Clinical trial NCT02488408
Conditions: Acute Myeloid Leukemia Myelodysplastic Syndromes
Keywords: BGB324 bemcentinib
Sponsor: BerGenBio ASA
Start date: 2014-10-22; Completion date: 2022-06-08
Enrollment: 122 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
A Phase Ib/II multicentre open label study of bemcentinib (BGB324) as a single agent in participants with Acute Myeloid Leukemia (AML) or Myelodysplastic syndrome (MDS) or in a combination with cytarabine or decitabine in AML participants.

Bemcentinib is a potent selective small molecule inhibitor of AXL a surface membrane protein kinase receptor which is overexpressed in up to half of AML cases.

Detailed description:
This study is a dose-escalation of bemcentinib (BGB324), a selective AXL kinase inhibitor, in participants with AML and MDS, followed by a cohort expansion study of bemcentinib either as a single agent in participants with AML or MDS, or in combination with cytarabine (cytosine arabinoside, Ara-C) or decitabine in participants with AML.

The study will run in Germany, Norway, Italy and the US and may enrol up to approximately 90 participants with AML or MDS.

The study consisted of a dose-escalation phase to determine the MTD (maximum tolerated dose) and/or recommended dose for Phase II (RP2D) of bemcentinib in participants with relapsed or refractory AML or MDS (Part A) followed by a cohort expansion phase in five disease-specific cohorts (Part B).

Bemcentinib was administered orally according to a daily schedule, with the first three doses of Cycle 1 serving as a 'loading' dose. Each 21-day (three week) period will constitute 1 cycle of treatment.

Arms: arm 1: Bemcentinib will be administered as monotherapy in participants with relapsed or refractory AML following previous treatment with cytotoxic chemotherapy (with or without hematopoietic stem cell transplantation) or a gene expression modulator, such as a demethylating agent. arm 2: Single agent bemcentinib will be administered to participants with AML who are unsuitable for intensive chemotherapy as a result of advanced age and/or existing co-morbidities. arm 3: Bemcentinib will be administered in combination with low dose cytarabine in participants with AML who are unsuitable for intensive chemotherapy as a result of advanced age or existing co-morbidities. arm 4: Bemcentinib will be administered in combination with decitabine in participants with AML who are unsuitable for intensive chemotherapy as a result of advanced age or existing co-morbidities. arm 5: Bemcentinib will be administered as a monotherapy to participants with previously treated MDS (including high risk and intermediate with the exception of deletion 5q MDS). arm 6: Bemcentinib will be administered in combination with low dose cytarabine in participants with relapsed or refractory who have received at least one prior treatment for. Participants must be unsuitable for intensive chemotherapy as a results of advanced age or existing co-morbidities.
Interventions: intervention 1: Bemcentinib intervention 2: Cytarabine intervention 3: Decitabine
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
BerGenBio ASA 
 
Jonas Lies vei 91 
 
5009 Bergen 
 
Norway 
 
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CLINICAL STUDY PROTOCOL 
 
 
Investigational Product: 
Bemcentinib (BGB324) 
Protocol Number: 
BGBC003 
Phase 
Phase Ib/II 
Protocol Title: 
An open label, multicenter, phase Ib/II study of BGB324 
(bemcentinib) administered as a single agent or in 
combination with cytarabine or decitabine in patients with 
acute myeloid leukemia or as a single agent in patients with 
myelodysplastic syndrome   
EudraCT Number: 
2014-000165-46 
IND Number: 
124255 
Version and Date: 
10.0 (US); 14 July 2021 
 
 
 
 
 
 
 
 
This study will be conducted in compliance with International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 
guidelines on Good Clinical Practice (GCP), the Declaration of Helsinki (with 
amendments), and in accordance with local legal and regulatory requirements 
 
 
 
CCI


 
 
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1. Protocol Approval Signatures 
Protocol BGBC003 Version 10.0 (US), 14 July 2021 
Sponsor’s Approval: 
This protocol has been approved by BerGenBio ASA 
Signature:  
 
Date: 
Prof 
 
 
 
 
 
Investigator’s Approval: 
 
I, the undersigned, have reviewed the Protocol, including Appendices and I will conduct 
the BGBC003 clinical study as described and in accordance with International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) guidelines on Good Clinical Practice (GCP) and all the ethical and regulatory 
considerations stated. I have read and understood the contents of the bemcentinib 
Investigator’s Brochure 
Signature: 
Date: 
 
 
 
 
 
 
 
 
 
 
PPD
PPD


 
 
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2. Study Personnel 
Full contact details for each Investigational site, the Sponsor and other key coordinating and 
operational personnel involved in this clinical trial (including vendors), are maintained and 
available for reference in each Site Study File and in the Trial Master File. 
 
 
 
 


 
 
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3. Table of Contents 
1. 
Protocol Approval Signatures ..................................................................... 2 
2. 
Study Personnel ......................................................................................... 3 
3. 
Table of Contents ....................................................................................... 4 
4. 
Tables and Figures .................................................................................. 10 
5. 
List of Abbreviations ................................................................................. 12 
6. 
Protocol Synopsis .................................................................................... 15 
7. 
Introduction .............................................................................................. 32 
7.1. 
Pre-clinical Studies with Bemcentinib ....................................................... 32 
7.1.1. 
Summary of Pre-clinical Activity ............................................................... 32 
7.1.2. 
Summary of Pre-clinical Toxicology ......................................................... 33 
7.1.3. 
High Dose Steroids and Mouse Model ..................................................... 34 
7.2. 
Clinical Studies with Bemcentinib ............................................................. 34 
7.2.1. 
Summary of Clinical Safety ...................................................................... 35 
7.2.1.1. 
ECG Findings ........................................................................................... 35 
7.2.2. 
Summary of Clinical Pharmacokinetics .................................................... 36 
7.2.3. 
Selection of the Starting Dose for Clinical Study BGBC003 ..................... 37 
7.2.3.1. 
Formulation 1 and Formulation 2 ............................................................. 40 
8. 
Study Objectives and Endpoints .............................................................. 41 
8.1. 
Objectives ................................................................................................ 41 
8.1.1. 
Primary Objectives ................................................................................... 41 
8.1.2. 
Secondary Objectives .............................................................................. 41 
8.1.3. 
Exploratory Objectives ............................................................................. 42 
8.2. 
Endpoints ................................................................................................. 42 
8.2.1. 
Safety Endpoints ...................................................................................... 42 
8.2.2. 
Efficacy Endpoints .................................................................................... 42 
8.2.3. 
Pharmacokinetic Endpoints ...................................................................... 43 
8.2.4. 
Pharmacodynamic and Predictive Endpoints ........................................... 43 
9. 
Study Design ............................................................................................ 45 
9.1. 
Overview .................................................................................................. 45 
9.2. 
Study Specifics ......................................................................................... 47 
9.2.1. 
Phase I DLT Assessment Period ............................................................. 47 
9.2.1.1. 
Dose Escalation Scheme ......................................................................... 48 


 
 
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9.2.1.2. 
Dose Limiting Toxicity .............................................................................. 49 
9.2.2. 
Part B ....................................................................................................... 50 
9.3. 
Overall Study Duration and Follow Up ..................................................... 50 
9.3.1. 
Screening ................................................................................................. 51 
9.3.2. 
Treatment ................................................................................................. 51 
9.3.3. 
Final Study Visit ....................................................................................... 52 
9.3.4. 
Follow Up ................................................................................................. 52 
9.4. 
Study Stopping Rules ............................................................................... 53 
9.5. 
End of Study ............................................................................................. 53 
10. 
Selection of Subjects ................................................................................ 55 
10.1. 
Inclusion Criteria ...................................................................................... 55 
10.2. 
Exclusion Criteria ..................................................................................... 56 
11. 
Study Procedures and Assessments ....................................................... 60 
11.1. 
Enrolment ................................................................................................. 69 
11.1.1. 
Blinding Procedures ................................................................................. 69 
11.2. 
Screening ................................................................................................. 69 
11.3. 
Treatment Period ..................................................................................... 70 
11.3.1. 
Part A ....................................................................................................... 70 
11.3.1.1. Cycle 1 ..................................................................................................... 70 
11.3.1.2. Cycle 2 ..................................................................................................... 73 
11.3.1.3. Cycle 3 and Subsequent Cycles .............................................................. 74 
11.3.2. 
Parts B1 and B4 ....................................................................................... 74 
11.3.2.1. Cycle 1 ..................................................................................................... 75 
11.3.2.2. Cycle 2 ..................................................................................................... 77 
11.3.2.3. Cycle 3 and Subsequent Cycles .............................................................. 78 
11.3.3. 
Part B2, Part B3 and Part B5 ................................................................... 78 
11.3.3.1. Cycle 1 ..................................................................................................... 79 
11.3.3.2. Cycle 2 ..................................................................................................... 81 
11.3.3.3. Cycle 3 and Subsequent Cycles .............................................................. 82 
11.4. 
Final Study Visit ....................................................................................... 83 
11.5. 
Survival Follow-up .................................................................................... 84 
12. 
Treatment of Subjects .............................................................................. 85 
12.1. 
Treatment Schedule and Administration .................................................. 85 


 
 
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12.1.1. 
Bemcentinib ............................................................................................. 85 
12.1.2. 
Cytarabine ................................................................................................ 86 
12.1.3. 
Decitabine ................................................................................................ 86 
12.2. 
Dose Modification ..................................................................................... 87 
12.2.1. 
Bemcentinib ............................................................................................. 87 
12.3. 
Concomitant Medication and Procedures................................................. 89 
12.4. 
Continuation of Treatment ........................................................................ 90 
12.5. 
Discontinuation of Treatment and Withdrawal of Patients ........................ 90 
13. 
Study Assessments .................................................................................. 92 
13.1. 
Clinical Safety Assessments .................................................................... 92 
13.1.1. 
Resting 12-lead ECG ............................................................................... 92 
13.1.2. 
Physical Examination ............................................................................... 93 
13.1.3. 
Vital Signs ................................................................................................ 93 
13.1.4. 
Subject Symptomatology.......................................................................... 93 
13.2. 
Laboratory Safety Assessments ............................................................... 93 
13.2.1. 
Hematology and Clinical Chemistry ......................................................... 93 
13.2.2. 
Urinalysis .................................................................................................. 94 
13.3. 
Pharmacokinetic Assessments ................................................................ 94 
13.3.1. 
Determination of Bemcentinib Concentration in Plasma .......................... 95 
13.4. 
Clinical Efficacy Assessments .................................................................. 95 
13.5. 
Pharmacodynamic and Predictive Biomarkers ......................................... 96 
13.5.1. 
Bone Marrow Aspirates ............................................................................ 97 
13.5.2. 
Pharmacodynamic Blood Samples .......................................................... 97 
13.6. 
Volume of Blood and Bone Marrow Sampling .......................................... 98 
14. 
Study Treatment Management ................................................................. 99 
14.1. 
Study Medication ...................................................................................... 99 
14.1.1. 
Bemcentinib ............................................................................................. 99 
14.1.1.1. Bemcentinib Storage ................................................................................ 99 
14.1.1.2. Bemcentinib Accountability ...................................................................... 99 
14.1.2. 
Cytarabine and Decitabine ..................................................................... 100 
14.1.2.1. Cytarabine and Decitabine Storage ....................................................... 101 
14.1.2.2. Cytarabine and Decitabine Accountability .............................................. 101 
15. 
Safety Definitions, Monitoring and Reporting ......................................... 102 


 
 
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15.1. 
Definitions .............................................................................................. 102 
15.1.1. 
Adverse Event ........................................................................................ 102 
15.1.2. 
Adverse Reaction ................................................................................... 103 
15.1.3. 
Serious Adverse Event ........................................................................... 103 
15.2. 
Monitoring and Reporting Events ........................................................... 104 
15.2.1. 
Adverse Events ...................................................................................... 104 
15.2.2. 
Serious Adverse Events ......................................................................... 104 
15.2.3. 
All Events ............................................................................................... 105 
15.3. 
Safety Classifications ............................................................................. 105 
15.3.1. 
Assessment of Severity .......................................................................... 105 
15.3.2. 
Assessment of Causality ........................................................................ 105 
15.3.3. 
Assessment of Expectedness ................................................................ 106 
15.3.4. 
Immediate Reporting of Serious Adverse Events ................................... 106 
15.3.5. 
Annual Safety Updates .......................................................................... 107 
15.3.6. 
Deaths .................................................................................................... 107 
15.3.7. 
Procedures for Handling Special Situations ........................................... 107 
15.3.7.1. Pregnancy .............................................................................................. 107 
15.3.8. 
Medical Emergency ................................................................................ 108 
15.3.8.1. Unblinding for a Medical Emergency ...................................................... 108 
15.4. 
Investigator’s Safety Responsibilities ..................................................... 108 
15.5. 
Sponsor’s Safety Responsibilities .......................................................... 109 
15.6. 
Overdose ................................................................................................ 109 
16. 
Statistical Methods and Determination of Sample Size .......................... 110 
16.1. 
Description of Objectives ........................................................................ 110 
16.2. 
Description of Endpoints ........................................................................ 110 
16.3. 
Demography and Baseline Disease Characteristics .............................. 110 
16.4. 
Safety ..................................................................................................... 111 
16.4.1. 
Analysis Population ................................................................................ 111 
16.4.2. 
Methods of Analysis ............................................................................... 111 
16.5. 
Efficacy................................................................................................... 112 
16.5.1. 
Analysis Population ................................................................................ 112 
16.5.2. 
Methods of Analysis ............................................................................... 112 
16.6. 
Pharmacokinetics ................................................................................... 113 


 
 
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16.6.1. 
Analysis Population ................................................................................ 113 
16.6.2. 
Methods of Analysis ............................................................................... 113 
16.7. 
Pharmacodynamics ................................................................................ 113 
16.7.1. 
Analysis Population ................................................................................ 113 
16.7.2. 
Methods of Analysis ............................................................................... 113 
16.8. 
Safety Monitoring Committee ................................................................. 114 
16.9. 
Sample Size Considerations .................................................................. 114 
16.10. 
Clinical Study Report .............................................................................. 115 
17. 
Ethical Requirements ............................................................................. 116 
17.1. 
Good Clinical Practice Statement ........................................................... 116 
17.2. 
Ethics Committee ................................................................................... 116 
17.3. 
Patient Information and Consent ............................................................ 116 
17.4. 
Subject Data Protection ......................................................................... 117 
18. 
Administrative Procedures ..................................................................... 118 
18.1. 
Quality Assurance .................................................................................. 118 
18.2. 
Case Report Form and Source Document Verification .......................... 118 
18.3. 
Study Monitoring .................................................................................... 118 
18.4. 
Notification of Serious Breaches ............................................................ 119 
18.5. 
Retention of Study Data ......................................................................... 119 
18.6. 
Use of Information and Publication Policy .............................................. 119 
18.7. 
Contract Research Organisations .......................................................... 120 
18.8. 
Changes to the Final Study Protocol ...................................................... 120 
18.9. 
Investigator Responsibilities ................................................................... 120 
19. 
References ............................................................................................. 122 
20. 
Appendices ............................................................................................ 123 
Appendix 1:  Eastern Cooperative Oncology Group (ECOG) Performance Status 123 
Appendix 2:  The New York Heart Association (NYHA) Functional Classification in a 
Patient with Heart Disease ................................................................ 124 
Appendix 3: Drugs Associated with a Risk of QT Prolongation and Cardiac 
Arrhythmias ....................................................................................... 125 
Appendix 4:  CYP3A4 Substrates .......................................................................... 127 
Appendix 5:  Modified International Working Group Response Criteria in Acute 
Myeloid Leukemia (Cheson, 2003, Döhner, 2017) ............................ 128 


 
 
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Appendix 6: International Working Group Response Criteria in Myelodysplastic 
Syndromes (Cheson, 2006) .............................................................. 129 
 
 
 


 
 
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4. Tables and Figures 
List of Tables 
 
Table 1:  Bemcentinib Kinase Selectivity Profile ....................................................... 32 
Table 2:  Bemcentinib-Related Adverse Events Reported Following a Single Oral 
Administration of Bemcentinib (50 mg to 1500 mg) to Healthy Male 
Subjects ..................................................................................................... 35 
Table 3:  Possible Bemcentinib Dosing Levels Involving A Loading Dose and Daily 
Dose for Part A .......................................................................................... 48 
Table 4:  Part A Schedule of Events ......................................................................... 61 
Table 5:  Parts B1 and B4 Schedule of Events ......................................................... 63 
Table 6:  Parts B2, B3 and B5 Schedule of Events .................................................. 66 
Table 7:  Dose Modification of Bemcentinib Daily Dose for Toxicity ......................... 87 
Table 8:  Dose Modification of Bemcentinib Daily Dose for QTc Prolongation ......... 88 
Table 9:  Hematology, Clinical Chemistry and Coagulation Parameters .................. 93 
Table 10: Urinalysis Parameters .............................................................................. 94 
Table 11: Bemcentinib PK Sampling Time Points and Permitted Windows ............. 94 
Table 12: Volume of blood and BM aspirate to be drawn per Patient during 
Screening and at Cycle 1 .......................................................................... 98 
Table 13: Volume of Blood and BM aspirate to be drawn per Patient during Cycle 2
 .................................................................................................................. 98 
Table 14: Volume of Blood and BM aspirate to be drawn per Patient per Cycle >3 (up 
to and including Cycle 15 for PK and Blood Pharmcodynamics) & at Final 
Study Visit ................................................................................................. 98 
Table 15: Plasma PK parameters .......................................................................... 113 
Table 16: Operating Characteristics of the 3+3 Study Design ................................ 115 
 
 
 
List of Figures 
Figure 1: Mean Plasma CoBGBC003 Protocol v10.0 (US) dated 
14July2021_trackedncentrations of Bemcentinib Following a Single Oral 
Administration of Bemcentinib at 50, 100, 150, 200, 400, 600, 1000 and 
1500 mg to Healthy Male Subjects ............................................................ 36 
Figure 2: Simulated Plasma Concentrations of Bemcentinib for 600 mg Loading 
Dose on Days 1 and 2 and Daily Dose of 200 mg from Day 3 (fed) .......... 38 


 
 
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Figure 3: Simulated Plasma Concentrations of Bemcentinib for 600 mg Loading 
Dose on Days 1 and 2 and Daily Dose of 200 mg from Day 3 (fasted) ..... 39 
Figure 4: Predicted Plasma Concentrations of Bemcentinib after 1200 mg Loading 
Dose Given as 600 mg on Days 1 and 2 or 400 mg on Days 1, 2 and 3, 
followed by Daily Dose of 200 mg (fasted) ................................................ 39 
Figure 5: BGBC003 Study Design ............................................................................ 47 
Figure 6: The 3+3 Dose Escalation Design .............................................................. 49 
 
 


 
 
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5. List of Abbreviations 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ALP 
Alkaline phosphatase 
AML 
Acute myeloid leukemia 
ANC 
Absolute neutrophil count 
APTT 
Activated Partial Thromboplastin Time 
Ara-C 
Cytosine arabinoside, cytarabine 
AST 
Aspartate aminotransferase 
AUC0-∞ 
Area under the curve from time zero to infinity 
AUC0-48h 
Area under the curve from time zero to 48 hours 
AUC0-t 
Area under the concentration-time curve 
AUC0-tau 
Area under the curve within a dosing interval 
BM 
Bone marrow 
BP 
Blood pressure 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CI 
Confidence interval 
Cmax 
Maximum concentration achieved 
CNS 
Central nervous system 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTD 
Clinical Trials Directive 
CV 
Cardiovascular 
DHA 
Directions for Handling and Administration 
DLT 
Dose limiting toxicity 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EU 
European Union 
FCM 
Flow cytometry 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
h 
Hour 
hERG 
Human ether-à-go-go related gene  
HIV 
Human immunodeficiency virus 
HPMC 
Hydroxypropyl methylcellulose 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH  
International Council for Harmonisation  
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational medicinal product 


 
 
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IMPD 
Investigational medicinal product dossier 
IND 
Investigational new drug 
IP 
Inorganic phosphate 
IRB 
Institutional Review Board 
IWG 
International Working Group 
K 
Potassium 
LC/MS/MS 
Liquid chromatography/tandem mass spectrometry 
LDAC 
"Low-dose” cytarabine 
MCH 
Mean cell hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
Maximum tolerated dose 
MUGA 
Multi Gated Acquisition Scan 
Na 
Sodium 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
OR 
Objective response 
ORR 
Objective response rate 
OS 
Overall Survival 
pAXL 
Phospho AXL 
PBMC 
Peripheral blood mononuclear cell(s)  
PCR 
Polymerase chain reaction 
PD 
Progressive Disease 
PII 
Personally identifiable information 
PK 
Pharmacokinetic 
PR 
Partial Remission 
PT 
Prothrombin time 
QA 
Quality Assurance 
QTcF 
QTc interval according to Fridericia’s correction 
REC 
Research Ethics Committee 
RP2D 
Recommended Phase 2 dose 
RSI 
Reference Safety Information 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SAS 
Safety analysis set 
sAXL 
Soluble AXL 
SD 
Stable disease 
SMC 
Safety Monitoring Committee 
SmPC 
summary of product characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
T½ 
Terminal half-life 
TdP 
Torsade de Pointes 
TEAE 
Treatment Emergent Adverse Events 
Tmax 
Time to maximum concentration 


 
 
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TMF 
Trial Master File 
ULN 
Upper limit of normal 
WT 
Wild Type 
 


 
 
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6. Protocol Synopsis 
PROTOCOL TITLE: 
An open label, multicenter, phase Ib/II study of BGB324 
(bemcentinib) administered as a single agent or in 
combination with cytarabine or decitabine in patients with 
acute myeloid leukemia or as a single agent in patients 
with myelodysplastic syndrome   
PROTOCOL No: 
BGBC003 
SPONSOR: 
BerGenBio ASA, Jonas Lies vei 91, 5009, Bergen, 
Norway 
INVESTIGATIONAL 
PRODUCT: 
Bemcentinib (BGB324) 
PHASE OF DEVELOPMENT: 
Phase Ib/II 
INDICATION AND 
RATIONALE: 
Acute myeloid leukemia (AML) (with the exception of 
AML M3) and myelodysplastic syndrome (MDS) with the 
exception of deletion 5q MDS. 
This is the first clinical study of bemcentinib in patients. 
Bemcentinib is a potent selective small molecule inhibitor 
of AXL, a surface membrane protein receptor tyrosine 
kinase which is overexpressed in up to half of AML 
cases. AXL expression has been identified as a marker 
of a poor prognosis in AML. 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. In vitro studies indicate that 
activation of AXL enables malignant cells to develop 
resistance to conventional chemotherapies. Preliminary 
in vitro studies using AML cell lines indicate that 
treatment with bemcentinib is at least additive in effect 
when administered with cytarabine). Early in vitro and ex 
vivo studies also indicate that AXL inhibition with 
bemcentinib inhibits proliferation of mononucleated bone 
marrow (BM) derived from patients with MDS. 
OBJECTIVES: 
Part A 
PRIMARY 
• 
To identify the maximum tolerated dose (MTD) of 
bemcentinib in AML patients who have received 
previous treatment with cytotoxic chemotherapy 
(with 
or 
without 
hematopoietic 
stem 
cell 
transplantation) or a targeted or biologic agent 
(e.g. hypomethylating agent, tyrosine kinase 


 
 
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inhibitor, antibody), and have relapsed after or 
have been refractory to treatment with such prior 
therapy 
SECONDARY 
• 
To identify the dose limiting toxicity (DLT) profile 
of bemcentinib 
• 
To explore the safety and efficacy of bemcentinib  
• 
To characterize the pharmacokinetic (PK) profile 
of bemcentinib  
Part B 
PRIMARY 
• 
To identify the safety and tolerability of 
bemcentinib as a single agent in patients with 
AML or MDS (Parts B1 and B4), in combination 
with low dose cytarabine in patients with AML 
(Part B2 and Part B5), or in combination with 
decitabine in patients with AML (Part B3)  
SECONDARY 
• 
To explore the efficacy of bemcentinib as a single 
agent in patients with AML or MDS (Parts B1 and 
B4), in combination with low dose cytarabine in 
patients with AML (Part B2 and Part B5), or in 
combination with decitabine in patients with AML 
(Part B3) 
• 
To assess bemcentinib PK (all Part B cohorts) 
EXPLORATORY (Parts A and B1, B2, B3, B4 and B5) 
• 
To identify and evaluate potential predictive 
biomarkers, e.g. soluble AXL [sAXL] and other 
associated soluble biomarkers. Pre-treatment 
levels of biomarkers will be correlated with clinical 
endpoints  
• 
To establish the effects of bemcentinib on 
relevant biological endpoints in peripheral blood 
(including sAXL, peripheral blood mononuclear 
cells [PBMC]) and BM samples 
• 
To assess pharmacodynamic biomarkers in 
tissue and blood to support the clinical 
development of bemcentinib  


 
 
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• 
To evaluate other biomarkers relevant to the 
investigational agents for exploratory purposes 
ENDPOINTS: 
 
 
 
 
 
 
 
 
 
 
 
SAFETY: 
Treatment emergent adverse events (TEAE), physical 
examination. Vital signs (i.e. blood pressure (BP) and 
heart rate (HR), respiration rate and temperature), 
electrocardiogram 
(ECG), 
echocardiograms 
and 
laboratory 
findings 
including 
clinical 
chemistry, 
hematology and urinalysis. 
EFFICACY:  
AML Response criteria:  
• 
Objective response (OR) or Stable Disease 
(SD) according to the revised recommendations 
of the International Working Group (IWG) in 
AML Appendix 5 [Cheson, 2003 and Döhner, 
2017]. SD is defined as having unchanged 
disease for at least 3 treatment cycles. 
• 
Proportion of patients with an OR + SD as an 
estimate of clinical benefit  
• 
Relapse Free Survival 
• 
Event Free Survival 
• 
Overall Survival 
• 
To explore the correlation between baseline 
biomarker levels and clinical endpoints  
MDS 
Response criteria:  
• 
OR 
or 
SD 
according 
to 
the 
revised 
recommendations of the IWG in MDS Appendix 
6 [Cheson, 2006]. SD is defined as failure to 
achieve at least Partial Remission (PR), but not 
evidence of Progressive Disease (PD) for at 
least 3 treatment cycles.  
• 
Proportion of patients with an OR + SD as an 
estimate of clinical benefit  
• 
Relapse Free Survival  
• 
Event Free Survival 
• 
Overall Survival  
• 
To explore the correlation between baseline 
biomarker levels and clinical endpoints  
PHARMACOKINETIC: 
As a minimum, area under the curve within a dosing 
interval (AUC0-tau), maximum concentration achieved 


 
 
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(Cmax) and time to maximum concentration (Tmax) for 
bemcentinib will be determined from plasma. Additional 
parameters may also be reported, as deemed 
appropriate once data are reviewed. 
PHARMACODYNAMIC AND PREDICTIVE 
BIOMARKERS: 
The effects of bemcentinib on pharmacodynamic 
endpoints of AXL inhibition will be determined in BM 
aspirates and blood samples:  
• 
To identify and evaluate potential predictive 
biomarkers, e.g. sAXL and other associated 
soluble biomarkers. Pre-treatment levels of 
biomarkers will be correlated with clinical 
endpoints  
• 
To establish the effects of bemcentinib on 
relevant biological endpoints in peripheral blood 
(including sAXL, PBMC) and BM samples  
• 
To assess pharmacodynamic biomarkers in 
tissue and blood to support the clinical 
development of bemcentinib  
• 
To evaluate other biomarkers relevant to the 
investigational agents for exploratory purposes  
• 
 Effect of bemcentinib on AXL, sAXL and 
phospho AXL (pAXL) and downstream effectors 
of AXL signaling, such as Akt, pAkt, Erk, pErk, 
SLFN11, Bcl2, Puma by appropriate methods 
(e.g. flow cytometry (FCM), western blotting, 
proteomics, transcriptomics) 
• 
Effect of bemcentinib on gene expression by 
appropriate methods (e.g. FCM, western 
blotting, 
proteomics, 
transcriptomics, 
quantitative polymerase chain reaction (PCR), 
DNA-methylation analysis) 
• 
Effect of bemcentinib on relevant Immune cell 
populations 
• 
Effect of bemcentinib on the spectrum of 
mutations present within the cancer cell 
population by genomic analysis 
• 
To explore the correlation between baseline 
biomarker levels and clinical endpoints 
STUDY DESIGN: 
This 
Phase 
Ib/II 
open-label 
study 
will 
run 
at 
approximately 20 clinical sites (in Europe and the United 
States) and may enroll up to approximately 102 
evaluable patients with AML or MDS. Additional 


 
 
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countries and sites may be added as required to meet 
the enrolment needs of the study. In all parts of the study 
patients with AML who have a matched donor and who 
are candidates for allogeneic BM transplantation are not 
eligible to participate. 
In order to be eligible for Part A, patients must have 
received 
previous 
treatment 
with 
cytotoxic 
chemotherapy (with or without hematopoietic stem cell 
transplantation) or targeted or biologic agent (e.g. 
hypomethylating 
agent, 
tyrosine 
kinase 
inhibitor, 
antibody) and have relapsed after or have been 
refractory to treatment with such prior therapy.  
The study consists of a dose-escalation phase to 
determine the MTD of single agent bemcentinib in 
patients with relapsed or refractory AML (Part A). 
In the cohort expansion phase (Part B), bemcentinib will 
be investigated in up to four cohorts:  
In Part A dose-escalation will continue until DLT occurs, 
at which point an MTD will be selected and used in Part 
B. The dose of bemcentinib selected will be either the 
MTD or a Recommended Phase 2 dose (RP2D) as 
agreed by the Safety Monitoring Committee (SMC) and 
which is supposed to be clinically effective. 
Bemcentinib will be administered orally according to a 
daily schedule, with the first two to three doses of Cycle 1 
serving as a ‘loading’ dose. Each 21-day (three week) 
period will constitute 1 cycle of treatment.  
As part of the development program the formulation has 
been enhanced to Formulation 2. Therefore from 2017 
onwards Formulation 2 will be applied, first in an 
additional dose-escalation cohort. The starting dose for 
Formulation 1 consisted of a loading dose of 400 mg on 
Cycle 1, Days 1 and 2, followed by a daily maintenance 
dose of 100 mg. Dosing with Formulation 1 was 
completed in 2016. 
Currently, dosing with Formulation 2 will consist of a 
loading dose of 200 mg administered on Days 1, 2 and 3 
followed by a daily maintenance dose of 100 mg. This 
dose may be escalated as agreed by the SMC to a 
maximum daily loading dose of 400 mg on Days 1, 2 and 
3 followed by a maximum daily maintenance dose of 200 
mg.  
Patients will be instructed to take bemcentinib on an 
empty stomach at a similar time each morning when they 
wake or more than 2 hours after a light meal with water. 


