324 when administered in combination with 
erlotinib, and to establish the recommended Phase 2 dose 
(RP2D) of the combination of BGB324 and erlotinib in 
patients with Stage IIIb or Stage IV NSCLC. 
STUDY DESIGN 
This is a multi-center, multi-arm open-label Phase 1/2 study 
that will be conducted at approximately 10 clinical sites; the 
number of sites may be revised to reflect changes in 
recruitment rates. 
 
Up to 60 patients with histologically- or cytologically-
confirmed Stage IIIb or Stage IV NSCLC will receive BGB324 
as a single agent (Run-in Cohort) or in combination with 
erlotinib (Arms A, B and C).  
 
At the time of Amendment 5, patient recruitment into the 
Run-In Arm (BGB324 monotherapy) and Arm A (BGB324 
dose escalation in combination with erlotinib) was complete 
and the RP2D has been confirmed. Patients that remain on 
treatment in the Run-in Cohort or Arm A should be followed 
up in accordance with the protocol schedule.  


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Run-in Cohort (Phase 1) 
Prior to commencing dosing of BGB324 in combination with 
erlotinib, the safety and tolerability of single agent BGB324 
will be assessed in a minimum of 6 patients. The safety data 
from the first cycle in these 6 patients will be reviewed by the 
safety monitoring committee (SMC) before enrolment into 
Arm A can commence. 
 
Arm A (Phase 1) 
Arm A is designed to determine the daily dose and loading 
schedule of BGB324 that can be safely administered in 
combination with erlotinib in patients who have received prior 
treatment with erlotinib. The starting dose of erlotinib will be 
150mg daily. Lower doses of erlotinib may be explored at the 
request of the SMC. In addition to safety and tolerability, the 
pharmacokinetics (PK) and pharmacodynamics (PD) of 
BGB324 and erlotinib will be evaluated. 
 
In Arm A, dose and dosing schedules will be explored to 
assess tolerability of the loading and daily doses and to 
select the RP2D for expansion into Phase 2 (Arms B and C). 
 
The dose of BGB324 will be escalated in a standard 3+3 
design. The starting dose level of BGB324 will be 600 mg 
loading dose (2 days) and 200 mg daily dose. It is anticipated 
that a maximum of 3 BGB324 Dose Levels will be evaluated 
with up to 18 patients enrolled. Alternative loading dose 
schedules may be explored in combination with daily dosing 
schedules (see Table 4). 
 
Dose escalation may be stopped prior to achieving the 
maximum tolerated dose (MTD) if it is considered that a 
clinically acceptable recommended Phase 2 dose (RP2D) 
has been achieved. Safety will be reviewed by the Safety 
Monitoring Committee (SMC). 
 
When the RP2D of BGB324 is identified and the dose of 
erlotinib to be administered in combination with BGB324 is 
confirmed, the Phase 2 part of the study will commence and 
Arms B and C will open simultaneously to enrolment. 
 
Arm B (Phase 2) 
Arm B will follow a Simon-like 2-stage design with relaxed 
stopping for futility to evaluate the PK of BGB324 and the 
safety and tolerability, PD, and clinical efficacy of BGB324 in 
combination with erlotinib in patients with an activating EGFR 
mutation who have progressed after receiving an approved 
EGFR inhibitor (i.e., erlotinib, afatinib, or gefitinib) 
 
For patients to be eligible for Arm B, their EGFR T790M 
status should be confirmed during the screening period prior 
to receiving the first BGB324 dose. This can be done either 
via blood test (circulating tumor DNA [ctDNA]; serum or 
plasma;) or tumor biopsy. Patients who test negative for 
T790M in ctDNA testing will require a confirmatory result from 


BGBC004 V5 16 May 2017  
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a tumour biopsy. Both the blood test/biopsy should be 
undertaken in accordance with local procedures and do not 
require central analysis. For patients to be eligible for Arm 
B, a negative EGFR T790M result must be documented. 
Patients who have previously been treated with a T790M 
inhibitor (i.e., osimertinib) and who subsequently progressed 
will not require T790M testing. 
 
If clinical response (complete response or partial response) 
or disease control (stable disease) is not evident after 4 
cycles of treatment in at least 1 patient among the first 9 
patients, no further patients will be enrolled. If at least 1 
patient in the first 9 patients demonstrates evidence of clinical 
response or disease control, an additional 16 patients will be 
enrolled.  
 
Recruitment will continue whilst data from the first 9 patients 
are being analyzed. Thus, up to 25 patients are anticipated 
to be enrolled in Arm B. 
 
Arm C (Phase 2) 
Arm C will evaluate the safety and tolerability, PD, and 
clinical efficacy (time to progression) of BGB324 when 
administered in combination with erlotinib in patients with an 
activating EGFR mutation who have received ≥12 weeks of 
erlotinib without disease progression. Up to 14 patients will 
be enrolled. Recruitment into Arm C may be stopped if Arm 
B completes recruitment or is stopped before the 14 patient 
target is reached. Patients already enrolled into Arm C at this 
time will be allowed to continue in the study in accordance 
with the protocol. 
 
 
In all parts of the study, patients will be allowed to continue 
BGB324 treatment (in combination with erlotinib or as a 
single agent) for as long as, in the opinion of the Investigator, 
they continue to derive clinical benefit or until unacceptable 
toxicity, disease progression, death or withdrawal of consent. 
 
In the event of erlotinib-related toxicities in Arms A, B, or C, 
patients who stop treatment with erlotinib will be allowed to 
continue receiving BGB324 as a single agent until disease 
progression 
(unless 
unacceptable 
toxicity, 
disease 
progression, death or withdrawal of consent). Patients who 
stop BGB234 treatment will be withdrawn from the study.  
OBJECTIVES 
Run-In Cohort (Phase 1) 
Primary Objective 
To explore the safety and tolerability of single agent BGB324 
in patients with NSCLC. 
 
Arm A (Phase 1) 
Primary Objective 
To identify RP2D of BGB324 administered in combination 
with erlotinib in patients with NSCLC. 
Secondary Objectives 


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• 
To explore the safety and tolerability of BGB324 
administered in combination with erlotinib in patients 
with NSCLC. 
• 
To identify the dose limiting toxicity (DLT) profile of 
BGB324 administered in combination with erlotinib in 
this population. 
• 
To assess the PK of BGB324 and erlotinib and the 
potential effect of BGB324 on erlotinib. 
 
Exploratory Objective 
• 
To evaluate the PD effects of BGB324 administered 
in combination with erlotinib. 
 
Arm B (Phase 2) 
Primary Objective 
To explore the safety and tolerability of the combination of 
BGB324 and erlotinib in patients with NSCLC with an 
activating EGFR mutation who have progressed after 
receiving an approved EGFR inhibitor (i.e., erlotinib, afatinib, 
or gefitinib) and who are T790M negative. 
 
Secondary Objectives 
• 
To assess the PK of BGB324  
• 
To explore the clinical efficacy of the combination of 
BGB324 and erlotinib in this setting. 
 
Exploratory Objectives 
• 
To evaluate the PD effects of BGB324 administered 
in combination with erlotinib. 
• 
To investigate any correlation between the PD effects 
of BGB324 administered in combination with erlotinib 
and clinical efficacy. 
 
Arm C (Phase 2) 
Primary Objective 
To explore the safety and tolerability of the combination of 
BGB324 and erlotinib in the first-line setting in patients with 
advanced NSCLC with an activating EGFR mutation. 
 
Secondary Objectives 
• 
To explore the time to progression of the combination 
of BGB324 and erlotinib in this setting. 
 
Exploratory Objectives 
• 
To evaluate the PD effects of BGB324 administered 
in combination with erlotinib. 
• 
To investigate any correlation between the PD effects 
of BGB324 administered in combination with erlotinib 
and clinical efficacy. 
DOSE LIMITING TOXICITY 
In Arm A DLTs will be evaluated using the National Cancer 
Institute (NCI) Common Toxicity Criteria for Adverse Events 
(CTCAE) Version 4.03 criteria during the first cycle (21 days) 
of treatment for the purposes of establishing the dose of 
BGB324 that can safely be given in combination with 
erlotinib. DLTs will include: 


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• 
Any non-hematological toxicity ≥Grade 3 except 
Grade 3 nausea, vomiting or diarrhea that resolves 
within 72 hours with optimal therapy. 
• 
Grade 
4 
thrombocytopenia 
or 
Grade 
3 
thrombocytopenia with bleeding. 
• 
Grade 4 neutropenia persisting for ≥5 days or 
Grade 3 or 4 febrile neutropenia. 
• 
Treatment discontinuation or dose reduction for 
>72 hours during the first cycle as a result of 
treatment-related toxicity. 
INCLUSION CRITERIA  
General Criteria 
 
1. Provision of written informed consent to participate in this 
investigational study. 
2. Histological or cytological confirmation of Stage IIIb or 
Stage IV (unresectable) NSCLC. 
3. Eastern 
Cooperative 
Oncology 
Group 
(ECOG) 
performance status 0 or 1. 
4. Age 18 years or older at the time of consent. 
5. Female patients of childbearing potential must have a 
negative serum pregnancy test within 7 days prior to 
taking their first dose of BGB324. Male patients and 
female patients of reproductive potential must agree to 
practice highly effective methods of contraception (such 
as hormonal implants, combined oral contraceptives, 
injectable 
contraceptives, 
intrauterine 
device 
with 
hormone spirals, total sexual abstinence, vasectomy) 
throughout the study and for ≥3 months after the last dose 
of BGB324. Female patients are considered NOT to be of 
childbearing potential if they have a history of surgical 
sterility, including tubal ligation, or evidence of 
post--menopausal status defined as any of the following: 
• 
Natural menopause with last menses >1 year ago. 
• 
Radiation induced oophorectomy with last menses 
>1 year ago. 
• 
Chemotherapy induced menopause with last menses 
>1 year ago. 
 
Additional Inclusion Criteria for Run-in Cohort 
6. Has received previous systemic therapy for unresectable 
NSCLC. 
7. Has exhausted existing licensed therapies, or is 
unsuitable for treatment with existing licensed therapies 
for NSCLC. 
 
Additional Inclusion Criteria for Arm A 
8. Known EGFR mutation status. 
9. Either: 
a) Has received ≥6 weeks historical treatment with 
erlotinib. Erlotinib treatment must be re-started 
≥1 week before the first dose of BGB324 (Cycle 1, 
Day 1). 
Or: 


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b) Is currently receiving erlotinib treatment for NSCLC 
and will have received ≥6 weeks treatment at the 
time of the first dose of BGB324 (Cycle 1, Day 1). 
10. Erlotinib-related toxicities being well-controlled and 
<Grade 3 in severity at the time of the first dose of 
BGB324 (Cycle 1, Day 1). 
11. Toxicity from other prior therapy has resolved to ≤Grade 1 
(previous treatment with bevacizumab and other licensed 
antibody therapies is permitted). 
 
Additional Inclusion Criteria for Arm B 
 
12. Patients must have documented EGFR mutation 
(including exon 19 deletion or exon 21 L85R substitution 
or other rearrangement of the EGFR gene. EGFR 
mutation may be confirmed historically prior to study 
entry) and during the 28 day1 screening period 
confirmation of negative T790M status (confirmed with 
blood test or biopsy from a progressing tumor). Patients 
who have previously been treated with a T790M inhibitor 
and have progressed (i.e., osimertinib) will not require 
T790M testing 
13. Disease that is measurable according to the response 
evaluation criteria in solid tumors (RECIST) Version 1.1 
14. Has progressed after receiving an approved EGFR 
inhibitor (i.e., erlotinib, afatinib, or gefitinib) at any time 
during therapy for advanced disease. 
15. Erlotinib-related toxicities being well-controlled and 
<Grade 3 in severity at the time of the first dose of 
BGB324 (Cycle 1, Day 1). Toxicities associated with other 
EGFR inhibitors to be <Grade 2 in severity at the time of 
first dose of BGB324. 
16.  Patients must have completed afatinib and/or gefitinib 
treatment at least 1 week before the first dose of BGB324. 
There is no requirement to discontinue ongoing treatment 
with erlotinib. 
17. Toxicity from other prior therapy has resolved to ≤Grade 1 
(previous treatment with bevacizumab and other licensed 
antibody therapies is permitted). 
18. Patients who have an activating EGFR mutation may 
have up to 4 lines of previous treatment in the advanced 
setting. Additional chemotherapy may also have been 
given for treatment of limited stage disease in 
the adjuvant setting provided this was completed at least 
6 months prior to study treatment 
 
Additional Inclusion Criteria for Arm C  
19. Known EGFR mutation status: 
 
1  The screening window may be extended to allow for confirmation of T790M status through tumor biopsy. Other 
assessments including CT should be conducted in the 28-day screening period. 


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20. Presence of an activating EGFR mutation (including exon 
19 deletion or exon 21 [L858R] substitution mutation or 
other rearrangement of the EGFR gene). 
21. Disease that is measurable or evaluable according to 
RECIST Version 1.1.  
22. Is currently receiving erlotinib for NSCLC and will have 
received ≥12 weeks’ treatment at the time of the first dose 
of BGB324 (Cycle 1, Day 1). 
23. Have erlotinib-related toxicities that are well-controlled 
and <Grade 3 in severity the time of the first dose of 
BGB324 (Cycle 1, Day 1). 
24. No prior treatment for advanced NSCLC except erlotinib 
and/or previous surgery (patients who have received 
treatment for their NSCLC while awaiting confirmation of 
EGFR status, may be eligible to participate and the 
inclusion of such patients should be discussed with the 
Medical Monitor). 
EXCLUSION CRITERIA 
1. Pregnant or lactating. 
2. Abnormal left ventricular ejection fraction (less than the 
lower limit of normal for a patient of that age at the treating 
institution or <45%). 
3. Treatment with any of the following; histamine receptor 2 
inhibitors, proton pump inhibitors or antacids within 
3 days or 5 half-lives of administration of BGB234, 
whichever is longer. The Investigator may initiate rescue 
treatment with these medications during the study, 
providing they are taken in the evening. 
4. History of an ischemic cardiac event, including 
myocardial infarction, within 3 months of consent. 
5. Pulmonary hemorrhage or hemoptysis >2.5 mL blood 
within 6 weeks of consent unless cause has been 
addressed and is medically resolved. 
6. Congestive cardiac failure of >Class II severity according 
to the New York Heart Association (NYHA) defined as 
symptomatic at less than ordinary levels of activity. 
7. Unstable cardiac disease, including unstable angina or 
unstable hypertension, as defined by the need for change 
in medication for lack of disease control within 3 months 
of consent. 
8. History or presence of sustained bradycardia (≤60 bpm) 
or history of symptomatic bradycardia, left bundle branch 
block, 
cardiac 
pacemaker 
or 
significant 
atrial 
tachyarrythmias, as defined by the need for treatment. 
9. Current treatment with agents that may prolong QT 
interval and may cause Torsade de Points which cannot 
be discontinued at least 2 weeks prior to treatment. 
10. Known family or personal history of long QTc syndrome 
or ventricular arrhythmias including ventricular bigeminy. 
11. Previous history of ≥Grade 3 drug-induced QTc 
prolongation.  
12. Screening 12-lead triplicate electrocardiogram (ECG) 
with an average measurable QTc interval utilizing 
Fridericia’s correction (QTcF) >450 ms.  
13. Inadequate liver function as demonstrated by: 


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Serum bilirubin ≥1.5 times the upper limit of normal range 
(ULN); or 
Alanine 
aminotransferase 
(ALT) 
or 
aspartate 
aminotransferase (AST) ≥2.5 times the ULN (up to 5 
times the ULN in the presence of liver metastases). 
14. Inability to tolerate oral medication. 
15. Impaired coagulation as evidenced by: 
a) International normalized ratio (INR) >1.5 times 
ULN (or equivalent); or 
b) Activated partial thromboplastin time (aPTT) 
>1.5 times ULN. 
16. Existing 
gastrointestinal 
disease 
affecting 
drug 
absorption, such as celiac disease or Crohn’s disease. 
17. Previous bowel resection that may impair study drug 
absorption. 
18. Impaired renal function as demonstrated by creatinine 
clearance of ≤50 mL/min determined by Cockcroft-Gault 
formula. 
19. Absolute neutrophil count <1.5 x 109/L, hemoglobin 
<9.0 g/dL, platelet count <100 x 109/L in the absence of 
blood product support. 
20. Any evidence of severe or uncontrolled systemic 
conditions (e.g., severe hepatic impairment) or current 
unstable or uncompensated respiratory or cardiac 
conditions which makes it undesirable for the patient to 
participate in the study or which could jeopardize 
compliance with the protocol. 
21. Treatment with any medication which is predominantly 
metabolized by CYP3A4 and has a narrow therapeutic 
index. 
22. Active, uncontrolled central nervous system (CNS) 
disease; (previously-treated CNS metastases that are 
asymptomatic and do not require steroid treatment are 
allowed). Note: Patients with known CNS metastases 
who have completed radiotherapy at least 2 weeks prior 
to BGB324 treatment are eligible. 
23. Known active infection with human immunodeficiency 
virus (HIV), hepatitis B or C viruses (screening not 
required): 
• 
Patients who have a history of hepatitis B infection 
are eligible provided they are hepatitis B surface 
antigen negative. 
• 
Patients who have a history of hepatitis C infection 
are eligible provided they have no evidence of 
hepatitis C ribonucleic acid using a quantitative 
polymerase chain reaction assay at least 
6 months after completing treatment for hepatitis 
C infection. 
24. Major surgery requiring general anesthesia within 
28 days prior to the start of BGB324, excluding biopsies 
and procedures for insertion of central venous access 
devices. 
25. Treatment with cytotoxic chemotherapy, within the 
3 weeks prior to the first dose of BGB324 (Cycle 1, Day 
1) with the exception of treatment with other EGFR 


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Page 23 of 80 
inhibitors which must be completed 1 week prior to 
commencing treatment with BGB324. There is no 
requirement to discontinue ongoing treatment with 
erlotinib. 
26. Treatment with other non-cytotoxic agents for NSCLC in 
the 10 days or 4 half-lives, prior to the first dose of 
BGB324 (Cycle 1, Day 1) whichever is shorter. 
27. Prior biological therapies in the 4 weeks (or 5 half-lives, 
whichever is shorter) before the first dose of BGB324 
(Cycle 1, Day 1). Note prior treatment with an alternative 
EGFR inhibitor and/or PD-1 blockade is permitted.  
TREATMENTS AND 
INTERVENTIONS 
Patient eligibility for the study, including assessment of EGFR 
mutation/T790M status in Arm B, and disease status 
according RECIST Version 1.1 will be performed within 
28 days prior to the first dose of BGB324. The 28-day 
screening window may be extended to confirm T790M status, 
however all other assessments including scans will be 
conducted in the 28-day screening window. Patients who 
have previously been treated with a T790M inhibitor (i.e., 
osimertinib) and who subsequently progressed and fulfil all 
other eligibility criteria will not require T790M testing. 
 
The treatment period will consist of continuous 21-day 
treatment cycles. Patients will be monitored through daily 
clinic visits on Day 1 to Day 4, Days 8, 9, and 15 in Cycle 1 
(and Day -1 in Arms A and B) and weekly during Cycle 2. 
Beginning with Cycle 3, patients will have a clinic visit on 
Day 1 of each cycle.  Patients who remain on treatment for 
12 months will need to return for a clinic visit every 2 cycles ( 
i.e. 6 weekly). 
Patients receiving BGB324 who require the support of 
prednisolone (or equivalent) at 10mg to 40 mg daily should 
be monitored at weekly intervals whilst receiving treatment.  
Disease assessment will be performed at the end of every 2 
cycles or to confirm disease progression. The frequency of 
scans may be extended to the end of every 3 cycles after 
12 weeks (4 cycles) and every 4 cycles after 24 weeks 
(8 cycles). Patients who remain on treatment for 12 months 
or longer may have their scans extended to a frequency of 6 
months, unless disease progression is suspected in which 
case a scan should be conducted at an earlier time point. 
 
The end of study (EOS) visit will occur 28 days after the last 
dose of study drug (including study withdrawal). 
STUDY DRUG DOSE, 
SCHEDULE, ROUTE of 
ADMINISTRATION 
In the Run-in Cohort, BGB324 will be administered as a 
single agent. In Arms A, B, and C, BGB324 will be 
administered in combination with erlotinib. At the time of 


BGBC004 V5 16 May 2017  
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Page 24 of 80 
Amendment 5 the Run in Cohort and Arm A have completed 
recruitment. 
 
BGB324 
BGB324 is prepared in size zero capsules each containing 
100 mg of drug substance for oral administration. 
 
BGB324 will be self-administered orally on an empty stomach 
according to a daily schedule during continuous 21-day 
treatment cycles. In Cycle 1, a loading dose of BGB324 may 
be administered followed by smaller daily dose (see Table 4).  
 
Dose escalation can only occur in Arm A. If unacceptable 
toxicity is reported, the Sponsor and Investigators may agree 
to implement a lower dose for investigation or other dosing 
schedules. 
 
In Arms B and C, BGB324 will be administered at the RP2D 
(the dose identified in Arm A that can be safely administered 
in combination with erlotinib). 
 
Erlotinib 
Erlotinib will be self-administered orally on an empty stomach 
according to a daily schedule during continuous 21-day 
treatment cycles in Arms A, B, and C. 
 
The starting erlotinib dose in Arm A will be 150 mg daily. 
Patients requiring a dose reduction before the end of Cycle 1 
will not be evaluable for toxicity and may be replaced. 
 
The prescribing information for erlotinib recommends a 
150mg dose for NSCLC patients, however if local clinical 
judgement/standards require, a patient in Arm B or C may be 
treated at a lower erlotinib dose (i.e., 100 mg). 
 
If a patient presents with erlotinib toxicities that warrant dose 
reduction, the dose may be reduced in accordance with the 
current prescribing information. If the patient is required to 
cease treatment with erlotinib due to toxicity, they should 
either be withdrawn from the study or allowed to continue 
receiving BGB324 as a single agent until disease progression 
(unless unacceptable toxicity, death or withdrawal of 
consent). 
 
Both drugs will be taken with water in the morning on a fasted 
stomach. BGB324 should be administered in the hour 
following erlotinib administration and at least 2 hours before 
breakfast (except on those days when the patient attends the 
clinic). 
DURATION OF 
PARTICIPATION 
Patients may remain on study until disease progression, 
development of unacceptable toxicity or withdrawal of 
consent. 
 
Patients in Arms A, B, or C who discontinue treatment with 
erlotinib may remain on BGB324 as a single agent.  
 


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A patient who discontinues treatment with BGB324 but 
remains on erlotinib therapy will be considered to have 
withdrawn from the study. 
 
With the exception of erlotinib, no other anti-cancer agent 
may be given while participating in the study. 
CRITERIA FOR 
EVALUATION 
Safety 
Safety will be assessed through the monitoring of adverse 
events (AEs), including serious adverse events (SAEs), 
clinical 
laboratory 
parameters 
(hematology, 
clinical 
chemistry, coagulation, urinalysis) vital sign measurements, 
ECG monitoring, ECOG performance status and physical 
examinations. 
 
Clinical Efficacy  
Clinical efficacy will be estimated based on imaging 
assessments of disease status performed after every 2 
cycles (6 weeks) of treatment.  
 
The frequency of scans may be extended to the end of every 
3 cycles after 12 weeks (4 cycles) and every 4 cycles after 24 
weeks (8 cycles). Patients who remain on treatment for 12 
months or longer may have their scans extended to a 
frequency of 6 months, unless disease progression is 
suspected in which case a scan should be conducted at an 
earlier time point. 
Identification 
of 
target 
and 
non-target 
lesions 
and 
assessment of treatment response and progression will be 
conducted according to RECIST Version 1.1. Endpoints will 
include time to progression. 
 
Pharmacokinetics (Run-in Cohort, Arm A and Arm B only) 
Blood samples for assessment of PK for BGB324 and 
erlotinib (Arm A) will be collected at specified time points 
before and after beginning treatment with BGB324:  
• 
Cycle 1 Day -1: 0 (pre-dose), 2, 4, 6, and 8 hours2. 
• 
Cycle 1 Day 1: 0 (pre-dose). 
• 
Cycle 1 Day 2: 0 (pre-dose). 
• 
Cycle 1 Day 3: 0 (pre-dose), 2, 4, 6, and 8 hours. 
• 
Cycle 1 Day 4: 0 (pre-dose). 
• 
Cycle 1 Day 8: 0 (pre-dose), 2, 4, 6, and 8 hours. 
• 
Cycle 1 Day 9: 0 (pre-dose. 
• 
Cycle 1 Day 15:0 (pre-dose). 
• 
Cycle 2 Day 1, Day 8, Day 15: 0 (pre-dose). 
• 
Cycle 3 Day 1: 0 (pre-dose). 
• 
End-of-study visit. 
Pharmacodynamics  
Blood and tissue samples for the evaluation of PD endpoints 
will be collected at baseline (within 28 days before the first 
dose of study drug after patient eligibility has been 
 
2 Sampling for erlotinib and BGB324. In Arm B PK sampling for BGB324 only. In Arm B there is no requirement for 
Day -1 PK sampling. 
 


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confirmed), after 14 consecutive days of treatment with 
BGB324 and at the time of disease progression. 
The tissue samples for PD testing are optional and require 
additional consent. The tissue specimen collected at the time 
of disease progression should be derived from a lesion 
exhibiting progression.  
 
Pharmacodynamic samples will be analyzed to determine 
endpoints associated with Axl. 
STATISTICAL METHODS 
The primary objectives of this Phase 1/2 study are to 
determine the safety and tolerability of BGB324 administered 
in combination with erlotinib and to establish a RP2D. 
 
Arm B will incorporate a 2-stage design that is intended to 
minimize patient exposure if preliminary evaluation of activity 
suggests the combination may not be active. 
 
The statistical analysis will be primarily descriptive in nature 
and will account for all dose levels studied. Although all 
clinical efficacy analysis for this study is to be regarded as 
essentially exploratory, there will be a formal hypothesis test 
for the objective response rate in Arm B.  
 
This will consist of 1-sided, within-group tests of proportion of 
responders, against the null hypothesis of a response rate 
≤5% (this being the observed response rate under current 
treatment). Values of p <0.2 will be taken as sufficient 
evidence of a trend to justify further study. 
 
The PK of erlotinib in combination with BGB324 will be 
compared to that when erlotinib is administered alone. 
 
 
 


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INTRODUCTION 
In patients with non-small cell lung cancer (NSCLC), there is a progressive decline in response 
to repeated lines of therapy, primarily due to development of biologic resistance within the 
underlying tumor and a progressive decline in patient performance status resulting from 
treatment- and disease-related morbidities (NCCN Treatment Guidelines Version 4.2014). 
There is a significant need for development of strategies that can prolong response and 
prevent development of resistance to earlier-stage treatment regimens. 
 
BGB324 is a potent selective small molecule inhibitor of Axl, a surface membrane protein 
kinase receptor that is over-expressed in many metastatic solid tumors (Linger, 2008) and has 
been identified as a marker of a poor prognosis in patients with NSCLC (Ishikawa, 2013; 
Zhang, 2012). In vitro studies indicate that signaling through Axl stimulates a number of 
pro-survival pathways, some of which are mediated by AKT phosphorylation and up-regulation 
of the epithelial receptor kinase pathway (Korshunov, 2012). Recent non-clinical data 
implicate Axl in development of resistance to a number of agents used in the treatment of 
NSCLC, especially epidermal growth factor receptor (EGFR) inhibitors including erlotinib 
(Brand, 2014; Byers, 2013; Zhang, 2012). The current study is designed primarily to evaluate 
the safety of the Axl inhibitor BGB324 when administered in combination with erlotinib, and to 
establish the recommended Phase 2 dose (RP2D) of the combination of BGB324 and erlotinib 
in patients with Stage IIIb or Stage IV NSCLC. 
 
6.1 
Non-clinical Studies with BGB324 
 
6.1.1 Specificity of inhibition of Axl kinase activity 
BGB324 demonstrates potent inhibition of Axl in biochemical and cell-based kinase inhibition 
assays. The selectivity of BGB324 for Axl is illustrated in Table 1. 
 
Table 1 
BGB324 Kinase Selectivity Profile 
 
Kinome Scan binding 
assay 
(Kd) 
KinaseProfiler kinase 
activity assay 
(IC50) 
BaF3 cell-based 
kinase activity assay 
(IC50) 
Kinase 
nM 
Fold 
nM 
fold 
nM 
Fold 
Axl 
0.4 
1 
4.6 
1 
63 
1 
Ysk4 
1.6 
4 
n/a 
 
n/a 
 
Stk10 
9.2 
23 
22 
4.7 
n/a 
 
Tie2 
270 
680 
30 
6.4 
355 
5.5 
Wee1 
17 
42 
32 
6.9 
n/a 
 
Ret 
73 
180 
38 
8.1 
>316 
>5 
Flt1 
400 
>1000 
40 
8.7 
>1000 
>15 
Flt4 
460 
>1000 
41 
8.8 
>1000 
>15 
Yes 
810 
>1000 
43 
9.2 
n/a 
n/a 
Abbreviations: IC50=half maximal inhibitory concentration; n/a=not applicable 
 
6.1.2 Inhibition of proliferation of NSCLC cells 
The anti-proliferative activity of BGB324 was demonstrated in a panel of human NSCLC cell 
lines by either resazurin cell viability assay or colony formation assay. As summarized in Table 
2, BGB324 inhibited proliferation of several human lung cancer cell lines with half maximal 
inhibitory concentration (IC50) values of 0.4 - 0.8 μM; the anti-proliferative effect was 
dose--responsive (not shown). 
 
 


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Table 2 
Effect of BGB324 on Proliferation of Human NSCLC Cell Lines 
Tumor Type 
Cell Line 
IC50 (µM) 
NSCLC 
A549 
0.56 
NCI-H1299 
0.67 
HCC827 
0.76 
H358 
0.43 
Abbreviations: IC50=half maximal inhibitory concentration 
 
The ability of BGB324 to inhibit cell proliferation was investigated in a panel of 654 human 
tumor cell lines. When administered at a concentration of 1 µM, BGB324 inhibited proliferation 
by >50% in 48 of the cell lines tested, including 10/101 NSCLC. 
 
6.1.3 Re-sensitization to erlotinib in a NSCLC cell line by BGB324 
It has been reported that Axl mediates chemoresistance in a variety of cancer types, including 
NSCLC (Zhang, 2012), breast cancer (Liu, 2009), and esophageal adenocarcinoma (Alvarez, 
2010). In vitro and in vivo models also suggest that Axl activation is one of the main 
mechanisms of acquired resistance to EGFR targeted therapies in NSCLC (Zhang, 2012) and 
inhibition of Axl may restore drug sensitivity. 
 
To evaluate whether BGB324 can restore sensitivity to the EGFR inhibitor erlotinib, the 
erlotinib-resistant human NSCLC cell line NCI-H1299 was treated with BGB324 
(concentrations of 200, 500 and 750 nM) and erlotinib (concentrations of 1 and 3 μM) and 
evaluated in a colony formation assay. As can be seen in Figure 1, the combination of BGB324 
and erlotinib restored erlotinib-sensitivity, in an additive or synergistic manner, as 
demonstrated by the substantial inhibition of proliferation. 
 
Figure 1 
Restoration of Erlotinib Sensitivity in NSCLC Cells 
  
 
 
To confirm these results, a 3-dimensional (3-D) tumorsphere assay was performed in 
NCI-H1299 NSCLC cells treated with BGB324 ± erlotinib. This study showed that BGB324 in 
combination with erlotinib demonstrates an additive or synergistic effect (p <0.05) in inhibiting 
the growth and establishment of NCI-H1299 lung cancer cells in Matrigel (Figure 2). 
 


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Figure 2 
Inhibition of NSCLC Colony Formation by BGB324 and Erlotinib 
 
 
6.1.4 In vivo anti-tumor activity of BGB324 and erlotinib 
The anti-tumor activity of BGB324 in combination with erlotinib was evaluated in the human 
A549 NSCLC xenograft model. Treatment was initiated when tumors reached 100 mm3. 
BGB324 alone at doses of 50, 75, and 100 mg/kg orally twice daily (BID) were evaluated, as 
well as BGB324 at 50 and 100 mg/kg orally BID with erlotinib at 75 mg/kg orally once daily. 
Single agent BGB324 showed minimal anti-tumor activity, while the combination of BGB324 
and erlotinib resulted in significant (p <0.005) anti-tumor activity (, left panel). BGB324 alone 
and in combination with erlotinib was well-tolerated, as evidenced by evaluation of body weight 
(Figure 3, right panel), and there was no drug-related mortality. 
 
Figure 3 
Anti-Tumor Effect (left panel) and Tolerability (right panel) of BGB324 and 
Erlotinib in the A549 Human NSCLC Xenograft Model 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: BID=twice daily; QD=once daily 
 
The anti-tumor activity of BGB324 in combination with erlotinib was further evaluated in a 
xenograft model of the human HCC827 NSCLC, which bears an EGFR exon 19 deletion. Mice 
were treated with vehicle alone, BGB324 at 50 and 100 mg/kg orally BID, erlotinib at 50 mg/kg 
orally once daily (QD) or a combination of both drugs, using a 5-day on and 2-day off dosing 
schedule. As shown in Figure 4, animals receiving single agent erlotinib began to develop 
acquired drug resistance at approximately Day 100. However, combination dosing with 


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BGB324 significantly delayed the onset of acquired resistance to erlotinib by at least 40 days 
(n=7-8, p <0.001). 
 
Figure 4 
BGB324 Blocks Acquired Resistance to Erlotinib in the HCC827 Human 
NSCLC Xenograft Model 
 
Abbreviations: BIDBID=twice daily; QDQD=once daily 
 
6.1.5 High Dose Steroids and Mouse Model 
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 out 
of 7 animals 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. 
 
 
6.2 
Clinical Studies with BGB324 
There has been1 previous clinical study conducted with BGB324 (Protocol BGBC001). This 
study explored the effect of a single administration of BGB324 in healthy male subjects. Eight 
dose levels (50 mg, 100 mg, 150 mg, 200 mg, 400 mg, 600 mg, 1000 mg and 1500 mg) were 
evaluated under fasted conditions in cohorts of 4 subjects (32 subjects in total). Seven of these 
subjects went on to receive a single administration of the same dose of BGB324 under fed 
conditions. 
 
The current Investigator’s Brochure (IB) contains a description of ongoing studies and 
preliminary safety data and should be used as a reference in conjunction with the protocol. 
 
6.2.1 Summary of clinical safety to date 
In general, exposure to BGB324 in healthy subjects was well tolerated with all toxicities being 
spontaneously reversible and predominantly gastrointestinal in nature. No serious adverse 
events (SAE) were reported. Adverse events (AE) judged as related to BGB324 are 
summarized in Table 3.  
 
 


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Table 3 
BGB324-Related AEs Reported Following a Single Oral Administration of 
BGB324 to Healthy Male Subjects 
BGB324 Dose 
(mg) 
Number of Subjects 
Treated 
Adverse Event 
Maximum Grade 
50 
4 fasted; 1 fed 
Non-cardiac chest pain 
1 
100 
4 fasted; 2 fed 
Orthostatic hypotension 
1 
150 
4 fasted; 1 fed 
Abdominal 
distension 
(2 
subjects) 
1 
400 
4 fasted; 2 fed 
Diarrhea 
1 
600 
4 fasted 
Diarrhea 
Flatulence 
Nausea (2 subjects) 
1 
1 
1 
1000 
4 fasted 
Nausea 
1 
1500 
4 fasted 
Diarrhea 
Nausea 
Vomiting 
Headache 
Dizziness 
1 
2 
2 
1 
1 
 
In addition to this study there is one other clinical study of BGB324 recruiting patients with 
either relapsed/refractory Acute Myeloid Leukemia or high-risk Myelodysplastic Syndrome. 
Treatment with BGB324 has been generally well tolerated with most AEs being mild or 
moderate in severity and reversible. Approximately one half of patients who receive treatment 
with BGB324 experience gastrointestinal AEs including diarrhea and nausea. Further details 
can be found in the current version of the IB. 
 
ECG findings 
In light of the recoverable, non-adverse decreases in heart rate and corresponding increases 
in the RR interval durations observed in the cardiovascular study in monkeys, each subject in 
Study BGBC001 underwent serial electrocardiogram (ECG) assessment after administration 
of BGB324. At the 1500 mg dose level, 3 subjects had increases from baseline in QT interval 
utilizing Fridericia’s correction (QTcF) of >30 ms, with subject exceeding 60 ms. Three 
subjects (1 in the 400 mg group and 2 in the 1000 mg group) had noticeable, mild changes in 
T-wave morphology from baseline (flattening and, in one case, broadening). 
 
6.2.2 BGB324 pharmacokinetics 
Concentrations of BGB324 were quantified in plasma samples from subjects enrolled in Study 
BGBC001 using a fully-validated liquid chromatography/tandem mass spectrometry 
(LC/MS/MS) method with a lower limit of quantitation of 2.0 ng/mL. Pharmacokinetic 
parameters were derived by non-compartmental analysis using WinNonlin Phoenix 
Version 6.3 (Pharsight Corporation Inc., Mountain View, CA). 
 
Following a single oral administration of BGB324 at doses of 50 - 1500 mg, mean maximum 
plasma concentrations achieved (Cmax) of 7.6 to 388 ng/mL were reached 8-23 hours 
post-dose. 
 
The mean apparent terminal half-life of BGB324 was 45.6 to 88.7 hours. Between-subject 
variability in systemic exposure (area under the curve extrapolated to infinity [AUC0-∞] and Cmax) 
to BGB324 at 50 mg to 1500 mg was generally high (coefficient of variation of 25.8% to 96.7% 
for area under the curve within a dosing interval [AUC0-t] and Cmax), most probably reflecting 
variable absorption. Across this dose range, Cmax of BGB324 increased approximately dose 


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proportionately, although the AUC0-∞ of BGB324 increased slightly greater than dose 
proportionately 
Figure 5 
Mean Plasma Concentrations of BGB324 Following a Single Oral 
Administration of BGB324 at 50, 100, 150, 200, 400, 600, 1000, and 1500 mg 
to Healthy Male Subjects 
 
 
Following administration of BGB324 with food (whole milk and buttered toast) to 7 subjects 
who had previously received BGB324, there was an overall reduction in the between-subject 
variability with an increase in systemic exposure to BGB324 in 3 subjects, no appreciable 
change in 3 subjects and an apparent reduction in 1 subject. It was estimated that 
administration with food would achieve an increase in exposure in some subjects of up to 2-
fold. 
 
6.2.3 Rationale for BGB324 starting dose 
In healthy subjects who received a single oral dose of BGB324, the elimination of BGB324 
was slow, with mean apparent terminal half-life >24 hours. The administration schedule and 
starting dose of BGB324 proposed for Study BGBC004 is based on fitting a 1e-compartment 
model, incorporating a lag time and no weighting, to the available clinical PK data. It is 
anticipated that administration of a loading dose of BGB324 on Days 1 and 2 of Cycle 1, 
followed by daily dosing at a lower level, will deliver the optimum exposure of BGB324. The 
application of a loading dose will facilitate achievement of therapeutic levels, while daily dosing 
will prevent wide changes in systemic concentration during therapy. The simulated mean 
plasma concentration-time profile of BGB324, based on the PK model, following dosing of 
BGB324 at 600 mg on Days 1 and 2 and 200 mg daily thereafter is presented in Figure 6. 
 
In Arm A, dose and dosing schedules have been explored to assess tolerability of the loading 
and daily doses and to select the RP2D for expansion into Phase 2 (Arms B and C). 
 
 
1
10
100
1000
0
12
24
36
48
60
72
84
96
108
120
Concentration (ng/mL)
Time (h)
50 mg
100 mg
150 mg
200 mg
400 mg
600 mg
1000 mg
1500 mg


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Figure 6 
Simulated Plasma Concentrations of BGB324 Following Repeat Once Daily 
Oral Administration of 200 mg BGB324 to Healthy Male Subjects Under 
Fasted Conditions (Loading Dose of 600 mg on Day 1 and Day 2) 
 
On the basis of the PK profile identified in healthy subjects, it is anticipated that a loading dose 
of 600 mg on Days 1 and 2 of Cycle 1, followed by 200 mg daily thereafter will maintain mean 
systemic concentrations of approximately 400 ng/mL. PK-ECG modeling performed on the 
data collected in healthy subjects showed that a plasma concentration of 400 ng/mL would be 
expected to result in a mean increase in QTcF of 54.3 ms (90% CI of mean increase of 47.7 
and 58.2 ms) from baseline. 
 
 
OBJECTIVES AND ENDPOINTS 
 
7.1 
Run-In Cohort (Phase 1) 
 
7.1.1 Primary objective 
To explore the safety and tolerability of single agent BGB324 in patients with NSCLC. 
 
7.2 
Arm A (Phase 1) 
 
7.2.1 Primary objective 
To identify the RP2D of BGB324 administered in combination with erlotinib in patients with 
NSCLC. 
 
7.2.2 Secondary objective 
• 
To explore the safety and tolerability of BGB324 administered in combination with 
erlotinib in patients with NSCLC. 
• 
To identify the dose limiting toxicity (DLT) profile of BGB324 administered in 
combination with erlotinib in this population. 
• 
To assess the PK of BGB324 and erlotinib and the potential effect of BGB324 on 
erlotinib. 
 
0
50
100
150
200
250
0
48
96
144
192
240
288
336
384
432
480
528
Concentration (ng/mL)
Time (h)
Predicted (healthy subjects)


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7.2.3 Exploratory objective 
• 
To evaluate the PD effects of BGB324 administered in combination with erlotinib. 
 
7.3 
Arm B (Phase 2) 
 
7.3.1 Primary objective 
To explore the safety and tolerability of the combination of BGB324 and erlotinib in patients 
with NSCLC with an activating EGFR mutation and who have progressed after receiving an 
approved EGFR inhibitor (i.e., prior erlotinib, afatinib, or gefitinib).  
 
7.3.2 Secondary objective 
• 
To assess the PK of BGB324.  
• 
To explore the clinical efficacy of the combination of BGB324 and erlotinib in this 
setting. 
 
7.3.3 Exploratory objective 
• 
To evaluate the PD effects of BGB324 administered in combination with erlotinib. 
• 
To investigate any correlation between the PD effects of BGB324 administered in 
combination with erlotinib and clinical efficacy. 
 
7.4 
Arm C (Phase 2) 
 
7.4.1 Primary objective 
To explore the safety and tolerability of the combination of BGB324 and erlotinib in the first-line 
setting in patients with advanced NSCLC with an activating EGFR mutation. 
 
7.4.2 Secondary objective 
• 
To explore the time to progression of the combination of BGB324 and erlotinib in this 
setting. 
 
7.4.3 Exploratory objective 
• 
To evaluate the PD effects of BGB324 administered in combination with erlotinib. 
• 
To investigate any correlation between the PD effects of BGB324 administered in 
combination with erlotinib and clinical efficacy. 
 
7.5 
Safety Endpoints 
Safety and tolerability will be assessed by conducting the following safety assessments at 
pre--defined time points during the study: 
• 
Treatment-emergent AEs. 
• 
Physical examination. 
• 
Vital signs including blood pressure and heart rate. 
• 
Echocardiogram or multi-gated acquisition (MUGA) scan. 
• 
12-lead triplicate ECG. 
• 
Clinical laboratory parameters including clinical chemistry, hematology, coagulation 
and urinalysis. 
• 
Eastern Co-operative Oncology Group performance status. 
 
7.6 
Clinical Efficacy Endpoints 
Disease assessment will be performed after every 2 cycles (6 weeks) of treatment prior to 
administering study drug in the subsequent cycle. The frequency of scans may be extended 
to the end of every 3 cycles after 12 weeks (4 cycles) and every 4 cycles after 24 weeks 
(8 cycles). Patients who remain on treatment for 12 months or longer may have their scans 
extended to a frequency of 6 months, unless disease progression is suspected in which case 
a scan should be conducted at an earlier time point. 
 


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Clinical efficacy will be assessed using the Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1. Clinical efficacy endpoints will include time to progression.  
 
7.7 
Pharmacokinetic Endpoints 
Pharmacokinetics of BGB324 and erlotinib will include AUC0-t, Cmax and time to maximum 
concentration (tmax) measured in plasma. Additional parameters may also be reported as 
deemed appropriate once data are reviewed. 
 
7.8 
Pharmacodynamic Endpoints 
The effects of BGB324 on PD endpoints of Axl inhibition may be determined in blood samples 
and tissue specimens:  
• 
Evaluation of changes in the phosphorylation status or levels of signaling proteins. 
• 
Evaluation of circulating markers in the blood including sAxl, Gas6, cytokines and 
cell-free nucleic acids. 
• 
Evaluation of changes in gene expression profile of tumor tissue or circulating nucleic 
acids. 
• 
Evaluation of the spectrum of mutations present within the cancer cell population or in 
circulating nucleic acids, including EGFR mutations. 
• 
Evaluation of the epithelial-mesenchymal transition gene signature. 
• 
The Sponsor may evaluate other biomarkers associates with Axl as part of ongoing 
development plans. 
 
 
STUDY DESIGN 
 
8.1 
Overview 
This is a multi-center open-label Phase 1/2 study of BGB324 as a single agent (Run-in Cohort) 
and in combination with erlotinib (Arms A, B and C) in patients with Stage IIIb or Stage IV 
NSCLC.  
 
At the time of Amendment 5, patient recruitment into the Run-In Cohort (BGB324 
monotherapy) and Arm A (BGB324 dose escalation in combination with erlotinib) has 
completed and the RP2D has been confirmed. Patients that remain on treatment in the Run-
in Cohort or Arm A must be followed up in accordance with the protocol schedule.  
 
This study is anticipated to be conducted at approximately 10 sites in the US and in Europe 
(the number of sites and the involvement of European sites may be revised to reflect changes 
in recruitment rates), and will enroll approximately 60 patients with histologically- or 
cytologically-confirmed Stage IIIb or Stage IV NSCLC.  
 
It is anticipated that up to 6 patients will be enrolled in the Run-in Cohort, 18 patients in Arm 
A, up to 25 patients in Arm B, and up to 14 patients in Arm C. Recruitment into Arm C may be 
stopped if Arm B completes recruitment or is stopped before the 14 patient target is reached. 
Patients already enrolled into Arm C at that time will be allowed to continue in the study in 
accordance with the protocol 
 
Prior to starting dosing of BGB324 in combination with erlotinib, the safety and tolerability of 
single agent BGB324 will be assessed in the Run-in Cohort (Phase 1) in patients who have 
either exhausted existing licensed therapies or are unsuitable for existing licensed therapies 
for NSCLC. A minimum of 6 patients must each receive at least 1 continuous 21-day cycle of 
BGB324 before enrolment into Arm A can commence. 
 
Arm A (Phase 1) incorporates a standard 3+3 design to determine the dose of BGB324 that 
can be safety administered in combination with erlotinib in patients who have received prior 
treatment with erlotinib. To confirm the RP2D for Arms B and C, loading dose schedules, 


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loading doses and daily dose levels will be explored in Arm A. Dosing schedules will be revised 
in response to reported toxicities, DLT experience and SMC recommendations (Table 4). 
 
When the RP2D dose of BGB324 is identified and the dose of erlotinib to be administered in 
combination with BGB324 is confirmed, the Phase 2 part of the study will start and Arms B 
and C will open simultaneously to enrolment. 
 
Arm B will incorporate a 2-stage design to evaluate the safety and tolerability, PK, PD and 
clinical activity of BGB324 in combination with erlotinib in patients with an activating EGFR 
mutation (including exon 19 deletion or exon 21 [L858R] substitution or other rearrangement 
of the EGFR gene) who are T790M negative and who have progressed after receiving 
treatment with an approved EGFR inhibitor (i.e., erlotinib, afatinib, or gefitinib). Patients who 
have previously been treated with a T790M inhibitor (i.e., osimertinib) and who subsequently 
progressed will not require T790M testing. 
 
Arm C will evaluate the safety and tolerability, PD and clinical activity (time to progression) of 
BGB324 when administered in combination with erlotinib in patients with an activating EGFR 
mutation (including exon 19 deletion or exon 21 [L858R] substitution or other rearrangement 
of the EGFR gene mutation) who have received ≥12 weeks treatment with erlotinib without 
disease progression.  
 
In all parts of the study, BGB324 will be self-administered orally on an empty stomach 
according to a daily schedule during continuous 21-day treatment cycles.  
 
Erlotinib will be self-administered orally on an empty stomach as specified by a daily schedule 
during continuous 21-day treatment cycles (Arms A, B, and C only). 
 
Both drugs will be taken with water in the morning. BGB324 should be administered in the 
hour following erlotinib administration and at least 2 hours before breakfast. 
 
Patients will be allowed to continue BGB324 treatment (as a single agent or in combination 
with erlotinib) if, in the opinion of the Investigator, they continue to derive clinical benefit or 
until unacceptable toxicity, disease progression, death or withdrawal of consent. Patients who 
stop BGB324 treatment will be withdrawn from the study. 
 
An outline of the study design is provided in Figure 7. 
 


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Figure 7 
BGBC004 Study Design Outline 
 
Arm C will recruit up to a maximum of 14 patients. Recruitment into Arm C may be stopped if Arm B 
completes recruitment or is stopped before the 14 patient target is reached. Patients already enrolled 
into Arm C will be allowed to continue in the study in accordance with the protocol. 
 
8.2 
Run-in Cohort (Phase 1) 
The primary goal of the Run-in Cohort is to establish the safety and tolerability of BGB324 
administered as a single agent. Eligible patients will have either exhausted existing licensed 
therapies or be unsuitable for treatment with existing licensed therapies for NSCLC. BGB324 
will be administered at a loading dose of 600 mg on Day 1 and Day 2 of Cycle 1, followed by 
200 mg daily thereafter. 
 
The safety data from a minimum of 6 patients who have each received at least 1 cycle of 
treatment with BGB324 will be reviewed by the Safety Monitoring Committee (SMC) before 
enrolment into Arm A can commence. The SMC will be comprised of a representative from 
each actively-recruiting investigational site and a representative of the Sponsor study team. 
 
8.3 
Arm A (Phase 1) 
The primary goal of Arm A is to establish the dose of BGB324 administered in combination 
with erlotinib to be used in Arms B and C.  
 
Patients in Arm A will have received ≥6 weeks treatment with erlotinib. This may either be 
historical treatment in which case there may have been an interval prior to the study and 
erlotinib treatment must be re-started ≥1 week immediately before the first dose of BGB324 
or the treatment may be current and ongoing at the time of the first dose of BGB324 (Cycle 1, 
Day 1). 
 
All erlotinib toxicities must be well controlled and <Grade 3 at the time of the first dose of 
BGB324 (Cycle 1, Day 1). 
 
Erlotinib is typically administered in patients with activating EGFR mutations and it is 
anticipated that the majority of patients enrolled in Arm A will have activating mutations in 
EGFR; however, patients with wild-type EGFR who are receiving erlotinib for treatment of their 
NSCLC are eligible to participate in Arm A. 
Phase I- BGB324 Monotherapy and BGB324 Dose Escalation 
Phase II- BGB324 in Combination with Erlotinib 
NSCLC III-IV 
EGFR+VE 
Monotherapy 
Dose escalation (3+3) + 
erlotinib 
Arm A (dose 
escalation) 
BGC324+ erlotinib 
(n=18) 
Run in 
(monotherapy) 
Safety/ 
tolerability of 
single agent 
Safety/ 
tolerability of 
combination  
RP2D 
confirmation 
NSCLC III-IV 
EGFR+VE 
Progressive disease 
First line setting 
RP2D 
Arm B (progressive 
disease) 
RP2D + erlotinib  
Arm C (first line 
setting) 
Safety  
Tolerability  
Clinical activity 
Time to progression 


BGBC004 V5 16 May 2017  
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In addition to safety and tolerability, the PK of BGB324/erlotinib and the PD of BGB324 and 
erlotinib will be evaluated. 
 
When the RP2D of BGB324 is identified the Phase 2 part of the study will start and Arms B 
and C will open simultaneously to enrolment. 
 
8.3.1 BGB324 and erlotinib dose levels 
The dose of BGB324 will be escalated following a standard 3+3 design in combination with 
erlotinib. The starting dose level of Arm A (600 mg loading dose administered over 2 days with 
a 200 mg daily) was selected based on the results of PK modelling. 
 
The total loading dose may be given over 2 days (Days 1 and 2) or 3 days (Days 1, 2, and 3)*. 
Possible dosing levels are illustrated in  Table 4 also describes the maximum dose escalation 
step for any increase in loading or daily dose. Note that although the half-life of BGB324 has 
resulted in the recommendation to give a BGB324 loading dose over 2 days to achieve steady 
state by Day 4, the use of the loading dose will depend on tolerability and DLT evaluation, and 
the SMC may recommend the dose is reduced. This may be achieved by giving the total 
loading dose over 3 days, giving a lower (including intermediate) loading dose, or not giving a 
loading dose at all. 
* At the time of Amendment 5 a 3 day loading dose schedule has been confirmed 
 
In Arm A, at least 3 evaluable patients will be entered per dose cohort according to the 3+3 
study design as described below. A dose cohort will include at least 3 patients on the same 
loading dose schedule and daily dose level. 
 
The SMC may consider that data from 3 patients at any dose level is sufficient to confirm the 
RP2D. In addition, the SMC may recommend that alternative dose levels or dosing schedules 
are explored as part of the study. At the time of patient registration, the loading dose schedule, 
loading dose and daily dose will be confirmed. 
 
Table 4 
Possible BGB324 Dosing Levels Involving A Loading Dose and Daily Dose  
Total  
Loading Dose 
(mg) 
Day 1 and 2 
Loading Dose 
(mg) 
Days 1, 2 and 3  
Loading Dose 
(mg) 
 
Daily Dose 
(mg) 
600 
-- 
200 
100 
800 
400 
-- 
100 
1200 
600 
400 
200 
If 2 DLTs occur in the combination treatment at the Arm A BGB324 starting dose, a lower dose level may be 
investigated (see Section 8.3.2) 
 
If a patient withdraws or is withdrawn for reasons other than DLT prior to completing Cycle 1, 
the patient will be replaced for the purposes of toxicity evaluation. Patients who experience a 
DLT during Cycle 1 may continue on BGB324 treatment (at their assigned daily dose or lower). 
 
In Arm A the starting erlotinib dose will be 150 mg daily during the first continuous 21-day 
treatment cycle. Patients who require an erlotinib dose reduction prior to completing 1 cycle 
of treatment will not be evaluable for toxicity and may be replaced. After completion of Cycle 1 
the daily dose of erlotinib may be reduced in accordance with the patient prescribing 
information. In response to potential toxicity the SMC may recommended evaluating lower 
doses of erlotinib. 
 
The prescribing information for erlotinib recommends a 150mg dose for NSCLC patients, 
however if local clinical judgement/standards require, a patient in Arm B or C may be treated 
at a lower erlotinib dose (i.e.,100 mg). 


BGBC004 V5 16 May 2017  
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8.3.2 Dose escalation scheme 
In Arm A, initially 3 patients will be recruited at a starting dose of 600 mg on Days 1 and 2 
followed by 200 mg daily, and must complete 1 21-day cycle of treatment before a dose 
evaluation is made. A patient must receive all loading doses and miss no more than 3 daily 
doses in Cycle 1 to be considered as informative to support dose escalation, unless the 
inability to administer BGB324 was a result of treatment-related toxicity. 
 