 
 
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To maintain a fasted state, patients should be told not to 
eat or drink anything other than water for at least 1 hour 
after taking the drug. 
Part A – Dose Escalation: 
Open label, dose-escalation study of repeat doses of 
bemcentinib as a single agent. Escalation will be 
performed according to a “3+3” design to determine the 
MTD. Between 6-10 patients will be treated at the MTD 
or RP2D as determined by the SMC.  
The DLT assessment period will comprise the first 21-
day treatment cycle. Patients who do not complete the 
DLT assessment period for reasons other than toxicity 
will be replaced for the purpose of toxicity evaluation. A 
patient must receive all loading doses and miss no more 
than 3 maintenance doses in Cycle 1 in order to be 
considered as informative to support dose escalation, 
unless missed doses are due to DLT. 
The decision to dose-escalate (or not) will be made by 
the SMC comprising a representative from each actively 
recruiting investigational site and a representative of the 
BerGenBio ASA study team. The decision to dose 
escalate will be based upon the tolerability of the 
bemcentinib loading dose and daily maintenance dose 
observed at the previous dose level. 
 Part B – Cohort Expansion 
The decision to proceed to Part B of the study will be 
made by the SMC on the basis of the observed 
tolerability and efficacy seen in Part A. Up to 5 distinct 
patient cohorts of up to 14 evaluable patients per cohort 
in B1, B2, B3, B4 and up to 20 evaluable patients in 
cohort B5 may be explored.  
Depending upon the safety profile of bemcentinib 
observed in Part A, the initial starting dose in 
combination with cytarabine (Part B2) or decitabine (Part 
B3) may be reduced by a single dose level (i.e. MTD -1) 
which will be evaluated in at least three patients in each 
cohort before the introduction of the MTD identified in 
Part A. The bemcentinib dose level to be investigated in 
Part B2 and Part B3 will be dependent upon the MTD 
confirmed in Part A. A dose lower than 100 mg daily is 
not available.  
Part B1: Single agent bemcentinib in patients with AML 
who are unsuitable for intensive chemotherapy as a 
result of advanced age or co-morbidities. Patients should 


 
 
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have relapsed following at least one line of therapy or be 
refractory to such prior therapy.  
Part 
B2: 
Bemcentinib 
will 
be 
administered 
in 
combination with low dose cytarabine in patients with 
AML who are unsuitable for intensive chemotherapy as 
a result of advanced age or existing co-morbidities.  
Cytarabine 
will 
be 
administered 
subcutaneously 
according to standard practice (i.e. 20 mg twice daily for 
10 days followed by a rest period of <1 month according 
to persisting myelosuppression). Cytarabine should be 
administered approximately 30 minutes after the 
bemcentinib dose.  
The bemcentinib dose to be investigated in combination 
will be confirmed by the SMC. If the SMC-recommended 
dose of bemcentinib is less than the single agent MTD, 
further dose escalation of bemcentinib may be 
considered until an MTD for the combination is identified, 
although the dose administered will not escalate beyond 
the single-agent MTD.  
Part 
B3: 
Bemcentinib 
will 
be 
administered 
in 
combination with decitabine in patients with AML who are 
unsuitable for intensive chemotherapy as a result of 
advanced age or co-morbidities.  
Decitabine will be administered at a maximum dose of 
20 mg/m2 body surface area by intravenous infusion, 
repeated daily for 5 consecutive days (i.e. a total of 
5 doses per 28-day treatment cycle). The total dose per 
treatment cycle must not exceed 100 mg/m2. Decitabine 
should be administered within approximately 30 minutes 
of the bemcentinib dose. 
In Part B3 bemcentinib will be administered at a dose 
identified by the SMC in combination with decitabine. 
The dose of bemcentinib administered must not exceed 
the MTD. 
Part B4: Single agent bemcentinib in patients with 
previously treated MDS (including high risk and 
intermediate with the exception of deletion 5q MDS). The 
bemcentinib dose to be investigated will be confirmed by 
the SMC and will be no higher than the MTD dose 
explored in part A. 
Part B5: The Part B5 bemcentinib dose is based on the 
bemcentinib dose that was identified as safe and well 
tolerated in Part B2. Bemcentinib will be administered in 
combination with low dose cytarabine in patients with 
relapsed or refractory AML who have received at least 


 
 
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one prior treatment for AML. Patients must be unsuitable 
for intensive chemotherapy as a result of advanced age 
or existing co-morbidities.  
The bemcentinib dose will be 400 mg orally daily for the 
first 3 days of treatment (loading dose) and 200 mg orally 
daily thereafter (maintenance dose). 
Cytarabine will be administered at a dose of 20 mg 
subcutaneously twice daily for 10 days every 28 days. 
Cytarabine should be administered approximately 30 
minutes after the bemcentinib dose. 
DOSE LIMITING TOXICITIES 
(Part A):  
DLTs will be assessed during the first 3 weeks of 
treatment with bemcentinib (Cycle 1), according to the 
National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) [NCI CTCAE] 
version 4 considered unrelated to leukemia progression 
or intercurrent illness, and defined as any of the 
following:  
• 
CTCAE Grade 3 or 4 nausea, vomiting, or 
diarrhea 
that 
persists 
despite 
maximum 
prophylactic and supportive care. 
• 
Any other CTCAE Grade 3 or 4 non-
hematological toxicity that is considered to be 
clinically significant and causally related to 
bemcentinib, excluding isolated changes in 
laboratory results if no clinical significance or no 
clinical sequelae and adequately improve within 
7 days. 
• 
Prolonged neutropenia with ANC <500 and 
platelet count <75000 after Day 42 from the start 
of treatment in the absence of residual leukemia  
• 
Treatment discontinuation, inability to administer 
one or more bemcentinib loading dose, or 
inability 
to 
administer 
three 
bemcentinib 
maintenance doses as a result of bemcentinib-
related toxicity. 
• 
Any ventricular arrhythmia. 
STUDY POPULATION: 
INCLUSION CRITERIA:  
1. Provision of signed written informed consent 
2. Histological, 
molecular, 
or 
cytological 
confirmation of: 
AML (with the exception of AML M3) 
• Part A: Patients with relapsed or refractory 
AML following treatment with cytotoxic 
chemotherapy or a targeted or biologic agent 


 
 
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(e.g. hypomethylating agent, tyrosine kinase 
inhibitor, antibody) 
• Part B1: Patients with AML who are 
unsuitable for intensive chemotherapy as a 
result of advanced age or co-morbidities. 
Patients should have relapsed following at 
least one line of therapy or be refractory to 
such prior therapy 
• Part B2: Patients with AML who are 
unsuitable for intensive chemotherapy as a 
result of advanced age or co-morbidities and 
who are suitable to receive treatment with 
cytarabine 
• Part B3: Patients with AML who are 
unsuitable for intensive chemotherapy as a 
result of advanced age or co-morbidities and 
who are suitable to receive treatment with 
decitabine 
• Part B4 Patients with previously treated MDS 
(with the exception of deletion 5q MDS) 
including intermediate and high risk patients 
who must have received prior treatment for 
their disease. Prior treatment may include 
those 
patients 
who 
have 
received 
hypomethylating agents, decitabine or other 
approved treatments for MDS.  
Or  
• Part B5: Patients with relapsed or refractory 
AML who are unsuitable for intensive 
chemotherapy as a result of advanced age or 
co-morbidities meeting the following criteria:  
o Must have received at least one prior 
treatment for AML.  
o Are suitable to receive treatment with 
"low-dose" cytarabine (LDAC). LDAC is 
defined as 20 mg cytarabine administered 
subcutaneously twice daily for 10 days 
every 28 days.  
The number of patients with refractory AML, defined 
as no hematological response to last AML treatment 
and/or patients who have received 2 or more prior 
treatments for AML, will be restricted to 1/3 of the 
sample size (i.e. no more than 6 evaluable patients).  


 
 
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3. Eastern Cooperative Oncology Group (ECOG) 
performance status 0, 1 or 2 [Appendix 1] 
4. Age 18 years or older 
5. Female patients of childbearing potential must 
have a negative serum pregnancy test within 
3 days prior to taking their first dose of 
bemcentinib. 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, tubal 
ligation, total sexual abstinence, vasectomy) 
throughout the study and for >3 months after the 
last dose of bemcentinib. Female patients are 
considered NOT of childbearing potential if they 
have a history of surgical sterility or evidence of 
post-menopausal status defined as any of the 
following: 
a) Natural menopause with last menses >1 year 
ago 
b) Radiation induced oophorectomy with last 
menses >1 year ago 
c) Chemotherapy induced menopause with last 
menses >1 year ago 
EXCLUSION CRITERIA:  
1. Patients with a matched donor who are 
candidates for allogeneic BM transplantation 
2. Pregnant or lactating 
3. History of the following cardiac conditions: 
• Congestive cardiac failure of >Class II 
severity according to the New York Heart 
Association (NYHA) (Appendix 2: defined as 
symptomatic at less than ordinary levels of 
activity) 
• Ischemic cardiac event including myocardial 
infarction within 3 months prior to first dose. 
Patients with prior history or ECG evidence of 
old myocardial infarction should be discussed 
with the Sponsor to confirm eligibility. 
• Uncontrolled 
cardiac 
disease, 
including 
unstable angina, uncontrolled hypertension 
(i.e. sustained systolic BP >160 mmHg or 
diastolic BP >90 mmHg), or need to change 


 
 
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medication within 6 weeks of provision of 
consent due to lack of BP control 
• History or presence of sustained bradycardia 
(≤55 beats per minute), left bundle branch 
block, cardiac pacemaker or ventricular 
arrhythmia.  
Note: 
Patients 
with 
supraventricular 
arrhythmia should be discussed with the 
Sponsor to confirm eligibility.  
• Family history of long QTc syndrome; 
personal history of long QTc syndrome or 
previous drug-induced QTc prolongation of at 
least Grade 3 (QTc >500 ms) 
• Presence of any factors that increase the risk 
for QTc prolongation, e.g. resistant or 
inadequately treated heart failure, presence of 
hypokalemia 
or 
hypomagnesemia 
not 
corrected 
by, 
or 
not 
responding 
to, 
replacement therapy or inadequately treated 
hypothyroidism as defined by the thyroid-
stimulating hormone not within the expected 
range of the institution. 
4. Abnormal left ventricular ejection fraction on 
echocardiography or Multi Gated Acquisition 
Scan (MUGA) (less than the lower limit of normal 
for a patient of that age at the treating institution 
or <45%, whichever is lower) 
5. Current treatment with any agent known to cause 
QT prolongation and have a risk for Torsades de 
Pointes which cannot be discontinued at least 
five half-lives or two weeks prior to the first dose 
of study treatment. Please see Appendix 3 for list 
of relevant medications 
6. Screening 12-lead ECG with a measurable QTc 
interval according to Fridericia’s correction 
>450 ms 
7. Ongoing infection requiring systemic treatment. 
Patients who are on prophylactic antimicrobials 
or who have been afebrile for 48 hours following 
the initiation of antimicrobials are eligible 
8. Inadequate liver function as demonstrated by 
serum bilirubin ≥1.5 times the upper limits of 
normal range (ULN) or alanine aminotransferase 
(ALT) or aspartate aminotransferase (AST) ≥2.5 
times the ULN (or ≥5 times the ULN for ALT or 


 
 
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AST in the presence of liver involvement by 
leukemia) 
9. Inability to tolerate oral medications 
10. Existing gastrointestinal disease affecting drug 
absorption such as celiac disease or Crohn’s 
disease 
11. Known lactose intolerance 
12. Requires vitamin K antagonists. Note: Patients 
receiving low doses prescribed to maintain the 
patency of venous access devices may be 
included 
13. 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 bemcentinib, whichever is 
longer 
14. Treatment 
with 
any 
medication 
which 
is 
predominantly metabolized by CYP3A4 and has 
a narrow therapeutic index 
15. Previous bowel resection that would interfere with 
drug absorption 
16. Evidence of ongoing gastrointestinal graft versus 
host disease 
17. Hematopoietic stem cell transplantation within 
6 months  
18. Impaired renal function as demonstrated by a 
creatinine clearance of <30 mL/min determined 
by Cockcroft-Gault formula 
19. Radiotherapy 
or 
chemotherapy 
within 
the 
14 days prior to the first dose of bemcentinib 
being administered (other than hydroxyurea)  
20. Receiving 
an 
investigational 
anti-cancer 
treatment concurrently or within 14 days or five 
half-lives (whichever is shorter) of either the 
parent drug or any known active metabolite prior 
to the start of bemcentinib 
21. Unresolved CTCAE >Grade 2 toxicity (other than 
stable toxicity) from previous anti-cancer therapy 
excluding alopecia 
22. 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 


 
 
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for the patient to participate in the study or which 
could jeopardize compliance with the protocol 
23. Known active, uncontrolled central nervous 
system (CNS) disease including CNS leukemia 
24. Known 
active 
infection 
with 
human 
immunodeficiency virus (HIV), hepatitis B or C 
viruses – screening for viral infections is not 
required for entry to this study 
25. Major surgery within 28 days prior to the start of 
bemcentinib – excluding skin biopsies and 
procedures for insertion of central venous access 
devices 
26. Hypersensitivity to cytarabine, decitabine or any 
of their excipients 
27. Prior exposure to Astellas ASP2215 (FLT3/AXL 
inhibitor-Gilteritinib) 
TREATMENT AND 
INTERVENTIONS: 
Patient eligibility for the study will be determined within 
14 days prior to the first dose of bemcentinib. Screening 
assessments will be conducted according to the 
Schedule of Events (Tables 4-6) in Section 11. 
Eligible patients will visit the study site to receive study 
treatment and protocol-specified procedures according 
to the relevant Schedule of Events (Tables 4-6) in 
Section 11. 
In order to reduce the risk of tumor lysis syndrome all 
patients will be asked to drink up to two liters of fluid in 
the 24-hour period prior to starting treatment with 
bemcentinib and on Day 0, Day 1, Day 2 and Day 3. All 
patients will receive treatment with allopurinol (or 
equivalent) for at least the first week of treatment or until 
their serum uric acid is within the normal range or 
considered as not clinically significant. If a patient has a 
pre-existing condition where uric acid levels are higher 
(i.e. gout) pre-bemcentinib uric acid levels may be 
considered as normal).  
The treatment period will consist of continuous 21-day 
treatment cycles. Patients will be intensively monitored 
throughout Day 1 to Day 4 inclusive of Cycle 1, and in 
addition will attend the clinic on Day 8, and Day 15. 
Patients will attend the clinic once a week during Cycle 2 
(Day 1, 8 and 15) and then once per cycle thereafter.  
The study period will consist of screening, treatment, 
Final Study Visit, and follow-up. The Final Study Visit will 
occur 28 days after the patient has discontinued study 
treatment. The patients will be followed by the site for 


 
 
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survival even after the final study visit. Follow-up can be 
conducted by phone or visit, contact with family members 
or community health care providers (family practitioner, 
nurse or family liaison/social worker), or public health 
records (where applicable). Every effort should be made 
to establish the patient’s survival status at 3-monthly 
intervals, or less. 
BEMCENTINIB: 
FORMULATION/DOSE/ROUTE 
OF ADMINISTRATION: 
Bemcentinib is presented for oral dosing in capsules 
each containing 100 mg bemcentinib.  
Patients will be instructed to take bemcentinib on an 
empty stomach at a similar time each morning when they 
wake or more than 2 hours after a light meal, with water. 
To maintain a fasted state, patients should be told not 
eat or drink anything other than water for at least 1 hour 
after taking the drug. 
Bemcentinib will be administered orally according to a 
daily dosing schedule during each week of continuous 
21-day treatment cycles. During Cycle 1 ONLY the first 
three doses may comprise of a ‘loading’ dose. 
Part A: Dose is ascending per dose cohort. The starting 
dose of bemcentinib (Cohort 1) will be 200 mg on Cycle 
1, Days 1, 2 and 3 (loading dose), followed by a daily 
maintenance dose of 100 mg. This dose may be 
escalated as agreed by the SMC to a maximum daily 
loading dose of 400 mg on Days 1, 2 and 3 followed by 
a maximum daily maintenance dose of 200 mg. 
Please refer to Section 9.2.1.1 for more details on dose 
escalation rules. 
Part B: Bemcentinib will be administered at the MTD or 
RP2D in Part B1 and Part B4 
In Parts B2 and B3 bemcentinib will be administered at a 
dose identified by the SMC, which may be lower than the 
bemcentinib dose confirmed in Part A. Depending upon 
the safety profile of bemcentinib observed in Part A the 
initial starting dose in combination with cytarabine or 
decitabine may be reduced by a single dose level (e.g., 
MTD -1) which will be evaluated in at least 3 subjects 
before introduction of the MTD or RP2D identified in 
Part A.  
The bemcentinib dose in Part B will be 400 mg orally 
daily for the first 3 days of treatment (loading dose) and 
200 mg orally daily thereafter (maintenance dose).  
DURATION AND FREQUENCY 
Patients 
may 
continue 
to 
receive 
bemcentinib for as long as, in the opinion 
of the investigator, they continue to derive 


 
 
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clinical benefit. When there is confirmed 
disease progression in the absence of 
clinical benefit, development of severe 
toxicity, or withdrawal of consent, study 
treatment 
must 
be 
discontinued. 
However, patients experiencing disease 
progression may be permitted to continue 
treatment with bemcentinib, where the 
investigator 
believes 
patients 
may 
continue to derive some clinical benefit 
from continued treatment. 
Clinical benefit in this context is defined as meeting one 
or several of the following criteria: evidence of disease 
stabilization after documented initial progression (patient 
is stably worse), tolerance of drug(s), absence of rapid 
progression based on peripheral or bone marrow blasts 
and 
clinical 
hematology 
and 
clinical 
chemistry 
parameters, maintenance of good performance status 
(PS of 2 or less and not deteriorating], absence of 
worsening clinical symptoms (i.e., no symptomatic 
deterioration) and/or improvements in patient’s quality of 
life). 
The decision to continue treatment must be discussed 
and agreed between the treating investigator, the patient 
and the Sponsor. All decisions will be documented in 
writing. Patients dosed beyond progression will continue 
to be evaluated for potential clinical benefit and safety. 
This will not affect the time point of disease progression 
from the perspective of trial analysis. 
Patients who permanently discontinue treatment with 
one of the combination agents in Parts B2, B3 and B5 
may continue to receive the other study drug alone if it is 
safe to do so (at investigator discretion) in the absence 
of disease progression or intolerable toxicity. The 
investigator may also decide to discontinue both study 
treatments at this time.  
EVALUATION: 
  
As outlined in the relevant Schedule of Events 
(Tables 6-8). 
Safety: 
Physical examination 
Vital signs  
ECG 
Echocardiogram 


 
 
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Routine blood panel (hematology, clinical chemistry and 
coagulation panel) 
Adverse events (AEs) (CTCAE) 
Efficacy: 
Peripheral blood count; BM aspirate 
Pharmacokinetics: 
Bemcentinib PK parameters in plasma (Part A and Part 
B) 
Pharmacodynamics: 
The effects of bemcentinib on pharmacodynamic 
endpoints, gene expression and genomics in BM 
aspirates and PBMC.  
FOLLOW UP: 
AEs will be monitored for 28 days after the last dose of 
study 
treatment. 
If 
bemcentinib-related 
toxicities 
continue beyond the follow up period, patients will be 
followed until all bemcentinib-related toxicities have 
resolved to <Grade 1 or less, stabilized or returned to 
baseline. Follow up monitoring for AEs may be 
conducted over the telephone. Serious adverse events 
(SAEs) with a suspected relationship to bemcentinib will 
be collected indefinitely. 
The study will be completed when all patients have 
completed their final study visit. 
All patients will be followed for survival after they have 
permanently discontinued from study treatment at 
≤3 monthly intervals by the site. Subsequent anticancer 
therapies for AML or MDS must be collected in the 
electronic case report form (eCRF). 
The study will be completed when all patients have an 
OS event, unless the Sponsor terminates OS follow-up 
once all patients have discontinued study treatment. 
STATISTICAL METHODS 
As this is an early study of bemcentinib only descriptive 
analysis will be performed on safety data. Preliminary 
statistical analysis will be performed on objective 
response rates in Part B.  
Safety:  
All safety and tolerability assessments will be based on 
the safety analysis set (all patients who have received at 
least one dose of study medication).  
Efficacy: 
Efficacy assessments will be based on the safety 
analysis set. 


 
 
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Note: patients treated with bemcentinib beyond disease 
progression will be followed for the same safety and 
efficacy assessments as for all other patients enrolled 
into the study until they are withdrawn from the study. 
The data for patients treated beyond progression will be 
presented in both a combined output (with all patients) 
and also a separate output (to reflect a new period of 
analysis). All data collected will be included in the study 
CSR. 
Pharmacokinetics: 
Individual and mean bemcentinib plasma concentration-
time data will be presented in tabular and graphical form. 
PK parameters for bemcentinib will be derived from an 
appropriate PK model will be determined using a 
non-compartmental analysis. Full details of the PK 
analysis will be presented in a PK Analysis Plan. 
Pharmacodynamics: 
Pharmacodynamic data will be listed and summarized by 
dose cohort and time point as appropriate.  
 
 
 


 
 
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7. Introduction 
This study is a dose-escalation of bemcentinib, an AXL kinase inhibitor, in patients with acute 
myeloid leukemia (AML), followed by a cohort expansion study of bemcentinib either as a 
single agent in patients with AML or MDS, or in combination with cytarabine (cytosine 
arabinoside, Ara-C) or decitabine in patients with AML.  
7.1. Pre-clinical Studies with Bemcentinib 
7.1.1. Summary of Pre-clinical Activity 
Bemcentinib demonstrates potent inhibition of AXL in biochemical and cell-based kinase 
inhibition assays. The selectivity of bemcentinib for AXL is illustrated in Table 1. 
Table 1: Bemcentinib Kinase Selectivity Profile 
Kinase 
Kinome Scan 
binding assay 
(Kd) 
KinaseProfiler 
kinase activity assay 
(IC50) 
BaF3 cell-based kinase 
activity assay 
(IC50) 
nM 
fold 
nM 
fold 
nM 
fold 
AXL 
0.4 
1 
4.6 
1 
63 
1 
Tie2 
270 
680 
30 
6.4 
355 
5.5 
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 
n/a = not applicable 
Bemcentinib inhibits the growth and survival of tumor cell lines derived from a range of solid 
and leukemic tumors. In vitro activity of bemcentinib has been examined in a range of different 
AML cell lines where exposure-induced differentiation and arrest in the G1 phase of the cell 
cycle was accompanied by a reduction in levels of phosphorylated AXL and phosphorylated 
ERK. Early in vitro and ex vivo studies indicate that AXL inhibition with bemcentinib also 
inhibits proliferation of clonal cells derived from patients with MDS. 
The in vivo efficacy of bemcentinib has been evaluated in two different murine models of AML. 
Studies in the MDV4-11 xenograft model showed a dose-dependent reduction in tumor burden 
following oral treatment with bemcentinib. A dose-dependent reduction in both AXL and ERK 
phosphorylation levels were noted. Bemcentinib treatment also significantly inhibited tumor 
growth in the OCI-AML5 xenograft model. Furthermore, bemcentinib has been shown to 
significantly prolong survival in the syngeneic bone marrow (BM) transplantation Hoxa9/Meis1 
mouse model [Ben-Batalla, 2013]. 
As described by Ben-Batalla, BM cells from 7 out of 11 patients with primary AML were 
sensitive to bemcentinib (IC50 = 1.9  0.5µM), and this inhibition was independent of FLT3 
status since FLT3 WT AML cells were similarly sensitive to bemcentinib (n=3/8; p=0.4212). 