If 1 patient in a cohort experiences a DLT during Cycle 1, the cohort will be expanded to 6 
patients. If2 of 3 or 2 of6 patients in a cohort experience DLT, no further dose-escalation will 
take place and the prior dose level will be nominated as the RP2D. 
 
Safety reviews and recommendations for dose escalation or reduction will be made by the 
SMC. Minutes of the SMC meetings will be placed in the Trial Master File. The decision to 
dose escalate will be based on the safety and tolerability of BGB324 in combination with 
erlotinib observed in the first cycle of treatment. 
 
If dose escalation occurs, 3 patients will be recruited at Dose Level 2 and will complete 1 cycle 
of treatment before a dose escalation evaluation is made, as outlined above.  
 
Dose escalation may be stopped prior to achieving the MTD if it is considered by the Sponsor 
and SMC that a clinically acceptable RP2D has been achieved. If the starting dose exceeds 
the MTD, a lower dose, or dosing schedule (including an extended loading dose schedule) 
may be explored if recommended by the SMC. 
 
If a patient withdraws or is withdrawn for reasons other than DLT prior to completing Cycle 1, 
the patient will be replaced for the purposes of evaluation of BGB324 dose. The operating 
characteristics of the 3+3 dose escalation process are summarized in Figure 8.


 
BerGenBio ASA  
Jonas Lies vei 91 
5009 Bergen, Norway  
 
 
BGBC004 V5 16 May 2017 
CONFIDENTIAL 
Page 40 of 80 
 
Figure 8 
Operating Characteristics of the 3+3 Dose Escalation Process 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: DLT=dose limiting toxicity; MTD=maximum tolerated dose 
 
8.3.3 Assessment of DLTs 
AEs will be assessed using the National Cancer Institute (NCI) CTCAE Version 4.03 (See 
Appendix 4) during the first cycle (21 days) of treatment in Arm A for the purposes of 
establishing the dose of BGB324 that can be safely given in combination with erlotinib. 
 
DLTs will include:  
• 
Any non-hematological toxicity ≥Grade 3, except Grade 3 nausea, vomiting or diarrhea 
that resolves within 72 hours with optimal therapy. 
• 
Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding. 
• 
Grade 4 neutropenia persisting for ≥5 days or Grade 3 or 4 febrile neutropenia. 
• 
Treatment discontinuation or dose reduction for >72 hours during the first cycle as a 
result of treatment-related toxicity. 
 
8.4 
Arm B (Phase 2) 
Arm B will follow a Simon-like 2-stage design with relaxed stopping for futility to evaluate the 
safety and tolerability, PK, PD and clinical efficacy of BGB324 in combination with erlotinib in 
patients with an activating EGFR mutation(s) (including exon 19 deletion or exon 21 [L858R] 
substitution or other rearrangement of the EGFR gene mutations) who during screening have 
been confirmed as T790M negative, who have progressed after receiving an approved EGFR 
inhibitor (i.e., prior erlotinib, afatinib, or gefitinib) and who have radiological confirmation of 
progressive disease.  Patients who have progressed on osimertinib and fulfill all other Arm B 
criteria will not require testing of T790M status. 
0 DLT 
Escalate to 
next dose level 
1 DLT 
>1 DLT 
Enter 3 eligible patients 
Enter 3 more 
patients at same 
dose level 
STOP 
MTD = Previous 
dose level 
1 DLT in  
6 evaluable 
patients 
>1 DLT in  
6 evaluable 
patients 


BGBC004 V5 16 May 2017  
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Page 41 of 80 
If clinical response (complete response or partial response) or disease control (stable disease) 
is not evident after 4 cycles of treatment in at least 1 patient among the first 9 patients enrolled, 
no further patients will be enrolled in Arm B. If at least 1 patient in the first 9 patients 
demonstrates evidence of clinical response or disease control, an additional 16 patients will 
be enrolled. Recruitment will continue whilst data from the first 9 patients are being analyzed. 
Thus, up to 25 patients are anticipated to be enrolled in Arm B. 
 
The daily dose of erlotinib may be reduced in accordance with the erlotinib prescribing 
information and in line with standard practice. If a patient presents with erlotinib toxicities that 
warrant that they stop treatment with erlotinib, then they should be either withdrawn from the 
study or they may continue receiving BGB324 as a single agent until disease progression 
(unless unacceptable toxicity, death or withdrawal of consent). 
 
8.5 
Arm C (Phase 2) 
Arm C will evaluate the safety and tolerability, PD and clinical efficacy (time to progression) of 
BGB324 in combination with erlotinib in the first-line setting. Eligible patients will have 
activating EGFR mutation(s) (including exon 19 deletion or exon 21 [L858R] substitution or 
other rearrangement of the EGFR gene mutations) ≥12weeks of erlotinib without disease 
progression at the time of the first dose of BGB324 (Cycle 1, Day 1), with erlotinib-related 
toxicities well-controlled and <Grade 3.  
 
The daily dose of erlotinib may be reduced in accordance with the erlotinib prescribing 
information. If a patient presents with erlotinib toxicities that warrant that they stop treatment 
with erlotinib, then they should be either withdrawn from the study or may continue receiving 
BGB324 as a single agent until disease progression (unless unacceptable toxicity, death or 
withdrawal of consent). 
 
Recruitment into Arm C may be stopped if Arm B completes recruitment or is stopped before 
the 14 patient target is reached. Patients already enrolled into Arm C will be allowed to 
continue in the study in accordance with the protocol. 
 
8.6 
Overall Study Duration and Follow-Up 
The study period will consist of screening, treatment and an EOS visit. The EOS visit will occur 
28 days after the patient has discontinued BGB324 treatment. 
 
8.7 
Screening 
Patient eligibility for the study will be determined within 28 days prior to the first dose of 
BGB324 (Cycle 1, Day 1). Screening assessments will be conducted according to 
Section 10.1.1 and Table 5.  
 
In Arm B, the screening period may be extended to accommodate T790M confirmation from 
tumor biopsy Patients who have previously been treated with a T790M inhibitor (i.e., 
osimertinib) and who subsequently progressed will not require T790M testing. All other 
assessments including scans should be conducted in the 28-day screening period. 
 
8.8 
Treatment 
Eligible patients will visit the study site to receive study drug and protocol-specified procedures 
according to Section 10.1.2 to Section 10.1.4 and Table 5. The treatment period will consist 
of continuous 21-day treatment cycles.  
 
All patients will be carefully monitored throughout Day 1 to Day 4 in Cycle 1 and will attend 
the clinic on Cycle 1, Day 8, Cycle 1, Day 9 and Cycle 1, Day 15 (and Day -1 in Arm A).  
 
Patients will attend the clinic once per week (on Cycle 2, Day1, Cycle 2, Day 8 and Cycle 2, 
Day 15) during Cycle 2 and then once per cycle (on Day 1) thereafter up to 12 months of 


BGBC004 V5 16 May 2017  
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Page 42 of 80 
treatment (Cycle 17). Patients who remain on study after 12 months will attend the clinic every 
2 cycles (6 weekly).  
 
Patients who do not receive loading doses as assigned but are considered suitable for daily 
dose treatment should attend the clinic for additional ECG assessments. Twice weekly 
triplicate ECGs should be conducted during Cycle 1, Day 8 – Day 15 and Cycle 1, 
Day 15 -Day 21. 
 
Additional visits will be scheduled for disease assessment at the end of every 2 cycles 
(6 weeks) cycles. The frequency of scans may be extended to the end of every 3 cycles after 
12 weeks (4 cycles) and every 4 cycles after 24 weeks (8 cycles). Patients who remain on 
treatment for 12 months or longer may have their scans extended to a frequency of 6 months 
unless disease progression is suspected in which case a scan should be conducted at an 
earlier time point. 
 
Patients will continue to receive BGB324 (in combination with erlotinib or as a single agent) 
for as long as, in the opinion of the Investigator, they continue to derive clinical benefit or until 
disease progression, unacceptable toxicity, death or withdrawal of consent.  
 
In the event of erlotinib-related toxicities in Arms A, B, and C, patients may be allowed to 
continue receiving BGB324 as a single agent until disease progression unless unacceptable 
toxicity, death or withdrawal of consent. Patients who stop BGB234 treatment will be 
withdrawn from the study. 
 
8.9 
End-of-Study Visit 
Patients will return to the study site for an EOS visit 28 days after the last dose of study drug 
(or at study withdrawal) according to Section 10.1.5 and Table 5.  
 
If BGB324-related toxicities continue beyond this follow-up period, patients will be followed 
until all BGB324-related toxicities have resolved to ≤Grade 1, stabilized or returned to 
baseline. If necessary, follow-up monitoring for AEs may be conducted over the telephone. 
 
8.10 Study Stopping Rules 
The Sponsor may close a site or terminate the study or arm of the study at any time. The 
Investigator may also terminate the study at his/her clinical site at any time, provided there is 
reasonable cause and sufficient notice is given in advance of the intended termination. 
 
Advance notice is not required by either party if the study is stopped due to safety concerns.  
 
The reason for closure of an investigational site or termination of a study or arm of the study 
by the Sponsor may include but is not limited to: 
• 
The discovery of an unexpected, serious or unacceptable risk to patients enrolled in 
the study. 
• 
Failure of the Investigator to comply with the protocol and Good Clinical Practice (GCP) 
guidelines. 
• 
Inadequate recruitment of patients. 
• 
Attainment of the study objectives. 
• 
As a result of commercial considerations, including discontinuation of further clinical 
development of BGB324 in NSCLC. 
 
8.11 End of Study 
The EOS is defined as when all patients have completed or withdrawn and the EOS visit has 
been completed. Patients who continue to receive clinical benefit while receiving BGB324 may 
remain on treatment until such time of unacceptable toxicity or disease progression. Patients 


BGBC004 V5 16 May 2017  
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Page 43 of 80 
who remain on treatment after 12 months of treatment (Cycle 17) will have a revised visit and 
assessment schedule.  
 
 
SELECTION OF PATIENTS 
 
9.1 
Inclusion Criteria 
 
9.1.1 General inclusion criteria 
1. Provision of written informed consent to participate in this investigational study. 
2. Histological or cytological confirmation of Stage IIIb or Stage IV (unresectable) NSCLC. 
3. ECOG performance status 0 or 1. 
4. Age 18 years or older at the time of consent. 
5. Female patients of childbearing potential must have a negative serum pregnancy test 
within 7 days prior to taking their first dose of BGB324. Male patients and female 
patients of reproductive potential must agree to practice highly effective methods of 
contraception (such as hormonal implants, combined oral contraceptives, injectable 
contraceptives, intrauterine device with hormone spirals, total sexual abstinence, 
vasectomy) throughout the study and for ≥3 months after the last dose of BGB324. 
Female patients are considered NOT of childbearing potential if they have a history of 
surgical sterility, including tubal ligation, or evidence of post-menopausal status 
defined as any of the following: 
• 
Natural menopause with last menses >1 year ago. 
• 
Radiation induced oophorectomy with last menses >1 year ago. 
• 
Chemotherapy induced menopause with last menses >1 year ago. 
 
9.1.2 Additional inclusion criteria for run-in cohort 
6. Has received previous systemic therapy for unresectable NSCLC. 
7. Has exhausted existing licensed therapies, or is unsuitable for treatment with existing 
licensed therapies for NSCLC. 
 
9.1.3 Inclusion criteria for Arm A 
8. Known EGFR mutation status. 
9. Either: 
• 
Has received ≥6 weeks historical treatment with erlotinib. Erlotinib treatment must 
be re-started ≥1 week before the first dose of BGB324 (Cycle 1, Day 1); 
Or: 
• 
Is currently receiving erlotinib treatment for NSCLC and will have received 
≥6 weeks treatment at the time of the first dose of BGB324 (Cycle 1, Day 1). 
10. Erlotinib-related toxicities being well-controlled and <Grade 3 in severity at the time of 
the first dose of BGB324 (Cycle 1, Day 1) 
11. Toxicity from other prior therapy has resolved to ≤Grade 1 (previous treatment with 
bevacizumab and other licensed antibody therapies is permitted) 
 
9.1.4 Inclusion criteria for Arm B 
12. Patients must have documented EGFR mutation (including exon 19 deletion or exon 
21 [L858R] substitution or other rearrangement of the EGFR gene). EGFR mutation 
may be confirmed historically (prior to study entry) and during the 28-day screening 
period confirmation of negative T790M status (confirmed with blood test or biopsy from 


BGBC004 V5 16 May 2017  
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Page 44 of 80 
a progressing tumor). Patients who have previously been treated with a T790M 
inhibitor i.e., osimertinib) and who have progressed will not require T790M testing.3  
13. Disease that is measurable according to RECIST Version 1.1. 
14. Has progressed after receiving erlotinib or any other approved EGFR inhibitor (i.e., 
afatinib, or gefitinib) at any time during therapy for advanced disease. 
15. Erlotinib-related toxicities being well-controlled and <Grade 3 in severity at the time of 
the first dose of BGB324 (Cycle 1, Day 1. Toxicities associated with other EGFR 
inhibitors to be <Grade 2 in severity at the time of first dose of BGB324). 
16.  Patients must have completed afatinib and/or gefitinib treatment at least 1 week before 
the first dose of BGB324. 
17. Toxicity from other prior therapy has resolved to ≤Grade 1 (previous treatment with 
bevacizumab and other licensed antibody therapies is permitted). 
18. Patients who have an activating EGFR mutation may have up to 4 lines of previous 
treatment in the advanced setting. Additional chemotherapy may also have been given 
for treatment of limited stage disease in the adjuvant setting provided this was 
completed at least 6 months prior to study treatment 
 
 
9.1.5 Inclusion criteria for Arm C 
19. Known EGFR mutation status: 
20. Presence of an activating EGFR mutation (including exon 19 deletion or exon 21 
[L858R] substitution mutation or other rearrangement of the EGFR gene.). 
21. Disease that is measurable or evaluable according to RECIST Version 1.1. 
22. Is currently receiving erlotinib for NSCLC and will have received ≥12 weeks of 
treatment at the time of the first dose of BGB324 (Cycle 1, Day 1). 
23. Erlotinib-related toxicities well-controlled and <Grade 3 in severity at the time of the 
first dose of BGB324 (Cycle 1, Day 1). 
24. No prior treatment for advanced NSCLC except erlotinib and/or previous surgery 
(patients who have received treatment for their NSCLC while awaiting confirmation of 
EGFR status, may be eligible to participate and the inclusion of such patients should 
be discussed with the Medical Monitor) 
 
9.2 
Exclusion Criteria 
1. Pregnant or lactating. 
2. Abnormal left ventricular ejection fraction (less than the lower limit of normal for a 
patient of that age at the treating institution or <45%). 
3. Treatment with any of the following: histamine receptor 2 inhibitors, proton pump 
inhibitors or antacids within 3 days or 5 half-lives, whichever is longer. The Investigator 
may initiate rescue treatment with these medications during the study, providing they 
are taken in the evening. 
4. History of an ischemic cardiac event including myocardial infarction within 3 months of 
consent. 
5. Pulmonary hemorrhage or hemoptysis >2.5 mL blood within 6 weeks of consent unless 
cause has been addressed and is medically resolved. 
6. Congestive cardiac failure of >Class II severity according to the New York Heart 
Association (NYHA) defined as symptomatic at less than ordinary levels of activity (see 
Appendix 2). 
 
3 The 28-day screening period may be extended to allow for confirmation of the T790M status. Other assessments 
including CT should be conducted in the 28-day screening period. (see Section 10.12.11 for additional information 
on T790M testing). 
 


BGBC004 V5 16 May 2017  
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7. Unstable cardiac disease, including unstable angina or unstable hypertension, as 
defined by the need for change in medication for lack of disease control within 3 months 
of consent. 
8. History or presence of sustained bradycardia (≤60 bpm) or history of symptomatic 
bradycardia, left bundle branch block, cardiac pacemaker or significant atrial 
tachyarrythmias, as defined by the need for treatment. 
9. Current treatment with agents that may prolong QT interval and may cause Torsade 
de Points which cannot be discontinued at least 2 weeks prior to treatment.  
10. Known family or personal history of long QTc syndrome or ventricular arrhythmias 
including ventricular bigeminy. 
11. Previous history of ≥Grade 3 drug-induced QTc prolongation. 
12. Screening triplicate 12-lead ECG with an average measureable QTcF >450 ms. 
13. Inadequate liver function as demonstrated by: 
• 
Serum bilirubin ≥1.5 times the upper limit of normal range (ULN); or 
• 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2.5 times 
the ULN (up to 5 times the ULN in the presence of liver metastases. 
14. Inability to tolerate oral medication. 
15. Impaired coagulation as evidenced by: 
• 
International normalized ratio (INR) >1.5 times ULN (or equivalent); or 
• 
Activated partial thromboplastin time (aPTT) >1.5 times ULN. 
16. Existing gastrointestinal disease affecting drug absorption, such as celiac disease or 
Crohn’s disease. 
17. Previous bowel resection that may impair study drug absorption. 
18. Impaired renal function as demonstrated by creatinine clearance of ≤50 mL/min 
determined by Cockcroft-Gault formula. 
19. Absolute neutrophil count <1.5 x 109/L, hemoglobin <9.0 g/dL, platelet count 
<100 x 109/L in the absence of blood product support. 
20. Any evidence of severe or uncontrolled systemic conditions (e.g., severe hepatic 
impairment) or current unstable or uncompensated respiratory or cardiac conditions 
which makes it undesirable for the patient to participate in the study or which could 
jeopardize compliance with the protocol. 
21. Treatment with any medication which is predominantly metabolized by CYP3A4 and 
has a narrow therapeutic index. 
22. Active, uncontrolled central nervous system (CNS) disease (previously-treated CNS 
metastases that are asymptomatic and do not require steroid treatment are allowed). 
Note: Patients with known CNS metastases who have completed radiotherapy at least 
2 weeks prior to BGB324 treatment are eligible 
23. Known active infection with human immunodeficiency virus (HIV), hepatitis B or C 
viruses (screening not required). 
• 
Patients who have a history of hepatitis B infection are eligible provided they are 
hepatitis B surface antigen negative. 
• 
Patients who have a history of hepatitis C infection are eligible provided they have 
no evidence of hepatitis C ribonucleic acid using a quantitative polymerase chain 
reaction assay at least 6 months after completing treatment for hepatitis C 
infection. 
24. Major surgery requiring general anesthesia within 28 days prior to the start of BGB324, 
excluding biopsies and procedures for insertion of central venous access devices. 
25. Treatment with cytotoxic chemotherapy, within 3 weeks prior to the first dose of 
BGB324 (Cycle 1, Day 1) with the exception of treatment with other EGFR inhibitors 
which must be completed 1 week prior to commencing treatment with BGB324.There 
is no requirement to discontinue ongoing treatment with erlotinib. 
26. Treatment with other non-cytotoxic agents for NSCLC in the 10 days or 4 half-lives 
prior to the first dose of BGB324 (Cycle 1, Day 1), whichever is shorter. 


BGBC004 V5 16 May 2017  
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Page 46 of 80 
27. Prior biological therapies in the 4 weeks (or 5 half-lives, whichever is shorter) before 
the first dose of study BGB324 (Cycle 1, Day 1). Note prior treatment with an alternative 
EGFR inhibitor and/or PD-1 blockade are permitted 
 
 STUDY PROCEDURES AND ASSESSMENTS 
 
The schedule of events is summarized in Table 5.  
 


 
BGBC004 V5 16 May 2017  
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Page 47 of 80 
Table 5 
Schedule of Events 
Cycle 
1 
2 
≥3 w 
End-of-
Study 
Week 
1(x) 
2(x) 
3(x) 
4(x) 
5(x) 
6(x) 
>7 
28 days 
after last 
dose 
Cycle Day 
28 to 0 
Screening 
-1 
Arm A 
1 2 3 4 
5-7 
8 
9 
10-14 
15 
16-21 
1 
2-7 
8 9-14 
15 16-20 21 
1 
2-20 
21 
Visit window (+/-) 
days 
 
0 
0 0 0 0 
0 
0 
0 
0 
0 
0 
+2 
0 
+
1 
0 
+1 
0 
+-5 
+2 
0 
 +5 
+7 
Clinic visit 
X 
X 
X X X X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cancer history and 
treatments 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG performance 
status 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
X 
Physical 
examinationa 
Xa 
X 
X  
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Xa 
Vital signsb 
X 
X 
X X X X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
12-Lead triplicate 
ECG c, v 
X 
X 
X X X X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
Pregnancy testd 
X 
Xe 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
Clinical chemistryf 
X 
Xe 
X X X X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
Hematologyg 
X 
Xe 
X X X X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
Coagulationh 
X 
Xe 
X  
 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
X 
 
 
X 
Urinalysisi 
X 
Xe 
X  
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
Echocardiogram or 
MUGA scant 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
PK blood samplingj  
 
X 
X X X X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
Tissue collection for 
PDl, m,k,q 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Xr 
Blood collection for 
PDm, l,k 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Xs 
EGFR T70M status 
(Arm B) 
Xu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease 
assessmentp,n 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
X 


 
BGBC004 V5 16 May 2017  
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Page 48 of 80 
BGB324 
administration0 
 
 
 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Erlotinib 
administration0 
 
X 
X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Drug accountability 
 
 
X  
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
Adverse events 
 
 X ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
Concomitant 
medications 
 
 X-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------X 
Abbreviations: ECOG=Eastern Co-operative Oncology Group; MUGA=multi-gated acquisition; PD=pharmacodynamics; PK=pharmacokinetics 
 
 
 
a. 
Physical examination conducted at the screening and end-of-study (EOS) visits. A symptom-directed examination will be conducted at other visits. 
b. 
Blood pressure, pulse, respiratory rate, temperature. In addition, at screening, weight and height to be recorded. 
c. 
Triplicate 12-lead ECG, at least 5 minutes apart, after resting for ≥10 minutes in supine position during screening and during each visit (pre-dose). Patients who re-start BGB324 
following interruption for QTc prolongation should also have ECGs performed according to this schedule.  
d. 
For women of child-bearing potential to be repeated every 3 months, or if possibility of pregnancy is identified. A serum test must be performed at screening and the EOS visits; 
interim tests may be performed on urine samples. 
e. 
Unless conducted as part of the screening procedures within 3 days prior to Day 1. 
f. 
Clinical chemistry laboratory parameters: potassium, calcium, uric acid, electrolytes, blood urea nitrogen, total protein, total bilirubin, alanine aminotransferase, aspartate 
aminotransferase, creatinine, creatine phosphokinase, alkaline phosphatase, albumin, phosphorus, glucose, magnesium (plus amylase and lipase during screening ONLY). 
g. 
Hematology laboratory parameters: full blood count including differential white cell count, hemoglobin, hematocrit and platelets. 
h. 
Coagulation parameters: prothrombin time and/or international normalized ratio, activated partial thromboplastin time.  
i. 
Dipstick measurement of blood, nitrite, glucose, ketones, leukocytes, protein and pH. (Microscopic analysis is not required unless clinically indicated).  
j. 
Blood sampling for the determination of BGB324 / erlotinib in plasma will be collected in accordance with Table 6. 
k. 
In consenting patients (Arms A, B and C), tissue specimens may be collected for analysis of pharmacodynamics endpoints of Axl inhibition. The baseline tissue specimen should 
be collected after enrollment within 28 days before the first dose of BGB324. The on-study tissue collection may be performed any time after 14 days of continuous exposure to 
BGB324 in Cycle 1 or in Cycle 2. The EOS tissue collection should be made at the time of disease progression and prior to the end-of-study visit (derived from the lesion exhibiting 
disease progression). Detailed procedures for the collection, processing, storage and shipment of the samples will be provided in the laboratory manual. 
l. 
Blood will be collected for analysis of pharmacodynamic endpoints of Axl inhibition. The baseline sample should be collected after enrollment within 28 days before the first dose 
of BGB324. The on-study sample collection may be performed any time after 14 days of continuous exposure to BGB324 in Cycle 1 or in Cycle 2. The EOSEOS sample should 
be taken at the time of disease progression and prior to the EOS-visit. 
m. If a tissue specimen is being collected, the PD blood sample should be collected at the same visit. 
n. 
Disease assessment via RECIST Version 1.1. 
o. 
BGB324 and erlotinib (not Run-in Cohort) will be administered on an empty stomach. Both drugs will be taken with water in the morning. BGB324 should be administered in the 
hour following erlotinib administration and at least 2 hours before breakfast (except on those days when the patient attends the clinic). Patients should record dosing in the dosing 
diary provided.  
p. 
Disease assessment will be performed at the end of every 2 cycles (6 weeks) beginning with Cycle 2 (Day 21); the assessment may be performed up to 5 days before Day 21 
(Day 17-Day 21) but attempts should be made to conduct the assessment as close to Day 21 as possible. Disease assessment may be performed prior to initiation of the next 
cycle, but results must be available prior to initiation of treatment and must confirm continued eligibility for next cycle. The frequency of scans may be extended to the end of 
every three cycles after 12 weeks (4 cycles) and every 4 cycles after 24 weeks (8 cycles). Patients who remain on study for 12months may have their scan frequency reduced 
to 6 monthly. 


 
BGBC004 V5 16 May 2017  
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q. 
For consenting patients´ only (Arms A, B and C); performed any time after documentation of disease progression and prior to EOS visit. The tissue specimen should be derived 
from a lesion exhibiting progression. 
r. 
If not performed within previous 28 days. 
s. 
To be performed at the time of disease progression and prior to the EOS visit.  
t. 
Cycle 4 Day 1 and then at 6 monthly intervals and at EOS. 
u. 
Patients in Arm B must have EFGR T790M status confirmed during screening – Patients who have progressed on osimertinib and have previously progressed on an approved 
EGFR inhibitor i.e. afatinib, gefitinib) will not require additional T790M testing. T790M testing may be confirmed by blood test or biopsy. Samples collected and analyzed according 
to local procedures. The screening window of 28 days may be extended to allow for confirmation of T790M status. 
v. 
Patients who do not receive their assigned loading doses and continue to receive daily dose BGB324 should attend the clinic for additional ECG assessments between C1 D8 
and D15 and between C1 D15 and the end of Cycle 1. 
w. Patients who remain on study post C17 will have a reduced visit schedule and will return to clinic every 2 cycles (+/-7 days)  
x. 
Patients receiving BGB324 who require daily steroids at doses of 10mg to 40mg (prednisolone equivalent) should be monitored at weekly intervals until the steroid  dose level is 
less than 10mg: Assessment should include physical exam, vital signs, hematology, chemistry. 


 
BGBC004 V5 16 May 2017                             CONFIDENTIAL 
Page 50 of 80 
 
10.1 Procedures at each Visit 
 
10.1.1 Screening and enrollment 
Patients must provide written informed consent before any screening procedures are 
performed. The screening period covers up to 28* days prior to the first dose of BGB324.  
 
During screening, the following procedures will be performed: 
• 
Demographics. 
• 
Medical history. 
• 
Cancer history and treatments (medications and surgeries).  
• 
EGFR mutation recorded 
• 
T790M status confirmed in the screening period (Arm B)4 
• 
Performance status assessment (ECOG). 
• 
Physical examination. 
• 
Vital signs (including height and weight) 
• 
Serial 12-lead ECGs, in triplicate.  
• 
Serum pregnancy test, if applicable. 
• 
Clinical chemistry, (including amylase and lipase), hematology, urinalysis, coagulation 
• 
Echocardiogram or MUGA scan. 
• 
Disease assessment.  
• 
Review of inclusion/exclusion criteria. 
 
Male patients and female patients of reproductive potential must agree to practice highly 
effective methods of contraception throughout the study and for ≥3 months after the last dose 
of BGB324. Highly effective methods of contraception are defined as: 
 
• 
Hormonal implants, combined oral contraceptives, injectable contraceptives. 
• 
An intrauterine device with hormone spirals. 
• 
Tubal ligation. 
• 
True total sexual abstinence. 
• 
Vasectomy. 
 
If it is not possible to use one of these highly effective methods of contraception, 2 barrier 
methods used simultaneously are acceptable. 
 
The following baseline samples should be taken in the 28 days before the first dose of BGB324 
after the patient has been confirmed as otherwise eligible: 
 
• 
Blood collection for PD (Arms A, B, and C only). 
• 
Tissue collection for PD (consenting patients only) (Arms A, B, and C). 
 
Patients who meet all inclusion/exclusion criteria will be allocated a study-specific patient 
number.  
 
10.1.2 Cycle 1 
All AEs and concomitant medication use will be recorded throughout the cycle.  
 
 
4 The screening period for Arm B may be extended to allow for confirmation of T790M status all other assessments 
are to be conducted in the 28-day screening period. Patients who have previously been treated with a T790M 
inhibitor (i.e., osimertinib) and who subsequently progressed will not require T790M testing. 
 


 
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In addition, tissue (in consenting patients) and blood will be collected for pharmacodynamic 
assessment at one on-study time point after 14 consecutive days of BGB324 administration 
either in Cycle 1 or Cycle 2 (Arms A, B, and C).  
 
Patients who do not receive loading doses as assigned but are considered suitable for daily 
dose treatment should attend the clinic for additional triplicate ECG assessments. Twice 
weekly ECGs should be conducted during Cycle 1, Day 8 – Day 15 and Cycle 1 Day 15 – 
Day 21. 
 
 Day -1 (Arm A) 
• 
Symptom-directed physical examination. 
• 
Vital signs. 
• 
Serial 12-lead ECGs, in triplicate.  
• 
Serum pregnancy test (does not have to be repeated on Day -1 if conducted as part 
of screening procedures within 3 days prior to Day 1).  
• 
Clinical chemistry, hematology, coagulation, urinalysis (does not have to be repeated 
on Day -1 if conducted as part of screening procedures within 3 days prior to Day 1).  
• 
Blood sampling for erlotinib PK 
• 
Erlotinib administration orally, on an empty stomach. 
 
 Day 1, Day 8, Day 15 
• 
Symptom-directed physical examination  
• 
Vital signs  
• 
Serial 12-lead ECGs, in triplicate.  
• 
Clinical chemistry, hematology, coagulation, urinalysis. 
• 
Blood sampling for PK (Run-in Cohort, Arms A and B). 
o PK sampling in Arm B will be for BGB324 only- see Table 6. 
• 
BGB324 administration orally on an empty stomach. 
• 
Erlotinib administration (Arms A, B, and C) orally, on an empty stomach. 
• 
Drug accountability. 
 
 Day 2, Day 3, Day 4 
• 
Vital signs. 
• 
Pre-dose serial 12-lead ECGs, in triplicate.  
• 
Clinical chemistry and hematology. 
• 
Blood sampling for PK (Run-in Cohort, Arms A and B) 
o PK sampling in Arm B will be for BGB324 only- see Table 6. 
• 
BGB324 administration orally on an empty stomach. 
• 
Erlotinib administration (Arms A, B, and C) orally, on an empty stomach. 
 
 Day 9 
• 
Vital signs. 
• 
Serial 12-lead ECGs in triplicate. 
• 
Blood sampling for PK (Run-in Cohort, Arms A and B) 
o PK sampling in Arm B will be for BGB324 only-see Table 6. 
• 
BGB324 administration orally, on an empty stomach. 
• 
Erlotinib administration (Arms A, B, and C) orally, on an empty stomach. 
 
 Days 5-7, 10-14, 16-21 
• 
BGB324 and erlotinib (Arms A, B, and C) will be self-administered orally on an empty 
stomach by the patient at home.  
 


 
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10.1.3 Cycle 2 
 Day 1, Day 8, Day 15 
All AEs and concomitant medication use will be recorded throughout the cycle.  
 
In addition, tissue (in consenting patients) and blood will be collected for PD assessment at 
one on-study time point after 14 consecutive days of BGB324 administration in Cycle 1 or 
Cycle 2 (Arms A, B, and C). 
 
• 
Performance status assessment (Day 1 only). 
• 
Symptom-directed physical examination. 
• 
Vital signs. 
• 
Serial 12-lead ECGs, in triplicate.  
• 
Clinical chemistry, hematology, urinalysis 
• 
Coagulation (Day 1 only). 
• 
Blood sampling for PK (Run-in Cohort, Arms A and B). 
o PK sampling in Arm B will be for BGB324 only- see Table 6. 
• 
BGB324 administration orally, on an empty stomach. 
• 
Erlotinib administration (Arms A, B, and C) orally, on an empty stomach. 
• 
Drug accountability. 
 
 Days 2-7, 9-14, 16-20 
• 
BGB324 and erlotinib (Arms A, B, and C) will be self-administered orally on an empty 
stomach by the patient at home.  
 
 
10.1.4 Cycles ≥3-C17 
All AEs and concomitant medication use will be recorded throughout each cycle. 
 
 Day 1 
• 
Performance status assessment. 
• 
Symptom-directed physical examination. 
• 
Vital signs. 
• 
Serial 12-lead ECGs, in triplicate.  
• 
Urine pregnancy test at 3 month intervals. 
• 
Clinical chemistry, hematology, urinalysis, coagulation (+/- 3 days). 
• 
Blood sampling for PK.  
o PK sampling in Arm B will be for BGB324 only- and will continue to Cycle 3, 
Day 1 - see Table 6 
• 
Echocardiogram or MUGA scan (Cycle 4 only). 
• 
BGB324 administration orally, on an empty stomach. 
• 
Erlotinib administration (Arms A, B, and C) orally, on an empty stomach. 
• 
Drug accountability. 
 
 Days 2-20 
• 
BGB324 and erlotinib (Arms A, B, and C) will be self-administered orally, on an empty 
stomach, by the patient at home.  
 
10.1.5 End-of-study visit 
The following assessments will then be carried out at the EOS visit (28 days after the last dose 
of study drug) for every patient enrolled into the study.  
 
• 
Performance status assessment. 
• 
Physical examination. 


 
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• 
Vital signs. 
• 
Serial 12-lead ECGs, in triplicate  
• 
MUGA/ECHO. 
• 
Serum pregnancy test. 
• 
Clinical chemistry, hematology, coagulation and urinalysis. 
• 
Blood sampling for PK  
o 
PK sampling in Arm B will be for BGB324 only - see Table 6. 
• 
Disease assessment (if not performed within previous 28 days). 
• 
Drug accountability. 
• 
AEs assessment. 
• 
Concomitant medications assessment. 
 
10.1.6 Assessments at disease progression 
The following assessments are required at disease progression 
• 
Tissue collection for PD (in consenting patients) (Arms A, B, and C). 
• 
Blood collection for PD (Arms A, B, and C). 
• 
CT scan and RECIST evaluation (as per local standards). 
 
10.1.7 Visit schedule after 12 months of treatment  
Patients who remain on BGB324 for 12 months or more will be able to reduce the frequency 
and number of assessments required at each visit.  
Patients will return to clinic every 6 weeks (every 2 cycles). The following assessments will be 
undertaken: 
• 
Symptom-directed physical examination (every 3 months). 
• 
Serial 12-lead ECGs, in triplicate.  
• 
Clinical chemistry, hematology, urinalysis (every 3 months). 
• 
Drug accountability. 
• 
AE and concomitant medication reporting. 
• 
Pregnancy test as applicable (every 3 months). 
 
10.1.8 Visit schedule while on corticosteroids 
Patients receiving BGB324 who require the support of prednisolone (or equivalent) at 10mg 
to 40mg daily should be monitored at weekly intervals whilst receiving steroid treatment until 
the steroid dose is 10mg or less daily or is stopped. 
Patients will be requested to return weekly at which time the following assessments will be 
undertaken: 
• 
Physical examination 
• 
Vital signs 
• 
Clinical chemistry, hematology 
• 
AE reporting/concomitant medication reporting 
Patients who require daily steroids of more than 40mg prednisolone (or equivalent) should 
interrupt BGB324 until the steroid dose is 40mg or less daily. 
Steroid restrictions do not apply to topical/ inhaled/ eye or nasal drops.  
If required, additional advice on the concomitant use of steroids with BGB324 should be 
obtained from the BerGenBio Medical Monitor 
Patients who are already attending weekly visits for C1 and C2 do not require additional visits. 


 
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10.2 Details of Study Procedures 
 
 Clinical Laboratory Assessments 
The following clinical laboratory parameters will be measured at a local laboratory: 
• 
Clinical chemistry (serum): potassium, calcium, uric acid, electrolytes, blood urea 
nitrogen, total protein, total bilirubin, ALT, AST, creatinine, creatine phosphokinase, 
alkaline phosphatase, albumin, phosphorus, glucose, magnesium plus amylase and 
lipase (during screening only). 
• 
Hematology: full blood count including differential white cell count, hemoglobin, 
hematocrit and platelets. 
• 
Coagulation parameters: prothrombin time and/or INR, aPPT. 
• 
Urinalysis: Dipstick measurement of blood, nitrite, glucose, ketones, leukocytes, 
protein, and pH. (microscopic analysis is not required unless clinically indicated). 
• 
EGFR T790M to be undertaken in accordance with local standard practice. 
 
All tests will be performed at screening (and on Cycle 1, Day -1 for patients in Arm A)  
 
Thereafter, clinical chemistry and hematology will be performed at each study visit. 
Coagulation will be performed on Days 1, 8, and 15 in Cycle 1, Day 1 in all subsequent cycles 
and the end-of-study visit.  
 
Urinalysis will be performed on Days 1, 8, and 15 in Cycle 1 and Cycle 2, Day 1 in all 
subsequent cycles and the EOS visit. 
 
10.2.2 Pregnancy test 
In women of child bearing potential a serum pregnancy test should be taken at screening and 
Day 1 (and on Cycle 1, Day -1 for patients in Arm A unless conducted as part of screening 
procedures within 3 days prior to Cycle 1, Day 1) and at the EOS visit.  
 
During the study, a urine pregnancy test should be repeated every 3 months.  
 
Should a patient suspect that pregnancy may have occurred an unscheduled pregnancy test 
should be conducted. The patient must have negative tests for eligibility and continuation on 
the study. 
 
10.2.3 Vital signs 
Blood pressure, pulse, respiratory rate and oral temperature will be consistently recorded at 
all study visits (with the exception of visits performed for disease assessment). 
 
10.2.4 Triplicate 12-lead ECG 
Triplicate 12-lead ECGs, at least 5 minutes apart, will be performed after resting for 
≥10 minutes in supine position during screening and pre-dose on Day -1 (Arms A and B) then 
Day 1, 2, 3, 4, 8, 9, and 15 in Cycle 1, pre-dose on Days 1, 8, and 15 in Cycle 2, pre-dose on 
Day 1 in Cycle 3 onwards, and at the EOS visit.  
 
Patients who do not receive loading doses as assigned but are considered suitable for daily 
dose treatment should attend the clinic for additional ECG assessments. Twice weekly ECGs 
should be conducted during Cycle 1, Day 8 - Day 15 and Cycle 1, Day 15 – Day 21. 
 
Continuous variables (PR interval, RR interval, QRS duration, QT and QTcF intervals) and an 
overall assessment will be recorded in the electronic case report form (eCRF). 
 
QTc values recorded should be calculated as the average from the 3 traces taken.  


 
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10.2.5 Echocardiogram/MUGA 
An ECG or MUGA scan will be performed at screening at 6 monthly intervals and at the EOS 
visit. 
 
10.2.6 Physical examination 
A full physical examination of each body system will be performed at screening and the EOS 
visit. Note genitalia/pelvic/rectal examinations only need to be performed if clinically indicated. 
 
A symptom-directed examination will be performed pre-dose on Day -1 (Arm A) then Days 1, 
8, and 15 in Cycles 1 2 and Day 1 in Cycle 3 onwards. 
 
10.2.7 Performance status 
Performance status will be assessed using the ECOG scale (see Appendix 1) at screening, 
Day 1 of each cycle starting on Cycle 2 and the EOS visit. 
 
10.2.8 Pharmacokinetic assessments 
Detailed procedures for the collection, processing, storage and shipment of samples will be 
provided in the laboratory manual. Approximate blood volumes required for PK analysis will 
be included in the patient information sheet, actual volumes will depend upon the arm to which 
the patient has been enrolled and the duration of treatment. 
 
Blood samples will be taken for the determination of BGB324 in plasma in the Run-in Cohort 
and Arm B and for the determination of BGB324 and erlotinib in Arm A at the time points 
shown in Table 6. 
 
If there is sufficient PK data from the first 9 patients in Arm B, consideration may be given to 
omitting PK sampling in the second 16 patients. In addition, sampling on Day 1 of each cycle 
will be discontinued after Cycle 3. 
 
Table 6 
Time points for Pharmacokinetic Sample Collection (Run-in Cohort, Arms A 
and B Only) 
 
 
Arm A 
Run in  
Arm B (3-day loading dose)  
Study Day 
Time (hours) 
Erlotinib and BGB324 BGB324  
C1-Day1 
0 (pre-dose) 
X 
 
2 
X 
 
4 
X 
 
6 
X 
 
8 
X 
 
C1 Day 1 
0 (pre-dose) 
X 
X  
C1 Day 2 
0 (pre-dose) 
X 
X 
C1 Day 3 
0 (pre-dose) 
X 
X 
2 
 
X 
4 
 
X 
6 
 
X 
8 
 
X 
C1 Day 4 
0 (pre-dose) 
X 
X 
C1 Day 8 
0 (pre-dose) 
X 
X 
2 
X 
X 
4 
X 
X 
6 
X 
X 
8 
X 
X 
C1 Day 9 
0 (pre-dose) 
X 
X 


 
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C1 Day 15 
0 (pre-dose) 
 
X 
C2 Day 1 
0 (pre-dose) 
 
X 
C2 Day 8 
0 (pre-dose) 
 
X 
C2 Day 15 
0 (pre-dose) 
 
X 
C3 Day 1 
0 (pre-dose) 
X 
X 
End-of-Study Visit 
NA 
X 
X 
C = Cycle; NA = Not applicable 
 
Pharmacokinetic schedules should be adhered to where possible. Pre-dose samples should 
be taken has close to the erlotinib/BGB324 dose as possible (and within a maximum of 
20 minutes prior to the erlotinib dose). At each post-dose time point an approximate 
±20 minute window is allowed.  
 
Standard procedure should be followed for the collection of blood and the preparation of 
plasma samples for pharmacokinetic analysis. Sufficient blood (approximately 3 mL) should 
be collected and processed to support the preparation of duplicate 1 mL plasma samples 
(primary sample for analysis and secondary sample for retention).  
 
 
 
 
10.2.9 Pharmacodynamic assessments (Arms A, B and C) 
 
 Pharmacodynamic tissue and blood samples  
Detailed procedures for the collection, processing, storage and shipment of samples will be 
provided in the laboratory manual. The effects of BGB324 on PD endpoints of Axl inhibition 
will be determined in blood samples and tissue specimens (see Section 7.8).  
 
A tumor tissue sample for analysis of PD endpoints should be taken using a core needle 
biopsy at baseline (within 28 days before the first dose of BGB324, after patient eligibility has 
been confirmed), 1 on-study collection time point performed any time after 14 days of 
continuous exposure to BGB324 during Cycle 1 or in Cycle 2 and 1 collection time point at the 
time of disease progression and prior to the EOS visit (derived from the lesion exhibiting 
disease progression).  
 
Standard clinical site practice should be followed for the collection of core needle tumor tissue 
samples. These samples are optional and will only be taken from patients providing separate 
consent in Arms A, B and C.  
 
10 mL (2 x 5 mL) blood samples (for the preparation of plasma and buffy coat fractions) will 
be collected for all patients enrolled in Arms A, B, and C at baseline (within 28 days before the 
first dose of BGB324 and after patient eligibility has been confirmed), 1 on-study collection 
time point performed any time after 14 days of continuous exposure to BGB324 during Cycle 1 
or in Cycle 2 and 1 collection time point at the time of disease progression and prior to the 
EOS visit.  
 
Note: If a patient has consented to have optional tumor biopsy samples taken, the PD blood 
samples should be taken at the same time.  
 
10.2.10 
Clinical efficacy 
Disease assessment will be performed at screening and at the end of every 2 cycles (6 weeks) 
beginning with Cycle 2, Day 21; the assessment may be performed up to 5 days before Day 21 
(Day 17 - Day 21) but attempts should be made to conduct the assessment as close to Day 
21 as possible.  
 


 
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Disease assessment may be performed prior to initiation of the next cycle, but results must be 
available prior to initiation of treatment and must confirm continued eligibility for next cycle.  
 
• 
Patients who remain on treatment for 12 months or longer may have their scans extended 
to a frequency of 6 months, unless disease progression is suspected in which case a scan 
should be conducted at an earlier time point. 
 
Disease assessment and confirmation of response will be performed according to RECIST 
Version 1.1 guidelines (Eisenhauer, 2009).  
 
10.2.11 
T790M confirmation 
 
For patients to be eligible for Arm B, their latest EGFR T790M status should be confirmed 
during the screening period. This can be done either via blood test (circulating tumour DNA 
[ctDNA], serum or plasma) or tumour biopsy. Both the blood test/biopsy should be undertaken 
in accordance with local standard procedures 
  
Patients who have previously been treated with a T790M inhibitor (i.e., osimertinib) will not 
require T790M testing and will be eligible providing they meet all other inclusion/exclusion 
criteria. 
 
For those patients who have not been on a T790M inhibitor, blood-based testing using 
circulating tumor DNA for the presence of the mutation may be utilised, however if a negative 
T790M blood result is obtained, the result requires confirmation on biopsy material. 
 
 STUDY TREATMENT 
The Sponsor will provide BGB324 to each study site. 
 
Erlotinib will be obtained locally and administered following institutional practices.  
 
11.1 Treatment Schedule and Administration of BGB324 
BGB324 will be self-administered orally on an empty stomach according to a daily schedule 
during continuous 21-day treatment cycles.  
 
The BGB324 dose will be based on the cohort and study arm to which the patient is enrolled. 
BGB324 should be administered with water in the morning at least 2 hours before breakfast 
and best efforts should be made to administer BGB324 at the same time each day, other than 
study visit days when BGB324 should be administered during the visit.  
 
Patients will record their dosing at home in a dosing diary that will be reviewed at each study 
visit by the site staff. Patients will be instructed as to the importance of following the dosing 
instructions they have been provided with and for maintaining an accurate and up-to-date 
dosing record. Patients will also be instructed to bring their dosing diary and all BGB324 
bottles, including unused and empty bottles, with them to each study visit. The site staff will 
record the amount of used and unused BGB324 capsules at study visits.  
 
11.2 Treatment Schedule and Administration of Erlotinib 
Erlotinib will be self-administered orally with BGB324 on an empty stomach according to a 
daily schedule during continuous 21-day treatment cycles. Best efforts should be made to 
administer erlotinib in the morning at the same time each day, other than on the morning of 
study visit days when erlotinib should be administered during the visit. Erlotinib should be 
administered with water. Patients will be instructed to take their erlotinib dose first followed by 
BGB324 within the next hour.  
 


 
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Patients will record their dosing at home in a dosing diary that will be reviewed at each study 
visit by the site staff. Patients will be instructed as to the importance of following the dosing 
instructions they have been provided with and for maintaining an accurate and up-to-date 
dosing record. Patients will also be instructed to bring their dosing diary and all boxes of 
erlotinib, including unused and empty boxes, with them to each study visit. The site staff will 
record the amount of used and unused erlotinib at study visits. 
 
11.3 Dose Modification 
The AE profile for BGB324 suggests that diarrhea and gastrointestinal disturbances are 
frequently reported (see current IB for further information). As BGB324 and erlotinib have the 
potential for overlapping toxicities patients should be advised accordingly and provided 
with antidiarrheals for symptomatic management. 
 
Dose modifications and dose interruptions to manage toxicities should be considered for both 
BGB324 and erlotinib. Dose modifications for erlotinib should be undertaken in line with the 
current prescribing information.  
 
Dose modifications and recommendations for the management of toxicities suspected to be 
related to BGB324 are provided in Table 7 and Table 8. 
 
 
11.3.1 BGB324 toxicities and dose modification 
 
 BGB324 loading dose toxicities  
If the patient is unable to tolerate the loading doses (i.e. for example more than a single 
CTCAE grade worsening of any adverse event or the appearance of any new Grade 3 
toxicities), they may continue with the assigned daily dose, but will be required to attend the 
clinic for additional ECG assessments between Cycle 1, Days 8 and 15 and between Cycle 1, 
Day 15 and the end of Cycle 1. 
 
 BGB324 daily dose toxicities 
Recommended BGB324 dose modifications are provided in Table 7 and Table 8. 
If, after a 14-day delay, treatment-related toxicity has not resolved, the patient may be 
discussed with the Medical Monitor prior to being withdrawn from the study.  
 
For those patients who experience a BGB324 dose delay of ≥7 days, the BGB324 loading 
dose assigned should be repeated. If the patient was unable to tolerate the loading dose in 
Cycle 1 the repeat loading dose can be omitted. The requirement to reintroduce the loading 
dose should be discussed with the Medical Monitor. 
 
Drug holidays for reasons other than BGB324 or erlotinib toxicity may be permitted on a 
case--by-case basis and should be discussed with the Medical Monitor. 
 
Table 7 
Daily Dose Modification of BGB324 for Toxicity 
Grade (CTCAE) 
Recommended Dose Modification 
Grade 1 and Grade 2 (tolerable) 
Any occurrence 
Maintain dose if toxicity is tolerated by the patient 
Grade 2 (intolerable) 
1st or 2nd occurrence  
of same event  
Interrupt treatment until toxicity returns to baseline, Grade 1 
or tolerable Grade 2. 
Resume dosing at same dose 
3rd occurrence of same 
event  
Interrupt treatment until toxicity returns to baseline, Grade 1 
or tolerable Grade 2. 
Dose reduce by 100 mg 


 
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Grade (CTCAE) 
Recommended Dose Modification 
4th occurrence of same 
event 
Discontinue permanently 
Grade 3 
1st occurrence 
Interrupt treatment until toxicity returns to baseline, Grade 1 
or tolerable Grade 2. 
Dose reduce by 100 mg or, 
Discontinue permanently if dose has already been reduced  
2nd occurrence  
of same event at Grade 3 
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 the Medical Monitor, 
 
 BGB324 dose modification for QTC 
BGB324 demonstrates some potential for 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). If a patient presents with QTcF prolongation of ≥Grade 2, 
the dose modification / dose interruption recommendations (Table 8) are recommended. 
 
Table 8 
Daily Dose Modification of BGB324 for QTc Prolongation 
QTcF 
Recommended BGB324 Dose Modification 
Grade 1 (451-480 ms) 
Any occurrence 
No dose modification required 
Grade 2 (481-500 ms)  
1st occurrence 
  
Continue dosing and conduct weekly ECGs; 
i) if QTcF reduces to ≤Grade 1 by 14 days from initial recording, 
no dose modification is required 
ii) if QTcF does not reduce to ≤Grade 1 by 14 days from initial 
recording, dose reduce by 100 mg 
≥2nd occurrence  
(without dose 
modification) 
Repeat procedure for “1st occurrence” 
 
≥2nd occurrence  
(at reduced dose) 
  
Continue dosing and conduct weekly ECGs; 
 i) if QTcF reduces to ≤Grade 1 by 14 days from initial recording, 
no further dose modification is required 
ii) if QTcF does not reduce to ≤Grade 1 by 14 days from initial 
recording, interrupt treatment for ≤14 days 
- if QTcF reduces to ≤Grade 1, no dose modification is 
required and dosing can recommence; if treatment 
interruption is required on more than 2 occasions at 
reduced dose, dose reduce by another 100 mg or 
discontinue treatment if dose reduction is not possible 
- if QTcF does not reduce to ≤Grade 1, dose reduce by 
another 100 mg or discontinue treatment if dose reduction 
is not possible 
≥Grade 3 (>501 ms)  
1st occurrence 
Interrupt treatment for ≤14 days; 


 
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QTcF 
Recommended BGB324 Dose Modification 
- if QTcF reduces to ≤Grade 1, dose reduce by 100 mg or 
discontinue treatment if dose reduction is not possible 
- if QTcF does not reduce to ≤Grade 1, discontinue treatment 
2nd occurrence  
Discontinue permanently 
Ventricular arrythmia 
1st occurrence 
Discontinue 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 
• 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 should be discussed 
with the Medical Monitor. 
 
 
 BGB324 dose modification for steroids doses over 40mg daily (prednisolone 
equivalent) 
If a patient requires prednisolone (or equivalent) at daily doses above 40mg then BGB324 
should be interrupted until the steroid dose is equivalent to or less than 40mg daily, at which 
time weekly monitoring will be undertaken until the steroid dose is equivalent or less than 
10mg (Section 10.1.8)   
 
For those patients who experience a BGB324 dose delay of ≥7 days, the BGB324 loading 
dose assigned should be repeated. If the patient was unable to tolerate the loading dose in 
Cycle 1 the repeat loading dose can be omitted. The requirement to reintroduce the loading 
dose should be discussed with the Medical Monitor. 
 
Steroid restrictions do not apply to topical/ inhaled/ eye or nasal drops. If required, additional 
advice on the concomitant use of steroids with BGB324 should be obtained from 
the BerGenBio Medical Monitor. 
 
 
 
11.3.2 Erlotinib dose reduction 
In Arm A Cycle 1, the erlotinib dose should be maintained at 150mg daily for at least 21 days, 
after which dose reductions may be made in accordance with the erlotinib prescribing 
information. 
  
In Arms B and C, erlotinib dose reductions may be made in accordance with the current 
erlotinib prescribing information. The prescribing information for erlotinib recommends a 
150mg dose for NSCLC patients, however if local clinical judgement/standards require, a 
patient in B and C may be treated at a lower erlotinib dose (i.e., 100mg). 
 
11.4 Prior and Concomitant Therapies 
No additional treatment for NSCLC may be taken during the study period. 
 
Previous adjuvant therapy is permitted provided it has been completed for ≥6 months.  
 
Previous radiotherapy for cerebral metastases is permitted providing this is completed 
≥2 weeks before the first dose of BGB324 and provided the patient is neurological stable and 
does not require corticosteroids. 
 


 
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11.5 Concomitant Medication and Procedures 
All prescription, non-prescription, or over-the-counter medications, including herbal remedies, 
taken by the patient at entry and during the study must be clearly documented in the eCRF.  
 
The patients must be instructed that no additional medication will be allowed without the prior 
consent of the Investigator. Any medication considered necessary for the patient’s safety and 
well-being may be given at the discretion of the Investigator.  
 
Hematopoietic growth factors may be administered for the treatment of AEs such as 
neutropenic infections but should not be used to maintain the dose intensity of BGB324 in the 
Run-in Cohort or Arm A.  
 
Patients who have evidence of treatment benefit after ≥1 cycle (21 days) of treatment in 
Arms B or C may receive hematopoietic growth factors to maintain BGB324 dosing. 
 
Concurrent treatment with any agent known to cause Torsade de Points is an exclusion 
criterion for the study. A comprehensive list of these prohibited medications is provided in 
Appendix 3. 
 
Anti-diarrheal medications (e.g. loperamide) may be administered according to standard 
practice for the management of diarrhea. Patients must be provided with anti-diarrheal 
medications to take home, which may be used if required. 
 