 
 
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Furthermore, the EC50 of response to bemcentinib correlated with AXL protein expression 
levels (n=10; R2=0.84; p<0.05), with AXL negative cells being almost completely resistant to 
bemcentinib. Bemcentinib treatment also significantly sensitized BM cells from primary patient 
AML cells to cytarabine [Ben-Batalla, 2013].  
Population studies have identified both AXL expression and circulating levels of Gas 6 as 
independent predictors of prognosis [Whitman, 2013].  
A modest substrate and time-dependent inhibition of CYP3A4/5 activity by bemcentinib was 
observed in an in vitro study with human liver microsomes. Preliminary results from a 
cytarabine in vitro metabolism study indicate that cytarabine does not undergo extensive 
metabolism by CYP3A4. Consequently, it is considered unlikely that there will be an interaction 
between bemcentinib and cytarabine. Decitabine does not undergo CYP450 mediated 
metabolism; therefore, there is no rationale for the evaluation of its interaction with 
bemcentinib. 
A comprehensive summary of the pre-clinical activity of bemcentinib is presented in the current 
version of the Investigator’s Brochure (IB). 
7.1.2. Summary of Pre-clinical Toxicology 
To support clinical studies with bemcentinib a series of animal toxicology and safety studies, 
including 28-day repeat dosing studies in rodents and monkeys and a single dose telemetered 
cardiovascular (CV) safety study in monkeys, have been conducted. Comparisons of the data 
reported in the rodent and monkey studies indicate that primates are more sensitive to 
bemcentinib on a per body weight basis. 
The results of the repeat dose 28-day study in monkeys identified the liver, reticuloendothelial 
system and hematopoietic system as target organs. These events were largely thought to be 
due to macrophage accumulation, consistent with phospholipidosis, and were only partially 
reversible across the planned 16-day recovery period, although this was anticipated to be due 
to the slow elimination of the compound. Similar findings were identified in mice treated across 
a range of dose levels with partial recovery noted 16 days later. 
In the CV safety study, single oral administration of bemcentinib (7.5 mg/kg – 60 mg/kg) was 
associated with recoverable, non-adverse decreases in heart rate and corresponding 
increases in the RR interval durations. Dose-dependent increase in QTc interval was noted at 
all dose levels; the magnitude of the QTc effect at the highest dose level was 17%, whilst at 
7.5 mg/kg and 15 mg/kg, the change generally fell below 10% compared to vehicle control 


 
 
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and pre-dose values. These observations were consistent with the previously identified IC50 
for human ether-à-go-go related gene (hERG) channel inhibition of 0.53 M bemcentinib. 
Bemcentinib was negative in the Ames bacterial mutation assay, suggesting that bemcentinib 
is not mutagenic. Bemcentinib was also negative in an in vitro mammalian cell cytogenetic 
study in human lymphocytes suggesting that bemcentinib is not clastogenic.  
7.1.3. High Dose Steroids and Mouse Model 
In an academic model of osteoporosis, bemcentinib 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 bemcentinib used in this model was 50 mg/kg which is 6-fold higher 
than the maximum exposure observed in human clinical studies. 
In a follow-up study, the equivalent dose of prednisolone (0.208 mg/kg) was given as an oral 
bolus once a day for 9 days. The prednisolone dosed orally was well tolerated and no major 
issues were reported upon necropsy (336-TR-324-TOX). It was concluded that the toxicity 
observed when the prednisolone was continually administered by subcutaneous implantation, 
was a direct consequence of sustained exposure to steroid which would not occur when it is 
dosed orally once a day. 
Please refer to the current version of the IB for further information on the results of the 
preclinical studies when bemcentinib was combined with steroids. 
7.2. Clinical Studies with Bemcentinib 
There has been one previous clinical study completed with bemcentinib (Protocol BGBC001). 
This study explored the effect of a single dose of bemcentinib (dose range: 50, 100, 150, 200, 
400, 600, 1000 and 1500 mg) in healthy male volunteers under fasted conditions, with a sub-
study in limited number of the volunteers to assess dosing under fed conditions. Eight dose 
levels (50 mg, 100 mg, 150 mg, 200 mg, 400 mg, 600 mg, 1000 mg and 1500 mg) were 
administered under fasted conditions to cohorts of four subjects (32 subjects in total). Seven 
of these subjects went on to receive the same dose of bemcentinib administered under fed 
conditions. Other studies with bemcentinib are being conducted in triple negative breast 
cancer or triple negative inflammatory breast cancer, Stage IIIb or Stage IV non-small cell lung 


 
 
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cancer (NSCLC), advanced adenocarcinoma of the lung and melanoma (please refer to the 
current version of the bemcentinib IB or clinicaltrials.gov for further details). 
7.2.1. Summary of Clinical Safety 
Please refer to the current version of the bemcentinib IB for the most up-to-date safety 
information.  
In general exposure to bemcentinib in BGBC001 bemcentinib was well tolerated with all 
toxicities being spontaneously reversible and predominantly gastrointestinal in nature. No 
serious adverse events (SAE) were reported. Reported adverse events (AE) are summarized 
in Table 2.  
Table 2: Bemcentinib-Related Adverse Events Reported Following a Single Oral 
Administration of Bemcentinib (50 mg to 1500 mg) to Healthy Male Subjects 
Dose 
(mg) 
Number of Subjects 
Toxicity 
Maximum Grade  
(CTCAE version 4.0) 
50 
4 fasted; 1 fed 
Non-Cardiac Chest Pain 
One 
100 
4 fasted; 2 fed 
Paraesthesia  
Orthostatic hypotension 
One 
150 
4 fasted; 1 fed 
Abdominal Distension (n=2) 
One 
200 
4 fasted; 1 fed 
Respiratory tract infection 
One 
400 
4 fasted; 2 fed 
Diarrhoea 
One 
600 
4 fasted 
Diarrhoea 
Flatulence 
Nausea (n=2) 
One 
One 
One 
1000 
4 fasted 
Nausea 
One 
1500 
4 fasted 
Diarrhoea 
Nausea 
Vomiting 
Headache 
Dizziness 
Oropharyngeal pain 
One 
Two 
Two 
One 
One 
One 
 
 
7.2.1.1. 
ECG Findings 
In light of the findings reported in the safety pharmacology studies described in Section 7.1.2, 
all subjects in study BGBC001 underwent serial ECG recordings following the administration 
of bemcentinib. The overall pattern indicated that bemcentinib administration was 
accompanied by a variable increase in QTc interval according to Fridericia’s correction 
(QTcF), the magnitude of which was related to systemic exposure. The maximum QTcF 
recorded was Grade 1 in severity.  


 
 
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7.2.2. Summary of Clinical Pharmacokinetics 
Concentrations of bemcentinib 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 quantification of 2.0 ng/mL. Pharmacokinetic (PK) 
parameters were derived by non-compartmental analysis using WinNonlin Phoenix Version 
6.3 (Pharsight Corporation Inc., Mountain View, CA, USA, 2012). 
Following a single oral dose of bemcentinib at doses between 50 mg and 1500 mg, 
administered under fasted conditions, mean maximal plasma concentrations of 7.63 ng/mL to 
388 ng/mL were reached at 8 hours (h) to 23 h post-dose as presented in Figure 1.  
Figure 1: Mean Plasma Concentrations of Bemcentinib Following a Single Oral 
Administration of Bemcentinib at 50, 100, 150, 200, 400, 600, 1000 and 1500 mg to 
Healthy Male Subjects 
 
 
 
The mean apparent terminal half-life (t1/2) of bemcentinib was 45.6 h to 88.7 h. Between-
subject variability in systemic exposure (area under the curve from time zero to infinity 
(AUC0-∞) and maximum concentration achieved (Cmax)) to bemcentinib at 50 mg to 1500 mg 
was generally high (coefficient of variation of 25.8% to 96.7% for area under the concentration-
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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time curve (AUC0-t) and Cmax), most probably reflecting variable absorption. Across this dose 
range Cmax of bemcentinib increased approximately dose proportionately, although the AUC0-
∞ of bemcentinib increased slightly greater than dose proportionately. 
Following administration of bemcentinib with food (whole milk and buttered toast) to 7 subjects 
who had previously received bemcentinib, there was an overall reduction in the between-
subject variability with an increase in systemic exposure to bemcentinib 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. 
7.2.3. Selection of the Starting Dose for Clinical Study BGBC003 
Bemcentinib clinical development studies to date have involved two formulations. The first 
study in healthy volunteers, Study BGBC001, used Formulation 1. Study BGBC004, in patients 
with non-small cell lung cancer has used Formulation 2 and given bemcentinib when patients 
have fasted. This study, BGBC003, will evaluate both Formulation 1 (taken when patients are 
fed), and Formulation 2 (taken when patients are fasted). Please see Section 7.2.3.1 and the 
current version of the bemcentinib IB for more details. 
In Study BGBC001, 32 subjects received doses of bemcentinib in the range 50 to 1500 mg 
under fasted conditions, of which seven also received the same dose of bemcentinib under 
fed conditions. The time to maximum concentration (tmax) and the apparent t½ were generally 
comparable between fed and fasted conditions; tmax ranged from 6 to 30 hours and t½ ranged 
from 30.2 to 77.2 hours (except in one subject where t½ was reliably estimated as 165 hours). 
There was an increase in systemic exposure to bemcentinib in three subjects, no appreciable 
change in three subjects and an apparent reduction in systemic exposure in one subject when 
bemcentinib was given with food compared to under fasted conditions. 
Overall, Cmax and area under the curve from time zero to 48 hours (AUC0-48h) under fed 
conditions were 29% and 21% greater, respectively compared to fasted conditions; however, 
the 95% confidence interval (CI) of the ratio (fed/fasted) included 100%, indicating that the 
apparent effect of food was not statistically significant. The elimination of bemcentinib was 
slow with a t½ of longer than 24 hours. A consequence of this prolonged t½ is the delay in the 
time taken to achieve steady state, which is estimated to be approximately two weeks following 
the initiation of bemcentinib administration. Such a delay would not be therapeutically 
acceptable in patients with advanced cancers. 


 
 
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The proposed starting dose and dosing schedule for clinical studies of bemcentinib in patients 
was therefore based on a one-compartment model, incorporated a lag time and no weighting 
to available clinical PK data. According to this model it was anticipated that the application of 
a loading dose (on Days 1 and 2) would enable a rapid achievement of therapeutic levels of 
bemcentinib, with a maintenance daily dosing from Day 3 to maintain optimum exposures 
whilst preventing wide changes in systemic concentration during therapy (see Figure 2 and 
Figure 3). 
Current PK data suggest that bemcentinib would be best administered as a loading dose on 
up to the first three days of treatment, followed by a daily maintenance dose (see Figure 2 and 
Figure 3).  
Figure 2: Simulated Plasma Concentrations of Bemcentinib for 600 mg Loading Dose 
on Days 1 and 2 and Daily Dose of 200 mg from Day 3 (fed) 
 
 
0
50
100
150
200
250
300
350
400
450
0
24
48
72
96
120
144
168
192
216
240
264
Concentration (ng/mL)
Time (h)


 
 
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Figure 3: Simulated Plasma Concentrations of Bemcentinib for 600 mg Loading Dose 
on Days 1 and 2 and Daily Dose of 200 mg from Day 3 (fasted) 
 
AE data to date suggest that gastrointestinal toxicities are more pronounced during and shortly 
after administration of the bemcentinib loading dose. It remains desirable to achieve 
bemcentinib steady-state as soon as possible in patients with advanced cancer, and in order 
to improve compliance during initial bemcentinib dosing, a 3-day loading dose is 
recommended, whilst ensuring steady-state is still reached by Day 4 (see Figure 4). 
Figure 4: Predicted Plasma Concentrations of Bemcentinib after 1200 mg Loading Dose 
Given as 600 mg on Days 1 and 2 or 400 mg on Days 1, 2 and 3, followed by Daily Dose 
of 200 mg (fasted) 
 
 


 
 
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For study BGBC003, dosing will consist of a loading dose of 200 mg administered on Days 1, 
2 and 3 followed by a daily maintenance dose of 100 mg. This dose may be escalated as 
agreed by the SMC to a maximum daily loading dose of 400 mg on Days 1, 2 and 3 followed 
by a maximum daily maintenance dose of 200 mg. A Recommended Phase 2 dose (RP2D) 
will be selected in Part A for further evaluation in Part B. 
7.2.3.1. 
Formulation 1 and Formulation 2 
As part of the formulation development program, recommendations for Formulation 1 
consisted of a loading dose of 400 mg on Cycle 1, Days 1 and 2, followed by a daily 
maintenance dose of 100 mg. Dosing with Formulation 1 was completed in 2016.  
Formulation 2 includes additional excipients resulting in an improved solubility profile when 
compared to Formulation 1. Repeated doses of Formulation 2 have already been administered 
to NSCLC patients in the fasting state in Study BGBC004, where drug absorption was 
increased and less variable when compared to data from patients receiving Formulation 1. pH 
studies suggest that bemcentinib exhibits increased solubility in an acid environment, thus 
patients should receive Formulation 2 in the fasted state upon waking and should not be 
receiving baseline gastric protectants including Proton Pump Inhibitors, Histamine Receptor 
two antagonists or antacids when starting therapy with bemcentinib. They may receive 
treatment with these agents in the evening if required for symptoms; but only when established 
on bemcentinib therapy (i.e. following at least one week of treatment with bemcentinib).  
The increased absorption of bemcentinib seen with Formulation 2 in Study BGBC004 was well 
tolerated following a loading dose of 600 mg on Days 1 and 2, followed by a daily dose of 
200 mg, but because of the increased bioavailability of this preparation, a starting loading dose 
of 200 mg administered on Days 1, 2 and 3 followed by a daily maintenance dose of 100 mg 
will be introduced for Formulation 2 in Study BGBC003. 
This dose may be escalated as agreed by the SMC to a maximum daily loading dose of 
400 mg on Days 1, 2 and 3 followed by a maximum daily maintenance dose of 200 mg. 
Further details of the physicochemical properties of Formulation 1 and Formulation 2 and 
ongoing clinical studies with Formulation 2 can be found in the current version of the 
bemcentinib IB and the investigational medicinal product dossier (IMPD). 


 
 
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8. Study Objectives and Endpoints 
8.1. Objectives 
8.1.1. Primary Objectives 
Part A 
To identify the maximum tolerated dose (MTD) of bemcentinib in AML patients who have 
received previous treatment with cytotoxic chemotherapy (with or without hematopoietic stem 
cell transplantation) or a targeted or biologic agent (e.g. hypomethylating agent, tyrosine 
kinase inhibitor, antibody), and have relapsed after or have been refractory to treatment with 
such prior therapy. 
Part B 
To identify the safety and tolerability of bemcentinib as a single agent in patients with AML or 
MDS (Parts B1 and B4), or in combination with low dose cytarabine (Part B2 and Part B5) or 
decitabine (Part B3), in patients with AML who are unsuitable for intensive chemotherapy as 
a result of advanced age or existing co-morbidities. 
8.1.2. Secondary Objectives 
Part A 
• 
To identify the Dose Limiting Toxicity (DLT) profile of bemcentinib 
• 
To explore the safety and efficacy of bemcentinib  
• 
To characterize the PK profile of bemcentinib  
Part B 
• 
To explore the efficacy of bemcentinib, as a single agent in patients with AML or MDS 
(Parts B1 and B4) 
• 
To explore the efficacy of bemcentinib in combination with low dose cytarabine 
(Part B2 and Part B5) or decitabine (Part B3), in patients with AML who are unsuitable 
for intensive chemotherapy 
• 
To evaluate bemcentinib PK (all Part B cohorts) 


 
 
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8.1.3. Exploratory Objectives 
Parts A and B 
• 
To identify and evaluate potential predictive biomarkers, e.g. soluble AXL (sAXL) and 
other associated soluble biomarkers. Pre-treatment levels of biomarkers will be 
correlated with clinical endpoints 
• 
To establish the effects of bemcentinib on relevant biological endpoints in peripheral 
blood (including sAXL peripheral blood mononuclear cells [PBMC]) and BM samples 
• 
To assess pharmacodynamic biomarkers in tissue and blood to support the clinical 
development of bemcentinib 
• 
To evaluate other biomarkers relevant to the investigational agents for exploratory 
purposes 
8.2. Endpoints 
8.2.1. 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 (BP), heart rate (HR), respiration rate and 
temperature 
• 
Electrocardiogram (ECG) 
• 
Echocardiogram 
• 
Laboratory findings including clinical chemistry, hematology and urinalysis 
8.2.2. Efficacy Endpoints 
In AML, efficacy endpoints will be measured using the following response criteria. 
• 
Objective Response (OR) or Stable Disease (SD) according to the revised 
recommendations of the International Working Group (IWG) in AML [Cheson, 2003 


 
 
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and Döhner, 2017] (see Appendix 5). SD is defined as having unchanged disease for 
at least 3 treatment cycles. 
• 
Proportion of patients with an OR + SD as an estimate of clinical benefit. 
• 
Relapse Free Survival  
• 
Event Free Survival 
• 
Overall Survival 
• 
To explore the correlation between baseline biomarker levels and clinical endpoints  
In MDS, efficacy endpoints will be measured using the following response criteria. 
• OR or SD according to the revised recommendations of the IWG in MDS (see 
Appendix 6). SD is defined as failure to achieve at least PR but not evidence of PD for 
at least 3 treatment cycles. 
• Proportion of patients with an OR + SD as an estimate of clinical benefit. 
• Relapse Free Survival 
• Event Free Survival 
• Overall Survival 
• To explore the correlation between baseline biomarker levels and clinical endpoints  
8.2.3. Pharmacokinetic Endpoints 
As a minimum, area under the curve within a dosing interval (AUC0-tau), Cmax, and time to 
maximum concentration (Tmax) for bemcentinib will be determined from plasma. Additional 
parameters may also be reported, as deemed appropriate once data are reviewed. 
8.2.4. Pharmacodynamic and Predictive Endpoints 
The effects of bemcentinib on pharmacodynamic endpoints of AXL inhibition will be 
determined in BM aspirates and blood samples:  
• 
To identify and evaluate potential predictive biomarkers, e.g. sAXL and other 
associated soluble biomarkers. Pre-treatment levels of biomarkers will be 
correlated with clinical endpoints 


 
 
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• 
To establish the effects of bemcentinib on relevant biological endpoints in 
peripheral blood (including sAXL PMBCs) and BM samples 
• 
To assess pharmacodynamic biomarkers in tissue and blood to support the clinical 
development of bemcentinib 
• 
To evaluate other biomarkers relevant to the investigational agents for exploratory 
purposes 
• 
Effect of bemcentinib on AXL, sAXL and phospho AXL (pAXL) and downstream 
effectors of AXL signaling, such as Akt, pAkt, Erk, pErk, SLFN11, Bcl2, Puma by 
appropriate methods (e.g. flow cytometry (FCM), western blotting, proteomics, 
transcriptomics) 
• 
Effect of bemcentinib on gene expression by appropriate methods (e.g. FCM, 
western blotting, proteomics, transcriptomics, quantitative polymerase chain 
reaction (PCR), DNA-methylation analysis) 
• 
Effect of bemcentinib on relevant immune cell populations 
• 
Effect of bemcentinib on the spectrum of mutations present within the cancer cell 
population by genomic analysis 
• 
To explore the correlation between baseline biomarker levels and clinical 
endpoints 


 
 
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9. Study Design 
9.1. Overview 
This is a Phase Ib/II, open-label, dose-escalation and cohort expansion study to obtain a 
preliminary assessment of the safety, tolerability and efficacy of bemcentinib, a small molecule 
inhibitor of AXL kinase in patients with AML or MDS. The study will be conducted at up to 
approximately 20 sites in Europe and the US and will be performed in approximately 102 
evaluable patients with AML or MDS. Additional countries and sites may be added as required 
to meet the enrolment needs of the study. 
In Part A bemcentinib will be administered as monotherapy in patients with relapsed or 
refractory AML following previous treatment with cytotoxic chemotherapy (with or without 
hematopoietic stem cell transplantation) or a targeted or biologic agent (e.g. hypomethylating 
agent, tyrosine kinase inhibitor, antibody). 
In Part B bemcentinib will be administered as a single agent in patients with AML who are 
unsuitable for intensive chemotherapy (i.e. cytarabine/anthracycline on a 3+7 dose or 
equivalent) as a result of advanced age and/or existing co-morbidities (Part B1) or in MDS 
patients who have previously received treatment (Part B4) and a further 3 cohorts of 
bemcentinib administered in combination with low dose cytarabine (Part B2 and Part B5) or 
decitabine (Part B3) in patients with AML who are unsuitable for intensive chemotherapy 
because of advanced age or existing co-morbidities will be investigated 
In all parts of the study, AML patients with a matched donor and who are candidates for 
allogeneic BM transplantation are not eligible to participate.  
Bemcentinib will be administered orally according to a daily schedule during continuous 
21-day treatment cycles. During Cycle 1, Week 1 ONLY the first 3 doses of bemcentinib may 
serve as a ‘loading’ dose.  
Dosing will consist of a loading dose of 200 mg administered on Days 1, 2 and 3 followed by 
a daily maintenance dose of 100 mg. This dose may be escalated as agreed by the SMC to a 
maximum daily loading dose of 400 mg on Days 1, 2 and 3 followed by a maximum daily 
maintenance dose of 200 mg. 
Patients will be instructed to take bemcentinib on an empty stomach at a similar time each 
morning when they wake or more than 2 hours after a light meal, with water. To maintain a 
fasted state, patients should be told not eat or drink anything other than water for at least 
1 hour after taking the drug. 


 
 
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In Part A the study will follow a 3+3 design to explore the safety and tolerability of repeat 
dosing of bemcentinib, and to identify the MTD. A minimum of 6-10 patients will be treated at 
the MTD or RP2D, as determined by the SMC. Depending upon the results of this phase of 
the study, the safety and efficacy of bemcentinib may be established in up to 4 disease-specific 
cohorts in Part B.  
Part B1 
Single agent bemcentinib will be administered to patients with AML who are unsuitable for 
intensive chemotherapy (i.e. cytarabine/anthracycline on a 3+7 dose or equivalent) as a result 
of advanced age and/or existing co-morbidities. In order to be eligible patients should have 
received at least one line of previous therapy.  
Part B2 
Bemcentinib will be administered in combination with low dose cytarabine in patients with AML 
who are unsuitable for intensive chemotherapy as a result of advanced age or existing 
co-morbidities.  
Part B3 
Bemcentinib will be administered in combination with decitabine in patients with AML who are 
unsuitable for intensive chemotherapy as a result of advanced age or existing co-morbidities.  
Part B4 
Single agent bemcentinib will be administered to patients with previously treated MDS 
(including high risk and intermediate with the exception of deletion 5q MDS). 
Part B5  
Bemcentinib will be administered in combination with cytarabine in patients with AML who are 
unsuitable for intensive chemotherapy as a result of advanced age or existing co-morbidities. 
Patients must have received at least one prior treatment for AML. 
Please refer to Figure 5 for an outline of the overall study design. 
 