Patients being treated with antacid, histamine receptor 2 inhibitors or proton pump inhibitors 
on study entry will be excluded. The Investigator may initiate rescue treatment with these 
medications during the study, providing they are taken in the evening. 
 
Patients receiving BGB324 who require the support of prednisolone (or equivalent) at 10mg 
to 40mg daily should be monitored at weekly intervals whilst receiving treatment. If a patient 
requires prednisolone (or equivalent) at daily doses above 40mg then BGB324 should be 
interrupted until the steroid dose is equivalent or less than 40mg daily, at which time weekly 
monitoring will be undertaken until the steroid dose is equivalent or less than 10mg. 
 
 
Steroid restrictions do not apply to topical/ inhaled/ eye or nasal drops. If required, additional 
advice on the concomitant use of steroids with BGB324 should be obtained from 
the BerGenBio Medical Monitor. 
 
 
 
11.6 Discontinuation of Treatment and Withdrawal 
Patients may withdraw informed consent and discontinue from the study at any time, or for 
any reason, without prejudice to their future treatment.  
 
The reason for the patient’s withdrawal from the study must be recorded in the eCRF. 
 
A patient must be discontinued from the study if any of the following criteria are met: 
• 
Patient non-compliance with the protocol, as agreed by the Investigator and the 
Sponsor. 
• 
Patient lost to follow-up. 
• 
Termination of the study by the Sponsor. 
• 
Subject experiences an unacceptable toxicity that precludes continuation in the study, 
as agreed by the Investigator and the Sponsor. 
• 
Lack of recovery from a DLT to Grade 0 or 1 within 14 days of occurrence. 
• 
Female patient becomes pregnant. 


 
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• 
Disease progression. 
 
11.7 Patient Replacement 
Patients in Arm A who discontinue during the DLT assessment period (Cycle 1 [21 days]) for 
any reason other than a DLT will be replaced. All other patients who discontinue study 
treatment will not be replaced. 
 
 MANAGEMENT OF STUDY MEDICATIONS 
Every patient enrolled in the study will receive BGB324 as a single agent (Run-in Cohort) or 
in combination with erlotinib (Arms A, B, and C). 
 
12.1 BGB324 
Accountability for study treatment BGB324 is the responsibility of the Investigator. The 
Investigator/designee must ensure that BGB324 will be dispensed to patients in accordance 
with the protocol and that any unused BGB324 will be reconciled in accordance with written 
instructions from the Sponsor. 
 
Study staff should refer to the pharmacy manual for specific instructions regarding the 
handling, storage, dispensing of BGB324.  
 
BGB324 has been manufactured in accordance with appropriate Good Manufacturing Practice 
(GMP) standards. BGB324 will be labelled in compliance with GMP Annex 13 requirements, 
US Food and Drug Administration (FDA) requirements and local regulatory guidelines. 
 
BGB324 will be supplied in size zero Swedish orange hydroxypropyl methylcellulose (HPMC) 
capsules at a dose strength of 100 mg for oral dosing.  
 
Please refer to the current version of the IB for additional information on the physical, chemical 
and pharmaceutical properties of BGB324. 
 
12.1.1 BGB324 storage 
BGB324 will be shipped to the site and must be stored at the site in a secure location under 
ambient temperature conditions (store below 770F). The patient dosing diary will provide 
guidance for storage at home. 
 
12.1.2 BGB324 accountability 
The Investigator/designee must maintain complete and accurate accountability records for 
BGB324, showing the date of receipt and quantity of all supplies of investigational product. 
These records must include accurate patient-specific dispensing information, including 
quantity, bottles dispensed, date dispensed and quantity and date returned.  
 
At the end of the study, reconciliation must be made between the amount of BGB324 supplied, 
dispensed with reconciliation of any discrepancies. The Pharmacy manual will contain 
additional information on the reconciliation and returns procedures.  
 
12.2 Erlotinib 
Erlotinib will be stored and dispensed following institutional guidelines.  
 
The Investigator or his/her designee must maintain complete and accurate erlotinib dispensing 
logs, including the amount administered and the date. 
 
 SAFETY MONITORING AND REPORTING 
Safety assessments will consist of monitoring and recording AEs, including SAEs; 
measurement of protocol-specified clinical laboratory assessments; 12-lead ECGs 
measurement of protocol-specified vital signs; and other protocol-specified tests that are 


 
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deemed critical to safety evaluation of each patient. Certain types of events require immediate 
reporting to the Sponsor, as outlined in Section 13.5. 
 
13.1 Adverse Event Definitions 
 
13.1.1 Adverse event 
According to the International Conference on Harmonisation (ICH) guideline for GCP, an AE 
is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product, regardless of causal attribution. An AE can therefore be any of the 
following: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
• 
Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency or severity of a known condition); worsening of the patient’s underlying 
cancer is not considered an AE. 
• 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline. 
• 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug. 
• 
AEs that are related to a protocol-mandated intervention, including those that occur 
prior to assignment of study treatment (e.g., invasive screening procedures, such as 
biopsy, blood sampling). 
 
13.1.2 Serious adverse event 
An SAE is any AE that meets any of the following criteria: 
• 
Is fatal (i.e., the AE actually causes or leads to death). 
• 
Is life-threatening (i.e., the AE, in the view of the Investigator, places the patient at 
immediate risk of death). This does not include any AE that had it occurred in a more 
severe form or was allowed to continue might have caused death. 
• 
Requires or prolongs inpatient hospitalization, with exception of those events 
described in Section 13.4.7. 
• 
Results in persistent or significant disability/incapacity (i.e., the AE results in 
substantial disruption of the patient‘s ability to conduct normal life functions). 
• 
Congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study 
drug. 
• 
Is a significant medical event in the Investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above). 
 
The terms severe and serious are not synonymous. Severity refers to the intensity of an AE 
(rated as mild, moderate, severe or life threatening or according to NCI CTCAE criteria 
Version 4.03 [Appendix 4]; see Section 13.3.1). The event itself may be of relatively minor 
medical significance (such as severe headache without any further findings). Severity and 
seriousness need to be independently assessed for each AE recorded on the eCRF. 
 
SAEs must be reported by the Investigator to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event; see Section 13.5 for reporting guidelines). 
 
The Investigator is responsible for ensuring that all AEs are recorded on the AE eCRF pages 
and appropriately reported to the Sponsor in accordance with instructions provided. 
 


 
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For each AE recorded on the AE eCRF, the Investigator will make an assessment of 
seriousness, severity (see Section 13.3.1), and causality. 
 
13.2 Adverse Event Reporting Period 
The AE reporting period will begin following the first dose of BGB324 (Run-in Cohort) or 
erlotinib (Arms A, B, and C) and will end 28 days after the last dose of BGB324. If study 
drug-related toxicities continue beyond this period, patients will be followed until these 
toxicities have resolved to ≤Grade 1 or less, stabilized or returned to baseline. Any study 
drug-related SAEs will be collected indefinitely. 
 
Any SAEs occurring between informed consent and the first dose of BGB324 or erlotinib must 
also be reported to the Sponsor according to the process in Section 13.5 and also recorded 
on the eCRF if the patient receives study treatment. 
 
Investigators will seek information on AEs at each patient contact.  
 
All AEs, whether reported by the patient or noted by study personnel, will be recorded in the 
patient‘s medical record and in the AE eCRF. A consistent methodology of non-directive 
questioning should be adopted for eliciting AE information at all patient evaluation time points. 
Examples of non-directive questions include the following: 
• 
How have you felt since your last clinic visit? 
• 
Have you had any new or changed health problems since you were last here? 
 
13.3 Assessment of Adverse Events 
 
13.3.1 Assessment of severity of adverse events 
The AE severity grading scale for the NCI CTCAE Version 4.03 (Appendix 4) will be used for 
assessing AE severity.  
 
For AEs not specifically listed in the NCI CTCAE, the guidelines in Table 9 will be used for 
assessing severity. 
 
Table 9 
Guidelines for Assessment of Severity for Adverse Events not Listed in 
CTCAE 
Grade 
Guideline 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; or intervention not indicated 
Grade 2 
Moderate; minimal, local, or non-invasive intervention indicated; or 
limiting age-appropriate instrumental activities of daily livinga 
Grade 3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily livingb,c 
Grade 4 
Life-threatening consequences or urgent intervention indicatedd 
Grade 5 
Death related to adverse eventd 
a. 
Instrumental activities of daily living refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
b. 
Examples of self-care activities of daily living include bathing, dressing and undressing, feeding one's self, 
using the toilet, and taking medications, as performed by patients who are not bedridden. 
c. 
If an event is assessed as a "significant medical event," it must be reported as a serious adverse event 
per the definition of serious adverse event in Section 113.1.2. 
d. 
Grade 4 and 5 events must be reported as serious adverse events per the definition of serious adverse 
event in Section 13.1.2.  


 
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13.3.2 Assessment of causality of adverse events 
Investigators should use their knowledge of the patient, the circumstances surrounding the 
event, and an evaluation of any potential alternative causes to determine whether or not an 
AE is considered to be related to BGB324 and/or related to erlotinib indicating "suspected" or 
"not related" accordingly. The following guidance should be taken into consideration: 
• 
Temporal relationship of event onset to the initiation of study drug. 
• 
Course of the event, considering especially the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (where applicable). 
• 
Known association of the event with the study drug or with similar treatments. 
• 
Known association of the event with the disease under study. 
• 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event. 
• 
Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event. 
 
Causality will be assessed individually for each protocol-mandated treatment. 
 
13.4 Recording Adverse Events 
Investigators should use correct medical terminology and concepts when recording AEs on 
the AE eCRF. Colloquialisms and abbreviations should be avoided. 
 
Only one AE term should be recorded in the event field on the AE eCRF. 
 
A diagnosis (if known) should be recorded on the AE eCRF rather than individual signs and 
symptoms (e.g., record only liver failure or hepatitis rather than jaundice, asterixis and 
elevated transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded on the AE eCRF. If a diagnosis is subsequently 
established, all previously reported AEs based on signs and symptoms should be nullified and 
replaced by one AE report based on the single diagnosis, with a starting date that corresponds 
to the starting date of the first symptom of the eventual diagnosis. 
 
A pre-existing medical condition which is present at the start of the study and described in the 
Medical History eCRF, 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 
eCRF, it is important to convey the concept that the pre-existing condition has changed by 
including applicable descriptors (e.g. “more frequent headaches”). 
 
13.4.1 Adverse events occurring secondary to other events 
In general, AEs occurring secondary to other events (e.g., cascade events or clinical 
sequelae) should be identified by their primary cause, with the exception of severe or serious 
secondary events. However, medically significant AEs occurring secondary to an initiating 
event that are separated in time should be recorded as independent events on the AE eCRF.  
 
For example: 
• 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
• 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
• 
If a severe hemorrhage leads to renal failure, both events should be reported 
separately in the eCRF. 
• 
If dizziness leads to a fall and subsequent fracture, all 3 events should be reported 
separately on the eCRF. 


 
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• 
If neutropenia is accompanied by a mild, non-serious infection, only neutropenia 
should be reported on the eCRF. 
• 
If neutropenia is accompanied by a severe or serious infection, both events should be 
reported separately on the eCRF. 
All AEs should be recorded separately on the AE eCRF if it is unclear as to whether the events 
are associated. 
 
13.4.2 Persistent and recurrent adverse events 
A persistent AE is one that extends continuously, without resolution, between patient 
evaluation time points. Such events should only be recorded once on the AE eCRF. The initial 
severity of the event should be recorded and the severity should be updated to reflect the 
most extreme severity any time the event worsens. If the event becomes serious, the AE 
eCRF should be updated to reflect this. A recurrent AE is one that resolves between patient 
evaluation time points and subsequently recurs. Each recurrence of an AE should be recorded 
separately on the AE eCRF. 
 
13.4.3 Abnormal laboratory and ECG values  
Not every laboratory abnormality qualifies as an AE.  
 
A laboratory test result should be reported as an AE if it is assessed to be clinically significant. 
Suggested criteria for the assessment of clinical significance are: 
• 
Is accompanied by clinical symptoms. 
• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption or treatment discontinuation). 
• 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy. 
• 
Requires more frequent follow-up assessments, further diagnostic investigation, etc. 
• 
Is judged as clinically significant in the Investigator‘s opinion. 
 
Abnormal laboratory results clearly consistent with the pattern of NSCLC disease or 
progression do not need to be reported as an AE. 
 
It is the Investigator‘s responsibility to review all laboratory findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated laboratory abnormality should 
be classified as an AE. If a clinically significant laboratory abnormality is a sign of a disease 
or syndrome (e.g., alkaline phosphatase and bilirubin 5 times the ULN associated with 
cholecystitis), only the diagnosis (i.e., cholecystitis) should be recorded on the AE eCRF. If a 
clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the AE eCRF, along with a descriptor indicating if the 
test result is above or below the normal range (e.g., "elevated potassium," as opposed to 
"abnormal potassium"). If the laboratory abnormality can be characterized by a precise clinical 
term per standard definitions, the clinical term should be recorded as the AE. 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 on the AE eCRF, unless the etiology changes. The initial severity 
of the event should be recorded and the severity or seriousness should be updated any time 
the event worsens. 
 
13.4.4 Abnormal vital sign values 
Not every vital sign abnormality qualifies as an AE. A vital sign result should be reported as 
an AE if it meets any of the following criteria: 
• 
Is accompanied by clinical symptoms. 


 
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• 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption or treatment discontinuation). 
• 
Results in a medical intervention or a change in concomitant therapy. 
• 
Is judged as clinically significant in the Investigator‘s opinion. 
It is the Investigator‘s responsibility to review all vital sign findings. Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality should 
be classified as an AE. If a clinically significant vital sign abnormality is a sign of a disease or 
syndrome (e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be 
recorded on the AE eCRF. 
 
Observations of the same clinically significant vital sign abnormality from visit to visit should 
not be repeatedly recorded on the AE eCRF unless the etiology changes. The initial severity 
of the event should be recorded, and the severity or seriousness should be updated any time 
the event worsens. 
 
13.4.5 Abnormal liver function tests 
An AE meeting the following criteria should be reported to the Sponsor within 24 hours of its 
initial discovery: 
 
An increase in ALT or AST greater than 3.0 times the ULN accompanied by an increase in 
serum bilirubin at least 2.0 times the ULN or in the presence of clinical jaundice in the absence 
of any non-drug related cause such as viral hepatitis. 
 
The event must then be reported to the Regulatory Authority following the process for SAEs 
(see Section 13.6). 
 
13.4.6 Deaths 
Deaths that occur during the AE reporting period that are attributed by the Investigator solely 
to cancer progression should be recorded only on the End of Treatment eCRF and not as an 
SAE. All other on-study deaths, regardless of relationship to study drug, must be recorded on 
the AE eCRF and immediately reported to the Sponsor. Death should be considered an 
outcome and not a distinct event.  
 
The event or condition that caused or contributed to the fatal outcome should be recorded as 
the single medical concept on the AE eCRF. Generally, only 1 such event should be reported. 
The term sudden death should only be used for the occurrence of an abrupt and unexpected 
death due to presumed cardiac causes in a patient with or without pre-existing heart disease, 
within 1 hour of the onset of acute symptoms or, in the case of an unwitnessed death, within 
24 hours after the patient was last seen alive and stable. If the cause of death is unknown and 
cannot be ascertained at the time of reporting, the term unexplained death should be recorded 
on the AE eCRF. If the cause of death later becomes available (e.g., after autopsy), the term 
unexplained death should be replaced by the established cause of death. 
 
13.4.7 Hospitalization or prolonged hospitalization 
Any AE that results in hospitalization or prolonged hospitalization should be documented and 
reported as an SAE, except as outlined below. The following hospitalization scenarios are not 
considered to be SAEs: 
• 
Hospitalization for respite care. 
• 
Hospitalization for a pre-existing condition, provided that all of the following criteria are 
met: 
− 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease; 
− 
The patient has not suffered an AE. 


 
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• 
Hospitalization due solely to progression of the underlying cancer. 
 
13.4.8 Overdoses 
Study drug overdose is the accidental or intentional use of the drug in an amount higher than 
the dose being studied. An overdose or incorrect administration of study drug is not an AE 
unless it results in untoward medical effects. An overdose is defined by a boundary of 15% 
above the prescribed dose of any medicinal product. 
 
Any study drug overdose or incorrect administration of study drug should be noted on the 
Study Drug Administration eCRF. All AEs associated with an overdose or incorrect 
administration of study drug should be recorded on the AE eCRF. If the associated AE fulfills 
serious criteria, the event should be reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event).  
 
13.5 Reporting of Serious Adverse Events 
Any SAE experienced by a patient between the time of consent and 28 days after the last 
dose of BGB324 is to be recorded on an SAE Report Form within 24 hours of knowledge by 
the Investigator of its occurrence, regardless of the severity and causality of the event. Study 
drug-related SAEs should continue to be reported indefinitely.  
 
The SAE Report Form should be faxed or e-mailed to the Chiltern Pharmacovigilance Group.  
 
GlobalSAEInbox@Chiltern.com  
Fax: + 888-726-8416 
 
A telephone report may only be made in exceptional circumstances and must be followed by 
completion of the SAE Report Form within 1 working day. Where applicable, information from 
relevant hospital case records and post-mortem reports should be obtained.  
 
All SAEs that have not resolved by the EOS, or that have not resolved upon the patient’s 
discontinuation from the study, must be followed until any of the following occur: 
• 
The event resolves. 
• 
The event stabilizes. 
• 
The event returns to baseline status. 
• 
The event can be attributed to agents other than study treatment or to factors unrelated 
to study conduct.  
• 
It becomes unlikely that any additional information can be obtained.  
 
13.6 Immediate Reporting of Serious Adverse Events 
Expedited safety reporting within this clinical study complies with the ICH Guideline for Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting (E2A), 
investigational new drug (IND) application safety reporting (under 21CFR312.32), and with 
applicable local regulatory requirements. 
 
The Sponsor assumes responsibility for appropriate reporting of AEs to the Regulatory 
Authorities and Institutional Review Boards (IRB). Although this responsibility can be 
delegated to the Sponsor’s Clinical Research organization (CRO), the Sponsor retains 
ultimate responsibility for safety reporting.  
 
All SAEs that are unexpected and associated with the use of the investigational product are 
classified as suspected, unexpected serious adverse reactions (SUSARs) and will be reported 
to the IRBs, Regulatory Authorities and to all investigational sites according to local 
requirements. 
 


 
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Any safety information from other observations that could change the risk-benefit evaluation 
of BGB324 should be promptly communicated to the Regulatory Authorities and IRBs.  
 
Any other SUSARs associated with BGB324 should be reported as soon as the Sponsor 
becomes aware of them, including SUSARs which occur in another clinical study conducted 
by the same Sponsor or which are identified by spontaneous reports, a publication, or which 
are transmitted to the Sponsor by another Regulatory Authority.  
 
Other safety issues that also qualify for expedited reporting where they might materially alter 
the current benefit-risk assessment of the BGB324 (sufficient to consider changes in the 
administration or in the overall conduct of the trial), include: 
• 
An increase in the rate of occurrence of an expected serious adverse reaction, which 
is judged to be clinically important. 
• 
Post-study SUSARs that occur after the patient has completed a clinical trial and are 
reported by the Investigator to the Sponsor. 
• 
New events relating to the conduct of the trial or the development of BGB324 likely to 
affect the safety of the patients, such as: 
− 
An SAE which could be associated with study procedures and which could modify 
the conduct of the study; 
− 
A major safety finding which differs from the underlying disease. 
 
Expedited reporting is not usually required for reactions which are serious but expected, and 
it is inappropriate to report events that are considered unrelated to the investigational product. 
The cause of death of a patient in a clinical study, unless it is associated with disease 
progression, is considered a SAE whether the event is expected or associated with the 
investigational agent. 
 
13.7 Procedures for Handling Special Situations 
 
13.7.1 Pregnancy 
In the event of a pregnancy occurring in female patients, or in the partners of male patients 
during the study, the pregnancy must be reported to: 
 
the 
Chiltern 
Pharmacovigilance 
Group 
(fax 
+ 
888-726-8416 
or 
email 
GlobalSAEInbox@Chiltern.com  
 
by the investigational staff within 1 working day of their knowledge of the event using a 
Pregnancy Notification Form. 
 
The reporting period for pregnancies will start with the first administration of BGB324 and end 
28 days after the final administration of BGB324. 
 
Any female patients who become pregnant while taking part in the study will be withdrawn; a 
male patient whose partner becomes pregnant can remain in the study. Female partners of 
male patients will be asked to provide details of the pregnancy (may be subject to additional 
consent). 
 
A patient who completes or withdraws from the trial before the full term of the pregnancy will 
be asked to consent to provision of follow-up information about the pregnancy and its outcome. 
 
13.7.2 Medical emergency 
In a medical emergency requiring immediate attention, study staff will apply appropriate 
medical intervention according to standard medical practice.  
 


 
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13.8 Investigator’s Safety Responsibilities 
The Investigator’s responsibilities include the following: 
• 
Monitor and record all AEs, including SAEs, regardless of the severity or relationship 
to BGB324. 
• 
Determine the seriousness, relationship and severity of each event. 
• 
Determine the onset and resolution of each event. 
• 
Complete an SAE form for each SAE. 
• 
Pursue SAE follow-up information actively and persistently. 
• 
Ensure all AE and SAE reports are supported by documentation in the patient medical 
records. 
• 
Report SAEs to their local IRB as required by local law. 
 
13.9 Sponsor’s Safety Responsibilities 
The Sponsor’s responsibilities include the following: 
• 
Ongoing safety evaluation of BGB324. 
• 
Reporting of SUSARs to the Regulatory Authorities, main IRB and Investigators 
according to required timelines. 
• 
Submission of annual updates to the Regulatory Authorities and main IRB. 
 
 STATISTICAL CONSIDERATIONS 
Detailed statistical analysis information will be provided separately in the Statistical Analysis 
Plan. Any deviations to the planned analyses will be justified in writing and presented within 
the final clinical study report (CSR). The database lock will take place when all data are 
reconciled. A single CSR will be generated for this study. All study data will be listed. 
 
14.1 Patient Disposition, Demography and Baseline Disease Characteristics 
Patient disposition, including reason for withdrawal will be summarized by dose group.  
 
Demographics and baseline characteristics will be performed on the Safety Analysis 
Population (see Section 14.2.1). Demographics and disease baseline characteristics, 
pregnancy test results, medical history and prior medications will be tabulated. 
 
14.2 Safety 
 
14.2.1 Safety analysis population 
The Safety Analysis Population will be defined as all patients who receive at least 1 dose of 
BGB324 or erlotinib.  
  
14.2.2 Methods of analysis 
No formal statistical analysis will be performed on safety data. AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) Version 15.0 or above. The number 
and percentage of patients reporting treatment-emergent AEs will be tabulated by preferred 
term, system organ class and dose cohort, and further summarized by both CTCAE grade 
and relationship to study drug. All AEs commencing prior to dosing with study drug will be 
excluded from the tabulation but will be fully listed. AEs that have missing onset dates will be 
considered to be treatment-emergent, unless the stop date is known to be prior to the first 
administration of BGB324. 
 
Separate listings will be produced for DLTs, SAEs, discontinuations due to AEs, and events 
of ≥Grade 3 severity.  
 
Summary statistics by dose cohort and time point will be produced for vital signs, 12-lead ECG 
parameters and laboratory safety data, together with changes from baseline. The incidence 
of laboratory test results showing shifts of more than one CTCAE grade will be summarized 


 
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by dose cohort, time point and overall. Laboratory test results outside the normal range will be 
individually listed for clinical review, including clinical significance and the baseline value. 
Abnormal ECG results will be summarized by dose cohort. Changes in continuous parameters 
will be analyzed according to administered dose. 
14.3 Efficacy 
 
14.3.1 Efficacy analysis population 
The Efficacy Analysis Population will include all patients who receive ≥1 cycle of BGB324 and 
undergo a post-treatment assessment of response. 
 
Patients who on review do not meet the protocol inclusion/exclusion criteria or have a major 
protocol deviation may be excluded from the efficacy analysis. This will be reviewed on a per 
patient basis at the pre-database lock meeting. 
 
14.3.2 Methods of analysis 
Data relating to efficacy will be summarized descriptively by dose cohort and time point, as 
appropriate. 
 
Although all efficacy analysis for this study is to be regarded as essentially exploratory, there 
will be a formal hypothesis test for the objective response rate in Arm B. This will consist of 
one-sided, within-group tests of proportion of responders, against the null hypothesis of a 
response rate ≤5% (this being the observed response rate under current treatment). Values 
of p <0.2 will be taken as sufficient evidence of a trend to justify further study.  
 
14.4 Pharmacokinetics  
 
14.4.1 Pharmacokinetic analysis population 
The Pharmacokinetic Analysis Population will include those patients in the Run-in Cohort and 
Arm B who receive at least 1 dose of BGB324 and have PK data available and those patients 
in Arm A who receive at least 1 dose of BGB324 and erlotinib and have BGB324 and erlotinib 
PK data available. 
 
14.4.2 Methods of analysis 
Full details of analysis of BGB324 PK will be provided in a Pharmacokinetics Analysis Plan. 
BGB324 plasma concentration-time data will be summarized descriptively mean, standard 
deviation and coefficient of variation). Mean plasma profiles will be illustrated in graphical form. 
An appropriate PK model will be fitted to the individual plasma profiles of BGB324.  
 
Pharmacokinetic parameters of BGB324 that will be estimated are summarized in Table 10. 
These parameters will be estimated at steady state. 
 
Table 10 
BGB324 Pharmacokinetic Parameters to be Evaluated 
Cmax 
The observed maximum plasma concentration after single dose administration 
tmax 
The time to reach Cmax  
AUC0-τ 
The area under the curve within a dosing interval, calculated by the linear up-log 
down trapezoidal method. 
 
 
14.5 Pharmacodynamics 
 
14.5.1 Pharmacodynamic analysis population 
The Pharmacodynamic Analysis Population will include all patients who receive at least 1 dose 
of BGB324 and erlotinib and have at least 1 PD biomarker sample collected for analysis. 
 


 
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14.5.2 Methods of analysis 
No formal analysis of PD will be performed. Pharmacodynamic biomarker results will be 
summarized descriptively by dose cohort and timepoint as appropriate.  
 
14.6 Sample Size Considerations 
Arm A will utilize a conventional algorithm (3+3 patients per dose level) to identify the dose of 
BGB324 that can be safely given in combination with erlotinib. Escalation between dose levels 
will occur if 0/3 or 1/6 patients experiences a DLT. Under this design, there is a 71% chance 
of escalation if the true but unknown rate of DLT is 20% and <50% chance of escalation if the 
true but unknown rate of DLT is >30%. The operating characteristics of this 3+3 design are 
outlined in Table 11. 
 
Table 11 
Operating Characteristics of the 3+3 Study Design 
True but Unknown Rate of DLT (%) 
Probability of Escalation (%) 
20 
71 
30 
49 
40 
31 
50 
17 
60 
8 
 
It is anticipated that a maximum of 3 BGB324 dose levels will be evaluated, with up to 
approximately 18 patients enrolled. The total sample size in Arm A will depend upon whether 
a DLT is experienced at a given dose level (i.e., whether 3 or 6 patients have been treated) 
and how many dose levels are tested to reach the dose that can be safely administered in 
combination with erlotinib.  
 
Arm B will follow a Simon-like 2-stage design with relaxed stopping for futility to evaluate the 
PK of BGB324 ,safety and tolerability,, PD and clinical efficacy of BGB324 in combination with 
erlotinib in patients with an activating EGFR mutation(s) (including exon 19 deletion or exon 
21 [L858R] substitution or other rearrangement of the EGFR gene mutations) who have 
progressed after receiving a prior EGFR inhibitor ( i.e., erlotinib, afatinib, or gefitinib). The null 
hypothesis (H0) that the true response rate is 0.05 will be tested against a 1-sided alternative 
in the first stage, 9 patients accrued. If the number of patients with response (complete 
response or partial response) after 2 cycles or stable disease after 4 cycles is equal to zero in 
these 9 patients, the study will be stopped. Otherwise, 16 additional patients will be accrued 
for a total of 25. The null hypothesis will be rejected if 4 or more responses are observed in 
25 patients. Assuming that the stable disease rate has a uniform distribution under H0, this 
design yields a type I error rate of at most 0.73 and power of at least 0.0367 when the true 
response rate is 0.2. 
 
Arm C will evaluate the safety, PD and clinical efficacy (time to progression) of BGB324 when 
administered in combination with erlotinib in patients with activating EGFR mutation(s) 
(including exon 19 deletion or exon 21 [L858R] substitution or other rearrangement of the 
EGFR gene mutations) who have received ≥12 weeks of erlotinib without disease progression. 
Up to 5 patients will be enrolled. Arm C will recruit up to a maximum of 14 patients. Recruitment into 
Arm C may be stopped if Arm B completes recruitment or is stopped before the 14 patient target is 
reached. Patients already enrolled into Arm C will be allowed to continue in the study in accordance 
with the protocol. A statistical analysis is not planned and it is anticipated that an assessment 
of general activity will be derived from the enrolled patients; further assessment will require 
protocol amendment.  
 
14.7 Clinical Study Report 
The results of the study will be presented in an integrated CSR in accordance with ICH 
guidelines. 


 
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 ETHICAL CONSIDERATIONS 
 
15.1 Good Clinical Practice Statement  
The clinical study will be performed in accordance with the protocol, the Declaration of 
Helsinki, ICH Guidelines, GCP and all applicable local regulatory requirements.  
 
15.2 Institutional Review Board 
The final study protocol and informed consent form (ICF) must be approved, in writing, by the 
relevant IRB before patient enrollment commences. 
 
The following information should be reported to the IRB (in accordance with local 
requirements) during the study: 
• 
All amendments to the clinical research study. 
• 
Annual progress reports. 
• 
Individual SUSARs. 
• 
Urgent safety measures.  
 
15.3 Patient Information and Consent 
Prior to performing any study-related activities, including screening tests and procedures, 
written informed consent must be obtained from the patient, in accordance with local 
regulations. 
 
The ICF must be in accordance with the principles that originated in the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements and Sponsor policy and 
must be approved by the prevailing IRB for each study center. 
 
15.4 Subject Data Protection 
Personally identifiable information, i.e., identifiable information from or about an individual 
subject, will not be collected by the Sponsor. The collection and processing of data from 
patients enrolled in this study will be limited to those data that are necessary to investigate the 
clinical activity, safety, tolerability, quality and utility of the study drug used in this study. These 
data must be collected and processed with adequate precautions to ensure confidentiality and 
compliance with applicable data privacy protection laws and regulations.  
 
The ICF must explain that identifying information will be kept by the Investigator on file and 
that portions of the patient’s medical records pertinent to the study will be reviewed by Sponsor 
personnel (or their designees) and possibly by Regulatory Agencies and the IRB for data 
verification purposes.  
 
 ADMINISTRATIVE PROCEDURES 
 
16.1 Quality Assurance 
In compliance with GCP and regulatory requirements, the Sponsor/designee, external 
Regulatory Agency and/or /IRB may conduct quality assurance (QA) audits at any time during 
or following completion of the study. The Investigator will be expected to cooperate with any 
audit and to provide assistance and documentation (including source data) as requested. 
 
16.2 Case Report Form and Source Document Verification 
Electronic CRFs will be provided for recording clinical data. Designated site personnel will 
record data in the eCRF for observations, tests and assessments as specified in the protocol. 
The Sponsor will provide eCRF completion guidelines to assist site personnel. 
 
 Data required for the eCRF should be completed in a timely manner so as to aide Sponsor 
and CRO management.  


 
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The Investigator must permit the Sponsor/designee reasonable direct access to designated 
source documentation (e.g., medical records) for the purpose of verifying that the data 
recorded in the eCRF are consistent with the original source data.  
 
16.3 Study Monitoring 
Before a patient can be screened for enrollment into the study, the Sponsor/designee will 
conduct a study initiation visit to: 
• 
Determine that site facilities are adequate. 
• 
Discuss responsibilities with regard to the protocol with the Investigator and the study 
team. 
• 
Conduct training on completion of the eCRF and other study- related documentation. 
• 
Review study procedures. 
 
During the conduct of the study, the Sponsor/designee will provide ongoing support to the 
Investigator and study team. The Sponsor/designee will conduct regular site visits, according 
to applicable ICH and GCP guidelines, to: 
• 
Confirm the facilities remain acceptable. 
• 
Confirm the site study team is adhering to the protocol and regulatory requirements. 
• 
Confirm that the investigational product is being properly maintained and accountability 
records are accurate and current. 
• 
Confirm data are being accurately recorded in the eCRF by performing source 
document verification. 
• 
To intervene and stop any serious protocol non-compliance by a site and if required 
report to IRB and the Regulatory Authority. 
 
16.4 Retention of Study Data 
A copy of all records and essential documents must be retained in the study files for a 
minimum of 2 years following the last approval of the drug in an ICH region and until there are 
no pending or contemplated marketing applications in an ICH region, or a minimum of 2 years 
have elapsed since the formal discontinuation of the clinical development of the drug. No 
documents should be destroyed without prior written agreement between the Sponsor and the 
Investigator and/or clinical site. 
 
Should the Investigator wish to assign the documents to another party or move them to 
another location, prior approval of the Sponsor must be obtained. The Sponsor will notify the 
Investigator in writing when any study-related documents are no longer needed. 
 
16.5 Use of Information and Publication Policy 
All information regarding BGB324 and the Sponsor’s operations (e.g., patent applications, 
formulas, manufacturing processes, basic scientific data, or formulation information) supplied 
by the Sponsor to the Investigator and not previously published is considered confidential. 
This confidential information remains the sole property of the Sponsor and shall not be 
disclosed to others without the written consent of the Sponsor. The Investigator agrees to use 
this information only to perform this study and will not use it for other purposes, including 
publication or presentation without the Sponsor’s written consent. The full terms of 
confidentiality, intellectual property and publication policy are detailed in the current Clinical 
Trial Agreement between the Sponsor and the site.  
 
16.5.1 Clinical research organizations 
Monitoring, data management, statistics and programming, pharmacovigilance, medical 
writing, auditing and QA services will be outsourced to the Sponsor’s CRO. 
 


 
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Pharmacokinetic and pharmacodynamic analyses will be outsourced to the Sponsor’s 
bioanalytical services vendors. 
 
16.5.2 Changes to the final study protocol 
All protocol amendments must be submitted to the IRB and Regulatory Authorities.  
 
Protocol amendments that affect patient safety, the scope of the investigation, or the scientific 
quality of the study should not be implemented without prior IRB approval, except where 
necessary to eliminate immediate hazards to the patients. 
 
16.5.3 Investigator responsibilities 
By signing the protocol the Investigator agrees to: 
• 
Conduct the study in accordance with the protocol and make changes only after so 
directed by the Sponsor, except to protect the safety, rights or welfare of patients. 
• 
Personally conduct or supervise the study. 
• 
Inform any patients enrolled in the study that BGB324 is being used for investigational 
purposes. 
• 
Ensure that the requirements relating to obtaining informed consent and IRB review 
and approval meet federal guidelines, as stated in 21CFR50 and 21CFR56. 
• 
Report to the Sponsor any AEs that occur during the course of the study, in accordance 
with 21CFR312.32, as well as ICH guidelines. 
• 
Have read and understood the Investigator’s Brochure for BGB324, including potential 
risks and side effects of the drug. 
• 
Maintain adequate and accurate records, in accordance with 21CFR312.62 and to 
make those records available for inspection by the Sponsor, its designated 
representatives, relevant Regulatory Authorities, the IRB or any agency authorized by 
law. 
• 
Ensure that an IRB that complies with the requirements of 21CFR56 will be responsible 
for initial and continuing review of the clinical study. 
• 
Report promptly to the IRB and the Sponsor all changes in the research activity and 
all unanticipated problems involving risks to patients or others (to include protocol 
amendments and IND safety reports). 
• 
Not make any changes in the research study without approval, except when necessary 
to eliminate hazards to the subject/subjects. 
• 
Comply with all other requirements regarding the obligations of Clinical Investigators 
and all other pertinent requirements listed in 21CFR312. 
• 
Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments. 
• 
Enter data collected from patients into the eCRF as soon as possible i.e. within 
5 working days of the respective visit. 
 
 


 
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 REFERENCES 
Alvarez H, Montgomery EA, Karikari C, et al. The Axl receptor tyrosine kinase is an adverse 
prognostic factor and a therapeutic target in oesophageal adenocarcinoma Cancer Biol 
Ther. 2010 10(10):1009–1018. 
 
Brand T, Lida M, Stein A, et al. Axl mediates resistance to Cetuximab therapy. Cancer Res. 
2014 74(18): 5152-5164. 
 
Byers LA, Diao L. Wang J, et al. An epithelial-mesenchymal transition gene signature predicts 
resistance to EGFR and PI3K inhibitors and identifies Axl as a therapeutic target for 
overcoming EGFR inhibitor resistance. Clin. Cancer Res. 2013 19:279-290. 
 
Eisenhauer EA, Therasse P, Bogaerts J, et al. Revised RECIST guideline (version 1.1). Eur. 
J. Cancer 2009 45: 228-247.  
 
Ishikawa M, Sonobe M, Nakayama E, et al. Higher Expression of Receptor Tyrosine Kinase 
Axl, and Differential Expression of its Ligand, Gas6, Predict Poor Survival in Lung 
Adenocarcinoma Patients. Ann Surg Oncol. 2013 Dec;20 Suppl 3: S467-478. 
 
Korshunov VA. Axl-dependent signalling: a clinical update. Clin. Sci. (Lond). 2012 
122:361-368. 
 
Linger RM, Keating AK, Earp HS, Graham DK. TAM receptor tyrosine kinases: biologic 
functions, signalling, and potential therapeutic targeting in human cancer. Adv Cancer Res 
2008 100:35–83. 
 
Liu L, Greger J, Shi H, et al. Novel mechanism of lapatinib resistance in HER2-positive breast 
tumor cells: activation of AXL. Cancer Res. 2009 69:6871-6878. 
 
National Comprehensive Cancer Network Treatment Guidelines V4.2014 Non-Small Cell 
Lung Cancer. www. NCCN.org 
 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982 5: 649–655. 
 
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. 
 
Zhang Z, Lee JC, Lin L, et al. Activation of the AXL kinase causes resistance to EGFR-targeted 
therapy in lung cancer. Nat. Genet. 2012 44:852-860.  
 
Thiele S et al. Instructions for producing a mouse model of glucocorticoid-induced 
osteoporosis BoneKey Reports July 2014; 552:47 
 
 
 
 


 
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 APPENDICES 
Appendix 1 
ECOG Performance Status Scale 
Grade 
ECOG Performance Status 
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 selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed 
or chair 
5 
Dead 
 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol (1982) 5: 649 – 655. 
 
 


 
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Appendix 2 The NYHA Functional Classification in a Subject with Heart Disease 
Overview: The NYHA developed a functional classification for subjects with heart disease.  
Subjects: Heart disease must be present.  
Parameters:  
• 
Limitations on physical activity  
Symptoms (undue fatigue palpitations dyspnea and/or anginal pain) with ordinary physical 
activity  
• 
Status at rest 
 
Functional Capacity 
Objective Assessment 
Class I. Patients with cardiac disease but without 
resulting limitation of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
A. No objective evidence of 
cardiovascular disease. 
Class II. Patients with cardiac disease resulting in slight 
limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, 
palpitation, dyspnea, or anginal pain. 
B. Objective evidence of 
minimal cardiovascular 
disease. 
Class III. Patients with cardiac disease resulting in 
marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes 
fatigue, palpitation, dyspnea, or anginal pain. 
C. Objective evidence of 
moderately severe 
cardiovascular disease. 
Class IV. Patients with cardiac disease resulting in 
inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or the anginal 
syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased. 
D. Objective evidence of 
severe cardiovascular 
disease. 
 
http://my.americanheart.org/professional/StatementsGuidelines/ByPublicationDate/PreviousYears/Classification-
of-Functional-Capacity-and-Objective-Assessment_UCM_423811_Article.jsp#.VsXt6ZOLR-U 
 
 


 
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Appendix 3 Drugs that are Generally Accepted to Have a Risk of Causing Torsades 
de Pointes 
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 
Thioridazine 
Mellaril 
Vandetanib 
Zactima 
Adapted from “The University of Arizona Center for Education and Research on Therapeutics.” 
See the following website for an updated list of drugs that cause Torsades de Pointes: 
www.AZCERT.org 
 
 


 
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Appendix 4 
NCI CTCAE, Version 4.03 
NCI CTCAE Version 4.03 of the, dated 14 June 2010, may be found at the following website: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
 

SAP_001.pdf: 
Protocol: BGBC004 
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BerGenBio ASA 
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Statistical Analysis Plan 
 
 
BerGenBio ASA 
 
 
 
 
Protocol: BGBC004 
 
IND Number: 124645 
 
Investigational Product: BGB324 
 
 
A Multi-Center Open-Label Phase 1/2 Study of 
BGB324 in Combination with Erlotinib in Patients with 
Stage IIIb or Stage IV Non-Small Cell Lung Cancer 
 
 
Author(s): 
Document Status: 
Version 1 Draft 1: 28JUL2017 
Version Dates: 
Version 1 Draft 2: 15NOV2019 
Version 1 Draft 3: 23DEC2020 
Version 1 Draft 4: 07MAY2021 
Version 1 Final Draft: 13SEP2021 
Version 1 Final: 11OCT2021 
Pages: 
34 
 
 
 
 
PPD
CCI


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Contents 
ABBREVIATIONS .................................................................................................................. 4 
1 
INTRODUCTION............................................................................................................ 6 
2 
STUDY OBJECTIVES .................................................................................................... 6 
2.1 
RUN-IN COHORT (PHASE 1) ........................................................................................ 6 
2.1.1 Primary Objective .................................................................................................. 6 
2.2 
ARM A (PHASE 1) ....................................................................................................... 6 
2.2.1 Primary Objective .................................................................................................. 6 
2.2.2 Secondary Objectives ............................................................................................. 6 
2.2.3 Exploratory Objective ............................................................................................ 6 
2.3 
ARM B (PHASE 2)........................................................................................................ 6 
2.3.1 Primary objective ................................................................................................... 6 
2.3.2 Secondary Objectives ............................................................................................. 6 
2.3.3 Exploratory objectives ........................................................................................... 7 
2.4 
ARM C (PHASE 2)........................................................................................................ 7 
2.4.1 Primary Objective .................................................................................................. 7 
2.4.2 Secondary Objectives ............................................................................................. 7 
2.4.3 Exploratory Objectives .......................................................................................... 7 
3 
END-POINTS ................................................................................................................... 7 
3.1 
SAFETY END-POINTS ................................................................................................... 7 
3.2 
EFFICACY END-POINTS ............................................................................................... 8 
3.2.1 Objective Response Rate (ORR) ............................................................................... 8 
3.2.2 Best Percentage change in target lesion ................................................................... 9 
3.2.3 Time To Progression (TTP) ...................................................................................... 9 
3.3 
PHARMACOKINETIC END-POINTS .............................................................................. 10 
3.4 
PHARMACODYNAMIC END-POINTS ............................................................................ 10 
4 
STUDY DESIGN ............................................................................................................ 10 
4.1 
DISCUSSION OF STUDY DESIGN ................................................................................. 10 
4.2 
STUDY TREATMENT .................................................................................................. 12 
4.2.1 Treatment Schedule and Administration of BGB324 ........................................... 12 
4.2.2 Treatment Schedule and Administration of Erlotinib .......................................... 12 
4.3 
STUDY SCHEDULE ..................................................................................................... 13 
4.3.1 Screening.............................................................................................................. 13 
4.3.2 Treatment ............................................................................................................. 13 
4.3.3 End of Study Visit ................................................................................................. 14 
4.4 
CONCOMITANT MEDICATION .................................................................................... 18 
4.4.1 Prior and Concomitant Therapies ....................................................................... 18 
4.4.2 Concomitant Medication and Procedures ........................................................... 18 
4.5 
STUDY ANALYSIS POPULATIONS ............................................................................... 19 
4.5.1 Enrolled Population ............................................................................................. 19 
4.5.2 Safety Population ................................................................................................. 19 
4.5.3 Efficacy Population .............................................................................................. 19 
4.6 
WITHDRAWN SUBJECTS ............................................................................................ 19 
4.7 
RANDOMISATION ...................................................................................................... 19 
4.8 
BLINDING .................................................................................................................. 19 
4.9 
SAMPLE SIZE ............................................................................................................. 19 


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5 
STATISTICAL METHODOLOGY............................................................................. 21 
5.1 
PLANNED ANALYSES ................................................................................................ 21 
5.2 
INTERIM ANALYSIS ................................................................................................... 21 
5.3 
DISPOSITION OF SUBJECTS ........................................................................................ 21 
5.4 
BASELINE AND DEMOGRAPHIC CHARACTERISTICS ................................................... 21 
5.5 
CONCOMITANT MEDICATION .................................................................................... 22 
5.6 
EXPOSURE AND COMPLIANCE ................................................................................... 22 
5.7 
EFFICACY ANALYSIS ................................................................................................. 22 
5.7.1 Normality assumption checking ........................................................................... 22 
5.7.2 Closed testing procedure for primary analysis .................................................... 22 
5.7.3 Method of analysis for efficacy outcome ............................................................. 22 
5.7.3.1 
Objective Response Rate (ORR) ................................................................. 22 
5.7.3.2 
Time to progression (TTP)........................................................................... 23 
5.8 
SAFETY ANALYSIS .................................................................................................... 23 
5.8.1 Adverse events ...................................................................................................... 24 
5.8.1.1 
Subsets ......................................................................................................... 24 
5.8.2 Physical Examination .......................................................................................... 25 
5.8.3 Vital Signs ............................................................................................................ 25 
5.8.4 Eastern Cooperative Oncology Group ................................................................ 25 
5.8.5 Electrocardiograms ............................................................................................. 25 
5.8.6 Laboratory findings ............................................................................................. 25 
5.9 
PHARMACOKINETIC ANALYSIS ................................................................................. 26 
5.10 
PHARMACODYNAMIC ANALYSIS ............................................................................... 26 
5.11 
PROTOCOL DEVIATIONS ............................................................................................ 26 
5.12 
MISSING VALUES – MISSING VISITS ......................................................................... 27 
5.13 
DEVIATIONS FROM SAP ............................................................................................ 27 
5.14 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL ................... 27 
5.15 
ALGORITHMS/SAS CODES ........................................................................................ 28 
6 
TABLES AND LISTINGS ............................................................................................ 29 
6.1 
TABLE FORMAT ........................................................................................................ 29 
6.2 
CONVENTIONS .......................................................................................................... 29 
6.1 
TABLES ..................................................................................................................... 30 
6.1.1 Section 14.1: Demographic and baseline ............................................................ 30 
6.1.2 Section 14.2: Primary and secondary .................................................................. 30 
6.1.3 Section 14.3: Safety .............................................................................................. 30 
6.1.3.1 
Adverse events ............................................................................................. 30 
6.1.3.2 
Laboratory results ........................................................................................ 31 
6.1.3.3 
Vital signs .................................................................................................... 31 
6.1.3.4 
ECG.............................................................................................................. 31 
6.1.3.5 
ECOG Performance Status .......................................................................... 31 
6.2 
LISTINGS ................................................................................................................... 32 
6.3 
FIGURES .................................................................................................................... 33 
6.4 
REFERENCES ............................................................................................................. 34 
 
 
 


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Abbreviations 
 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase  
AML 
Acute myeloid leukemia 
APTT 
Activated Partial Thromboplastin Time 
Ara-C 
Cytosine arabinoside 
AST 
Aspartate Aminotransferase 
BM 
Bone marrow 
BP 
Blood Pressure 
bpm 
Beats per minute 
BOR 
Best Overall Response 
BUN 
Blood Urea Nitrogen 
°C 
Celsius  
CI 
Confidential Interval 
cm 
Centimeter 
CRF 
Case Report Form 
CR 
Complete Response 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
HR 
Heart rate 
INR 
International Normalized Ratio 
IWG 
International Working Group 
kg 
Kilogram 
Max 
Maximum 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MDS 
Myelodysplastic Syndrome 
MedDRA  
Medical Dictionary for Regulatory Activities  
Min 
Minimum 
mmHg 
millimeter of mercury 
MTD 
Maximum tolerated dose 
MUGA 
Multigated Acquisition  
NA 
Not Applicable 
NCI 
National Cancer Institute 
NE 
Not Evaluable 
ORR 
Objective response rate 
PD 
Pharmacodynamic, Progressive Disease 
PK 
Pharmacokinetic 
PR 
Partial Response 
PT 
Prothrombin Time 
RBC 
Red Blood Cells 
RECIST  
Response Evaluation Criteria In Solid Tumours version  


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RP2D 
Recommended Phase II Dose  
SAE 
 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation, Stable Disease 
STLM 
Sum of Target Lesion Measurements  
SMC 
Safety Monitoring Committee 
TEAE 
Treatment-Emergent Adverse Event 
TTP 
Time To Progression 
WHO 
World Health Organization 
WBC 
White Blood Cells 
 


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1 Introduction 
This document presents the statistical analysis plan (SAP) for BerGenBio ASA, Protocol No. 
BGBC004: A Multi-Center Open-Label Phase 1/2 Study of BGB324 in Combination with 
Erlotinib in Patients with Stage IIIb or Stage IV Non-Small Cell Lung Cancer (NSCLC). This 
Statistical analysis plan (SAP) is based on the final protocol dated 16 May 2017 (Version 
5.0).  
This study is designed primarily to evaluate the safety of the Axl inhibitor BGB324 when 
administered as monotherapy, and to establish the recommended Phase 2 dose (RP2D) of the 
combination of BGB324 and erlotinib in patients with Stage IIIb or Stage IV NSCLC. 
 
2 Study Objectives 
2.1 Run-In Cohort (Phase 1) 
2.1.1 Primary Objective 
To explore the safety and tolerability of single agent BGB324 in patients with NSCLC. 
2.2 Arm A (Phase 1) 
2.2.1 Primary Objective 
 To identify the RP2D of BGB324 administered in combination with erlotinib in 
patients with NSCLC 
2.2.2 Secondary Objectives 
The secondary objectives are: 
 To explore the safety and tolerability of BGB324 administered in combination with 
erlotinib in patients with NSCLC. 
 To identify the dose limiting toxicity (DLT) profile of BGB324 administered in 
combination with erlotinib in this population. 
 To assess the pharmacokinetics (PK) of BGB324 and erlotinib and the potential effect 
of BGB324 on erlotinib. 
2.2.3 Exploratory Objective 
 To evaluate the pharmacodynamics (PD) effects of BGB324 administered in 
combination with erlotinib. 
2.3 Arm B (Phase 2) 
2.3.1 Primary objective 
 To explore the safety and tolerability of the combination of BGB324 and erlotinib in 
patients with NSCLC with an activating Epidermal Growth Factor Receptor (EGFR) 
mutation and who have progressed after receiving an approved EGFR inhibitor (i.e., 
prior erlotinib, afatinib or gefitinib). 
2.3.2 Secondary Objectives 
The secondary objectives are: 
 To assess the PK of BGB324. 


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 To explore the clinical efficacy of the combination of BGB324 and erlotinib in this 
setting. 
2.3.3 Exploratory objectives 
The exploratory objectives are: 
 To evaluate the PD effects of BGB324 administered in combination with erlotinib. 
 To investigate any correlation between the PD effects of BGB324 administered in 
combination with erlotinib and clinical efficacy. 
2.4 Arm C (Phase 2) 
2.4.1 Primary Objective 
 To explore the safety and tolerability of the combination of BGB324 and erlotinib in 
the first-line setting in patients with advanced NSCLC with an activating EGFR 
mutation. 
2.4.2 Secondary Objectives 
 To explore the time to progression of the combination of BGB324 and erlotinib in this 
setting. 
2.4.3 Exploratory Objectives 
The exploratory objectives are: 
 To evaluate the PD effects of BGB324 administered in combination with erlotinib. 
 To investigate any correlation between the PD effects of BGB324 administered in 
combination with erlotinib and clinical efficacy. 
 
3 End-points 
3.1 Safety End-points 
Safety and tolerability will be assessed by conducting the following safety assessments at 
pre-defined time-points during the study: 
 Treatment emergent adverse events (TEAE) 
 Physical examination 
 Vital signs including blood pressure (BP), heart rate (HR) 
 Electrocardiogram (ECG) or multi-gated acquisition (MUGA) scan 
 12-lead triplicate ECG 
 Clinical laboratory parameters including clinical chemistry, hematology coagulation 
and urinalysis 
 Eastern Co-operative Oncology Group (ECOG) performance status 
The primary objective of Arm A is to identify the RP2D of BGB324 administered in 
combination with erlotinib in patients with NSCLC.  This will be accomplished by evaluation 
of the safety and occurrence of DLTs at each dose level. 


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AEs will be assessed using the National Cancer Institute (NCI) Common Toxicity Criteria for 
Adverse Events (CTCAE) Version 4.03 criteria during the first cycle (21 days) of treatment 
for the purposes of establishing the dose of BGB324 that can safely be given in combination 
with erlotinib.  
DLTs will include: 
 Any non-hematological toxicity ≥Grade 3 except Grade 3 nausea, vomiting or 
diarrhea that resolves within 72 hours with optimal therapy; 
 Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding. 
 Grade 4 neutropenia persisting for ≥5 days or Grade 3 or 4 febrile neutropenia. 
 Treatment discontinuation or dose reduction for >72 hours during the first cycle as a 
result of treatment-related toxicity. 
A patient must receive all loading doses and miss no more than 3 daily doses in Cycle 1 (21 
day cycle of treatment) to be considered as informative to support dose escalation, unless the 
inability to administer BGB324 was a result of treatment-related toxicity. 
If 1 patient in a cohort experiences a DLT during Cycle 1, the cohort will be expanded to 6 
patients. If 2 of 3 or 2 of 6 patients in a cohort experience DLT, no further dose-escalation 
will take place and the prior dose level will be nominated as the RP2D (see section 8.3.2 of 
the protocol). 
 
3.2 Efficacy End-points 
Disease assessment will be performed after every two cycles (6 weeks) of treatment prior to 
administering study drug in the subsequent cycle. The frequency of scans may be extended to 
the end of every three cycles after 12 weeks (4 cycles) and every 4 cycles after 24 weeks (8 
cycles). Patients who remain on treatment for 12 months or longer may have their scans 
extended to a frequency of 6 months, unless disease progression is suspected in which case a 
scan should be conducted at an earlier time point. 
Clinical efficacy will be assessed using the Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1. Clinical efficacy endpoints will include time to progression. 
3.2.1 Objective Response Rate (ORR)  
Patients included in the study must be assessed for response to treatment, Overall Response 
(OR) determined by Investigator based on appropriate radiographic imaging and consistent 
with RECIST 1.1. 
Each patient will be assigned to one of the following ordered categories for OR (from best to 
worst responses): Complete response (CR), Partial response (PR), Stable disease (SD), 
Progressive disease, Not Evaluable (NE) or Not Applicable at each timepoint. 
The Best Overall Response (BOR) is determined once all the data for the patient is known 
and is defined as the best overall response recorded from the initiation of treatment until 
disease progression or date of subsequent therapy across all tumour assessment. 
ORR defined as percentage of patients with a BOR assessed as CR or PR, i.e. patients with 
response, divided by the number of patients in efficacy population. 