 


 
 
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Figure 5: BGBC003 Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.2. Study Specifics 
9.2.1. Phase I DLT Assessment Period 
During the dose-escalation phase (Part A), safety, tolerability, PK, and preliminary clinical 
activity of bemcentinib will be assessed, and the MTD established, in patients who have 
received previous treatment with cytotoxic chemotherapy or a targeted or biologic agent (e.g. 
hypomethylating agent, tyrosine kinase inhibitor, antibody) and have relapsed after or have 
been refractory to treatment with such prior therapy. Patients receiving an allograft in first 
remission would be eligible at the time of relapse. 
A loading dose (Cohort 1) of 200 mg administered on Cycle 1, Days 1, 2 and 3 followed by a 
daily maintenance dose of 100 mg during continuous 21-day treatment cycles will be 
evaluated. This dose may be escalated as agreed by the SMC to a maximum daily loading 
dose of 400 mg on Days 1, 2 and 3 followed by a maximum daily maintenance dose of 200 mg 
(see Section 9.2.1.2). At least 3 evaluable patients will be entered per cohort.  
Part A 
Enrolment 3+3 dose escalation 
3-6 patients per cohort to receive daily doses of bemcentinib (21day cycle) 
Safety, tolerability, PK efficacy assessed in relapsed/refractory (R/R) AML 
Dose allocation 
Part B5 
Bemcentinib + low 
dose cytarabine 
N ≤20 
Safety, tolerability, 
PK, efficacy 
AML Unsuitable for 
Intensive 
Chemotherapy 
Part B4 
Single Agent 
bemcentinib 
N ≤ 14 
Safety, tolerability, 
PK, efficacy 
Previously treated 
MDS 
Part B3 
Bemcentinib + 
decitabine 
N ≤ 14 
Safety, tolerability, 
PK, efficacy 
AML Unsuitable for 
Intensive 
Chemotherapy 
Part B2 
Bemcentinib + low 
dose cytarabine 
N ≤ 14 
Safety, tolerability, 
PK, efficacy 
AML Unsuitable for 
Intensive 
Chemotherapy 
Part B1 
Single Agent 
bemcentinib 
N ≤ 14 
Safety, tolerability, 
PK, efficacy 
R/R AML 
Unsuitable for 
Intensive 
Chemotherapy 
Assess 6-10 patients with R/R AML with proposed RP2D 
Ongoing Safety Review 


 
 
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9.2.1.1. 
Dose Escalation Scheme 
Initially three patients will be recruited into Cohort 1 and will complete 1 cycle of treatment 
before a dose-escalation evaluation is made. A patient must receive all loading doses and 
miss no more than 3 maintenance doses in Cycle 1 in order to be considered as informative 
to support dose escalation, unless the missed doses are due to bemcentinib toxicity (see 
Section 9.2.1.2. Dose Limiting Toxicity). 
The decision to dose-escalate (or not) will be made by the SMC comprising a representative 
from each actively recruiting investigational site and a representative of the BerGenBio ASA 
study team. Minutes of the SMC meeting will be recorded and circulated for final approval 
before being placed in the Trial Master File (TMF). The decision to dose escalate will be based 
upon the tolerability of bemcentinib. 
Where dose escalation occurs, 3 patients will be recruited to the next cohort (dose level) and 
will complete 1 cycle of treatment before a dose-escalation evaluation is made, as outlined 
above. 
If one 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 dose below will be nominated as the MTD. If the starting dose exceeds 
the MTD, a lower dose may be explored if recommended by the SMC. Provided treatment with 
the starting dose is considered safe by the SMC according to DLT evaluation, dose escalation 
may proceed. 
Possible dosing levels are illustrated in Table 3. Dosing with Formulation 2 will consist of a 
loading dose of 200 mg administered on Days 1, 2 and 3 followed by a daily maintenance 
dose of 100 mg. This dose may be escalated as agreed by the SMC to a maximum daily 
loading dose of 400 mg on Days 1, 2 and 3 followed by a maximum daily maintenance dose 
of 200 mg. The maximum daily dose that may be explored in this study will be 400 mg. 
Table 3: Possible Bemcentinib Dosing Levels Involving A Loading Dose and Daily Dose 
for Part A 
Total  
Loading Dose over 3 days (mg) 
Days 1, 2 and 3  
Loading Dose (mg) 
Daily maintenance dose 
(mg) 
600 
200* 
100* 
1200 
400 
200 
 
 
 
*starting dose 


 
 
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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. 
Please refer to Figure 6 for the operating characteristics of the Dose Escalation process. 
Figure 6: The 3+3 Dose Escalation Design 
 
 
9.2.1.2. 
Dose Limiting Toxicity 
DLT will be assessed during the first 3 weeks of treatment with bemcentinib (Cycle 1), 
according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) [NCI CTCAE] version 4 considered unrelated to leukemia progression or 
intercurrent illness, and defined as any of the following:  
• 
CTCAE Grade 3 or 4 nausea, vomiting, or diarrhea that persists despite maximum 
prophylactic and supportive care. 
• 
Any other CTCAE Grade 3 or 4 non-hematological toxicity that is considered to be 
clinically significant and causally related to bemcentinib, excluding isolated changes 


 
 
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in laboratory results if no clinical significance or no clinical sequelae and adequately 
improve within 7 days. 
• 
Prolonged neutropenia with ANC <500 and platelet count <75000 after Day 42 from 
the start of treatment in the absence of residual leukemia. 
• 
Treatment discontinuation, inability to administer one or more bemcentinib loading 
dose, or inability to administer three bemcentinib maintenance doses as a result of 
bemcentinib-related toxicity. 
• 
Any ventricular arrhythmia. 
9.2.2. Part B 
Following SMC review of all treatment emergent safety and efficacy data from Part A, up to 
14 evaluable patients (up to 20 evaluable patients in Part B5) will be recruited into each of up 
to five cohorts (Parts B1, B2, B3, B4 and B5). Depending upon the safety profile of bemcentinib 
observed in Part A the initial starting dose in combination with cytarabine (Part B2) or 
decitabine (Part B3), may be reduced by a single dose level (i.e. MTD -1) which may be 
evaluated in at least three subjects before introduction of the MTD or RP2D identified in Part A. 
Recruitment into Part B5 will be overseen by the Sponsor’s study team or designee. The 
number of recruitment slots for patients with refractory AML, defined as no hematological 
response to last AML treatment and/or patients who have received 2 or more prior treatments 
for AML, will be restricted to 1/3 of the sample size (i.e. no more than 6 evaluable patients).The 
study team will notify investigators when recruitment restrictions are applied. 
AML Treatment Status 
 
Pre-Screening Approval 
Requirement 
One prior treatment for AML and NOT refractory 
Sponsor approval not required prior 
to screening 
Two or more prior treatments for AML 
Sponsor approval mandatory prior to 
screening 
Refractory AML*  
Sponsor approval mandatory prior to 
screening 
 
* Refractory AML is defined as no hematological response to last AML treatment and/or patients who have received 
2 or more prior treatments for AML (see Appendix 5 of Protocol BGBC003: Modified International Working Group 
Response Criteria in Acute Myeloid Leukaemia [Cheson , 2003, Döhner, 2017]) 
9.3. Overall Study Duration and Follow Up 
The study period will consist of screening, treatment period, Final Study Visit, and follow-up 
period. The Final Study Visit will occur 28 days after the patient has discontinued study 


 
 
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treatment. All subjects will be followed up for survival after the Final Study Visit unless they 
withdraw consent or are lost to follow-up. Subsequent anti-cancer therapy for AML or MDS 
will be reported in the electronic case report form (eCRF) 
9.3.1. Screening 
Patient eligibility for the study will be determined within 14 days prior to the first dose of study 
treatment. Screening assessments will be conducted according to the Schedule of Events 
tables in Section 11. 
9.3.2. Treatment 
Eligible patients will visit the study site to receive study treatment and protocol-specified 
procedures according to the relevant Schedule of Events table in Section 11. The treatment 
period will consist of continuous 21-day treatment cycles of bemcentinib.  
Patients will be intensively monitored throughout Day 1 to Day 4 inclusive of Cycle 1, and in 
addition will attend the clinic on Day 8, and Day 15. Patients will attend the clinic once per 
week during Cycle 2 and then once per cycle thereafter. All patients will continue to receive 
bemcentinib or the combination for as long as, in the opinion of the investigator, they continue 
to derive clinical benefit. When there is unacceptable toxicity, confirmed disease progression 
in the absence of clinical benefit, or withdrawal of consent, bemcentinib or combination 
treatment must be discontinued. For patients in the combination arms (Part B2, B3 or B5), if 
treatment related toxicity requires permanent discontinuation, and the toxicity can be clearly 
assigned to one of the study treatments, the other study drug in the combination can be 
continued if it is safe to do so (investigator discretion) in the absence of disease progression 
or intolerable toxicity. The investigator may also decide to discontinue both study treatments 
at this time. 
9.3.2.1 Dosing patients beyond progression 
An important clinical observation in the last decade is that immune activation does not 
necessarily result in complete cancer regression for all patients, but nonetheless, clinical 
improvements are observed. In this context and for elderly patients with R/R AML, unfit for 
intensive chemotherapy and with no alternative treatments available for their disease, 
achieving stable disease and/or becoming transfusion independent, together with 
performance status improvement, can be viewed as a positive signal. Thus, where in the 
investigator’s opinion, the patient’s disease is considered “clinically stable” with clear 
improvement in the patient’s symptomatology and with no other treatment options available, 


 
 
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other than palliative care, it may be in the patient’s best interests to remain on treatment with 
bemcentinib. 
Therefore, patients experiencing disease progression are permitted to continue treatment with 
bemcentinib where the investigator believes patients may continue to derive clinical benefit 
from continued treatment.  
Clinical benefit in this context is defined as meeting one or several of the following criteria: 
evidence of disease stabilization after documented initial progression (patient is stably worse), 
tolerance of drug(s), absence of rapid progression based on peripheral or bone marrow blasts 
and clinical hematology and clinical chemistry parameters, maintenance of good performance 
status (PS of 2 or less and not deteriorating], absence of worsening clinical symptoms (i.e., 
no symptomatic deterioration) and/or improvements in patient’s quality of life). 
Importantly, the decision to continue treatment must be discussed and agreed by the treating 
investigator, the patient and the Sponsor. All decisions will be documented in writing. Patients 
dosed beyond progression will continue to be evaluated for potential clinical benefit and safety. 
This will not affect the time point of disease progression from the perspective of trial analysis. 
9.3.3. Final Study Visit 
Patients should return to the study site for the Final Study Visit 28 days after permanent 
discontinuation of all study treatments.  
9.3.4. Follow Up 
An AE will be monitored for 28 days after the last dose of bemcentinib although only events 
considered to be related to treatment need to be recorded in the eCRF between the last 
administration of bemcentinib and the end of the 28 day follow up period. If bemcentinib-
related toxicities continue beyond the follow up period, patients will be followed until all 
bemcentinib-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. 
SAEs with a suspected relationship to bemcentinib will be collected beyond the 28-day 
follow-up period until the event is resolved to ≤ Grade 1, stabilized or returned to baseline. 
All patients that have permanently discontinued study treatment for whatever reason must be 
followed for survival. The investigator or designee must confirm with the patient at the time of 
the Final Study Visit how the patient will be followed for survival (e.g. contact with family or 


 
 
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health care provider). Survival follow-up must be conducted at least every 3 months by the 
investigator or designee and the date-of-death reported in the eCRF. 
All subsequent anticancer therapy for AML or MDS must be reported in the eCRF. 
9.4. Study Stopping Rules 
BerGenBio ASA reserves the right to close a site or terminate the study at any time. The 
investigator may also terminate the study at their site at any time, provided there is reasonable 
cause for the intended termination. This action may be taken after appropriate consultation 
with the Sponsor and the Investigator. Conditions that may warrant termination of the study or 
involvement of a study site include, but are not limited to: 
• 
The discovery of an unexpected, serious or unacceptable risk to patients enrolled in 
the study 
• 
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 bemcentinib in AML 
9.5. End of Study 
Except in the case of early termination (Section 9.4), the end of the study is defined as the 
date when all patients have an OS event, unless the Sponsor terminates OS follow-up once 
all patients have discontinued study treatment. Should the last patient enrolled to the study be 
continuing to receive bemcentinib 52 weeks from their Cycle 1 Day 1, the Sponsor may choose 
to lock the data base to that point and prepare the clinical study report (CSR). Data collected 
as part of this study after this point, will be reported as an addendum to the CSR. 
A final CSR will be prepared when the last patient has completed their Final Study Visit and 
the database is locked. The Statistical Analysis Plan (SAP) will be finalized and signed before 
database lock. 


 
 
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Patients will continue to be followed for suspected SAEs until these are resolved to ≤ Grade 1, 
stabilized or returned to baseline. Refer to Section 15.2.2 for SAE reporting after the end of 
study. 


 
 
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10. Selection of Subjects 
10.1. 
Inclusion Criteria 
1. Provision of signed written informed consent 
2. Histological or cytological confirmation of: 
 AML (with the exception of AML M3) 
a) 
Part A: Patients with relapsed or refractory AML following treatment with cytotoxic 
chemotherapy (with or without hematopoietic stem cell transplantation) or a 
targeted or biologic agent (e.g. hypomethylating agent, tyrosine kinase inhibitor, 
antibody)   
b) 
Part B1: Patients with AML who are unsuitable for intensive chemotherapy as a 
result of advanced age or co-morbidities. Patients should have relapsed following 
at least one line of therapy or be refractory to such prior therapy 
c) 
Part B2: Patients with diagnosed AML who are unsuitable for intensive 
chemotherapy as a result if advancing age or co-morbidities and who are suitable 
to receive treatment with cytarabine 
d) 
Part B3: Patients with AML who are unsuitable for intensive chemotherapy as a 
result if advancing age or co-morbidities who are suitable to receive treatment with 
decitabine 
MDS (with the exception of deletion 5q MDS) 
e) 
Part B4: Patients with previously treated MDS (with the exception of deletion 5q 
MDS) including intermediate and high-risk patients who must have received prior 
treatment for their disease. Prior treatment may include those patients who have 
received hypomethylating agents, decitabine or other approved treatments for 
MDS. 
f) 
Part B5: Patients with relapsed or refractory AML who are unsuitable for intensive 
chemotherapy as a result of advanced age or co-morbidities meeting the following 
criteria: 
• 
Must have received at least one prior treatment for AML 


 
 
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• 
Are suitable to receive treatment with "low-dose" cytarabine (LDAC). 
LDAC is defined as 20 mg cytarabine administered subcutaneously twice 
daily for 10 days every 28 days. 
The number of patients with refractory AML, defined as no hematological 
response to last AML treatment and/or patients who have received 2 or more 
prior treatments for AML, will be restricted to 1/3 of the sample size (i.e. no 
more than 6 evaluable patients). Please refer to table in Section 9.2.2. 
3. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 
[Appendix 1] 
4. Age 18 years or older 
5. Female patients of childbearing potential must have a negative serum pregnancy test 
within 3 days prior to taking their first dose of bemcentinib. 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, tubal ligation, total sexual 
abstinence, vasectomy) throughout the study and for >3 months after the last dose of 
bemcentinib. Female patients are considered NOT of childbearing potential if they 
have a history of surgical sterility or evidence of post-menopausal status defined as 
any of the following: 
a) 
Natural menopause with last menses >1 year ago 
b) 
Radiation induced oophorectomy with last menses >1 year ago 
c) 
Chemotherapy induced menopause with last menses >1 year ago 
10.2. 
Exclusion Criteria 
1. Patients who have a matched donor and are candidates for allogeneic BM 
transplantation 
2. Pregnant or lactating 
3. History of the following cardiac conditions: 
• 
Congestive cardiac failure of >Class II severity according to the NYHA (Appendix 2: 
defined as symptomatic at less than ordinary levels of activity) 


 
 
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• 
Ischemic cardiac event including myocardial infarction within 3 months prior to first 
dose. Patients with prior history or ECG evidence of old myocardial infarction 
should be discussed with the Sponsor to confirm eligibility. 
• 
Uncontrolled cardiac disease, including unstable angina, uncontrolled hypertension 
(i.e. sustained systolic BP >160 mmHg or diastolic BP >90 mmHg), or need to 
change medication within 6 weeks of provision of consent due to lack of BP control 
• 
History or presence of sustained bradycardia (≤55 beats per minute), left bundle 
branch block, cardiac pacemaker or ventricular arrhythmia. Note: Patients 
with supraventricular arrhythmia should be discussed with Sponsor to confirm 
eligibility.  
• 
Family history of long QTc syndrome; personal history of long QTc syndrome or 
previous drug-induced QTc prolongation of at least Grade 3 (QTc >500 ms) 
• 
Presence of any factors that increase the risk for QTc prolongation, e.g. resistant 
or inadequately treated heart failure, presence of hypokalemia or hypomagnesemia 
not corrected by, or not responding to, replacement therapy or inadequately treated 
hypothyroidism as defined by the thyroid-stimulating hormone not within the 
expected range of the institution. 
4. Abnormal left ventricular ejection fraction on echocardiography or Multi Gated 
Acquisition Scan (MUGA) (less than the lower limit of normal for a patient of that age 
at the treating institution or <45%, whichever is lower) 
5. Current treatment with any agent known to cause QT prolongation and have a risk for 
Torsades de Pointes which cannot be discontinued at least five half-lives or two weeks 
prior to the first dose of study treatment. Please see Appendix 3 for list of relevant 
medications 
6. Screening 12-lead ECG with a measurable QTcF >450 ms 
7. Ongoing infection requiring systemic treatment. Patients who are on prophylactic 
antimicrobials or who have been afebrile for 48 hours following the initiation of 
antimicrobials are eligible 
8. Inadequate liver function as demonstrated by serum bilirubin ≥1.5 times the upper 
limits of normal range (ULN) or alanine aminotransferase (ALT) or aspartate 


 
 
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aminotransferase (AST) ≥2.5 times the ULN (or ≥5 times the ULN for AST or ALT in 
the presence of liver involvement by leukemia) 
9. Inability to tolerate oral medication 
10. Existing gastrointestinal disease affecting drug absorption such as celiac disease or 
Crohn’s disease 
11. Known lactose intolerance 
12. Requires vitamin K antagonists. Note: Patients receiving low doses prescribed to 
maintain the patency of venous access devices may be included 
13. 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 bemcentinib, 
whichever is longer 
14. Treatment with any medication which is predominantly metabolized by CYP3A4 and 
has a narrow therapeutic index. Please see Appendix 4 for details of CYP3A4 
substrates. 
15. Previous bowel resection that would interfere with drug absorption 
16. Evidence of ongoing gastrointestinal graft versus host disease 
17. Hematopoietic stem cell transplantation within 6 months  
18. Impaired renal function as demonstrated by a creatinine clearance of <30 mL/min 
determined by Cockcroft-Gault formula 
19. Radiotherapy or chemotherapy within the 14 days prior to the first dose of bemcentinib 
being administered (other than hydroxyurea)  
20. Receiving an investigational anti-cancer treatment concurrently or within 14 days or 
five half-lives (whichever is shorter) of either the parent drug or any known active 
metabolite prior to the start of bemcentinib 
21. Unresolved CTCAE >Grade 2 toxicity (other than stable toxicity) from previous 
anti-cancer therapy excluding alopecia 


 
 
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22. 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 
23. Known active, uncontrolled central nervous system (CNS) disease including CNS 
leukemia 
24. Active infection with human immunodeficiency virus (HIV), hepatitis B or C viruses – 
screening for viral infections is not required for entry to this study 
25. Major surgery within 28 days prior to the start of bemcentinib – excluding skin biopsies 
and procedures for insertion of central venous access devices 
26. Hypersensitivity to cytarabine, decitabine or any of their excipients 
27. Prior exposure to Astellas ASP2215 (FLT3/AXL inhibitor Gilteritinib) 


 
 
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11. Study Procedures and Assessments 
The Schedule of Events for specific parts of the study are summarized in the following tables 
as outlined below: 
• 
Part A in Table 4 
• 
Parts B1 and B4 in Table 5 
• 
Parts B2, B3 and B5 in Table 6 


 
 
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Table 4: Part A Schedule of Events  
Cycle 
1 
2 
>3 
End of Study 
Week 
1 
2 
3 
4 
5 
6 
>7 
 
Visit 
Screen 
1 
2 
3 
4 
5 
6 
7 
8 
9 
>10 
Cycle Day 
-14 to 0 
1 
2 
3 
4 
8 
15 
1 
8 
15 
1 
28 days after 
last dose 
Visit window (+/-) days 
 
0 
0 
0 
0 
0 
0 
2 
1 
1 
2 
1 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Physical examinationa 
X 
Xe 
 
 
 
X 
X 
X 
 
 
X 
X 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy testd 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
Clinical chemistryf 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyg 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation screenh 
X 
Xe 
 
 
 
X 
X 
X 
 
 
X 
X 
Urinalysis 
X 
Xe 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Bone marrow aspirate 
X 
 
 
 
 
 
 
Xk 
 
 
Xk 
 
Bone marrow aspirate 
(Pharmacodynamic) 
Xi 
(Xi) 
 
 
(Xj) 
 
 
Xk 
 
 
Xk 
 
Echocardiogram/MUGA 
X 
 
 
 
 
 
 
 
 
 
Xl 
 
PK blood samplingm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pharmacodynamic blood 
samplingn 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Response criteriao 
 
 
 
 
 
 
 
X 
 
 
X 
 
Bemcentinib administrationp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Bemcentinib accountability 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Overall survival 
 
If the patient dies during the study period, report the date-of-death in the eCRF. 
Xq 


 
 
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a. A full physical examination, excluding gynecological and rectal examinations, will be conducted at the Screening and End of Study visits. A symptom-
directed examination will be conducted at selected visits 
b. Vital signs (systolic and diastolic blood pressure (BP), heart and respiration rate and temperature) will be taken at every visit  
c. Triplicate 12-lead ECGs will be taken, ≤5 minutes apart, after resting for ≥10 minutes in supine position at every visit. During Cycle 1 Days 1-4 ECGs 
will coincide with selected PK sampling time-points i.e. pre-dose and 2, 4, 6 hr post-dose (Day 1); 24 (pre 2nd dose) and 30 hr post-Day 1 dose (Day 
2); 48 hr (pre 3rd dose) post-Day 1 dose (Day 3); pre-dose, 2, 4 and 6 hr post-dose (Day 4). Patients who re-start bemcentinib following interruption for 
>7 days are recommended to recommence with a loading dose, with ECGs performed per this intensive schedule. Patients who do not receive the 
loading dose should attend the clinic for additional ECG assessments between Day 8 and 15, and between Day 15 and the end of Cycle 1. All time-
points are approximate, but every effort must be made to make ECG assessment at specified time-points  
d. For women of child-bearing potential 
e. Unless conducted as part of the screening procedures within 3 days prior to Day 1 
f. 
Clinical chemistry laboratory parameters (uric acid, electrolytes, blood urea nitrogen (BUN), total protein, total bilirubin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), serum creatinine, creatine phosphokinase, alkaline phosphatase, albumin, calcium, magnesium, phosphorus, 
glucose,)  
g. Hematology laboratory parameters (full blood count including differential white cell count and blast count, hemoglobin, hematocrit and platelets) 
h. Coagulation parameters: prothrombin time (PT) and activated partial thromboplastin time (APTT) 
i. 
Bone marrow aspirate for diagnosis and baseline sample for pharmacodynamic biomarker analyses. If diagnostic bone marrow aspirate is routinely 
frozen, a repeat (fresh) bone marrow aspirate should be taken on Day -1 or Day 0 (pre-dose) for pharmacodynamic biomarker analyses  
j. 
Optional bone marrow aspirate for pharmacodynamic biomarker analyses.  
k. Bone marrow aspirate for clinical response assessment and pharmacodynamic biomarker analyses is mandatory at Cycle 2 Day 1 (pre-dose); optional 
assessments may be performed on Day 1 of every cycle thereafter and as clinically indicated.  
l. 
Echocardiogram/MUGA scan Cycle 4 Day 1 ONLY 
m. Blood sampling for the determination of bemcentinib in plasma will be conducted at the following Cycle 1 time-points:  
3-day loading dose schedule or no loading dose: pre-dose and 2, 4, 6 hr post-dose (Day 1); 24 (pre 2nd dose) and 30 hr post-Day 1 dose (Day 2); 
48 hr (pre 3rd dose) and 2, 4, 6, 8 hr post-dose (Day 3); and pre-dose (Day 4) 
A pre-dose sample will be collected at ALL study visits (including >3 Cycle 3 (up to and including Cycle 15) and End of Study). All time-points are 
approximate, but every effort must be made to take samples at specified time-points. Actual times must be recorded. Maximum sampling time-points 
are described. Please refer to the local Laboratory Manual for time-points required at each site   
n. Blood sampling for pharmacodynamic biomarker analyses will involve a maximum 33 mL blood volume at Cycle 1 Day 1 and Day 4, Day 1 of each 
cycle thereafter, (up to and including Cycle 15), and End of Study visit, or a multiple number of 4.5 mL blood samples to match the pharmacokinetic 
samples (see Tables 12-14). Please refer to the local Laboratory Manual for time-points required at each site.  
o. Assessment of clinical response (% blasts; neutrophil count; platelet count). Response assessment should be performed by the investigator according 
to the modified response criteria in Appendix 5 (Cheson, 2003 and Döhner, 2017).  
p. Bemcentinib should be taken on an empty stomach at a similar time each morning when they wake, or more than 2 hours after a light meal, with water. 
To maintain a fasted state, patients should be told not eat or drink anything other than water for at least 1 hour after taking the drug. Patients should 
record dosing in the dosing diary provided. On study visit days, bemcentinib should be administered on the unit. 
q. All patients that have not died prior to the Final Study Visit should be followed for survival at ≤3-monthly intervals. The date of death must be reported 
for all patients in the eCRF (unless they are lost to follow-up or withdraw consent. 


 
 
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Table 5: Parts B1 and B4 Schedule of Events  
Cycle 
1 
2 
>3 
End of 
Study 
Follow-Up 
Week 
1 
2 
3 
4 
5 
6 
>7 
 
 
Visit 
Screen 
1 
2 
3 
4 
5 
6 
7 
8 
9 
>10 
Cycle Day 
-14 to 0 
1 
2 
3 
4 
8 
15 
1 
8 
15 
1 
28 days 
after last 
dose 
 
Visit window (+/-) days 
 
0 
0 
0 
0 
0 
0 
2 
1 
1 
2 
1 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
Physical examinationa 
X 
Xe 
 
 
 
X 
X 
X 
 
 
X 
X 
 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead triplicate ECGc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum pregnancy testd 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
Clinical chemistryf 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematologyg 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation screenh 
X 
Xe 
 
 
 
X 
X 
X 
 
 
X 
X 
 
Urinalysis 
X 
Xe 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Bone marrow aspirate 
X 
 
 
 
 
 
 
Xk 
 
 
Xk 
 
 
Bone marrow aspirate (Pharmacodynamic) 
X 
(Xi) 
 
 
(Xj) 
 
 
Xk 
 
 
Xk 
 
 
Echocardiogram/MUGA 
X 
 
 
 
 
 
 
 
 
 
Xl 
 
 
PK blood samplingm 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacodynamic blood samplingn 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Response assessmento 
 
 
 
 
 
 
 
X 
 
 
X 
Xo 
Xo 
Bemcentinib administrationp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Bemcentinib accountability 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
 
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Cycle 
1 
2 
>3 
End of 
Study 
Follow-Up 
Week 
1 
2 
3 
4 
5 
6 
>7 
 
 
Visit 
Screen 
1 
2 
3 
4 
5 
6 
7 
8 
9 
>10 
Cycle Day 
-14 to 0 
1 
2 
3 
4 
8 
15 
1 
8 
15 
1 
28 days 
after last 
dose 
 
Record subsequent AML/MDS treatment in 
eCRF 
 
 
 
Xq 
Overall Survival 
 
If the patient dies during study period, please report the date-of-death 
in the eCRF 
 
 
a. A full physical examination, excluding gynecological and rectal examinations, will be conducted at the Screening and End of Study visits. A symptom-
directed examination will be conducted at selected visits 
b. Vital signs (systolic and diastolic blood pressure (BP), heart and respiration rate and temperature) will be taken at every visit  
c. Triplicate 12-lead ECGs will be taken, ≤5 minutes apart, after resting for ≥10 minutes in supine position at every visit. During Cycle 1 Days 1-4 ECGs 
will coincide with selected PK sampling time-points i.e. pre-dose and 2, 4, 6 hr post-dose (Day 1); 24 (pre 2nd dose) and 30 hr post-Day 1 dose (Day 
2); 48 hr (pre 3rd dose) post-Day 1 dose (Day 3); pre-dose, 2, 4 and 6 hr post-dose (Day 4). All time-points are approximate, but every effort must be 
made to make ECG assessment at specified time-points 
d. For women of child-bearing potential 
e. Unless conducted as part of the screening procedures within 3 days prior to Day 1 
f. 
Clinical chemistry laboratory parameters (uric acid, electrolytes, blood urea nitrogen (BUN), total protein, total bilirubin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), serum creatinine, creatine phosphokinase, alkaline phosphatase, albumin, calcium, magnesium, phosphorus, 
glucose)  
g. Hematology laboratory parameters (full blood count including differential white cell and blast count, hemoglobin, hematocrit and platelets) 
h. Coagulation parameters: prothrombin time (PT) and activated partial thromboplastin time (APTT) 
i. 
Bone marrow aspirate for diagnosis and baseline sample for pharmacodynamic biomarker analyses. If diagnostic bone marrow aspirate is routinely 
frozen, a repeat (fresh) bone marrow aspirate should be taken on Day -1 or Day 0 (pre-dose) for pharmacodynamic biomarker analyses 
j. 
Optional bone marrow aspirate for pharmacodynamic biomarker analyses. 
k. Bone marrow aspirate for response assessment and pharmacodynamic biomarker analyses are mandatory at Cycle 2 Day 1 (pre-dose), Cycle 4 Day 1 
and every 3rd cycle thereafter until PD is confirmed. For patients that remain on study for more than 12 months without PD, response assessments can 
be performed after every 5 cycles until the patient experiences PD or permanently withdraws from study treatment for other reasons. Optional 
assessments may be performed at any time during the study as clinically indicated. 
l. 
Echocardiogram Cycle 4 Day 1 ONLY 
m. Blood sampling for the determination of bemcentinib in plasma will be conducted at the following Cycle 1 time-points:  
3-day loading dose schedule or no loading dose: pre-dose and 2, 4, 6 hr post-dose (Day 1); 24 (pre 2nd dose) and 30 hr post-Day 1 dose (Day 2); 
48 hr (pre 3rd dose) and 2, 4, 6, 8 hr post-dose (Day 3); and pre-dose (Day 4) 


 
 
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A pre-dose sample will be collected at ALL study visits (including ≥3 Cycle 3 (up to and including Cycle 15) and End of Study). All time-points are 
approximate, but every effort must be made to take samples at specified time-points. Actual times must be recorded. Maximum sampling time-points 
are described. Please refer to the local Laboratory Manual for required time-points.  
n. Blood sampling for pharmacodynamic biomarker analyses will involve a maximum 33 mL blood volume taken at pre-dose at Cycle 1 Day 1 and Day 4, 
Day of each cycle thereafter (up to and including Cycle 15) and End of Study visit   
o. Assessment of response (% blasts; neutrophil count; platelet count) until treatment failure is confirmed. Response assessment should be performed by 
the investigator according to the modified response criteria in Appendix 5 (Cheson, 2003 and Döhner, 2017) for AML and Appendix 6 (Cheson, 2006) 
for MDS. 
p. Bemcentinib should be taken on an empty stomach at a similar time each morning when they wake, or more than 2 hours after a light meal, with water. 
To maintain a fasted state, patients should be told not eat or drink anything other than water for at least 1 hour after taking the drug. Patients should 
record dosing in the dosing diary provided. On study visit days, bemcentinib should be administered on the unit. The bemcentinib dose in Part B will be 
400 mg orally daily for the first 3 days of treatment (loading dose) and 200 mg orally daily thereafter (maintenance dose). 
q. All patients that have not died prior to the Final Study Visit should be followed for survival at ≤3-monthly intervals. The date of death must be reported 
for all patients in the eCRF (unless they are lost to follow-up or withdraw consent. 
 