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The one-sided, within-group tests of proportion of responders, against the null hypothesis of a 
response rate ≤5% (this being the observed response rate under current treatment). Values of 
p <0.2 will be taken as sufficient evidence of a trend to justify further study. 
For analysis of the ORR, summary tables will be generated, presenting the number and 
percentage of responders (i.e. patients with CR or PR) and non-responders in efficacy 
population.  
3.2.2 Best Percentage change in target lesion 
Percentage change in target lesion size from baseline across all tumour assessment, where 
target lesion size is measured by the sum of the product of diameters of all target lesion sizes 
by the Investigator. 
The Best percentage change is largest percentage change across all tumour assessment. 
 Patients who die due to progression of their disease prior to the first planned protocol 
assessment of response will be considered as having BOR of PD. 
The first response assessed during the follow-up period will be used to confirm any previous 
CR or PR observed during the treatment period, provided that no new anti-tumoral treatment 
has been initiated during the follow-up period. 
3.2.3 Time To Progression (TTP)  
- 
The Time to Progression (TTP) will be calculated as the number of days from the date 
of first administration of BGB324 to the date of radiological progression of disease first 
observed, according to the overall response evaluation (progressive disease, 
measurement proven or progressive disease, symptomatic deterioration). If a subject 
died without any radiological assessment, the progressive disease date is date of death; 
Patients who do not have progressive disease at the end of study or withdrawal will have their 
TPP censored. In these patients, the censoring date is defined as the last date on which 
progression status was assessed.  Censoring general rules for TTP are provided within Table 
1 below. 


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Table 1: Censoring Rules for TTP 
Reason for censoring 
Rule 
No baseline evaluable or post-baseline 
radiological assessment 
Date of first treatment administration 
Two or more not evaluable (NE) protocol 
specified assessments, i.e. scheduled 
assessments, before progressive disease  
Date of last evaluable disease protocol 
specified assessment before the second 
protocol specified NE assessment 
No progressive disease 
Date of last evaluable radiological 
assessment 
Treatment discontinuation for 
undocumented progression 
Date of last evaluable radiological 
assessment 
Treatment discontinuation for toxicity or 
other reason 
Date of last evaluable radiological 
assessment 
* An assessment is considered NE when no imaging/measurement is done at all at a particular time point, or 
only a subset of lesion measurements are made at the time point. The participant is considered NE at that time 
point. 
3.3 Pharmacokinetic End-points 
Pharmacokinetic analysis will be managed by Bergen Bio then will not be part of this SAP. 
3.4 Pharmacodynamic End-points 
Pharmacodynamic analysis will be managed by Bergen Bio then will not be part of this SAP. 
4 Study Design 
4.1 Discussion of Study Design 
This is a multi-center open-label Phase 1/2 study of BGB324 as a single agent (Run-in 
Cohort) and in combination with erlotinib (Arms A, B and C) in patients with Stage IIIb or 
Stage IV NSCLC.  
At time of amendment 5, patient recruitment into the Run-In cohort (BGB324 monotherapy) 
and Arm A (BGB324 dose escalation in combination with erlotinib) has completed and the 
RP2D has been confirmed. Patients that remain on treatment in the Run-In cohort or Arm A 
must be followed up in accordance with the protocol schedule. 
This study is anticipated to be conducted at approximately 10 sites in the US and in Europe 
(the number of sites and the involvement of European sites may be revised to reflect changes 
in recruitment rates), and will enroll up to approximately 60 patients with histologically- or 
cytologically-confirmed Stage IIIb or Stage IV NSCLC.  
It is anticipated that up to six patients will be enrolled in the Run-in Cohort, 18 patients in 
Arm A, up to 25 patients in Arm B, and up to 14 patients in Arm C. Recruitment into Arm C 
may be stopped if Arm B completes recruitment or is stopped before the 14 patient target is 
reached. Patients already enrolled into Arm C at that time will be allowed to continue in the 
study in accordance with the protocol. 
Prior to starting dosing of BGB324 in combination with erlotinib, the safety and tolerability 
of single agent BGB324 will be assessed in the Run-in Cohort (Phase 1) in patients who have 
either exhausted existing licensed therapies or are unsuitable for existing licensed therapies 


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for NSCLC. A minimum of 6 patients must each receive at least 1 continuous 21-day cycle of 
BGB324 before enrolment into Arm A can commence. 
Arm A (Phase 1) incorporates a standard 3+3 design to determine the dose of BGB324 that 
can be safety administered in combination with erlotinib in patients who have received prior 
treatment with erlotinib. To confirm the RP2D for Arms B and C, loading dose schedules, 
loading doses and daily dose levels will be explored in Arm A. Dosing schedules will be 
revised in response to reported toxicities, DLT experience and SMC recommendations (Table 
4 of the protocol). 
When the RP2D dose of BGB324 is identified and the dose of erlotinib to be administered in 
combination with BGB324 is confirmed, the Phase 2 part of the study will start and Arms B 
and C will open simultaneously to enrolment.  
Arm B will incorporate a two-stage design to evaluate the safety and tolerability, 
pharmacokinetics, pharmacodynamics and clinical activity of BGB324 in combination with 
erlotinib in patients with an activating EGFR mutation (including exon 19 deletion or exon 21 
[L858R] substitution or other rearrangement of the EGFR gene) who are T790M negative 
and who have progressed after receiving treatment with an approved EGFR inhibitor (i.e. 
erlotinib, afatinib or gefitinib). Patients who have previously been treated with a T790M 
inhibitor (i.e. osimertinib) and who subsequently progressed will not require T790M testing. 
Arm C will evaluate the safety and tolerability, PD and clinical activity (time to progression) 
of BGB324 when administered in combination with erlotinib in patients with an activating 
EGFR mutation (including exon 19 deletion or exon 21 [L858R] substitution or 
rearrangement of the EGFR gene mutation) who have received ≥12 weeks treatment with 
erlotinib without disease progression. 
In all parts of the study, BGB324 will be self-administered orally according to a daily 
schedule during continuous 21-day treatment cycles. 
Erlotinib will be self-administered orally according to a daily schedule during continuous 21-
day treatment cycles (Arms A, B and C only). 
Both drugs will be taken with water in the morning. BGB324 should be administered in the 
hour following erlotinib administration and at least 2 hours before breakfast. 
Patients will be allowed to continue BGB324 treatment (as a single agent or in combination 
with erlotinib) if, in the opinion of the Investigator, they continue to derive clinical benefit or 
until unacceptable toxicity, disease progression, death or withdrawal of consent. Patients who 
stop BGB324 treatment will be withdrawn from the study. 
An outline of the study design is provided in Figure 1. 


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Figure 1: BGB004 study Design Outline 
4.2 Study Treatment 
BerGenBio ASA will provide BGB324 to each study site. 
Erlotinib will be obtained and administered following institutional practices. 
4.2.1 Treatment Schedule and Administration of BGB324  
BGB324 will be self-administered orally on an empty stomach according to a daily schedule 
during continuous 21-day treatment cycles. 
The BGB324 dose will be based on the cohort and study arm to which the patient is enrolled. 
BGB324 should be administered with water in the morning at least 2 hours before breakfast 
and best efforts should be made to administer BGB324 at the same time each day, other than 
study visit days when BGB324 should be administered during the visit. 
Patients will record their dosing at home in a dosing diary that will be reviewed at each study 
visit by the site staff. Patients will be instructed as to the importance of following the dosing 
instructions they have been provided with and for maintaining an accurate and up-to-date 
dosing record. Patients will also be instructed to bring their dosing diary and all BGB324 
bottles, including unused and empty bottles, with them to each study visit. The site staff will 
record the amount of used and unused BGB324 capsules at study visits. 
4.2.2 Treatment Schedule and Administration of Erlotinib 
Erlotinib will be self-administered orally with BGB324 on an empty stomach according to a 
daily schedule during continuous 21-day treatment cycles. Best efforts should be made to 
administer erlotinib in the morning at the same time each day, other than on the morning of 
study visit days when erlotinib should be administered during the visit. Erlotinib should be 
administered with water. Patients will be instructed to take their erlotinib dose first followed 
by BGB324 within the next hour. 
Phase I- BGB324 Monotherapy and BGB324 Dose Escalation 
Phase II- BGB324 in Combination with Erlotinib 
NSCLC III-IV 
EGFR+VE 
Monotherapy 
Dose escalation (3+3) + 
erlotinib 
Arm A (dose 
escalation) 
BGC324+ erlotinib 
(n=18) 
Run in (monotherapy) 
600/200 (n=6) 
Safety/ 
tolerability of 
single agent 
Safety/ 
tolerability of 
combination  
RP2D 
confirmation 
NSCLC III-IV 
EGFR+VE 
Progressive disease 
First line setting 
RP2D 
Arm B (progressive 
disease) 
RP2D + erlotinib  
Arm C (first line setting) 
RP2D+erlotinib (n=5) 
Safety  
Tolerability  
Clinical activity 
Time to progression 


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Patients will record their dosing at home in a dosing diary that will be reviewed at each study 
visit by the site staff. Patients will be instructed as to the importance of following the dosing 
instructions they have been provided with and for maintaining an accurate and up-to-date 
dosing record. Patients will also be instructed to bring their dosing diary and all boxes of 
erlotinib, including unused and empty boxes, with them to each study visit. The site staff will 
record the amount of used and unused erlotinib at study visits. 
The details for management of dose modification are specified in the protocol section 11.3.  
4.3 Study Schedule 
The study period will consist of screening, treatment and an end-of-study visit. The end-of-
study visit will occur 28 days after the patient has discontinued BGB324 treatment. 
A detailed Schedule of Events can be found in the study protocol, Section 10. 
Table 2 provide the study schedule.  
4.3.1 Screening 
Patient eligibility for the study will be determined within 28 days prior to the first dose of 
BGB324 (Cycle 1 Day 1). Screening assessments will be conducted according to the study 
protocol Section 10.1.1 and Table 5. 
In Arm B, the screening period may be extended to accommodate T790M confirmation from 
tumor biopsy Patients who have previously been treated with a T790M inhibitor (i.e., 
osimertinib) and who subsequently progressed will not require T790M testing. All other 
assessments including scans should be conducted in the 28-day screening period.  
4.3.2 Treatment  
Eligible patients will visit the study site to receive study drug and protocol-specified 
procedures according to Section 10.1.2 to Section 10.1.4 and Table 5 of the protocol. The 
treatment period will consist of continuous 21-day treatment cycles. 
All patients will be carefully monitored throughout Day 1 to Day 4 in Cycle 1 and will attend 
the clinic on Cycle 1, Day 8, Cycle 1, Day 9 and Cycle 1, Day 15 (and Day -1 in Arms A).  
Patients will attend the clinic once per week (on Cycle 2, Day 1, Cycle 2, Day 8 and Cycle 2 
Day 15) during Cycle 2 and then once per cycle (on Day 1) thereafter up to 12 months of 
treatment (Cycle 17). Patients who remain on study after 12 months will attend the clinic 
every 2 Cycles (6 weekly).  
Patients who do not receive loading doses as assigned but are considered suitable for daily 
dose treatment should attend the clinic for additional ECG assessments. Twice weekly 
triplicate ECGs should be conducted during Cycle 1, Day 8 – Day 15 and Cycle 1, Day 15 – 
Day 21. 
Additional visits will be scheduled for disease assessment at the end of every two cycles (6 
weeks) cycles. The frequency of scans may be extended to the end of every 3 cycles after 12 
weeks (4 cycles) and every 4 cycles after 24 weeks (8 cycles). Patients who remain on study 
for 12 months or longer may have their scans extended to a frequency of 6 months unless 
disease progression is suspected in which case a scan should be conducted at an earlier time 
point.  
Patients will continue to receive BGB324 (in combination with erlotinib or as a single agent) 
for as long as, in the opinion of the Investigator, they continue to derive clinical benefit or 
until disease progression, unacceptable toxicity, death or withdrawal of consent. 


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In the event of erlotinib-related toxicities in Arms A, B and C, patients may be allowed to 
continue receiving BGB324 as a single agent until disease progression unless unacceptable 
toxicity, death or withdrawal of consent). Patients who stop BGB234 treatment will be 
withdrawn from the study. 
4.3.3 End of Study Visit 
Patients will return to the study site for an end-of-study visit 28 days after the last dose of 
study drug (or at study withdrawal) according to Section 10.1.5 and table 5 of the protocol. 
If BGB324-related toxicities continue beyond this follow-up period, patients will be followed 
until all BGB324-related toxicities have resolved to ≤Grade 1, stabilized or returned to 
baseline. If necessary, follow-up monitoring for AEs may be conducted over the telephone.  
 


 
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Table 2 
Schedule of Events 
Cycle 
1 
2 
w 
≥
3
End-
of-  
Week 
1(x) 
2(x) 
3(x) 
4(x) 
5(x) 
6(x) 
>7 
28 
days  
after 
last  
dose 
Cycle Day 
28 to 0  
Screening 
-1 
Arm A 
1 
2 
3 
4 
5-7 
8 
9 
10-14 
15 
16-
21 
1 
2-7 
8 
9-14 
15 
16-20 
21 
1 2-
20 
21 
Visit window (+/-) days 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
0 
+2 
0 
+ 
1 
0 
+1 
0 
+-5 
+2 0 +5 
+7 
Clinic visit 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Informed consent 
X 
Demographics 
X 
Medical history 
X 
Cancer history and treatments 
X 
Inclusion/Exclusion 
X 
ECOG performance status 
X 
X 
X 
X 
Physical examinationa 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
Xa 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead triplicate c, v 
ECG 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testd 
X 
Xe 
X 
X 
X 
Clinical chemistryf 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyg 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulationh 
X 
Xe 
X 
X 
X 
X 
X 
X 
Urinalysisi 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
echocardiogram or MUGA scant 
X 
X 
X 
PK blood samplingj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tissue collection for PDl, m,k,q 
X 
X 
Xr 
Blood collection for PDm, l,k 
X 
X 
Xs 
EGFR T70M status (Arm B) 
Xu 


 
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Disease assessmentp,n 
X 
X 
X 
X 
Abbreviations:; ECOG=Eastern Co-operative Oncology Group; MUGA=multi-gated acquisition; PD=pharmacodynamics; PK=pharmacokinetics 
 
a. 
Physical examination conducted at the screening and end-of-study (EOS) visits. A symptom-directed examination will be conducted at other visits. 
b. 
Blood pressure, pulse, respiratory rate, temperature. In addition, at screening, weight and height to be recorded. 
c. 
Triplicate 12-lead ECG, at least 5 minutes apart, after resting for ≥10 minutes in supine position during screening and during each visit (pre-dose). Patients who re-
start BGB324 following interruption for QTc prolongation should also have ECGs performed according to this schedule. 
d. 
For women of child-bearing potential to be repeated every 3 months, or if possibility of pregnancy is identified. A serum test must be performed at screening and the 
EOS visits; interim tests may be performed on urine samples. 
e. 
Unless conducted as part of the screening procedures within 3 days prior to Day 1. 
f. 
Clinical chemistry laboratory parameters: potassium, calcium, uric acid, electrolytes, blood urea nitrogen, total protein, total bilirubin, alanine aminotransferase, 
aspartate aminotransferase, creatinine, creatine phosphokinase, alkaline phosphatase, albumin, phosphorus, glucose, magnesium (plus amylase and lipase during 
screening ONLY). 
g. 
Hematology laboratory parameters: full blood count including differential white cell count, hemoglobin, hematocrit and platelets. 
h. 
Coagulation parameters: prothrombin time and/or international normalized ratio, activated partial thromboplastin time. 
i. 
Dipstick measurement of blood, nitrite, glucose, ketones, leukocytes, protein and pH. (Microscopic analysis is not required unless clinically indicated). 
j. 
Blood sampling for the determination of BGB324 / erlotinib in plasma will be collected in accordance with Table 6. 
k. 
In consenting patients (Arms A, B and C), tissue specimens may be collected for analysis of pharmacodynamics endpoints of Axl inhibition. The baseline tissue 
specimen should be collected after enrollment within 28 days before the first dose of BGB324. The on-study tissue collection may be performed any time after 14 
days of continuous exposure to BGB324 in Cycle 1 or in Cycle 2. The EOS tissue collection should be made at the time of disease progression and prior to the end-
of-study visit (derived from the lesion exhibiting disease progression). Detailed procedures for the collection, processing, storage and shipment of the samples will be 
provided in the laboratory manual. 
l. 
Blood will be collected for analysis of pharmacodynamic endpoints of Axl inhibition. The baseline sample should be collected after enrollment within 28 days before 
the first dose of BGB324. The on-study sample collection may be performed any time after 14 days of continuous exposure to BGB324 in Cycle 1 or in Cycle 2. The 
EOSEOS sample should be taken at the time of disease progression and prior to the EOS-visit. 
m. If a tissue specimen is being collected, the PD blood sample should be collected at the same visit. 
n. 
Disease assessment via RECIST Version 1.1. 
o. 
BGB324 and erlotinib (not Run-in Cohort) will be administered on an empty stomach. Both drugs will be taken with water in the morning. BGB324 should be 
administered in the hour following erlotinib administration and at least 2 hours before breakfast (except on those days when the patient attends the clinic). Patients 
should record dosing in the dosing diary provided. 
p. 
Disease assessment will be performed at the end of every 2 cycles (6 weeks) beginning with Cycle 2 (Day 21); the assessment may be performed up to 5 days 
before Day 21 (Day 17-Day 21) but attempts should be made to conduct the assessment as close to Day 21 as possible. Disease assessment may be performed 
prior to initiation of the next cycle, but results must be available prior to initiation of treatment and must confirm continued eligibility for next cycle. The frequency of 
scans may be extended to the end of every three cycles after 12 weeks (4 cycles) and every 4 cycles after 24 weeks (8 cycles). Patients who remain on study for 
12months may have their scan frequency reduced to 6 monthly.  
q. 
For consenting patients´ only (Arms A, B and C); performed any time after documentation of disease progression and prior to EOS visit. The tissue specimen should 
be derived from a lesion exhibiting progression. 
r. 
If not performed within previous 28 days. 
s. 
To be performed at the time of disease progression and prior to the EOS visit. 
t. 
Cycle 4 Day 1 and then at 6 monthly intervals and at EOS. 
u. 
Patients in Arm B must have EFGR T790M status confirmed during screening – Patients who have progressed on osimertinib and have previously progressed on an 
approved EGFR inhibitor i.e. afatinib, gefitinib) will not require additional T790M testing. T790M testing may be confirmed by blood test or biopsy. Samples collected 
and analyzed according to local procedures. The screening window of 28 days may be extended to allow for confirmation of T790M status. 


 
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v. 
Patients who do not receive their assigned loading doses and continue to receive daily dose BGB324 should attend the clinic for additional ECG assessments 
between C1 D8 and D15 and between C1 D15 and the end of Cycle 1. 
w. Patients who remain on study post C17 will have a reduced visit schedule and will return to clinic every 2 cycles (+/-7 days) 
x. 
Patients receiving BGB324 who require daily steroids at doses of 10mg to 40mg (prednisolone equivalent) should be monitored at weekly intervals until the steroid 
dose level is less than 10mg: Assessment should include physical exam, vital signs, hematology, chemistry. 
 
 


 
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4.4 Concomitant Medication 
4.4.1 Prior and Concomitant Therapies 
No additional treatment for NSCLC may be taken during the study period. 
Previous adjuvant therapy is permitted provided it has been completed for ≥6 months. 
Previous radiotherapy for cerebral metastases is permitted providing this is complete for ≥2 weeks 
before the first dose of study drug (BGB324 or Erlotinib whichever comes first) provided the 
patient is neurological stable and does not require corticosteroids. 
4.4.2 Concomitant Medication and Procedures 
All prescription, non-prescription, or over-the-counter medications, including herbal remedies, 
taken by the patient at entry and during the study must be clearly documented in the eCRF. 
The patients must be instructed that no additional medication will be allowed without the prior 
consent of the Investigator. Any medication considered necessary for the patient’s safety and 
well-being may be given at the discretion of the Investigator. 
Hematopoietic growth factors may be administered for the treatment of AEs such as neutropenic 
infections but should not be used to maintain the dose intensity of BGB324 in the Run-in Cohort 
or Arm A. 
Patients who have evidence of treatment benefit after ≥1 cycle (21 days) of treatment in Arms B 
or C may receive hematopoietic growth factors to maintain BGB324 dosing. 
Concurrent treatment with any agent known to cause Torsade de Points is an exclusion criterion 
for the study. A comprehensive list of these prohibited medications is provided in Appendix 3 of 
the protocol. 
Anti-diarrheal medications (e.g. loperamide) may be administered according to standard practice 
for the management of diarrhea. Patients must be provided with anti-diarrheal medications to take 
home, which may be used if required. 
Patients being treated with antacid histamine receptor 2 inhibitors or proton pump inhibitors on 
study entry will be excluded. The Investigator may initiate rescue treatment with these 
medications during the study, providing they are taken in the evening. 
Patients receiving BGB324 who require the support of prednisolone (or equivalent) at 10mg to 
40mg daily should be monitored at weekly intervals whilst receiving treatment. If a patient 
requires prednisolone (or equivalent) at daily doses above 40mg then BGB324 should be 
interrupted until the steroid dose is equivalent or less than 40mg daily, at which time weekly 
monitoring will be undertaken until the steroid dose is equivalent or less than 10mg. 
Steroid restrictions do not apply to topical/ inhaled/ eye or nasal drops. If required, additional 
advice on the concomitant use of steroids with BGB324 should be obtained from the BerGenBio 
Medical Monitor. 
 


 
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4.5 Study Analysis Populations 
There will be 3 analysis populations defined for the study analyses: 
4.5.1 Enrolled Population 
The Enrolled Population will include all patients who have signed the ICF and enrolled into the 
study (Enrolment date being defined as the date of the first protocol-defined screening procedure). 
4.5.2 Safety Population  
The Safety Population will be defined as all enrolled patients who receive at least one dose of 
BGB324 or Erlotinib. 
4.5.3 Efficacy Population  
The Efficacy Population will include all patients who receive ≥1 cycle of BGB324 and undergo an 
assessment of response post-baseline. 
Patients who on review do not meet the protocol inclusion/exclusion criteria or have a major 
protocol deviation may be excluded from the efficacy analysis. This will be reviewed (and 
documented) on a per patient basis at the pre-database lock meeting. 
4.6 Withdrawn Subjects 
Patients may withdraw informed consent and discontinue from the study at any time, or for any 
reason, without prejudice to their future treatment. 
The reason for the patient’s withdrawal from the study must be recorded in the eCRF. 
A patient must be discontinued from the study if any of the following criteria are met:  
 Patient non-compliance with the protocol, as agreed by the Investigator and the Sponsor. 
 Patient lost to follow-up. 
 Termination of the study by the Sponsor. 
 Subject experiences an unacceptable toxicity that precludes continuation in the study, as 
agreed by the Investigator and the Sponsor. 
 Lack of recovery from a DLT to Grade 0 or 1 within 14 days of occurrence. 
 Female patient becomes pregnant. 
 Disease progression. 
4.7 Randomisation 
This is a non-randomized study.  
4.8 Blinding 
This is an open-label study and consequently there are no blinding procedures in operation.  
4.9 Sample Size 
Run-in prior to commencing dosing of BGB324 in combination with erlotinib, the safety and 
tolerability of single agent BGB324 will be assessed in a minimum of 6 patients. The safety data 
from the first cycle in these 6 patients will be reviewed by the safety monitoring committee 
(SMC) before enrolment into Arm A can commence.  
Arm A will utilize a conventional algorithm 3+3 dose escalation algorithm for phase I cancer 
trials (3+3 patients per dose level) to identify the dose of BGB324 that can be safely given in 


 
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combination with erlotinib. Escalation between dose levels will occur if 0/3 or 1/6 patients 
experiences a DLT. Under this design, there is a 71% chance of escalation if the true but unknown 
rate of DLT is 20% and <50% chance of escalation if the true but unknown rate of DLT is >30%. 
The operating characteristics of this 3+3 design are outlined in. 
Table 3: Operating Characteristics of the 3+3 Study Design 
True but Unknown Rate of DLT (%) 
Probability of Escalation (%) 
20 
71 
30 
49 
40 
31 
50 
17 
60 
8 
It is anticipated that a maximum of three BGB324 dose levels will be evaluated, with up to 
approximately 18 patients enrolled. The total sample size in Arm A will depend upon whether 
DLT(s) is experienced at a given dose level (i.e., whether 3 or 6 patients have been treated) and 
how many dose levels are tested in order to reach the dose that can be safely administered in 
combination with erlotinib. 
Arm B will follow a Simon-like two-stage design with relaxed stopping for futility to evaluate the 
safety and tolerability, pharmacodynamics and clinical efficacy of BGB324 in combination with 
erlotinib in patients with an activating EGFR mutation(s) (including exon 19 deletion or exon 21 
[L858R] substitution or rearrangement of EGFR gene mutations) who have progressed after or 
gefitinib). The null hypothesis (H0) that the true response rate is 0.05 receiving a prior EGFR 
inhibitor (i.e. erlotinib, afatinib, will be tested against a 1-sided alternative. In the first stage, 9 
patients will be accrued. If the number of patients with response (complete response or partial 
response) after 2 cycles or stable disease after 4 cycles is equal to zero in these 9 patients, the 
study will be stopped. Otherwise, 16 additional patients will be accrued for a total of 25. The null 
hypothesis will be rejected if 4 or more responses are observed in 25 patients. Assuming that the 
stable disease rate has a uniform distribution under H0, this design yields a type I error rate of at 
most 0.73 and power of at least 0.0367 when the true response rate is 0.2. 
 
Arm C will evaluate the safety, pharmacodynamics and clinical efficacy (time to progression) of 
BGB324 when administered in combination with erlotinib in patients with activating EGFR 
mutation(s) (including exon 19 deletion or exon 21 [L858R] substitution or other rearrangement 
of the EGFR gene mutations) who have received ≥12 weeks of erlotinib without disease 
progression. Up to 5 patients will be enrolled. Arm C will recruit up to a maximum of 14 patients. 
Recruitment into Arm C may be stopped if Arm B completes recruitment or is stopped before the 
14 patient target is reached. Patients already enrolled into Arm C will be allowed to continue in 
the study in accordance with the protocol. A statistical analysis is not planned and it is anticipated 
that an assessment of general activity will be derived from the enrolled patients; further 
assessment will require protocol amendment.  
 