 


 
 
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Table 6: Parts B2, B3 and B5 Schedule of Events  
Cycle 
1 
2 
>3 
End of 
Study 
Follow-Up 
Week 
1 
2 
3 
4 
5 
6 
>7 
 
 
Visit 
Screen 
1 
2 
3 
4 
5 
6 
7 
8 
9 
>10 
Cycle Day 
-14 to 0 
1 
2 
3 
4 
8 
15 
1 
8 
15 
1 
28 days 
after last 
dose 
 
Visit window (+/-) days 
 
0 
0 
0 
0 
0 
0 
2 
1 
1 
2 
1 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
 
Physical examinationa 
X 
Xe 
 
 
 
X 
X 
X 
 
 
X 
X 
 
Vital signsb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-lead triplicate ECGc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum pregnancy testd 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
Clinical chemistryf 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematologyg 
X 
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Coagulation screenh 
X 
Xe 
 
 
 
X 
X 
X 
 
 
X 
X 
 
Urinalysis 
X 
Xe 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Bone marrow aspirate 
X 
 
 
 
 
 
 
Xk 
 
 
Xk 
 
 
Bone marrow aspirate 
(Pharmacodynamic) 
X 
(Xi) 
 
 
(Xj) 
 
 
Xk 
 
 
Xk 
 
 
Echocardiogram/MUGA 
X 
 
 
 
 
 
 
 
 
 
Xl 
 
 
PK blood sampling (bemcentinib)m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pharmacodynamic blood samplingn 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Response assessmento 
 
 
 
 
 
 
 
X 
 
 
X 
Xo 
Xo 
Bemcentinib administrationp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Bemcentinib accountability 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Cytarabine/decitabine administrationq 
 
X 
 
 


 
 
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Cycle 
1 
2 
>3 
End of 
Study 
Follow-Up 
Week 
1 
2 
3 
4 
5 
6 
>7 
 
 
Visit 
Screen 
1 
2 
3 
4 
5 
6 
7 
8 
9 
>10 
Cycle Day 
-14 to 0 
1 
2 
3 
4 
8 
15 
1 
8 
15 
1 
28 days 
after last 
dose 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Record subsequent AML treatment in 
eCRF 
 
 
 
X 
Overall Survival 
 
If the patient dies during study period, please report the date-of-death in the 
eCRF 
X 
Xr 
 
a. A full physical examination, excluding gynecological and rectal examinations, will be conducted at the Screening and End of Study visits. A symptom-
directed examination will be conducted at selected visits 
b. Vital signs (systolic and diastolic blood pressure (BP), heart and respiration rate and temperature) will be taken at every visit  
c. Triplicate 12-lead ECGs will be taken, ≤5 minutes apart, after resting for ≥10 minutes in supine position at every visit. During Cycle 1 Days 1-4 ECGs 
will coincide with selected PK sampling time-points i.e. pre-dose and 2, 4, 6 hr post-dose (Day 1); 24 (pre 2nd dose) and 30 hr post-Day 1 dose (Day 2); 
48 hr (pre 3rd dose) post-Day 1 dose (Day 3); pre-dose, 2, 4 and 6 hr post-dose (Day 4). All time-points are approximate, but every effort must be made 
to make ECG assessment at specified time-points 
d. For women of child-bearing potential 
e. Unless conducted as part of the screening procedures within 3 days prior to Day 1 
f. 
Clinical chemistry laboratory parameters (uric acid, electrolytes, blood urea nitrogen (BUN), total protein, total bilirubin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), serum creatinine, creatine phosphokinase, alkaline phosphatase, albumin, calcium, magnesium, phosphorus, 
glucose)  
g. Hematology laboratory parameters (full blood count including differential white cell and blast count, hemoglobin, hematocrit, and platelets) 
h. Coagulation parameters: prothrombin time (PT) and activated partial thromboplastin time (APTT) 
i. 
Bone marrow aspirate for diagnosis and baseline sample for pharmacodynamic biomarker analyses. If diagnostic bone marrow aspirate is routinely 
frozen, a repeat (fresh) bone marrow aspirate should be taken on Day -1 or Day 0 (pre-dose) for pharmacodynamic biomarker analyses 
j. 
Optional bone marrow aspirate for pharmacodynamic biomarker analyses.  
k. Bone marrow aspirate for response assessment and pharmacodynamic biomarker analyses are mandatory at Cycle 2 Day 1 (pre-dose), Cycle 4 Day 1 
and every 3rd cycle thereafter until PD is confirmed. For patients that remain on study for more than 12 months without PD, response assessments can 
be performed after every 5 cycles until the patient experiences PD or permanently withdraws from study treatment for other reasons. Optional 
assessments may be performed at any time during the study as clinically indicated. 
l. 
Echocardiogram to be performed at Screening and on Cycle 4 Day 1 ONLY; or at any time during the study as clinically indicated. 


 
 
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m. Blood sampling for the determination of bemcentinib in plasma will be conducted at the following Cycle 1 time-points: 
3-day loading dose schedule or no loading dose: pre-dose and 2, 4, 6 hr post-dose (Day 1); 24 (pre 2nd dose) and 30 hr post-Day 1 dose (Day 2); 
48 hr (pre 3rd dose) and 2, 4, 6, 8 hr post-dose (Day 3); and pre-dose (Day 4) 
A pre-dose sample will be collected at ALL study visits (including ≥3 Cycle 3 (up to and including Cycle 15) and End of Study). All time-points are 
approximate, but every effort must be made to take samples at specified time-points. Actual times must be recorded. Maximum sampling time-points 
are described. Please refer to the local Laboratory Manual for required time-points   
n. Blood sampling for pharmacodynamic biomarker analyses will involve a maximum 33 mL blood volume taken at pre-dose at Cycle 1 Day 1 and Day 4, 
Day 1 of each cycle thereafter, (up to and including Cycle 15), and End of Study visit   
o. Assessment of response (% blasts; neutrophil count; platelet count) until treatment failure is confirmed. Response assessment should be performed by 
the investigator according to the modified response criteria in Appendix 5 (Cheson, 2003 and Döhner, 2017) 
p. Bemcentinib should be taken on an empty stomach at a similar time each morning when they wake, or more than 2 hours after a light meal, with water. 
To maintain a fasted state, patients should be told not eat or drink anything other than water for at least 1 hour after taking the drug. Patients should 
record dosing in the dosing diary provided. On study visit days, bemcentinib should be administered on the unit. The bemcentinib dose in Part B will be 
400 mg orally daily for the first 3 days of treatment (loading dose) and 200 mg orally daily thereafter (maintenance dose). 
q. Please refer to Section 12.1.2 for administration details. 
r. 
All patients that have not died prior to the Final Study Visit should be followed for survival at ≤3-monthly intervals. The date of death must be reported 
for all patients in the eCRF (unless they are lost to follow-up or withdraw consent. 
 
  


 
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11.1. 
Enrolment 
Patients must provide written informed consent before any study-specific screening 
procedures are performed. Patients who meet all inclusion/exclusion criteria will be allocated 
a study-specific patient number. 
11.1.1. Blinding Procedures 
This is an open-label study and consequently there are no blinding procedures in operation. 
11.2. 
Screening 
During screening, the following procedures will be performed: 
• 
Obtain written informed consent  
• 
Demographic data, including date of birth, sex, height, and race 
• 
Medical and surgical history 
• 
Concomitant medication 
• 
Physical examination, including weight 
• 
Echocardiogram or MUGA scan 
• 
Vital sign measurements (systolic and diastolic BP, heart and respiration rate and 
temperature) 
• 
Serial 12-lead ECGs, in triplicate (<5 minutes apart), performed after the patient has 
been supine for >10 minutes) 
• 
ECOG performance status [Appendix 1] 
• 
Collection of blood sample for hematology (including neutrophil and platelet count), 
clinical chemistry profile 
• 
Coagulation panel 
• 
Routine urinalysis 
• 
Serum pregnancy test, where appropriate 
• 
BM aspirate for confirmation of the diagnosis and baseline sample for 
pharmacodynamic biomarker analyses 
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 bemcentinib. Highly effective methods of contraception are defined as: 
• 
Hormonal implants, combined oral contraceptives, injectable contraceptives, 


 
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• 
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 two barrier 
methods used in conjunction are acceptable. 
In order to reduce the risk of tumor lysis syndrome all patients will be asked to drink up to two 
liters of fluid in the 24-hour period prior to starting treatment with bemcentinib and on Day 0, 
Day 1, Day 2 and Day 3. All patients will receive treatment with allopurinol (or equivalent) for 
at least the first week of treatment or until their serum uric acid is within the normal range or 
has returned to baseline levels. 
11.3. 
Treatment Period 
The following sections outline the assessments to be conducted in each part of the study. For 
Cycle 2 and beyond a visit window of +/-48 hours is allowed for the Day 1 visit and +/-24 hours 
for other visits, per protocol. For details of allowable windows around specific PK/PD sampling 
time-points please refer to the relevant footnotes for Tables 4-6. The timing of the Cycle 1 Day 
1 and Day 4 post-dose ECGs should approximate to the PK sampling time-points. Details of 
allowable windows around visits and specific procedures will be included in the eCRF 
completion guidance documentation. 
11.3.1. Part A 
Please refer to the Schedule of Events outlined in Table 4. 
11.3.1.1. Cycle 1 
In addition to the assessments below, AEs and concomitant medications will be recorded on 
each visit. Patients will be intensively monitored throughout Day 1 to Day 4 inclusive during 
Cycle 1.  
Visit 1 (Day 1): 
• 
Physical examination, including weight (unless conducted as part of the screening 
procedures within 3 days prior to Day 1) 
• 
BM aspirate for baseline sample for pharmacodynamic biomarker analyses (pre-dose) 
ONLY if the diagnostic BM aspirate was frozen (and therefore unsuitable for PD 
analyses)  


 
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• 
Collection of additional PD biomarker blood sample (pre-dose) ONLY if BM aspirate 
sample is not collected 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile (unless conducted as part of the screening procedures within 
3 days prior to Day 1) 
• 
Coagulation panel (unless conducted as part of the screening procedures within 3 days 
prior to Day 1) 
• 
Routine urinalysis unless conducted as part of the screening procedures within 3 days 
prior to Day 1) 
• 
Serum pregnancy test, where appropriate (unless conducted as part of the screening 
procedures within 3 days prior to Day 1) 
• 
12-lead ECGs per screening procedures (pre-dose and 2, 4, and 6 hr post-dose) 
• 
Vital signs per screening procedures 
• 
Collection of PK blood samples (at time-points outlined in Table 4) 
• 
Collection of pharmacodynamic biomarker blood samples (at time-points outlined in 
Table 4) 
• 
Bemcentinib administration 
Visit 2 (Day 2): 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile 
• 
12-lead ECGs per screening procedures (24 and 30 hr post Day 1 dose) 
• 
Vital signs per screening procedures 
• 
Collection of PK blood samples (at time-points outlined in Table 4) 
• 
Collection of pharmacodynamic biomarker blood samples (at time-points outlined in 
Table 4) 
• 
Bemcentinib administration 
Visit 3 (Day 3): 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile 
• 
12-lead ECGs per screening procedures (48 hr post Day 1 dose) 
• 
Vital signs per screening procedures 
• 
Collection of PK blood samples (at time-points outlined in Table 4) 
• 
Collection of pharmacodynamic biomarker blood samples (at time-points outlined in 
Table 4) 
• 
Bemcentinib administration 


 
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Visit 4 (Day 4): 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile 
• 
12-lead ECGs per screening procedures (pre-dose and 2, 4, and 6 hr post-dose) 
• 
Vital signs per screening procedures 
• 
Collection of PK blood samples (at time-points outlined in Table 4) 
• 
Collection of pharmacodynamic biomarker blood samples (at time-points outlined in 
Table 4) 
• 
BM aspirate for pharmacodynamic biomarker analyses (OPTIONAL) 
• 
Bemcentinib administration 
Visit 5 (Day 8): 
• 
Physical examination, including weight 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile 
• 
Coagulation panel 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Routine urinalysis 
• 
Collection of PK blood sample (pre-dose) 
• 
Collection of pharmacodynamic biomarker blood sample (pre-dose) 
• 
Bemcentinib administration 
• 
Bemcentinib accountability 
Interim Visit for additional ECG assessment (for patients who do not receive a loading 
dose only) 
Visit 6 (Day 15): 
• 
Physical examination, including weight 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile 
• 
Coagulation panel 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Collection of PK blood samples (pre-dose) 
• 
Collection of pharmacodynamic biomarker blood samples (pre-dose) 
• 
Routine urinalysis 


 
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• 
Bemcentinib administration 
• 
Bemcentinib accountability  
Interim Visit for additional ECG assessment (for patients who do not receive a loading 
dose only) 
11.3.1.2. Cycle 2 
In addition to the assessments below, AEs and concomitant medications will be recorded on 
each visit. 
Visit 7 (Day 1): 
• 
Physical examination, including weight 
• 
ECOG performance status [Appendix 1] 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile  
• 
Coagulation panel 
• 
Routine urinalysis 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Collection of PK blood sample (pre-dose) 
• 
Collection of pharmacodynamic biomarker blood sample (pre-dose) 
• 
Bemcentinib administration 
• 
Bemcentinib accountability 
• 
BM aspirate for clinical response criteria review and PD biomarker analyses (pre-dose) 
unless there is clear evidence of progression in the peripheral blood 
• 
Collection of additional pharmacodynamic biomarker blood sample (pre-dose) ONLY 
if BM aspirate sample is not collected  
• 
Clinical response criteria review according to IWG criteria (refer to Appendix 5) 
Visit 8 (Day 8) and Visit 9 (Day 15): 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile  
• 
Routine urinalysis 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Collection of PK blood sample (pre-dose) 
• 
Collection of pharmacodynamic biomarker blood sample (pre-dose) 


 
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• 
Bemcentinib administration 
• 
Bemcentinib accountability 
11.3.1.3. Cycle 3 and Subsequent Cycles 
In addition to the assessments below, AEs and concomitant medications will be recorded on 
each visit. 
BM aspirates, ECGs and laboratory investigations should be taken more frequently if clinically 
indicated. 
Visit >10 (Day 1): 
• 
Physical examination, including weight 
• 
ECOG performance status [Appendix 1] 
• 
Echocardiogram (Cycle 4 ONLY) 
• 
Collection of blood sample for hematology (including neutrophil and platelet count for 
clinical response criteria review) and clinical chemistry profile  
• 
Coagulation panel 
• 
Routine urinalysis 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Collection of PK blood sample (pre-dose) up to and including Cycle 15 
• 
Collection of pharmacodynamic biomarker blood sample (pre-dose) up to and 
including Cycle 15 
• 
BM aspirate for clinical response criteria review and pharmacodynamic biomarker 
analyses (pre-dose) unless there is clear evidence of progression in the peripheral 
blood (CYCLE 3 ONLY) 
o On Day 1 of Cycle 4 and beyond BM aspirate will be done only if clinically 
indicated 
• 
Clinical response criteria review according to IWG criteria (refer to Appendix 5) 
• 
Collection of additional pharmacodynamic biomarker blood sample (pre-dose) ONLY 
if BM aspirate sample is not collected 
• 
Bemcentinib administration 
• 
Bemcentinib accountability 
11.3.2. Parts B1 and B4 
Please refer to the Schedule of Events outlined in Table 5. 


 
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11.3.2.1. Cycle 1 
In addition to the assessments below, AEs and concomitant medications will be recorded on 
each visit. Patients will be intensively monitored throughout Day 1 to Day 4 inclusive of 
Cycle 1. 
Visit 1 (Day 1): 
• 
Physical examination, including weight (unless conducted as part of the screening 
procedures within 3 days prior to Day 1) 
• 
BM aspirate for baseline sample for pharmacodynamic biomarker analyses (pre-dose) 
ONLY if the diagnostic BM aspirate was frozen (and therefore unsuitable for 
pharmacodynamic analyses)  
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile (unless conducted as part of the screening procedures within 
3 days prior to Day 1) 
• 
Coagulation panel (unless conducted as part of the screening procedures within 3 days 
prior to Day 1) 
• 
Routine urinalysis unless conducted as part of the screening procedures within 3 days 
prior to Day 1) 
• 
Serum pregnancy test, where appropriate (unless conducted as part of the screening 
procedures within 3 days prior to Day 1) 
• 
12-lead ECGs per screening procedures (pre-dose and 2, 4, and 6 hr post-dose) 
• 
Vital signs per screening procedures 
• 
Collection of PK blood samples (at time-points outlined in Table 5) 
• 
Collection of pharmacodynamic biomarker blood sample (pre-dose) 
• 
Bemcentinib administration 
Visit 2 (Day 2): 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile 
• 
12-lead ECGs per screening procedures (24 and 30 hr post Day 1 dose) 
• 
Vital signs per screening procedures 
• 
Collection of PK blood samples (at time-points outlined in Table 5) 
• 
Bemcentinib administration 
Visit 3 (Day 3): 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile  


 
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• 
12-lead ECGs per screening procedures (48 hr post Day 1 dose) 
• 
Vital signs per screening procedures 
• 
Collection of PK blood samples (at time-points outlined in Table 5) 
• 
Bemcentinib administration 
Visit 4 (Day 4): 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile 
• 
12-lead ECGs per screening procedures (pre-dose and 2, 4, and 6 hr post-dose) 
• 
Vital signs per screening procedures 
• 
Collection of PK blood samples (at time-points outlined in Table 5) 
• 
BM aspirate for pharmacodynamic biomarker analyses (OPTIONAL) 
• 
Bemcentinib administration 
Visit 5 (Day 8): 
• 
Physical examination, including weight 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile 
• 
Coagulation panel 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Collection of PK blood sample (pre-dose) 
• 
Routine urinalysis 
• 
Bemcentinib administration 
• 
Bemcentinib accountability 
Visit 6 (Day 15): 
• 
Physical examination, including weight 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile 
• 
Coagulation panel 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Collection of PK blood sample (pre-dose) 
• 
Routine urinalysis 
• 
Bemcentinib administration 
• 
Bemcentinib accountability 


 
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11.3.2.2. Cycle 2 
In addition to the assessments below, AEs and concomitant medications will be recorded on 
each visit. 
Visit 7 (Day 1): 
• 
Physical examination, including weight 
• 
ECOG performance status [Appendix 1] 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile  
• 
Coagulation panel 
• 
Routine urinalysis 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Collection of PK blood sample (pre-dose) 
• 
Collection of pharmacodynamic biomarker blood samples (pre-dose) 
• 
Bemcentinib administration 
• 
Bemcentinib accountability 
• 
BM aspirate for clinical response criteria review and pharmacodynamic biomarker 
analyses (pre-dose) unless there is clear evidence of progression in the peripheral 
blood 
• 
Clinical response criteria review according to IWG criteria (refer to Appendix 5 for AML 
and Appendix 6 for MDS) 
Visit 8 (Day 8) and Visit 9 (Day 15): 
• 
Physical examination, including weight 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile  
• 
Routine urinalysis 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Collection of PK blood sample (pre-dose) 
• 
Bemcentinib administration 
• 
Bemcentinib accountability 


 
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11.3.2.3. Cycle 3 and Subsequent Cycles 
In addition to the assessments below, AEs and concomitant medications will be recorded on 
each visit. 
BM aspirate for response assessment and pharmacodynamic biomarker analyses are 
mandatory at Cycle 2 Day 1 (pre-dose), Cycle 4 Day 1 and every 3rd cycle thereafter until PD 
is confirmed. For patients that remain on study for more than 12 months without PD, response 
assessments can be performed after every 5 cycles until the patient experiences PD or 
permanently withdraws from study treatment for other reasons.  
Optional assessments may be performed at any time during the study as clinically indicated. 
Visit >10 (Day 1): 
• 
Physical examination, including weight 
• 
ECOG performance status [Appendix 1] 
• 
Echocardiogram (Cycle 4 ONLY) 
• 
Collection of blood sample for hematology (including neutrophil and platelet count for 
clinical response criteria review) and clinical chemistry profile  
• 
Coagulation panel 
• 
Routine urinalysis 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Collection of PK blood sample (pre-dose) up to and including Cycle 15 
• 
Collection of pharmacodynamic biomarker blood samples (pre-dose) up to and 
including Cycle 15 
• 
BM aspirate for clinical response criteria review and pharmacodynamic biomarker 
analyses (pre-dose) as per relevant Schedule of Events (Table 5) in Section 11  
• 
Clinical response criteria review according to IWG criteria (refer to Appendix 5 for AML 
and Appendix 6 for MDS) 
• 
Bemcentinib administration 
• 
Bemcentinib accountability 
11.3.3. Part B2, Part B3 and Part B5 
Please refer to the Schedule of Events outlined in Table 6, Section 12.1.2 for cytarabine 
administration and Section 12.1.3 for decitabine administration. 


 
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To accommodate the dosing schedules of decitabine and cytarabine patients will need to 
attend the clinic / unit more frequently than required by the dosing/ assessment schedules of 
bemcentinib. Patients are only required to take bemcentinib capsules at clinic/ unit on those 
study days where study related procedures are being conducted. 
In Part B2 and Part B5, bemcentinib should be administered prior to cytarabine (i.e. 
approximately 30 minutes) and in Part B3, decitabine should be administered within 
30 minutes of the bemcentinib dose.  
Please refer to the Schedule of Events outlined in Table 6. Cytarabine will be administered at 
a dose of 20 mg administered subcutaneously twice daily for up to ten consecutive days 
repeated approximately every 28 days.  
Decitabine will be administered at a dose of 20 mg/m2 body surface area by intravenous 
infusion over 1 hour repeated daily for 5 consecutive days (i.e., a total of 5 doses per treatment 
cycle). 
11.3.3.1. Cycle 1 
In addition to the assessments below, AEs and concomitant medications will be recorded on 
each visit. Patients will be intensively monitored throughout Day 1 to Day 4 inclusive of 
Cycle 1. 
Visit 1 (Day 1): 
• 
Physical examination, including weight (unless conducted as part of the screening 
procedures within 3 days prior to Day 1) 
• 
BM aspirate for baseline sample for pharmacodynamic biomarker analyses (pre-dose) 
ONLY if the diagnostic BM aspirate was frozen (and therefore unsuitable for 
pharmacodynamic analyses)  
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile (unless conducted as part of the screening procedures within 
3 days prior to Day 1) 
• 
Coagulation panel (unless conducted as part of the screening procedures within 3 days 
prior to Day 1) 
• 
Routine urinalysis unless conducted as part of the screening procedures within 3 days 
prior to Day 1) 
• 
Serum pregnancy test, where appropriate (unless conducted as part of the screening 
procedures within 3 days prior to Day 1) 
• 
12-lead ECGs per screening procedures (pre-dose and 2, 4, and 6 hr post-dose) 


 
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• 
Vital signs per screening procedures 
• 
Collection of PK blood samples for bemcentinib and cytarabine analysis (at time-points 
outlined in Table 6 as appropriate) 
• 
Collection of pharmacodynamic biomarker blood samples (at time-points outlined in 
Table 6) 
• 
Bemcentinib administration 
• 
Commence cytarabine (Part B2) or decitabine (Part B3) administration and continue 
per local practice 
Visit 2 (Day 2): 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile 
• 
12-lead ECGs per screening procedures (24, and 30 hr post Day 1 dose) 
• 
Vital signs per screening procedures 
• 
Collection of PK blood samples (at time-points outlined in Table 6) 
• 
Collection of pharmacodynamic biomarker blood samples (at time-points outlined in 
Table 6) 
• 
Bemcentinib administration 
Visit 3 (Day 3): 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile 
• 
12-lead ECGs per screening procedures (48 hr post Day 1 dose) 
• 
Vital signs per screening procedures 
• 
Collection of PK blood samples (at time-points outlined in Table 6) 
• 
Collection of pharmacodynamic biomarker blood samples (at time-points outlined in 
Table 6) 
• 
Bemcentinib administration 
Visit 4 (Day 4): 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile 
• 
12-lead ECGs per screening procedures (pre-dose and 2, 4, and 6 hr post-dose) 
• 
Vital signs per screening procedures 
• 
Collection of PK blood samples (at time-points outlined in Table 6) 
• 
Collection of pharmacodynamic biomarker blood samples (at time-points outlined in 
Table 6) 
• 
BM aspirate for pharmacodynamic biomarker analyses (OPTIONAL) 


 
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• 
Bemcentinib administration 
Visit 5 (Day 8): 
• 
Physical examination, including weight 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile 
• 
Coagulation panel 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Routine urinalysis 
• 
Collection of PK blood sample (pre-dose) 
• 
Collection of pharmacodynamic biomarker blood samples (at time-points outlined in 
Table 6) 
• 
Bemcentinib administration 
• 
Bemcentinib accountability 
 
Visit 6 (Day 15): 
• 
Physical examination, including weight 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile 
• 
Coagulation panel 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Collection of PK blood samples (pre-dose) 
• 
Collection of pharmacodynamic biomarker blood samples (at time-points outlined in 
Table 6) 
• 
Routine urinalysis 
• 
Bemcentinib administration 
• 
Bemcentinib accountability 
11.3.3.2. Cycle 2 
In addition to the assessments below, AEs and concomitant medications will be recorded on 
each visit. 
Visit 7 (Day 1): 
• 
Physical examination, including weight 
• 
ECOG performance status [Appendix 1] 


 
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• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile  
• 
Coagulation panel 
• 
Routine urinalysis 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Collection of PK blood sample (pre-dose) 
• 
Collection of pharmacodynamic biomarker blood sample (pre-dose) 
• 
Bemcentinib administration 
• 
Bemcentinib accountability 
• 
BM aspirate for clinical response criteria review and pharmacodynamic biomarker 
analyses (pre-dose) unless there is clear evidence of progression in the peripheral 
blood 
• 
Clinical response criteria review according to IWG criteria (refer to Appendix 5) 
Visit 8 (Day 8) and Visit 9 (Day 15): 
• 
Collection of blood sample for hematology (including neutrophil and platelet count) and 
clinical chemistry profile  
• 
Routine urinalysis 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Collection of PK blood sample (pre-dose) 
• 
Collection of pharmacodynamic biomarker blood samples (at time-points outlined in 
Table 6) 
• 
Bemcentinib administration 
• 
Bemcentinib accountability 
11.3.3.3. Cycle 3 and Subsequent Cycles 
In addition to the assessments below, AEs and concomitant medications will be recorded on 
each visit. BM aspirate for response assessment and pharmacodynamic biomarker analyses 
are mandatory at Cycle 2 Day 1 (pre-dose), Cycle 4 Day 1 and every 3rd cycle thereafter until 
PD is confirmed. For patients that remain on study for more than 12 months without PD, 
response assessments can be performed after every 5 cycles until the patient experiences 
PD or permanently withdraws from study treatment for other reasons.  
Optional assessments may be performed at any time during the study as clinically indicated. 
 


 
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Visit >10 (Day 1): 
• 
Physical examination, including weight 
• 
ECOG performance status [Appendix 1] 
• 
Echocardiogram (Cycle 4 ONLY) 
• 
Collection of blood sample for hematology (including neutrophil and platelet count for 
clinical response criteria review) and clinical chemistry profile  
• 
Coagulation panel 
• 
Routine urinalysis 
• 
12-lead ECGs per screening procedures 
• 
Vital signs per screening procedures 
• 
Collection of PK blood sample (pre-dose) 
• 
Collection of pharmacodynamic biomarker blood sample (pre-dose) 
• 
BM aspirate for clinical response criteria review and pharmacodynamic biomarker 
analyses (pre-dose) as per relevant Schedule of Events (Table 6) in Section 11 
• 
Clinical response criteria review if BM aspirate conducted according to IWG criteria 
(refer to Appendix 5) 
• 
Bemcentinib administration 
• 
Bemcentinib accountability 
11.4. 
Final Study Visit 
The following assessments will be carried out for every patient enrolled into the study 28 days 
after the last dose of study medication or at study withdrawal: 
• 
Collection of blood sample for hematology (including neutrophil and platelet count for 
clinical response criteria review) and clinical chemistry profile  
• 
Coagulation panel 
• 
Routine urinalysis 
• 
Recording of AEs 
• 
Concomitant medications 
• 
Physical examination, including weight 
• 
ECOG performance status [Appendix 1] 
• 
Vital signs per screening procedures 
• 
12-lead ECGs per screening procedures 
• 
Collection of PK blood sample 
• 
Collection of pharmacodynamic biomarker blood sample 


 
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• 
Bemcentinib accountability 
11.5. 
Survival Follow-up 
• 
All patients must have follow-up at ≤3-monthly intervals to confirm their survival status 
following the Final Study Visit unless they withdraw consent or are lost to follow-up. 
• 
All subsequent therapies must be recorded in the eCRF if the patient has received 
treatment of AML following permanent discontinuation of study treatment. 


 
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12. Treatment of Subjects 
BerGenBio ASA will provide bemcentinib to each study site.  
Please refer to Section 14 for the procedures for preparation, storage, handling, disposal and 
accountability of bemcentinib. 
In Part B2 cytarabine will be administered at a dose of 20 mg subcutaneously twice daily for 
up to 10 consecutive days repeated approximately every 28 days.  
In Part B3 decitabine will be administered per standard local practice up to a maximum dose 
of 20 mg/m2 body surface area by intravenous infusion over 1 hour, repeated daily for 5 
consecutive days (i.e., a total of 5 doses per treatment cycle).  
12.1. 
Treatment Schedule and Administration 
12.1.1. Bemcentinib 
In Part A, the starting dose of bemcentinib (Cohort 1) will be 200 mg on Cycle 1, Days 1, 2 
and 3 (loading dose), followed by a daily maintenance dose of 100 mg. 
Patients will take bemcentinib orally, fasted every day of continuous 21-day treatment cycles. 
Patients receiving Formulation 2 will be instructed to take bemcentinib on an empty stomach 
at a similar time each morning when they wake, or more than 2 hours after a light meal, with 
water. To maintain a fasted state, patients should be told not eat or drink anything other than 
water for at least 1 hour after taking the drug. 
Please note that patients in Parts B2 and B3 will also take bemcentinib according to a 21-day 
treatment cycle i.e. the length of the bemcentinib treatment cycle will not be change to reflect 
the cytarabine or decitabine treatment cycle described in Section 12.1.2.  
The bemcentinib dose in Part B5 (combination with low dose cytarabine) will be 400 mg orally 
daily for the first 3 days of treatment (loading dose) and 200 mg orally daily thereafter 
(maintenance dose). 
Patients will record their dosing at home in a dosing diary that will be reviewed regularly 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 bemcentinib 


 
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bottles, including unused and empty bottles, with them to each study visit. The site staff will 
record the amount of used and unused bemcentinib capsules at selected study visits. 
12.1.2. Cytarabine 
In Part B2 cytarabine will be administered subcutaneously according to standard practice (i.e. 
20 mg/m2 twice daily for 10 days followed by a rest period of <1 month according to persisting 
myelosuppression). Cytarabine should be administered approximately 30 minutes after the 
bemcentinib dose. 
For Part B5, cytarabine will be administered at a dose of 20 mg subcutaneously twice daily for 
10 days every 28 days. Cytarabine should be administered approximately 30 minutes after 
the bemcentinib dose. 
If toxicity presents then the cytarabine dose may be modified in accordance with the approved 
prescribing information or Summary of Product Characteristics (SmPC) and in accordance 
with local treatment guidelines. 
Cytarabine is considered to be standard of care for these patients and will not be supplied or 
reimbursed by BerGenBio ASA. 
12.1.3. Decitabine 
In Part B3 decitabine (Dacogen®) will be administered per standard local practice up to a 
maximum dose of 20 mg/m2 body surface area by intravenous infusion over 1 hour, repeated 
daily for 5 consecutive days (i.e., a total of 5 doses per treatment cycle). The total daily dose 
must not exceed 20 mg/m2 and the total dose per treatment cycle must not exceed 100 mg/m2. 
The cycle should be repeated every 4 weeks depending on the patient's clinical response and 
observed toxicity. It is recommended that patients be treated for a minimum of 4 cycles; 
however, a complete or partial remission may take longer than 4 cycles to be obtained. 
Treatment may be continued as long as the patient shows response, continues to benefit or 
exhibits stable disease, i.e., in the absence of overt progression, in accordance with local 
treatment practice. Decitabine is considered to be standard of care for these patients and will 
not be supplied or reimbursed by BerGenBio ASA. 


 
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12.2. 
Dose Modification 
12.2.1. Bemcentinib 
If a patient experiences drug-related toxicity which requires treatment with bemcentinib to be 
interrupted, a delay of up to 14 days is permitted to allow for resolution of toxicity. Toxicities 
must have resolved to Grade <1 or to baseline for treatment to recommence. For Grade 1 or 
Grade 2 (tolerable) toxicity, the patient may resume dosing at the same dose level. For 
>Grade 2 (intolerable) toxicity, the patient may resume dosing at a dose level defined by the 
grade of the toxicity and the number of occurrence(s) of prior toxicity as outlined in Table 7. 
A maximum of two dose reductions are permitted.  
Table 7: Dose Modification of Bemcentinib Daily Dose 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 adverse event  
Interrupt treatment until toxicity returns to baseline, 
Grade 1 or tolerable Grade 2 
Resume dosing at same dose 
3rd occurrence  
of same adverse event  
 
Interrupt treatment until toxicity returns to baseline, 
Grade 1 or tolerable Grade 2 
Dose reduce by 100 mg 
4th occurrence  
of same adverse event  
Discontinue permanently 
Grade 3 
1st occurrence 
Interrupt treatment until toxicity returns to baseline, 
Grade 1 or tolerable Grade 2 
Dose reduce by 100 mg or 
Discontinue permanently if dose has already been 
reduced  
2nd occurrence  
of same adverse event at G3 
Discontinue permanently 
Grade 4  
1st occurrence 
Discontinue permanently 
Notes: 
• Treatment interruption for bemcentinib-related toxicity should be limited to 14 days  
• Dose reduction below 100 mg daily is not possible (a single capsule contains 100 mg bemcentinib) 
• Patients being considered for dose reduction or permanent discontinuation of bemcentinib, should be 
discussed with the Medical Monitor 
 
 


 
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If after a 14-day delay, toxicity has not resolved to Grade <1 or to baseline the patient should 
be withdrawn from the study. 
In clinical study BGBC001 bemcentinib exhibited evidence of exposure-related QTc 
prolongation, and it is anticipated that QTc prolongation could be dose-limiting in this study. 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 bemcentinib and for 
2 weeks following completion of therapy. Serum calcium and magnesium should be measured 
and reasonable efforts made to maintain at normal levels throughout treatment. Patients with 
a QTc of >480 ms should be closely monitored on the clinical trial unit until their QTc falls 
below 480 ms and their electrolytes should be measured and corrected as necessary.  
If a patient experiences QTc prolongation despite normal serum potassium and magnesium 
levels, bemcentinib dosing should be modified as outlined in Table 8. All values refer to the 
mean of triplicate serial ECG recordings. If a patient experiences a ventricular arrhythmia at 
any time, they should be withdrawn from the study. 
Table 8: Dose Modification of Bemcentinib Daily Dose for QTc Prolongation 
QTcF 
Recommended Bemcentinib 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 


 
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≥Grade 3 (>501 ms)  
1st occurrence 
Interrupt treatment for ≤14 days; 
i) if QTcF reduces to ≤Grade 1, dose reduce by 100 mg or 
discontinue treatment if dose reduction is not possible 
ii) if QTcF does not reduce to ≤Grade 1, discontinue treatment 
2nd occurrence  
Discontinue permanently 
Ventricular arrhythmia 
1st occurrence 
Discontinue permanently 
Notes: 
• Serum calcium, magnesium and potassium should be measured regularly whilst receiving bemcentinib; all 
abnormal results should be corrected; check for use of concomitant medication that are associated with QT 
prolongation. 
• The mean QTcF value from triplicate ECG readings should be used when considering dose modification 
• Treatment interruption for bemcentinib-related toxicity should be limited to 14 days 
• Dose reduction below 100 mg daily is not possible (a single capsule contains 100 mg bemcentinib) 
• Patients being considered for dose reduction or permanent discontinuation of bemcentinib should be 
discussed with the Medical Monitor 
 
12.3. 
Concomitant Medication and Procedures 
All prescription, non-prescription, or over-the-counter medications including herbal remedies 
given to, or 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 bemcentinib in Part A. Patients who have evidence 
of treatment benefit after >1 cycle of treatment in Part B may receive hematopoietic growth 
factors to maintain bemcentinib dosing. 
Concurrent treatment with any agent known to cause QT prolongation and have a risk for 
Torsades de Pointes is an exclusion criterion for the study. A comprehensive list of these 
prohibited medications is provided in Appendix 3. Patients being treated with antacid histamine 
receptor 2 inhibitors or proton pump inhibitors within 3 days of administration of bemcentinib 
will be excluded. The Investigator may initiate treatment with these medications during the 
study, providing they are taken in the evening. 


 
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12.4. 
Continuation of Treatment 
It is acknowledged that the R/R AML setting is a high unmet need for effective therapies, more 
so for those elderly patients unsuitable for intensive chemotherapy enrolled into this study. 
Unlike intensive chemotherapy approaches where a clinical response may be observed 
relatively early in the treatment phase, the Sponsor has observed clinical responses occurring 
later in patients treated with bemcentinib in its immunotherapeutic mode of action when given 
as monotherapy or in combination with other agents. Given that AXL mediates multiple 
survival mechanisms used by cancers (chemotherapy drug resistance, immune evasion) and 
given AXL is found at high levels on immune cells in proximity to some tumors and on the 
tumor cells themselves, it is not unexpected that it may take longer to observe some clinical 
responses in some patients as bemcentinib inhibits the expression of AXL and allows the 
body’s own immune system to kill tumor cells. This would explain both the early (cytotoxic like 
consequences of reversal of EMT) and the late (activation of innate immune anti-tumor 
responses) responses which have been observed in this study. Therefore, it is recommended 
that study treatment is administered for at least 3 cycles as the time-to-response may be 
delayed. Patients will continue to receive study treatment for as long as, in the opinion of the 
investigator, they continue to derive clinical benefit.  
12.5. 
Discontinuation of Treatment and Withdrawal of Patients 
Patients may withdraw informed consent and discontinue from the study at any time, or for 
any reason, without prejudice to their future treatment. In addition, a patient must be 
discontinued from the study if any of the following criteria are met: 
• 
Significant 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 
• 
Patient experiences an unacceptable toxicity that precludes them from continuing 
in the study e.g. patient experiences a ventricular arrhythmia (see Section 12.2.1), 
as agreed by the investigator and the sponsor  
• 
Lack of adequate recovery from a first cycle DLT, see Section 9.2.1.2 
• 
Failure of toxicity to adequately resolve, as outlined in Table 7 
• 
Female patient becomes pregnant  


 
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• 
Patient experiences PD (unless in the opinion of the investigator, they continue to 
derive clinical benefit and are permitted to continue on study after discussion and 
agreement between investigator, the patient and Sponsor. All decisions will be 
documented in writing). 
Note: Clinical benefit in this context is defined as meeting one or several of the 
following criteria: evidence of disease stabilization after documented initial progression 
(patient is stably worse), tolerance of drug(s), absence of rapid progression based on 
peripheral or bone marrow blasts and clinical hematology and clinical chemistry 
parameters, maintenance of good performance status (PS of 2 or less and not 
deteriorating], absence of worsening clinical symptoms (i.e., no symptomatic 
deterioration) and/or improvements in patient’s quality of life). This will not affect the 
time point of disease progression from the perspective of trial analysis. 
• 
Patient and/or investigator decide that it is in the patient’s best interest to withdraw 
from study treatment or the patient withdraws consent 
AEs resulting in discontinuation will be followed as outlined in Section 9.3.4. 
Patients who discontinue during the DLT assessment period (Part A), for any reason other 
than a DLT, will be replaced. All other patients who discontinue study treatment will not be 
replaced. 
If a patient discontinues study treatment prior to study completion, and for reasons other than 
progression or non-tolerability, every effort should be made to conduct the Final Study Visit 
assessments as outlined in Section 11.5. The reason for the patient’s withdrawal from the 
study must be recorded in the eCRF. Patients that permanently discontinue either bemcentinib 
or the combination agent must continue to undergo all study assessments until all study 
treatments have been permanently discontinued after which they must attend the Final Study 
Visit. 


 
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13. Study Assessments 
Study assessments will be conducted according to the relevant Schedule of Events 
(Tables 4-6) in Section 11. 
13.1. 
Clinical Safety Assessments 
Before being entered into the study, patients will be assessed to ensure that eligibility criteria 
are met. Patients not meeting the criteria must not be entered into the study. 
The following tests and assessments will be performed at times specified in the relevant 
Schedule of Events (Tables 4-6) in Section 11 and at any other time required in the opinion of 
the investigator: 
• 
Serum pregnancy test on women of childbearing potential (Screening only) 
• 
Physical examination 
• 
Vital sign measurements (systolic and diastolic BP, heart and respiration rate and 
temperature) 
• 
Serial 12-lead ECGs, in triplicate (<5 minutes apart), performed after the patient has 
been supine for >10 minutes) 
• 
AE and SAE recording 
• 
Concomitant medication and procedures recording 
• 
Echocardiogram or MUGA scan 
13.1.1. Resting 12-lead ECG 
For timing of individual measurements please refer to relevant Schedule of Events 
(Tables 4-6) in Section 11. 
Twelve-lead ECGs will be obtained after the patient has rested in a supine position for 
>10 minutes in each case. All 12-lead ECGs should be recorded while the patient is in the 
supine position. The investigator or designated physician will review the paper copies of each 
of the timed 12-lead ECGs on each of the study days when they are collected. ECGs will be 
conducted in triplicate and performed <5 minutes apart. 
ECGs will be recorded at 25 mm/sec. A clinically significant ECG finding must be recorded as 
part of the medical history, if observed prior to start of dosing, and as an AE post-dose, where 
the finding represents a change from baseline. 


 
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13.1.2. Physical Examination 
The physical examination will be symptom-directed and will exclude rectal and gynecological 
(where applicable) examinations. 
13.1.3. Vital Signs 
For timing of individual measurements please refer to relevant Schedule of Events 
(Tables 4-6) in Section 11. 
BP and HR will be measured using a BP recording device with an appropriate cuff size. 
Measurements will be made after the patient has been resting supine for >10 minutes. 
Temperature and respiration rate will be measured as per clinical practice. 
13.1.4. Subject Symptomatology 
Symptoms reported spontaneously by the patient will be recorded throughout the study period. 
Symptoms reported will be reviewed by the investigator and recorded as an AE where this is 
a change from baseline or a new symptom reported. Please note that every effort should be 
made to report the actual medical condition rather than a symptom in the eCRF (see 
Section 15.1.1 Adverse Event for guidance).  
13.2. 
Laboratory Safety Assessments 
Blood and urine samples will be taken at times specified in the relevant Schedule of Events 
(Tables 4-6) in Section 11, and at any other time required in the opinion of the investigator, 
and analyzed at the designated local laboratory. 
13.2.1. Hematology and Clinical Chemistry 
Blood samples for the determination of clinical chemistry, hematology and coagulation 
parameters to be measured are outlined in Table 9. 
Table 9: Hematology, Clinical Chemistry and Coagulation Parameters 
Biochemistry 
Hematology 
Bilirubin 
Hemoglobin 
Aspartate aminotransferase (AST) 
Mean cell hemoglobin (MCH) 
Alanine aminotransferase (ALT） 
Mean corpuscular hemoglobin concentration (MCHC) 
Alkaline phosphatase (ALP） 
Total white cell count 
Creatine phosphokinase (CK)  
Differential white cell count 
Creatinine 
Platelets  
Peripheral blast percentage 


 
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Biochemistry 
Hematology 
Albumin 
Coagulation 
Total protein 
Prothrombin time (PT) 
Potassium (K) 
Activated Partial Thromboplastin Time (APTT) 
Sodium (Na) 
 
Calcium (Ca) 
Magnesium (Mg) 
 
Glucose  
 
Inorganic phosphate (IP) 
Uric acid 
 
Additional parameters may be performed as clinically indicated and per local practice 
 
 
13.2.2. Urinalysis 
Dipstick urinalysis for measurement of the parameters outlined in Table 10 will be conducted 
by the local laboratory: 
Table 10: Urinalysis Parameters 
pH 
Nitrite 
Glucose 
Blood 
Proteins 
Leukocytes 
Ketones 
Specific gravity 
Bilirubin 
Urine microscopy (if indicated) 
Additional parameters may be performed as clinically indicated and per local practice 
 
 
13.3. 
Pharmacokinetic Assessments 
Venous blood samples for the determination of concentrations of bemcentinib (all Parts) in 
plasma will be taken at times specified in the relevant Schedule of Events (Tables 4-6) in 
Section 11. Detailed procedures for the collection, processing, storage and shipment of the 
samples will be provided in the Study Laboratory Manual. 
Table 11: Bemcentinib PK Sampling Time Points and Permitted Windows 
Study Day 
Time Point (hr) 
Permitted Time Window 
Cycle 1 Day 1 
Pre-dose 
2.0 
+/-15 mins (from C1D1 dose) 
4.0 
+/- 30 mins (from C1D1 dose) 
6.0 
+/- 45 mins (from C1D1 dose) 
Cycle 1 Day 2 
24.0 
+/-2 hrs (from C1D1 dose) 


 
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30.0 
+/-3 hrs (from C1D1 dose) 
Cycle 1 Day 3 
48.0 (0) 
+/-4 hrs (from C1D1 dose) 
2.0 
+/-15 mins (from C1D3 dose) 
4.0 
+/- 30 mins (from C1D3 dose) 
6.0 
+/- 45 mins (from C1D3 dose) 
8.0 
+/-1 hrs (from C1D3 dose) 
Cycle 1 Day 4 
Pre-dose 
+/-2 hrs (from C1D3 dose) 
Day 1 of each cycle up to and 
including Cycle 15 
Pre dose 
EOS 
As collected- not time specific 
 
 
13.3.1. Determination of Bemcentinib Concentration in Plasma 
Plasma samples for determination of bemcentinib concentration will be analyzed by 
BerGenBio’s Bioanalytical Services vendor using the validated LC/MS/MS method.  
13.4. 
Clinical Efficacy Assessments 
All patients must undergo baseline disease assessments at Screening (peripheral blood and 
BM). Response assessments will be performed at Cycle 2 Day 1 (pre-dose), Cycle 4 Day 1 
and then repeated after every 3 cycles or when clinically indicated. Patients that complete 12 
months on study treatment, and have not experienced PD, will undergo response assessment 
every 5 cycles until PD is confirmed. A BM assessment may be performed at any time during 
the study as clinically indicated as outlined in the relevant Schedule of Events (Tables 4-6) in 
Section 11. Response assessment will be performed by the investigator according to the 
modified IWG response criteria for AML (Cheson, 2003 and Döhner, 2017). Please refer to 
Appendix 5. 
The assessment of the clinical efficacy of bemcentinib in AML will be made, according to the 
revised recommendations of the IWG in AML [Cheson, 2003 and Döhner, 2017] as follows:  
• 
Assessment of the % of blasts in a peripheral blood and BM aspirate sample 
• 
Measurement of absolute neutrophil count (ANC) 
• 
Measurement of Platelet count 
• 
Red cell transfusion requirement 


 
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The assessment of clinical efficacy of bemcentinib in patients with MDS will be made 
according to the modified IWG response criteria in myelodysplasia [Cheson, 2006]. Please 
refer to Appendix 6. 
• 
Assessment of the % of blasts in a peripheral blood and BM aspirate sample 
• 
Measurement of ANC 
• 
Measurement of Platelet count 
• 
Red cell transfusion requirement 
BM aspirate and PBMC samples will be analyzed at the designated local laboratory. Wherever 
possible, an aliquot of BM aspirate will be taken for pharmacodynamic biomarker assessment 
(see Section 13.5.1). 
13.5. 
Pharmacodynamic and Predictive Biomarkers 
The effects of bemcentinib on pharmacodynamic endpoints of AXL inhibition will be 
determined in BM aspirates with blood samples:  
• 
To identify and evaluate potential predictive biomarkers, e.g. sAXL and other 
associated soluble biomarkers. Pre-treatment levels of biomarkers will be correlated 
with clinical endpoints. 
• 
To establish the effects of bemcentinib on relevant biological endpoints in peripheral 
blood (including sAXL PBMC) and BM samples. 
• 
To assess pharmacodynamic biomarkers in tissue and blood to support the clinical 
development of bemcentinib. 
• 
To evaluate other biomarkers relevant to the investigational agents for exploratory 
purposes. 
• 
Effect of bemcentinib on AXL, sAXL and pAXL and downstream effectors of AXL 
signaling, such as Akt, pAkt, Erk, pErk, SLFN11, Bcl2, Puma by appropriate methods 
(e.g. FCM, western blotting, proteomics, transcriptomics) 
• 
Effect of bemcentinib on gene expression by appropriate methods (e.g. FCM, western 
blotting, proteomics, transcriptomics, quantitative PCR, DNA-methylation analysis) 
• 
Effect of bemcentinib on relevant immune cell populations. 
• 
Effect of bemcentinib on the spectrum of mutations present within the cancer cell 
population by genomic analysis. 
• 
To explore the correlation between baseline biomarker levels and clinical endpoints. 