 
 
 


 
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5 Statistical Methodology 
5.1 Planned Analyses 
Disposition analyses will be carried out using the Enrolled Population. Demographic and baseline 
characteristics analyses will be carried out using the Safety Population. Safety analyses will be 
carried out using the Safety Analysis Population. Efficacy analyses will be carried out using the 
Efficacy Population.  
Summary statistics will be presented for continuous variables, by way of n, mean, standard 
deviation (SD), median, minimum (Min) and maximum (Max) and by way of group frequencies 
and percentages for categories of categorical variables. No statistical comparison of dose levels 
will be performed. Percentages will be calculated using the total subjects per dose cohort in the 
given population unless otherwise noted.  
All data from this study will be presented in data listings.  Unless otherwise noted,  listings will be 
sorted by cohort dose level and subject. 
Baseline is the most recent assessment prior to the first dose of a study drug (BGB324 or 
erlotinib)administration, i.e within 28 days before the first dose of study drug and after patient 
eligibility has been confirmed. Typically, this will be Cycle 1 Day 1 or screening. Where 
calculated, absolute change from baseline will be presented using the following formula for each 
parameter: Value at the visit/timepoint – value at baseline. 
Data will be presented by dose/cohort and overall.  
5.2 Interim Analysis 
No formal statistical interim analyses are planned, however, data will be monitored by the Safety 
Monitoring Committee (SMC) to assess patient safety for Run-in cohort before enrolment into 
Arm A can start and for dose escalation within Arm A. 
5.3 Disposition of Subjects 
The number of subjects receiving study treatment in each analysis population and the reasons for 
any discontinuation from the study will be summarized by treatment arm.  
5.4 Baseline and Demographic Characteristics 
All baseline and demographic characteristics will be summarized. This will include age, age 
group, sex, ethnicity, race, height, weight, and Eastern Cooperative Oncology Group (ECOG) 
performance status at screening. Cancer history (Histologic Diagnosis, Stage at initial diagnosis, 
Stage at screening and sites), medical history by system organ class and preferred term, Mutation 
status and prior cancer therapies (chemotherapy, hormonal therapy, immunotherapy, monoclonal 
therapy, radiotherapy, other therapy, surgery) will also be summarized. 
Notes: 
 Age (years) will be calculated as (Date Informed Consent - Date of Birth + 1)/365.25. 
 Age groups are defined as: <65 years and ≥65 years of age. 
 Medical history will be coded according to Medical Dictionary for Regulatory Activities 
(MedDRA) version 15.0 or above. 
 Prior cancer therapies will be coded using World Health Organization (WHO) Drug 
Dictionary, Mar 2014 or above.  


 
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5.5 Concomitant Medication 
Medications taken on or after date of informed consent are collected. Prior medications are those 
that started and stopped before exposure to study medication; concomitant medications are all 
medications taken during the study period, including those started before but ongoing at first dose. 
Incidence of concomitant medication will be presented therapeutic area and preferred drug name. 
Where a medication start date is partially or fully missing, and it is unclear as to whether the 
medication is prior or concomitant, it will be assumed that it is concomitant. Medications will be 
coded using WHO Drug Dictionary, Mar 2014 or above. 
5.6 Exposure and Compliance 
BGB324 exposure will be summarized by the number of cycles started on BGB324/Erlotinib and 
duration of administration by dose cohort. Duration (days) of BGB324/Erlotinib administration 
will be defined as: 
Date of Last Study Drug Administration – Date of First study Drug Administration + 1 day 
Total treatment exposure to BGB324/Erlotinib will also be characterized by total cumulative dose 
(mg) over the whole study and summarized by dose cohort.  
Study drug percent compliance for BGB324/Erlotinib will be calculated as: 
((Expected number of doses – Missed number of doses) / Expected number of doses) * 100,  
where Expected Number of Doses is defined as duration of study drug administration in days at 
each cycle, i.e 21 days;  
Missed number of doses will be calculated as Last date of missed - First Date Missed; 
Overall percent compliance will be summarized by frequency count and percentage of subjects 
with compliance <80%, 80 to 120% and >120%. Overall percent compliance will also be 
summarized as a continuous variable using descriptive statistics. 
5.7 Efficacy Analysis 
Although all efficacy analysis for this study is to be regarded as essentially exploratory, there will 
be formal hypothesis tests (Arm B only).  
For Arm B, the data relating to efficacy response will be listed and summarized by time point, as 
appropriate. 
For Arm C, the data relating to time to progression will be summarized/analyzed and listed by 
time point, as appropriate. 
5.7.1 Normality assumption checking 
Not Applicable (NA). 
5.7.2 Closed testing procedure for primary analysis 
As the analyses of the efficacy endpoints are essentially exploratory in nature no adjustments for 
multiple comparisons will be made. 
5.7.3 Method of analysis for efficacy outcome 
5.7.3.1 Objective Response Rate (ORR) 
Response criteria for target lesions and non-target lesions (see Section 3.2) will be evaluated at 
each disease assessment and will be presented in a data listing by subject. 


 
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In addition, the presence/absence of new lesions will be collected at each disease assessment and 
will be presented in a data listing by subject. 
The investigator will evaluate the target/non-target lesion response criteria and status 
(presence/absence) of new lesions against the RECIST Version 1.1 criteria to determine overall 
response for the appropriate disease assessment time point.   
Although all efficacy analysis for this study is to be regarded as essentially exploratory, there will 
be a formal hypothesis test for the objective response rate here (Arm B only). Specifically, for a 
given disease assessment time point we denote subjects who achieve a CR or a PR Best overall 
response.  The null hypothesis is that the proportion of objective responders (i.e., the ORR) is less 
than or equal to 5%.   The alternative hypothesis is that the proportion of objective responders is 
greater than 5%. The binomial test will be used to conduct the hypothesis test at the one-sided 
significance level of 0.2. 
Overall response and the ORR will be presented within a data listing by subject and time point. 
Best overall Response (BOR) will also be listed. 
The number and percentage of each BOR class will be described by cohort.  
Moreover, the Sum of Target Lesion Measurements (STLM) will be analyzed from relative 
changes from baseline and graphically displayed with waterfall plot in order to visualize changes 
in sum of lesion without differentiating best response categories. 
Best response to therapy will be defined as the Best Changes from Baseline in Sum of Target 
lesions measurement for a patient during the study. 
The Best Percentage change in STLM will be calculated as, STLM =100*(Value of STLM – 
Baseline value STLM)/Baseline value STLM; 
In case of several post baseline assessments of STLM the one with the lowest change (i.e., 
showing the best diminution of sum of lesions relative to baseline) will be considered. 
5.7.3.2 Time to progression (TTP)  
For Arm C only, the TTP will be calculated as the time from first administration of BGB324 or 
Erlotinib to either progressive disease as follows: 
TTP (in months) = [(Date of event – date of first administration) + 1]/30.4375 
For censored participants, the TTP will be calculated as follows: 
TTP (in months) = [(Censored date – date of first administration) + 1]/30.4375 
TTP will be analyzed descriptively for Arm C patients. 
The Kaplan-Meier approach will be used to estimate TTP. The number and percent of subjects 
with progression, number and percent of subject censored, and median time to progression – along 
with its corresponding 95% confidential Interval – will be presented. 
Kaplan-Meier Survival curves will be presented for TTP. 
5.8 Safety Analysis 
No formal statistical analysis will be performed on safety data. Summary statistics by treatment 
groups and timepoint will be produced. 


 
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The safety endpoints will consist of treatment-emergent adverse events, serious adverse events, 
physical examinations, vital signs, ECOG, ECG, Echocardiograms, and laboratory tests (clinical 
chemistry, hematology and urinalysis).  
5.8.1 Adverse events 
The AE reporting period will begin following the first dose of BGB324 (Run-in Cohort) or 
erlotinib (Arms A, B and C) and will end 28 days after the last dose of BGB324. 
The number and percentage of patients reporting TEAEs will be tabulated by Medical Dictionary 
for Regulatory Activities (MedDRA) preferred term and system organ class, and summarized by 
CTCAE grade and relationship to study drug. All AEs commencing prior to dosing with study 
medication will be excluded from the tabulation but will be fully listed.  
A subject with more than one occurrence of the same adverse event in a particular system organ 
class will be counted only once in the total of those experiencing adverse events in that particular 
system organ class. If a subject experiences the same adverse event at more than one severity, or 
with more than one relationship to study drug, the most severe rating or the stronger causal 
relationship to study drug will be given precedence. For example, if the event of multiple 
occurrences of the same adverse events being reported by the same subject, the maximum 
intensity (Grade 5 > Grade 4 > Grade 3 > Grade 2 > Grade 1 > missing > not applicable) and the 
most serious causality (related> not related) will be chosen. 
Any missing severity, causality, or outcome will not be imputed and classed as unknown. 
An overall summary classifying subjects with events according to seriousness, severity, maximum 
relationship to BGB324, and maximum CTCAE grade will also be presented. 
Related events are defined as events that are ticked as suspected by investigator in eCRF . 
Treatment-Emergent AEs are any AEs that start or worsen after first dose of study drug regardless 
of causality. AEs with partial onset dates will be assumed to have the latest possible onset date 
(while accounting for stop date) for determining treatment emergence, but no formal imputation 
will be done. AEs that have missing onset dates will be considered to be treatment-emergent, 
unless the stop date is known to be prior to the first administration of study drug (BGB324 or 
Erlotinib whichever comes first). 
5.8.1.1 Subsets 
 Related (BGB324) adverse events will be presented by treatment, system organ class and 
preferred term. 
 Related (Erlotinib) adverse events will be presented by treatment, system organ class and 
preferred term. (Arm A, Arm B and Arm C). 
 Serious adverse events will be presented by treatment, system organ class and preferred 
term as:  
 
Related (BGB324) serious adverse events will be presented by treatment, system organ 
class and preferred term. 
 
Related (Erlotinib) serious adverse events will be presented by treatment, system organ 
class and preferred term.  
 
Serious adverse events will be presented by treatment group, system organ class, 
preferred term, and maximum CTCAE grade. 
 Adverse events leading to discontinuation will be presented by treatment group, system 
organ class and preferred term. 


 
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 Adverse events ≥ Grade 3 will be presented by treatment group, system organ class and 
preferred term. 
 The most frequent MedDRA preferred terms (≥10% subjects in the overall safety 
population) and system organ class will be presented by treatment group.  
 Separate listings will be produced for DLTs, SAEs, related AEs, discontinuations due to 
AEs, and events of ≥ Grade 3 severity. 
All other information collected (e.g. action taken) will be listed as appropriate.  
Notes: 
 AEs coded using MedDRA version17.0 or above. 
5.8.2 Physical Examination 
Any post-baseline new or worsened physical examination findings during the safety evaluation 
period will be recorded as AEs and summarized in terms of AEs as described in Section 5.8.1. 
Both the complete physical examination performed at screening and the symptom directed 
physical examination results will be presented in data listings. 
5.8.3 Vital Signs 
Results for systolic and diastolic blood pressure (mmHg), pulse rate (bpm), respiration rate 
(BREATHS/MIN), and temperature (°C) will be summarized by dose cohort and scheduled visit, 
as well as the corresponding change from Baseline.  
Weight (kg) and Height (cm) at screening will be summarized and listed with other vital signs 
data. 
5.8.4 Eastern Cooperative Oncology Group 
ECOG performance status will be summarized categorically at each scheduled visit with 
frequencies and percentage. 
5.8.5 Electrocardiograms 
Twelve-lead ECG triplicate will be collected the mean of the values will be analysed. In case, 
only one assessment is collected this value will be considered, if 2 or 3 assessments are performed 
the mean of available should be calculated.  
The quantitative ECG assessments (PR interval (ms), RR interval (ms), QRS Duration (ms), QT 
interval (ms), and QTcF interval (ms)) will be summarized for actual values and change from 
Baseline to each visit/timepoint will be also presented. 
ECG overall interpretation (normal, abnormal not clinically significant and abnormal clinically 
significant) will be presented as a categorical summary by treatment groups and scheduled visit. 
Any post-baseline new or worsened echocardiogram findings during the safety evaluation period 
will be recorded as AEs and summarized in terms of AEs as described in Section 5.8.1.  
All echocardiogram data, including MUGA scan results will be presented in a data listing. 
5.8.6 Laboratory findings 
Results from the following laboratory parameters, recorded at scheduled visits, will be presented 
in listings:  
Hematology: 
 


 
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Hemoglobin, Hematocrit, Red Blood Cells (RBC), White Blood Cells (WBC), Absolute 
Neutrophil Count, Neutrophils, Eosinophils, Basophils, Lymphocytes, Monocytes and Platelets. 
Coagulation: 
Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), International 
Normalized Ratio (INR), and Quick Test. 
Chemistry: 
Sodium, Potassium, calcium, chloride, magnesium, phosphorus, creatine phosphokinase (CPK), 
creatinine, total protein, total bilirubin, albumin, alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), glucose, uric acid, blood urea nitrogen 
(BUN), Bicarbonate (CO2), electrolytes, amylase and lipase (during screening ONLY).  
Urinalysis: 
pH, semi-quantitative "dipstick" evaluation of Proteins, Glucose, Ketones, Blood, Nitrite, 
Leukocytes, Bilirubin, Bacteria, Casts, Crystals, RBC, and WBC. 
Numeric Hematology and Chemistry parameters will be summarized along with each 
corresponding Change from Baseline for all scheduled visit by dose cohort. The incidence of 
laboratory test results outside the normal range will be listed by dose cohort and time point. 
Clinically significant treatment-emergent laboratory findings will be summarized as adverse 
events. 
Notes: 
 All results outside predefined normal ranges will be flagged in the data listings. 
 Repeat laboratory results within a visit will not be used in any summary calculations. 
Unscheduled and repeat results will be listed only 
 Serum Pregnancy Test results will be listed.  
 All other laboratory results will be listed only.  
 
5.9 Pharmacokinetic Analysis 
The Pharmacokinetic (PK) Analysis will be conducted separate by BergenBio from this analysis. 
Details will be found in a specific analysis plan. Subjects included in PK population can be 
identified in the clinical datasets.   
 
5.10 Pharmacodynamic Analysis 
The Pharmacodynamic Analysis will be conducted separate from this analysis. Details will be 
found in a specific analysis plan. 
 
5.11 Protocol Deviations 
Deviations from the protocol will be documented on an ongoing basis by the study monitors and 
project manager throughout the study period.  
At the time of database lock, prior to unblinding and while the protocol deviations are being 
reviewed, the project manager will forward all relevant documentation highlighting protocol 
deviations to the study statistician. These deviations will be included in the protocol violation 
document for agreement and will be listed with the protocol violations in the CSR. 


 
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5.12 Missing Values – Missing Visits 
Missing, unused and spurious data will be considered missing at random and dealt with as such. 
There is no intention to implement any procedure for replacing missing data. 
 
5.13 Deviations from SAP 
Any deviations from the original statistical plan will be described and justified in the final clinical 
study report, whether written post interim or final analysis. 
 
5.14 Changes in Conduct or Planned Analyses from the Protocol 
There have been no other changes in analyses from those defined in the protocol.  


 
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5.15 Algorithms/SAS Codes 
 
 Tables that need descriptive statistics – continuous variables: 
PROC UNIVARIATE DATA=dset NOPRINT; 
    VAR var1 var2 var3 …varn; 
   BY byvar; (optional) 
   OUTPUT OUT=outname 
   N=n MEAN=mean MIN=min MAX=max MEDIAN=median STD=std *Q1=q1 Q3=q3; 
RUN; 
 
 Tables that need frequency counts: 
PROC FREQ DATA=dset NOPRINT; 
  
BY byvar; (optional) 
   TABLES var1*var2; 
  
OUTPUT OUT=outname; 
RUN; 
 
 Tables that need life table with estimates of survival, with CIs:  
PROC LIFETEST DATA=dset OUTSURV=LIFE METHOD=KM; 
 
 
BY treatment; 
 
TIME duration*censor (0 or 1); 
RUN; 
 Tables that need 95% CIs within group for binomial proportions: 
PROC FREQ DATA=dset; 
  
BY byvar; (optional) 
   TABLES var1/binomial (p=.05) alpha=0.05; 
  
EXACT BINOMIAL; 
RUN; 
 
PROC FREQ data=dset order=freq; 
   TABLES var / binomial(ac wilson exact) alpha=.05; 
   WEIGHT Count; 
run; 
 
 
 


 
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6 Tables and Listings 
6.1 Table Format 
All output will be produced using SAS version 9.2 or a later version. 
In the top left portion of each table/listing, a table/listing number followed by the title of the 
table/listing will be presented. After the title line, optional sub-title or population information can 
be presented. Horizontal lines will appear before and after the column heading of the table/listing. 
Footnotes will be put under the main body of text at the bottom of the page.  
The sponsor name, protocol number, programmers User ID, status of the table/listing (i.e. draft or 
final) and SAS program name will appear bottom left in a string and the page number will appear 
on the bottom right corner of each table/listing. The date and time of creation of table/listing will 
appear bottom left under the sponsor name. The source listing number will appear bottom left.  
A landscape layout is proposed for both table and listing presentations. 
The left and right margins of all tables and listings will be a minimum of 2.1 cm from the left and 
1.9cm from the right. The top and bottom margins will be a minimum 2.92cm. Header and footer 
will be both 1.27 cm. 
There is no special requirement of font type and size, but an 8-point font size for tables and 7or 8-
point for listings is proposed using Courier New font. A maximum SAS line size=141 and page 
size=44 for 8-point font size, and line size=161 and page size=50 for 7-point will be used so as to 
fit on both UK and US paper sizes. 
In a listing, in the case that a subject’s record has been continued to the next page, an appropriate 
identification (e.g., the subject ID number) must be presented at the beginning of that page. 
6.2 Conventions 
Unless otherwise specified, in summary tables of continuous variables, the minimum and 
maximum values will be displayed to the same number of decimal places as the raw data, the 
mean and median will be presented to one extra decimal place compared to the raw data, and the 
standard deviation will be displayed to two extra decimal places compared to the raw data. 
Wherever possible data will be decimal aligned. 
Unless otherwise specified frequency tabulations will be presented by number and percentage, 
where the percentage is presented in parenthesis to 1 decimal place. 
P-values, if applicable, will be presented to 3 decimal places. If a p-value is less than 0.05 but is 
greater than or equal to 0.01, then an asterisk (*) will be added next to this value. If a p-value is 
less than 0.01 but is greater than or equal to 0.001, then two asterisks (**) will be added next to 
this value. Finally, if the p-value is less than 0.001 then three asterisks (***) will be added next to 
this value and it will be presented as <0.001. If the rounded result is a value of 1.000, it will be 
displayed as >0.999. Any date information in the listing will use the date9. format, for example, 
07MAY2002. In the listing, a unit associated with a variable will be presented only once within 
parentheses either below or next to that variable in the heading portion. If a parameter has 
multiple units, each unit will be displayed only once, as applicable. 
All tables will have their source listing referenced in a footnote. Listings should be sorted by 
treatment group, subject and visit and have the source data received by data management 
referenced in a footnote. All tables and listings will be converted into Microsoft Word documents 
and collated into two complete documents.  
 


 
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6.1 Tables 
  
6.1.1 Section 14.1: Demographic and baseline 
Table 14.1.1.1 
Subject Disposition (Enrolled Population) 
Table 14.1.1.2 
Important Protocol Violations (Enrolled Population) 
Table 14.1.2 
Demographics (Safety Population) 
Table 14.1.3 
Cancer History (Safety Population) 
Table 14.1.4 
Medical History (Safety Population) 
Table 14.1.5 
Prior Cancer Therapies (Safety Population) 
Table 14.1.6.1 
Prior Medications (excluding anti-cancer therapies) 
Table 14.1.6.2 
Concomitant Medications (Safety Population) 
Table 14.1.7.1 
Summary of Exposure to BGB324 (Safety Population) 
Table 14.1.7.2 
Summary of Exposure to Erlotinib (Safety Population) 
Table 14.1.7.3 
Summary of Exposure : Number of participants by cycle (Safety 
Population) 
Table 14.1.7.4 
Summary of dose modification during the study (Safety Population) 
Table 14.1.7.5 
Summary of Erlotinib dose modification during the study (Safety 
Population) 
Table 14.1.8 
Compliance (Safety Population) 
 
6.1.2 Section 14.2: Primary and secondary 
Table 14.2.1 
Assessment of anti-tumour activity – Best Overall Response 
(Confirmation not Required) (Efficacy Population) 
Table 14.2.2 
Assessment of anti-tumour activity – Sum of Target Lesions 
Measurement (Efficacy Population) 
Table 14.2.3 
Time to progression (TTP) – Kaplan-Meier Analysis (Efficacy 
Population) 
 
6.1.3 Section 14.3: Safety 
6.1.3.1 Adverse events  
Table 14.3.1.1 
Summary of Adverse Events (Safety Population) 
Table 14.3.1.2.1 
Adverse Events by System Organ Class and Preferred Term (Safety 
Population) 
Table 14.3.1.2.2 
Adverse Events by System Organ Class, Preferred Term, and CTCAE 
Grade (Safety Population) 
Table 14.3.1.2.3 
Adverse Events Related to BGB324 by System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.2.4 
Adverse Events Related to Erlotinib by System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.2.5 
Adverse Events by System Organ Class, Preferred Term and Severity of 
CTCAE Grade (Safety Population) 
Table 14.3.1.3.1 
Serious Adverse Events by System Organ Class and Preferred Term 
(Safety Population) 
Table 14.3.1.3.2  
Serious Adverse Events by System Organ Class, Preferred Term, and 
Severity of CTCAE Grade  (Safety Population) 
Table 14.3.1.3.3 
Serious Adverse Events Related to BGB324 by System Organ Class and 
Preferred Term  (Safety Population) 
Table 14.3.1.3.4 
Serious Adverse Events Related to Erlotinib by System Organ Class and 
Preferred Term  (Safety Population) 
Table 14.3.1.4.1 
Adverse Events Leading to Discontinuation by System Organ Class and 
Preferred Term  (Safety Population) 


 
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Table 14.3.1.5.1 
Adverse Events with CTCAE Grade >= 3 by System Organ Class and 
Preferred Term  (Safety Population) 
Table 14.3.1.5.2 
Adverse Events >= Grade 3 Related to BGB324 by System Organ Class 
and Preferred Term  (Safety Population) 
Table 14.3.1.5.3 
Adverse Events >= Grade 3 Related to Erlotinib by System Organ Class 
and Preferred Term  (Safety Population) 
Table 14.3.1.6.1 
Adverse Events Occurring >= 10% by System Organ Class and Preferred 
Term  (Safety Population) 
Table 14.3.1.7.1 
Adverse Events leading to death by System Organ Class and Preferred 
Term  (Safety Population) 
Table 14.3.1.8.1.1  
Summary of DLTs occurring during the study  (Safety Population) 
 
6.1.3.2 
Laboratory results 
Table 14.3.5.1.1 
Laboratory Results – Hematology - Summary and Change from Baseline  
(Safety Population) 
Table 14.3.5.2.1 
Laboratory Results – Coagulation - Summary and Change from Baseline  
(Safety Population) 
Table 14.3.5.3.1 
Laboratory Results –Chemistry - Summary and Change from Baseline 
(Safety Population) 
Table 14.3.5.4.1  
Laboratory Results for subjects  with CTCAE >= Grade 3  (Safety 
Population) 
Table 14.3.5.4.2 
Laboratory Results CTCAE Grade  >= 3  (Safety Population) 
 
6.1.3.3 Vital signs  
Table 14.3.6.1.1 
Vital Signs - Summary and Change from Baseline  (Safety Population) 
 
6.1.3.4 ECG 
Table 14.3.6.2.1 
ECG Results - Summary and Change from Baseline (Safety Population) 
Table 14.3.6.2.2 
ECG Results - Overall Interpretation  (Safety Population) 
Table 14.3.6.2.3   
QTcF (ms) by CTCAE Grade and Dose (Safety Population) 
Table 14.3.6.2.4   
Maximum QTcF Increase from Baseline (Safety Population) 
 
6.1.3.5 ECOG Performance Status 
Table 14.3.6.3.1 
Eastern Cooperative Oncology Group (ECOG) Performance Status  
(Safety Population) 
 


 
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6.2 Listings 
Listing 16.1.7.1 
Dose Escalation Cohort Assignment  (Safety Population) 
Listing 16.1.7.2 
Drug Accountability  (Safety Population) 
Listing 16.2.1.1 
Subject Disposition  (Enrolled Population) 
Listing 16.2.1.2 
Inclusion/Exclusion Descriptions  (Enrolled Population) 
Listing 16.2.1.3 
Inclusion/Exclusion Criteria Not Met  (Enrolled Population) 
Listing 16.2.2.1 
Important Protocol Deviations  (Enrolled Population) 
Listing 16.2.3 
Subjects Excluded from the Analysis Sets (Enrolled Population) 
Listing 16.2.4.1 
Demographics (Safety Population) 
Listing 16.2.4.2 
Cancer History (Safety Population) 
Listing 16.2.4.3 
Medical History (Safety Population) 
Listing 16.2.4.4 
Mutation Status  (Safety Population) 
Listing 16.2.4.5.1 
Prior Cancer Therapy  (Safety Population) 
Listing 16.2.4.5.2 
Prior Erlotinib Administration at Screening (Safety Population) 
Listing 16.2.4.6 
Prior Cancer-related Surgery  (Safety Population) 
Listing 16.2.4.7 
Prior and Concomitant Medications  (Safety Population) 
Listing 16.2.4.8.1 
Physical Examination - Complete  (Safety Population) 
Listing 16.2.4.8.2 
Physical Examination – Symptom Directed (Safety Population) 
Listing 16.2.4.9 
ECOG Performance Status  (Safety Population) 
Listing 16.2.5.1 
BGB324  Exposure  (Safety Population) 
Listing 16.2.5.2 
Erlotinib Exposure  (Safety Population) 
Listing 16.2.5.3 
BGB324 Administration (In-Clinic)  (Safety Population) 
Listing 16.2.5.4 
BGB324 Administration (By Cycle)  (Safety Population) 
Listing 16.2.5.5 
Erlotinib Administration  (Safety Population) 
Listing 16.2.6.1 
Tumour Assessment – Target Lesions  (Safety Population) 
Listing 16.2.6.2 
Tumour Assessment – Non-Target Lesions  (Safety Population) 
Listing 16.2.6.3 
Tumour Assessment – New Lesions  (Safety Population) 
Listing 16.2.6.4 
Assessment of anti-tumour activity (Safety Population) 
Listing 16.2.6.5 
Time to progression details 
Listing 16.2.7.1 
Adverse Events  (Safety Population) 
Listing 16.2.7.2  
Serious Adverse Events    (Safety Population) 
Listing 16.2.7.3  
Adverse Events Related to BGB325    (Safety Population) 
Listing 16.2.7.4  
Adverse Events Related to Erlotinib    (Safety Population) 
Listing 16.2.7.5  
Adverse Events Leading to Discontinuation   (Safety Population) 
Listing 16.2.7.6 
Adverse Events – Dose Limiting Toxicities   (Safety Population) 
Listing 16.2.7.7  
Adverse Events >= Grade 3   (Safety Population) 
Listing 16.2.7.8 
List of DLTs (Safety Population) 
Listing 16.2.8.1.1 
Laboratory Results: Hematology   (Safety Population) 
Listing 16.2.8.1.2 
Laboratory Results: Coagulation   (Safety Population) 
Listing 16.2.8.1.3 
Laboratory Results: Chemistry   (Safety Population) 
Listing 16.2.8.1.4 
Laboratory Results: Urinalysis   (Safety Population) 
Listing 16.2.8.1.5 
Laboratory Results: Urine/Serum Pregnancy Test 
Listing 16.2.8.1.6 
Clinically Significant Laboratory Results   (Safety Population) 
Listing 16.2.8.1.7  
Laboratory Results for patients with  CTCAE Grade >= 3 (Safety 
population) 


 
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Listing 16.2.8.2.1 
Vital Signs (Safety Population) 
Listing 16.2.8.3.1 
ECG Results   (Safety Population) 
Listing 16.2.8.3.2 
Maximum increase in QTcF, by CTCAE Grade and Treatment (safety 
population) 
Listing 16.2.8.4.1 
Echocardiogram/Muga Scan   (Safety Population) 
Listing 16.2.8.5.1 
Ancillary Procedures   (Safety Population) 
 
6.3 Figures 
Figure 14.2.1  
Time to progresssion – Kaplan Meier Survival Curves (Efficacy 
Population) 
Figure 14.2.2  
Waterfall Plots of Percentage of the Best Changes from Baseline of SLD   
(Efficacy Population) 
 


 
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6.4 References 
1. Eisenhauer EA1, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe 
D, Verwei J. New response evaluation criteria in solid tumours: revised RECIST 
guideline 
(version 
1.1). 
Eur 
J 
Cancer. 
2009 
Jan; 
45(2):228-47. 
doi: 
10.1016/j.ejca.2008.10.026.