 
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Biomarker samples will be collected at the time-points outlined in the relevant Schedule of 
Events (Tables 4-6) in Section 11. Detailed procedures for the collection, processing, storage 
and shipment of the samples will be provided in the Study Laboratory Manual.  
13.5.1. Bone Marrow Aspirates 
Aliquots of the BM aspirate samples collected for the assessment of clinical efficacy, as 
outlined in Section 13.4, will be processed for the pharmacodynamic investigation of AXL 
inhibition by bemcentinib.  
A BM aspirate sample will be taken on Cycle 1 Day 4 from patients who consent to this optional 
procedure.  
The samples collected will be analyzed for the following: 
• 
To identify and evaluate potential predictive biomarkers. Pre-treatment levels of 
biomarkers will be correlated with clinical endpoints. 
• 
To evaluate other biomarkers relevant to the investigational agents for exploratory 
purposes. 
• 
Effect of bemcentinib on AXL, sAXL and pAXL and downstream effectors of AXL 
signaling, such as Akt, pAkt, Erk, pErk, SLFN11 Bcl2, Puma by appropriate methods 
(e.g. western blotting, proteomics, transcriptomics) 
• 
Genomic analysis of normal tissue, and of cancer cells prior to and during treatment 
with bemcentinib, to investigate whether the spectrum of mutations present within the 
cancer cell population changes with bemcentinib treatment 
• 
BM mononuclear cells (CD34+) will be analyzed by transcriptomics and by the 
methods described by Ben-Batalla, 2013 
13.5.2. Pharmacodynamic Blood Samples 
Blood samples will be collected at the time-points outlined in the relevant Schedule of Events 
(Tables 4-6) in Section 11.  
• 
To assess pharmacodynamic biomarkers in tissue and blood to support the clinical 
development of bemcentinib 
• 
Effect of bemcentinib on AXL, sAXL and pAXL and downstream effectors of AXL 
signaling, such as Akt, pAkt, Erk, pErk, SLFN11 Bcl2, Puma by appropriate methods 
(e.g. FCM, western blotting, proteomics, transcriptomics) 


 
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13.6. 
Volume of Blood and Bone Marrow Sampling 
The approximate, maximum volume of blood and BM aspirate that will be drawn from each 
patient per cycle is detailed in the tables below:  
Table 12: Volume of blood and BM aspirate to be drawn per Patient during Screening 
and at Cycle 1 
Assessment 
Sample 
volume 
(mL) 
Part A 
Part B 
n 
Total volume 
(mL) 
n 
Total volume (mL) 
Pharmacokinetics 
4.5 
14 
63 
14 
63 
Pharmacodynamics 
33 
2 
66 
2 
66 
Coagulation  
5 
4 
20 
4 
20 
Clinical chemistry 
5 
7 
35 
7 
35 
Hematology 
2.5 
7 
17.5 
7 
17.5 
Total blood volume (mL) for screen and 
Cycle 1 
201.5 
201.5 
Pharmacodynamics 
20 
1(3)a 
20(60) 
1(3)a 
20(60) 
Clinical efficacy assessmentb 
1 
1 
1 
1 
1 
Total BM volume (mL) for screen and 
Cycle 1 
20(60) 
20(60) 
 
maximum of 3 samples if patient consents to optional BM aspirate on Day 4 and diagnostic BM aspirate is routinely frozen 
b 1 mL aliquot of total 20 mL BM aspirate draw 
 
Table 13: Volume of Blood and BM aspirate to be drawn per Patient during Cycle 2 
Assessment 
Sample 
volume 
(mL) 
Part A 
Part B  
n 
Total volume 
(mL) 
n 
Total volume (mL) 
Pharmacokinetics 
4.5 
3 
13.5 
3 
13.5 
Pharmacodynamics  
33 
1 
33 
1 
33 
Coagulation  
5 
1 
5 
1 
5 
Clinical chemistry 
5 
3 
15 
3 
15 
Hematology 
2.5 
3 
7.5 
3 
7.5 
Total blood volume (mL) for Cycle 2 
74 
74 
Pharmacodynamics 
20 
1 
20 
1 
20 
Clinical efficacy 
assessmenta 
1 
1 
1 
1 
1 
Total BM volume (mL) for Cycle 2 
20 
20 
a 1 mL aliquot of total 20 mL BM aspirate draw 
 
Table 14: Volume of Blood and BM aspirate to be drawn per Patient per Cycle >3 (up to 
and including Cycle 15 for PK and Blood Pharmacodynamics) & at Final Study Visit 
Assessment 
Sample 
volume 
(mL) 
Part A 
Part B 
n 
Total volume 
(mL) 
n 
Total volume (mL) 
Pharmacokinetics 
4.5 
1 
4.5 
1 
4.5 
Pharmacodynamics  
33 
1 
33 
1 
33 
Coagulation  
5 
1 
5 
1 
5 
Clinical chemistry 
5 
1 
5 
1 
5 
Hematology 
2.5 
1 
2.5 
1 
2.5 
Total blood volume (mL) per Cycle & 
Final Visit 
50 
50 
Pharmacodynamics 
20 
1 
20 
1 
20 
Clinical efficacy 
assessmenta 
1 
1 
1 
1 
1 
Total BM volume (mL) per Cycle  
20 
20 
1 mL aliquot of total 20 mL BM aspirate draw; optional assessment performed as clinically indicated 


 
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14. Study Treatment Management 
Every patient enrolled in the study will receive bemcentinib. Patients enrolled in Part B2 and 
B5 will receive bemcentinib in combination with low dose cytarabine. 
14.1. 
Study Medication 
The investigational medicinal product (IMP) bemcentinib must be stored in a secure location. 
Accountability for study treatment is the responsibility of the investigator. The 
investigator/designee must ensure that the IMP will only be dispensed to patients in 
accordance with the protocol and that any unused IMP will be disposed of or, if unopened, 
returned in accordance with the written instructions of the sponsor. 
Study staff should refer to the sponsor’s Directions for Handling and Administration (DHA) 
document for specific instructions regarding the handling, storage, dispensing and destruction 
of the IMP. 
Bemcentinib has been manufactured according to appropriate Good Manufacturing Practice 
(GMP) standards. Bemcentinib will be labelled in compliance with GMP Annex 13 
requirements, Food and Drug Administration (FDA) requirements and local regulatory 
guidelines. 
14.1.1. Bemcentinib 
Bemcentinib will be supplied in hydroxypropyl methylcellulose (HPMC) capsules at a dose 
strength of 100 mg for oral dosing. Please refer to Section 4 of the current version of the 
bemcentinib IB for additional information on the physical, chemical and pharmaceutical 
properties of bemcentinib. 
14.1.1.1. Bemcentinib Storage 
Bemcentinib will be shipped to the site and must be stored at the site in a secure location 
under ambient temperature conditions (<25 °C/ <77 °F).    
Detailed instructions for the storage of dispensed IMP at home will be provided to every patient 
enrolled in the clinical study. 
14.1.1.2. Bemcentinib Accountability 
The investigator/designee must maintain complete and accurate IMP accountability records 
showing the date of receipt and quantity of all supplies of IMP. These records must include 


 
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accurate patient-specific dispensing information including quantity of capsules/bottles 
dispensed, date dispensed, and quantity and date returned (or disposed of). 
At the end of the study, reconciliation must be made between the amount of IMP supplied, 
dispensed and subsequently returned to the sponsor or destroyed at site and any 
discrepancies accounted for.  
Destruction of the IMP at site will only be performed by authorized personnel following written 
receipt of approval from the sponsor. The procedure should be fully documented as outlined 
in the DHA. 
14.1.2. Cytarabine and Decitabine 
All patients in Part B2 and Part B5 will receive subcutaneous low-dose cytarabine. 
Name: Cytarabine  
Brand name: Ara-C  
Active Substance: Cytosine Arabinoside  
Pharmaceutical form: Solution for injection  
Route of administration: Subcutaneous  
Investigational Medicinal Product Status: Non-IMP  
ATC code: L01BC01  
Cytarabine will have commercial packaging and labels in accordance with its marketing 
authorization. It will be purchased by the participating hospital via their normal purchasing 
procedure and will not be reimbursed by BerGenBio ASA.  
All patients in Part B3 will receive intravenous decitabine per standard practice. 
Name: Decitabine 
Brand name: Dacogen  
Active Substance: Decitabine (5-aza-2'-deoxycytidine) 
Pharmaceutical form: Solution for injection  
Route of administration: Intravenous 
Investigational Medicinal Product Status: Non-IMP  
ATC code: L01BC08 


 
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Decitabine will be packaged and labelled in the standard manner according to the current 
marketing authorization by the manufacturer. It will be purchased by the participating hospital 
via their normal purchasing procedure and will not be reimbursed by BerGenBio ASA.  
14.1.2.1. Cytarabine and Decitabine Storage 
Cytarabine and decitabine will be stored in accordance with the specific manufacturer’s SmPC 
or US prescribing information. A copy of the SmPC or US prescribing information for the 
product used should be kept in the BGBC003 Pharmacy file, Investigator Site File and the 
TMF.  
14.1.2.2. Cytarabine and Decitabine Accountability 
The investigator/designee must maintain complete and accurate cytarabine and decitabine 
dispensing logs including the actual dose administered and the date.  


 
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15. Safety Definitions, Monitoring and Reporting 
Safety reporting in this clinical study will be undertaken in accordance with current regulatory 
and national requirements. 
15.1. 
Definitions 
The following definitions are according to the Directive 2001/20/EC. 
15.1.1. Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical study subject administered 
a pharmaceutical product and which does not necessarily have a causal relationship with the 
product. An AE can therefore be any unfavorable or unintended sign, symptom or disease 
temporally associated with the use of the IMP whether or not considered related to the IMP. 
This includes any occurrence that is new, an exacerbation of an existing disease (a worsening 
of the character, frequency or severity of a known condition) or abnormal results of diagnostic 
procedures, including clinically significant laboratory test abnormalities. 
Suggested criteria for the assessment of clinical significance for laboratory abnormalities are 
as follows.  
The laboratory abnormality: 
• 
is clearly consistent with the pattern of leukemia disease or progression; 
• 
is accompanied by clinical symptoms; 
• 
requires study drug dose modification or interruption or permanent discontinuation of 
study treatment; 
• 
requires more frequent follow-up assessments, further diagnostic investigation, etc.; 
• 
requires a change in concomitant medication, therapy, or treatment. 
If the clinically significant laboratory abnormality is a sign of a disease or syndrome (e.g. 
alkaline phosphatase and bilirubin 5X ULN associated with cholecystitis), only the diagnosis 
(e.g. cholecystitis) needs to be recorded on the AE eCRF. If the clinically significant laboratory 
abnormality is not a sign of a disease or syndrome, the abnormality itself should be recorded 
as an AE or SAE on the eCRF. If the laboratory abnormality can be characterized by a precise 
clinical term, the clinical term should be recorded as the AE or SAE. For example, an elevated 
serum potassium level of 7.0 mEq/L should be recorded as “hyperkalemia.”  Observations of 
the same clinically significant laboratory abnormality from visit to visit should not be repeatedly 


 
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recorded as AEs or SAEs on the eCRF, unless their severity, seriousness, or etiology 
changes. 
For all AEs, a diagnosis should be recorded on the eCRF rather than individual signs and 
symptoms (e.g. record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases) wherever possible. However, if a constellation of signs and/or 
symptoms cannot be medically characterized as a single syndrome at the time of reporting, 
each individual sign and/or symptom should be recorded as an AE or SAE on the eCRF. If a 
diagnosis is subsequently established, the reported event term should be updated to reflect 
the medical diagnosis. 
Note that AEs occurring secondary to an initiating event that are separated in time or medically 
significant should be recorded as independent events on the eCRF. For example, if a severe 
gastrointestinal hemorrhage leads to a renal failure, both events should be recorded 
separately on the eCRF. 
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”). 
15.1.2. Adverse Reaction 
An adverse drug reaction (ADR) is defined as all untoward and unintended responses to an 
IMP related to any dose administered. The definition implies a reasonable possibility of a 
causal relationship between the event and the IMP i.e. there are facts (evidence) or arguments 
to suggest a causal relationship.  
15.1.3. Serious Adverse Event 
An SAE as defined by the International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) is any untoward medical occurrence that meets any 
of the following conditions: 
• 
Results in death  
• 
Is life-threatening (i.e. the patient was at risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were more 
severe) 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  


 
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• 
Results in persistent or significant disability/incapacity 
• 
Results in a congenital anomaly/birth defect  
Important medical events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of 
the other outcomes listed in the definition above, should also be considered serious. 
15.2. 
Monitoring and Reporting Events 
15.2.1. Adverse Events 
Any AE experienced by a patient between signing the informed consent form (ICF) and 28 
days after the last administration of bemcentinib is to be recorded in the eCRF regardless of 
the severity and causality of the event, although only events considered to be related to 
treatment need to be recorded between the last administration of bemcentinib and the end of 
the 28-day follow up period. If bemcentinib-related toxicities continue beyond the Follow-up 
period, patients will be followed until all bemcentinib-related toxicities have resolved to Grade 
≤1, stabilized or returned to baseline.  
15.2.2. Serious Adverse Events 
Any SAE experienced by a patient between the time of the first administration of bemcentinib 
and 28 days after the last administration is to be recorded on an SAE Report Form as well as 
in the eCRF within 24 hours of knowledge by the investigator of its occurrence, regardless of 
the severity and causality of the event. The exception to this will be patients who experience 
an SAE due to a Screening assessment. Such events should also be reported and will be 
recorded in the CSR. SAEs with a suspected relationship with bemcentinib will be collected 
indefinitely. The SAE Report Form should be  e-mailed to the Syneos Health Safety and 
Pharmacovigilance Global Safety Mailbox safetyreporting@syneoshealth.com.  
All SAEs that have not resolved by the end of the study, 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 the IMP or to factors unrelated to 
study conduct  
• 
It becomes unlikely that any additional information can be obtained  


 
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Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of a patient’s participation in a clinical study must be reported as an SAE. Exclusions 
to this are hospitalizations:  
• 
For pre-scheduled or routine elective procedures (as long as the qualifying condition 
did not worsen or progress, in the opinion of the investigator, since signing the ICF) 
• 
For social reasons, in the absence of an AE e.g. for respite care 
• 
Due to expected deterioration caused by disease progression 
15.2.3. All Events 
All events must be assessed to determine the following: 
• 
If the event meets the criteria for an SAE as defined in Section 15.2.2 
• 
The severity of the event as defined in Section 15.3.1 
• 
The relationship to bemcentinib as defined in Section 15.3.2 
15.3. 
Safety Classifications 
15.3.1. Assessment of Severity 
The investigator/designee will rate the severity of each AE according to CTCAE. For each sign 
or symptom, the maximum or highest grade observed since the last visit should be reported. 
If the symptom or event cannot be graded according to CTCAE, the following grade (severity) 
rating guideline will be used: 
Grade 1 
Mild 
The AE is transient and easily tolerated by the 
subject 
Grade 2 
Moderate 
The AE causes the subject discomfort and 
interrupts the subject’s usual activities  
Grade 3 or 4 
Severe 
The AE causes considerable interference with the 
subject’s usual activities and may be incapacitating 
or life-threatening 
15.3.2. Assessment of Causality 
The investigator will assess the causality of the AE with respect to the IMP according to the 
following guidance: 
Unrelated 
The Adverse Event is clearly unrelated to bemcentinib 


 
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Unlikely 
The Adverse Event is doubtfully related to bemcentinib 
Possible 
The Adverse Event may be related to bemcentinib 
Probable 
The Adverse Event is likely to be related to bemcentinib 
Definite 
The Adverse Event is clearly related to bemcentinib 
If in the opinion of the investigator an SAE is considered not related an alternate etiology must 
be provided. The causality assessment given by the investigator should not be downgraded 
by the sponsor. If the sponsor disagrees with the investigator’s causality assessment, both the 
opinion of the investigator and the sponsor should be provided with the report. 
15.3.3. Assessment of Expectedness 
An unexpected adverse event is an event, the nature or severity of which is not consistent with 
the reference safety information (RSI) presented in the IB for the IMP. The responsibility for 
determining expectedness of an ADR falls to the sponsor. 
15.3.4. 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 main Research Ethics Committees (REC)/Institutional Review Boards (IRB). 
Although this responsibility can be delegated to the sponsor’s Contract Research organization 
(CRO), the sponsor retains ultimate responsibility for safety reporting.  
All SAEs that are unexpected and associated with the use of the IMP are classified as 
suspected unexpected serious adverse reactions (SUSARs) and must be reported to the main 
RECs/IRBs and Regulatory Authorities within 7 calendar days if fatal or life threatening, or 
within 15 calendar days if non-life threatening and non-fatal. The sponsor/designee must also 
report SUSARs to all investigational sites. 
Any safety information from other observations that could change the risk-benefit evaluation 
of the IMP should be promptly communicated to the Regulatory Authorities and main 
RECs/IRBs. Any other SUSARs associated with the IMP should be reported as soon as the 
sponsor becomes aware of them including SUSARs which occur in another clinical study 


 
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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 IMP (sufficient to consider changes in the 
administration or in the overall conduct of the trial), for instance 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 the IMP likely to 
affect the safety of the patients, such as: 
o An SAE which could be associated with the trial procedures and which could 
modify the conduct of the trial 
o A major safety finding (such as carcinogenicity, which differs to 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 IMP. 
15.3.5. Annual Safety Updates 
Once a year the sponsor/designee will submit an annual Development Safety Update Report 
(DSUR) to the Regulatory Authorities and main RECs/IRBs that lists all suspected serious 
adverse reactions occurring throughout the time period. 
15.3.6. Deaths 
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 IMP. 
The reporting periods for SAEs are detailed in Section 15.2.2. 
15.3.7. Procedures for Handling Special Situations 
15.3.7.1. Pregnancy 
As detailed in the inclusion/exclusion criteria, patients of childbearing potential who are not 
using adequate contraception will not be invited to participate in this study. Female patients of 
childbearing potential must have a negative serum pregnancy test within 3 days prior to the 
first dose of bemcentinib. In the event of any pregnancies occurring in female patients, or in 


 
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the partners of male patients during the study, the pregnancy must be reported to the Syneos 
Health 
Safety 
and 
Pharmacovigilance 
Global 
Safety 
mailbox 
safetyreporting@syneoshealth.com  by the investigational staff within one working day of their 
knowledge of the event using a Pregnancy Notification Form. 
The reporting period for pregnancies will start with the first study-related procedure and end 
28 days after the final administration of bemcentinib. 
Any female patients who become pregnant whilst taking part in the study will be withdrawn, 
whilst patients whose partners become pregnant can remain in the study. A patient who 
completes or withdraws from the trial before the full term of their/their partner’s pregnancy will 
be asked to consent to their doctor providing the sponsor with follow-up information concerning 
the pregnancy and its outcome. 
15.3.8. Medical Emergency 
In a medical emergency requiring immediate attention, study staff will apply appropriate 
medical intervention according to standard medical practice. The investigator/designee should 
contact BerGenBio’s Medical Monitor if guidance is needed to manage a case particularly if 
the medical emergency is suspected to be related to the IMP. 
15.3.8.1. Unblinding for a Medical Emergency 
Not applicable. 
15.4. 
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 bemcentinib 
• 
Determine the seriousness, relationship and severity of each event 
• 
Determine the onset and resolution of each event 
• 
Complete an SAE form for each SAE as outlined in Section 15.2.2 
• 
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 REC/IRB, as required by local law 


 
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15.5. 
Sponsor’s Safety Responsibilities 
The sponsor’s responsibilities include the following: 
• 
The ongoing safety evaluation of the IMP 
• 
Reporting of SUSARs to the Regulatory Authorities, main REC/IRB and investigators 
according to required timelines as outlined in Section 15.3.4 
• 
Submission of the annual DSUR to the Regulatory Authorities and main REC/IRB 
15.6. 
Overdose  
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).  


 
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16. Statistical Methods and Determination of Sample Size 
Detailed statistical analysis information will be provided separately in the SAP. Any deviations 
to the planned analyses specified within the SAP, will be justified in writing and presented 
within the final CSR. 
In the Tables, Listings and Figures presented in the CSR, patients enrolled in Part A will be 
reported separately. Where appropriate, the data for patients who received the MTD during 
Part A will be combined with that for patients who received the MTD in Part B for the purpose 
of data summarization. A clear distinction will be made in the relevant Tables to differentiate 
between the cohort who received the MTD during the dose escalation phase of Part A, the 
MTD cohort from the cohort expansion phase in Part A, and the combined MTD cohort. 
If necessary, after the clinical phase of the study has been completed, a decision will be made 
between the sponsor and the study statistician regarding management of missing values, data 
for withdrawn patients and data for protocol violators. 
Interim reports will be prepared as required during the study. The study will be completed 
when all patients have an OS event, unless the Sponsor terminates OS follow-up once all 
patients have discontinued study treatment. The database lock will take place when all data 
to this point, are reconciled, and the CSR will be generated. Should the last patient enrolled 
to the study be continuing to receive bemcentinib 52 weeks from their Cycle 1 Day 1, the 
Sponsor may choose to lock the data base to that point and prepare the CSR. Data collected 
as part of this study after this point, will be reported as an addendum to the CSR. 
16.1. 
Description of Objectives 
Please refer to Section 8.1. 
16.2. 
Description of Endpoints 
Please refer to Section 8.2. 
16.3. 
Demography and Baseline Disease Characteristics 
The Enrolled Population will include all patients who have signed the ICF and enrolled into the 
study. The enrolment date will be defined as the date of the first protocol-defined screening 
procedure. All patients in the Enrolled Population will be accounted for in patient disposition. 
Patient disposition will be summarized by dose group. Medical history and prior medications 
will be tabulated. 


 
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Data from patients who fail screening will not be collected. The exception to this will be patients 
who experience an SAE due to a Screening assessment. Such events should be reported and 
will be recorded in the CSR. 
16.4. 
Safety 
16.4.1. Analysis Population 
The safety analysis set (SAS) will be defined as all patients who receive at least one dose of 
bemcentinib. The SAS will be analyzed by dose group or combination in Part B.  
Patients enrolled to Part A who meet the eligibility criteria for Part B1 and who receive the 
RP2D, may contribute to the Part B1 analysis. 
Any patient who continues treatment with bemcentinib beyond confirmed disease progression 
will be followed for safety (AEs/SAEs) as well as general condition, performance status etc., 
as defined in protocol section 13. 
16.4.2. Methods of Analysis 
No formal statistical analysis will be performed. 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 and system 
organ class and summarized by both 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. 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 bemcentinib. 
Separate listings will be produced for DLTs, SAEs, discontinuations due to related AEs, and 
events of >Grade 3 severity.  
Summary statistics by dose cohort and time point will be produced for vital signs, ECG 
parameters and laboratory safety data, together with changes from baseline. The incidence of 
laboratory test results outside the normal range will be summarized by dose cohort and time 
point. Laboratory test results outside the normal range will be individually listed for clinical 
review. Abnormal ECG results will be summarized by dose cohort.  
Changes in PR, QT interval and QTcF duration will be analyzed according to administered 
dose and ultimately modelled with corresponding plasma concentrations of bemcentinib when 
available. 


 
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Any patient treated with bemcentinib beyond disease progression will be followed for the same 
safety and efficacy assessments as for all other patients enrolled into the study. The data for 
patients treated beyond progression will be presented in both a combined output (with all 
patients) and also a separate output (reflecting a new period of analysis with the data collected 
in this period). All data collected will be included in the study CSR and may be presented at 
congress/symposia. 
16.5. 
Efficacy 
16.5.1. Analysis Population 
The Efficacy Analysis Population will include all subjects who receive >1 dose of bemcentinib 
(Full Analysis Set). 
Any patient who continues treatment with bemcentinib beyond confirmed disease progression 
will be followed for efficacy assessments (hematology testing, physical examinations and bone 
marrow biopsy, if clinically indicated), as defined in protocol section 13. 
For the Per Protocol analysis set, the population will be defined as follows: 
Patients that 
• 
Meet key eligibility criteria, have assessable disease at baseline and have at least one 
post-baseline response assessment 
• 
Have received >1 dose of bemcentinib (and combination agent in Part B2, B3 and B5) 
16.5.2. Methods of Analysis 
Although all efficacy analysis for this study is to be regarded as essentially exploratory, there 
will be formal hypothesis tests for the objective response rate (ORR). These will consist of 
one-sided, within-group tests of proportion of responders for each criterion, 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 and significant efficacy will support the justification to proceed to pivotal studies of 
bemcentinib.  
Patients who on review  have received at least 1 dose of bemcentinib or have a major protocol 
violation that will impact on the safety or efficacy analysis (e.g. do not meet key eligibility 
criteria or do not have evaluable disease for response assessment at baseline) may be 
replaced. 


 
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Data relating to efficacy response will be listed and summarized by dose cohort and time point, 
as appropriate. 
16.6. 
Pharmacokinetics 
16.6.1. Analysis Population 
The Pharmacokinetics Analysis Population will include all patients who receive >1 dose of 
bemcentinib and have evaluable PK data available. 
16.6.2. Methods of Analysis 
The PK parameters listed in Table 15 (but not limited to) will be derived from the relevant 
concentration data of bemcentinib in each part of the study, derived from a PK model. Full 
details of the PK methodology will be written in a PK Analysis Plan. 
Table 15: Plasma PK parameters 
Cmax 
The observed maximum plasma concentration after single dose administration 
tmax 
The time to reach Cmax  
AUC0-tau 
The area under the curve within a dosing interval, calculated by the linear up-log 
down trapezoidal method. 
z 
The apparent terminal rate constant estimated from individual linear regression 
of the terminal part of the log concentration vs. time curve 
t½ 
The apparent terminal half-life, calculated by 0.693/z  
 
 
Where possible, individual, mean and median bemcentinib plasma concentration-time data 
will be presented in tabular and/or graphical form. 
16.7. 
Pharmacodynamics 
16.7.1. Analysis Population 
The Pharmacodynamic Analysis Population will include all patients who receive >1 dose of 
bemcentinib and have ≥1 pharmacodynamic sample collected for analysis. 
16.7.2. Methods of Analysis 
All pharmacodynamic biomarkers will be listed and summarized by dose cohort and time-point 
as appropriate. No formal statistical analysis will be performed, although descriptive terms will 
be used to describe the results. 


 
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16.8. 
Safety Monitoring Committee 
No formal statistical interim analyses are planned. 
Data will be monitored by the SMC, in an on-going manner, to assess patient safety as outlined 
in Section 9.2.1.1. During Part A, the SMC will be responsible for: 
• 
Reviewing the safety data from Cycle 1 of each dose cohort to determine whether dose 
escalation can proceed 
• 
Determining the MTD prior to commencing Part B 
• 
Defining the starting dose of bemcentinib to be administered with cytarabine/ 
decitabine in Part B2/Part B3. 
During the execution of Part B the SMC will convene after every 10 patients have completed 
Cycle 1 of treatment or 6 months have elapsed, whichever occurs first. Part A and Part B3 
have been fully completed (i.e. last patient last visit has been achieved in both parts). 
Enrolment in Part B2 has been completed with a number of patients ongoing, whereas Parts 
B1, B4 and B5 continue to enroll as of 17 Mar 2020.  
Independent Data Monitoring Committee (IDMC) has been established since 30 Oct 2019 at 
the request of The Federal Institute for Drugs and Medical Devices (BfArM). During execution 
of the remainder of Parts B1, B2, B4 and B5, patient safety data will be monitored and 
assessed by the IDMC in an on-going manner in accordance with the IDMC charter.  
16.9. 
Sample Size Considerations 
Part A of the study follows a conventional algorithm (3+3 patients per dose level) to identify 
the MTD, escalating on 0/3 or 1/6 patients experiencing 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 16. 


 
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Table 16: 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 
 
The total sample size of Part A depends 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 MTD. A minimum of 6- 10 patients will be treated at the MTD. 
The sample size of up to 14 evaluable patients for Parts B1, B2, B3 and B4 and up to 20 
evaluable patients in Part B5 in this study has been calculated on the basis of the following 
assumptions for a one-sided, within-group test of proportions, comparing an anticipated ORR 
of >20% against the null hypothesis rate of 5%, with power 80% for a test of size 0.2. This 
calculation is based on statistical significance at the 0.2 level, since this will be taken as 
evidence of a trend worthy of further study. Although this is offered as a formal sample size 
calculation, it is acknowledged that for this early-stage study the analyses will be exploratory 
in nature, and that no account has been taken of multiplicity inherent in the assessment of 
several, presumably non-independent criteria, for ORR. 
16.10. 
Clinical Study Report 
The results of the study will be presented in an integrated CSR according to ICH guidelines. 


 
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17. Ethical Requirements 
17.1. 
Good Clinical Practice Statement 
The clinical study will be performed in accordance with the protocol, the Declaration of 
Helsinki, ICH Guidelines, GCP, the European Union (EU) Clinical Trials Directive (CTD) 
2001/20/EC Guideline for GCP CPMP/ICH/135/95, and all applicable local regulatory 
requirements.  
Authorization of a Clinical Trial Application, IND, or equivalent will be obtained from the 
relevant Regulatory Authority prior to initiation of the study within a specific country. 
17.2. 
Ethics Committee 
The final study protocol and ICF must be approved, in writing, by the relevant REC/IRB before 
patient enrolment commences. 
The following information should be reported to the REC/IRB during the study: 
• 
All amendments to the research (substantial and non-substantial amendments) 
• 
Annual progress reports 
• 
Individual SUSARs 
• 
DSUR on an annual basis 
• 
Urgent Safety Measures  
The investigator/designee must notify the REC/IRB within 90 days of completion of the study. 
However if the study is terminated prematurely, written explanation of the reason(s) for the 
early termination must be provided within 15 days. 
17.3. 
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 reviewing REC/IRB. 


 
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17.4. 
Subject Data Protection 
Personally identifiable information (PII) i.e. identifiable information from or about an individual 
will not be collected by the sponsor. The collection and processing of personal data from 
patients enrolled in this study will be limited to those data that are necessary to investigate the 
efficacy, safety, tolerability, quality and utility of the IMP 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 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 REC/IRB for data verification 
purposes.  


 
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18. Administrative Procedures 
18.1. 
Quality Assurance 
In compliance with GCP and regulatory requirements, the sponsor/designee, external 
Regulatory Agency and/or REC/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. 
18.2. 
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 investigator must permit 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.  
18.3. 
Study Monitoring 
Before a patient can be screened for enrolment into the study, the sponsor/designee will 
conduct a study initiation visit to: 
• 
Determine that the site facilities are adequate 
• 
Discuss responsibilities with regard to the protocol with the investigator and 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 support to the investigator 
and study team via telephone/e-mail communication. 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 are adhering to the protocol and regulatory requirements 
• 
Confirm that the IMP 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 


 
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18.4. 
Notification of Serious Breaches 
In accordance with Regulation 29A of the Medicines for Human Use (Clinical Trials) 
Regulations 2004 and its amendments the sponsor of the trial is responsible for notifying the 
Regulatory Authorities in writing, within 7 days, of any serious breach of:  
• 
The conditions and principles of GCP in connection with the study 
• 
The protocol relating to the study  
Whilst under investigation, the site is requested to cooperate with the sponsor/designee in 
providing sufficient information to report the breach to the Regulatory Authorities where 
required, and in undertaking any corrective and/or preventive action. 
18.5. 
Retention of Study Data 
A copy of all records and essential documents must be retained in the study files for a minimum 
of two 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 two 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. 
Should the investigator wish to assign the documents to another party or move them to another 
location, the sponsor must be notified. The sponsor will notify the investigator in writing when 
the study-related documents are no longer needed. 
18.6. 
Use of Information and Publication Policy 
All information regarding bemcentinib 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 
publications and presentations 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.  


 
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18.7. 
Contract Research Organizations 
Monitoring, data management, statistics and programming,  medical writing, auditing and QA 
services will be outsourced to the sponsor’s CRO Covance  
Pharmacovigilance services will be outsourced to Syneos Health 
PK and pharmacodynamics analyses will be outsourced to the sponsor’s Bioanalytical 
services vendor. 
18.8. 
Changes to the Final Study Protocol 
All protocol amendments must be submitted to the REC/IRB and, if applicable, to the 
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 Regulatory Authority/REC/IRB 
approval (where applicable), except where necessary to eliminate immediate hazards to the 
patients. 
18.9. 
Investigator Responsibilities 
By signing the protocol, the investigator agrees to: 
• 
Conduct the study in accordance with the protocol and make changes only after 
notifying 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 the drug is being used for investigational 
purposes  
• 
Ensure that the requirements relating to obtaining informed consent and REC/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 IB for bemcentinib, including potential risks and side 
effects of the drug 
• 
Ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations in meeting the above commitments 
• 
Maintain adequate and accurate records, in accordance with 21CFR312.62 and to 
make those records available for inspection by the sponsor, their designated 


 
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representative, relevant Regulatory Authorities/REC/IRB or any agency authorized by 
law 
• 
Ensure that a REC/IRB that complies with the requirements of 21CFR56 will be 
responsible for initial and continuing review and approval of the clinical study 
• 
Report promptly to the REC/IRB and the sponsor all changes in the research activity 
and all unanticipated problems involving risks to subjects 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 the clinical 
investigators and all other pertinent requirements listed in 21CFR312 
 
 


 
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19. References 
Ben-Batalla I, Schultze A, Wroblewski M, et al., AXL a prognostic and therapeutic target in 
acute myeloid leukemia mediates paracrine crosstalk of leukemia cells with bone marrow 
stroma. Blood (2013) 122(14): 2443–2452. 
Cheson BD, Bennett JM, Kopecky KJ, et al., Revised recommendations of the International 
Working Group for Diagnosis, Standardisation of Response Criteria, Treatment Outcomes and 
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol (2003) 
21(24): 4642–4649. 
Cheson BD, Greenberg PL, Bennett JM et al., Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. 
Blood (2006) 108(2): 419–425. 
Döhner H, Estey E, Grimwade D, et al., Diagnosis and management of AML in adults: 2017 
ELN recommendations from an international expert panel. Blood (2017) 129(4): 424-447. 
Oken MM, Creech RH, Tormey DC, et al., Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol (1982) 5(6): 649–655. 
Whitman SP, Kohlschmidt J, Maharry K, et al., Gas6 expression identifies high-risk AML 
patients: 
potential 
implications 
for 
therapy. 
Leukemia 
(2013) 
Dec 
11. 
doi: 
10.1038/leu.2013.371. [Epub ahead of print]. 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. (1994). (9th ed.). Boston: Little, Brown 
& Co. 253–256. 
 
 
 
 


 
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20. Appendices 
Appendix 1: Eastern Cooperative Oncology Group (ECOG) Performance Status 
 
Grade 
ECOG 
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  
From Oken et al., 1982 with credit to the ECOG Chair Robert Comis M.D 
 
 


 
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Appendix 2: The New York Heart Association (NYHA) Functional Classification 
in a Patient with Heart Disease  
 
Overview: The New York Heart Association (NYHA) developed a functional classification for 
patients with heart disease.  
Patients: Heart disease must be present.  
Parameters:  
1) Limitations on physical activity  
2) Symptoms (undue fatigue palpitations dyspnea and/or anginal pain) with ordinary 
physical activity  
3) Status at rest 
 
Limitations on 
Physical Activity 
Symptoms with Ordinary 
Physical Activity 
Status at Rest 
Class 
none  
none  
comfortable 
I  
slight  
symptomatic 
with 
ordinary 
activities  
comfortable 
II  
marked  
symptomatic at less than 
ordinary levels of activity  
comfortable 
III  
unable to perform 
any activity  
discomfort with any activity  
symptomatic at rest 
IV  
From The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. (1994). (9th ed.). Boston: Little, Brown & Co. 
253 – 256 
 
 
 


 
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Appendix 3: Drugs Associated with a Risk of QT Prolongation and Cardiac 
Arrhythmias 
 
For any concomitant medication, please check the following website for the drug’s Torsades 
de Pointes (TdP) risk: https://crediblemeds.org/oncosupport/. Drugs with known TdP risk 
should be avoided. For drugs with a conditional risk, please review the product label and 
correct any abnormalities, e.g. hypokalemia. 
 
Known Risk of TdP 
Substantial evidence supports the conclusion that these drugs prolong the 
QT interval AND are clearly associated with a risk of TdP, even when taken 
as directed in official labelling. 
Possible Risk of TdP 
Substantial evidence supports the conclusion that these drugs can cause 
QT prolongation BUT there is insufficient evidence at this time that these 
drugs, when used as directed in official labelling, are associated with a risk 
of causing TdP. 
Conditional 
Risk 
of 
TdP 
Substantial evidence supports the conclusion that these drugs are 
associated with a risk of TdP BUT only under certain conditions (e.g. 
excessive dose, hypokalemia, congenital long QT or by causing a drug-
drug interaction that results in excessive QT interval prolongation) 
 
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® 


 
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Petamidine 
NebuPent/Pentam 
Pimozide 
Orap 
Probucol 
Lorelco 
Procainamide 
Pronestyl/Procan 
Propofol 
Diprivan 
Quinidine 
Cardioquin/Quinaglute 
Sevoflurane 
Ulane®, Sojourn® 
Sotalol 
Betapace 
Sparfloxacin 
Zagam 
Sulpiride 
Dogmatil®, Dolmatil® 
Terfenadine 
Seldane 
Thioridazine 
Mellaril 
Vandetanib 
Zactima 
 
Woosley RL, Heise CW , Gallo T, Tate J, Woosley D and Romero KA, www.CredibleMeds.org, QTdrugs 
List, [Accession Date], AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley, AZ 85755  
 
 


 
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Appendix 4: CYP3A4 Substrates 
 
Examples of CYP3A4 substrates are provided below. For most up-to-date information on 
CYP3A4 substrates, please check the Drug Interactions Flockhart Table™ 
https://drug-interactions.medicine.iu.edu/Main-Table.aspx.  
 
University of Indiana CYP3A4, 5, 7 P450 Drug Interactions Abbreviated "Clinically 
Relevant" Table of Substrates 
 
Macrolide antibiotics:  
HIV Antivirals:  
HMG CoA Reductase 
Inhibitors:  
clarithromycin  
indinavir  
atorvastatin  
erythromycin (not 3A5)  
ritonavir  
lovastatin  
NOT azithromycin  
saquinavir  
NOT pravastatin  
telithromycin  
nevirapine  
NOT rosuvastatin  
 
 
simvastatin 
Anti-arrhythmics:  
Prokinetics:  
 
quinidine→3-OH  
cisapride  
Others:  
 
 
alfentanyl 
Benzodiazepines:  
Antihistamines:  
aripiprazole  
alprazolam  
astemizole  
boceprevir  
diazepam→3OH  
chlorpheniramine  
buspirone  
midazolam  
terfenadine 
carbamazepine  
triazolam  
Calcium Channel 
Blockers:  
gleevec  
 
amlodipine 
haloperidol 
Immune Modulators:  
diltiazem  
pimozide  
cyclosporine  
felodipine  
quinine  
tacrolimus (FK506)  
nifedipine  
tamoxifen  
sirolimus  
nisoldipine  
telaprevir  
 
nitrendipine 
trazodone 
PDE-5 Inhibitors:  
verapamil  
vincristine  
sildenafil  
 
diergotamine & ergotamine 
tadalafil  
 
fentanyl 
vardenafil  
 
 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School 
of Medicine (2007). "/clinpharm/ddis/clinical-table/" Accessed 20 October 2016. 
 
 


 
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Appendix 5: Modified International Working Group Response Criteria in Acute 
Myeloid Leukemia (Cheson, 2003, Döhner, 2017) 
 
IWG Response 
Criteria in AML  
Bone Marrow 
Blasts/Myeloblast  
Circulating 
or Peripheral 
Blood 
Blastsa  
Absolute 
Neutrophil 
Count  
Platelet 
Count  
EMD  
Morphologic 
Complete 
Remission 
CR 
<5% and no 
myeloblasts with 
Auer rods 
None 
≥1.0 x 109/L 
or ≥1,000/μL 
≥100 x 109/L 
or 
≥100,000/μL  
None 
CR with 
Incomplete 
Blood 
Count 
Recovery  
CRi 
<5% and no 
myeloblasts with 
Auer rods  
None 
<1.0 x 109/L 
or <1,000/μL  
<100 x 
109/L or 
<100,000/μL  
None 
Morphologic 
leukemia-
free state 
MLFS 
<5% and no 
myeloblasts with 
Auer rodsb 
 
No hematologic recovery required 
None 
Partial 
Remission 
PR 
Decrease of 
myeloblasts % to 
5% to 25% and 
decrease of 
pretreatment 
myeloblast % by at 
least 50%  
All hematologic criteria of CR 
 
Unchanged  
UN  
Absence of CR, CRi or PR and criteria for PD not met  
Progressive 
Diseasec  
PD 
>50% increase in 
myeloblasts over 
the pretreatment 
value (a minimum 
15% increase is 
required if <30% 
myeloblasts 
pretreatment)  
>50% 
increase in 
PB to >25 × 
109/L or >25 
000/μLd  
 
 
New 
EMD 
disease  
a. PBs are quantified as an automated WBC times percentage of blasts by manual differential (100 
cells) per standard clinical laboratory procedures.  
b. BM examination should not be aplastic, and have at least 200 cells or cellularity should be at least 
10% 
c. PD is usually accompanied by a decline in ANC and platelets, increased transfusion requirement 
and decline in performance status and increase in symptoms.  
d. Certain targeted therapies may cause a differentiation syndrome, that is, a transient increase in 
the percentage of BM blasts (myeloblasts) and an absolute increase in PBs; in the setting of therapy 
with such compounds, an increase in blasts may not necessarily indicate PD. 
Abbreviations: AML, acute myeloid leukemia, ANC, Absolute Neutrophil Count; BL, EMD, Extramedullary 
Disease; IWG, International Working Group, PB, Peripheral Blood Blast; WBC, White Blood Cell. 
 
References  
• 
Cheson BD, Bennett JM, Kopecky KJ, et al. Revised Recommendations of the International Working 
Group for Diagnosis, Standardisation of Response Criteria, treatment Outcomes and Reporting Standards 
for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol (2003) 21 (24): 4642 – 4649.  
• 
Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN 
recommendations from an international expert panel. Blood (2017) Jan 26; 129(4): 424–447.  


 
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Appendix 6: International Working Group Response Criteria in Myelodysplastic 
Syndromes (Cheson, 2006) 
 
Category A: Altering the natural history of disease  
IWG 
Response 
Criteria in 
MDS  
Bone Marrowa  
Peripheral Blooda  
Additional 
Considerations  
Complete 
Remission 
(CR)  
≤5% myeloblasts with 
normal maturation of all cell 
lines with no evidence for 
dysplasiab 
Normalization of blood 
counts as defined by: 
  
• 
Hb ≥11g/dL (not 
supported by EPO or 
transfusions)  
• 
Platelets ≥100 x 109/L 
or 100,000/μL (not 
supported by transfusions)  
• 
Neutrophils ≥1.5 x 
109/L or 1,500/μL (not 
supported by G-CSF)  
• 
PB 0%  
 
Responses to be 
confirmed in two 
successive 
assessments; 
response parameters 
in peripheral blood 
needs to be 
maintained for at 
least 6 weeks.  
Partial 
Remission 
(PR)  
All CR criteria met if 
abnormal before treatment 
except for:  
• 
Myeloblasts decrease 
by 50% or more over 
pretreatment value but still 
>5%, or  
• 
Less advanced FAB or 
IPPS category compared to 
pretreatment value  
 
Hematologic improvement  
Absolute values must 
last at least 6 weeks.  
Marrow CR  
≤5% myeloblasts and 
decrease by ≥50% over 
pretreatment value  
If hematologic improved, 
these should be noted in 
addition to marrow CR 
(see Category B).  
 
 
Stable 
Disease (SD)  
Failure to achieve at least 
PR, but no evidence of PD 
for at least 3 treatment 
cycles.  
 
 
 
Progressive 
Disease (PD)  
• 
For patients with less 
than 5% myeloblasts: a 
50% or more increase in 
myeloblasts to more than 
5% myeloblasts.  
• 
For patients with 5% to 
10% myeloblasts: a 50% or 
more increase to more than 
10% myeloblasts.  
Myeloblast increase plus 
at least one of the 
following:  
• 
≥50% decrease in ANC 
or platelets  
• 
Reduction in Hb by 
≥2g/dL  
• 
Transfusion 
dependence.  
Death during 
treatment  


 
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• 
For patients with 10% to 
20% myeloblasts: a 50% or 
more increase to more than 
20% myeloblasts.  
• 
For patients with 20% to 
30% myeloblasts: a 50% or 
more increase to more than 
30% myeloblasts.  
 
Relapse after 
CR or PR  
Relapse is characterized by at least one of the following:  
• 
Return to pretreatment myeloblasts percentage  
• 
≥50% decrease in ANC or platelets  
Reduction in Hb by ≥2g/dL or transfusion dependence.  
Disease 
transformation  
Transformation to AML (30% or more blasts).  
Category B: Hematologic Improvement (HI) 
 
Hematopoietic Lineage 
Response Criteria 
Definitiona 
 
Erythroid (HI-E)  
 
Major response  
 
For patients with 
pretreatment Hb<11 
g/dL, greater than 2 
g/dL increase in Hb; 
for RBC transfusion-
dependent patients, 
transfusion 
independence.  
 
 
Minor response  
 
For patients with 
pretreatment Hb <11 
g/dL, 1 to 2 g/dL 
increase in Hb; for 
RBC transfusion-
dependent patients, 
50% decrease in 
transfusion 
requirements.  
 
Platelet (HI-P)  
 
Major response  
 
For patients with 
pretreatment PLT 
counts of <100 x 
109/L or 100,000/μL, 
an absolute increase 
of 30 x 109/L or 
30,000/μL or more; 
for PLT transfusion-
dependent patients, 
stabilization of PLT 
counts and PLT 
transfusion 
independence.  


 
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Minor response  
 
For patients with 
pretreatment PLT 
counts <100 x 109/L 
or 100,000/μL, a 50% 
or more increase in 
PLT count with a net 
increase >10 x 109/L 
or 10,000/μL but less 
than 30 x 109/L or 
30,000/μL.  
 
Neutrophil (HI-N)  
 
Major response  
 
For ANC <1.5 x 109/L 
or 1,500/μL before 
therapy, ANC 
increase of at least a 
100%, or an absolute 
increase of more than 
0.5 x 109/L or 500/μL, 
whichever is greater.  
 
 
Minor response  
 
For ANC less than 
1.5 x 109/L or 
1,500/μL before 
therapy, ANC 
increase of at least 
100%, but absolute 
increase less than 0.5 
x 109/L or 500/μL.  
Category C: Cytogenetic Response (CRc)b 
 
Major CRc 
No detectable cytogenetic abnormality, if preexisting 
abnormality was present.  
 
 
Minor CRc 
≥50% reduction of abnormal metaphases  
 
a. Improvements in BM and PB must be based on ≥2 successive assessments; response in PBN 
must be maintained for at least 6 weeks. 
b. IWG criteria require 20 analyzable metaphases assessed by conventional cytogenetic studies to 
diagnose or exclude the presence of a cytogenetic abnormality. For normal Karyotype, 20 
metaphases are optimal to ensure that enough metaphases have been examined. For 
cytogenetic response, 20 metaphases are optimal, but not necessary, to define the degree of 
cytogenetic response. FISH to assess changes in a specific cytogenetic abnormality is 
acceptable.  
Abbreviations: AML, acute myeloid leukemia; ANC, absolute neutrophil count; EPO, erythropoietin; G-
CSF, FAB, French-American-British (classification system); IPPS, International Prognostic Scoring 
System; granulocyte colony stimulating factor; Hb, hemoglobin; IWG, International Working Group; 
MDS, myelodysplastic syndrome; PB, peripheral blast; PLT, platelet; RBC, red blood cell. 
 
Reference  
Cheson BD, Greenberg PL, Bennett JM. Clinical application and proposal for modification of the 
International Working Group (IWG) response criteria in myelodysplasia. Blood. 2006; 108:419-425. 

SAP_001.pdf: 
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Statistical Analysis Plan 
 
BerGenBio AS 
 
 
 
Protocol: BGBC003 
 
EUDRACT: 2014-000165-46 
 
 
Investigational Product: BGB324 
 
 
An open label, multicentre, phase Ib/II study of BGB324 administered as a single 
agent or in combination with cytarabine or decitabine in patients with acute myeloid 
leukemia or as a single agent in patients with myelodysplastic syndrome 
 
 
 
Author(s): 
Document Status: 
Version 1 Final  
Version Dates: 
Version 1 Draft 1: 22Dec2015 
Version 1 Draft 2: 21Feb2017 
Version 1 Draft 3: 04Oct2017 
Version 1 Draft 4: 28Feb2019 
Version 1 Draft 5: 11May2021 
Version 1 Draft 6: 15Dec2021 
Version 1 Final Draft: 04AUG2022 
Version 1 Final: 06SEP2022 
 
Pages: 
35 
 
 
 
 
PPD
CCI


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Contents 
ABBREVIATIONS .................................................................................................................. 4 
1 
INTRODUCTION............................................................................................................ 6 
2 
STUDY OBJECTIVES .................................................................................................... 6 
2.1 
PRIMARY OBJECTIVES ................................................................................................. 6 
2.2 
SECONDARY OBJECTIVES ............................................................................................ 7 
2.3 
EXPLORATORY OBJECTIVES ........................................................................................ 7 
3 
ENDPOINTS .................................................................................................................... 7 
3.1 
SAFETY ENDPOINTS ..................................................................................................... 7 
3.2 
EFFICACY ENDPOINTS ................................................................................................. 8 
3.3 
PHARMACOKINETIC ENDPOINTS .................................................................................. 8 
3.4 
PHARMACODYNAMIC ENDPOINTS ................................................................................ 8 
4 
STUDY DESIGN .............................................................................................................. 8 
4.1 
DISCUSSION OF STUDY DESIGN ................................................................................... 8 
4.2 
STUDY TREATMENT .................................................................................................. 12 
4.2.1 Bemcentinib.......................................................................................................... 12 
4.2.2 Cytarabine (Part B2 and Part B5) ....................................................................... 12 
4.2.3 Decitabine ............................................................................................................ 13 
4.3 
STUDY SCHEDULE ..................................................................................................... 13 
4.3.1 Screening.............................................................................................................. 13 
4.3.2 Treatment ............................................................................................................. 13 
4.3.3 Final Study Visit ................................................................................................... 14 
4.3.4 Follow Up ............................................................................................................ 14 
4.3.5 End of Study ......................................................................................................... 14 
4.4 
CONCOMITANT MEDICATION AND PROCEDURES ...................................................... 14 
4.5 
STUDY ANALYSIS POPULATIONS ............................................................................... 15 
4.5.1 Enrolled Population ............................................................................................. 15 
4.5.2 Safety Analysis Population .................................................................................. 15 
4.5.3 Efficacy Analysis Population ............................................................................... 15 
4.5.1 Per protocol Analysis Population ........................................................................ 15 
4.6 
WITHDRAWN SUBJECTS ............................................................................................ 15 
4.7 
RANDOMISATION ...................................................................................................... 16 
4.8 
BLINDING .................................................................................................................. 16 
4.9 
SAMPLE SIZE ............................................................................................................. 16 
5 
STATISTICAL METHODOLOGY ............................................................................ 17 
5.1 
PLANNED ANALYSES ................................................................................................ 17 
5.2 
INTERIM ANALYSIS ................................................................................................... 18 
5.3 
DISPOSITION OF SUBJECTS ........................................................................................ 18 
5.4 
BASELINE AND DEMOGRAPHIC CHARACTERISTICS ................................................... 18 
5.5 
CONCOMITANT MEDICATION .................................................................................... 18 
5.6 
EXPOSURE AND COMPLIANCE ................................................................................... 18 
5.7 
EFFICACY ANALYSIS ................................................................................................. 19 
5.8 
SAFETY ANALYSIS .................................................................................................... 21 
5.8.1 Adverse events ...................................................................................................... 21 
5.8.1.1 
Subsets ......................................................................................................... 21 


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5.8.2 Physical Examination .......................................................................................... 23 
5.8.3 Vital Signs ............................................................................................................ 23 
5.8.4 Eastern Cooperative Oncology Group ................................................................ 23 
5.8.5 Electrocardiograms ............................................................................................. 23 
5.8.6 Echocardiograms ................................................................................................. 23 
5.8.7 Laboratory findings ............................................................................................. 23 
5.9 
PHARMACOKINETIC ANALYSIS ................................................................................. 24 
5.10 
PHARMACODYNAMIC ANALYSIS ............................................................................... 24 
5.11 
PROTOCOL DEVIATIONS ............................................................................................ 24 
5.12 
MISSING VALUES – MISSING VISITS ......................................................................... 25 
5.13 
DEVIATIONS FROM SAP ............................................................................................ 25 
5.14 
CHANGES IN CONDUCT OR PLANNED ANALYSES FROM THE PROTOCOL ................... 25 
5.15 
ALGORITHMS/SAS CODES ........................................................................................ 26 
6 
TABLES AND LISTINGS ............................................................................................ 27 
6.1 
TABLE FORMAT ........................................................................................................ 27 
6.2 
CONVENTIONS .......................................................................................................... 27 
6.3 
TABLES ..................................................................................................................... 28 
6.3.1 Section 14.1: Demographic and baseline ............................................................ 28 
6.3.2 Section 14.2: Efficacy Analysis ............................................................................ 28 
6.3.3 Section 14.3: Safety Analysis ............................................................................... 29 
6.3.3.1 
Adverse events ............................................................................................. 29 
6.3.3.2 
Laboratory results ........................................................................................ 30 
6.3.3.3 
Vital signs .................................................................................................... 31 
6.3.3.4 
ECG.............................................................................................................. 31 
6.3.3.5 
ECOG Performance Status .......................................................................... 32 
6.4 
LISTINGS ................................................................................................................... 32 
6.5 
FIGURES .................................................................................................................... 33 
6.6 
REFERENCES ............................................................................................................. 33 
6.7 
APPENDIX ................................................................................................................. 35 
6.7.1 Definitions of End Points for Clinical Trials in AML by Cheson & all 2003. ..... 35 
 
 
 


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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 
BUN 
Blood Urea Nitrogen 
°C 
Celsius  
cm 
centimeter 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 
EFS 
Event Free Survival 
ECOG 
Eastern Cooperative Oncology Group 
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  
mmHg 
millimeter of mercury 
Min 
Minimum 
MTD 
Maximum tolerated dose 
NCI 
National Cancer Institute 
ORR 
Objective response rate 
OS 
Overall survival 
PBMC 
Peripheral blood mononuclear cells 
PK 
Pharmacokinetic 
PT 
Prothrombin Time 
RBC 
Red Blood Cells 
RFS 
Relapse Free Survival 
RP2D 
Recommended Phase II Dose  
SAE 
 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SMC 
Safety Monitoring Committee 
TEAE 
Treatment-Emergent Adverse Event 


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WHO 
World Health Organization 
WBC 
White Blood Cells 
 


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1 Introduction 
This document presents the statistical analysis plan (SAP) for BerGenBio AS, Protocol No. 
BGBC003 study submitted in four countries:  
• Germany: A Phase Ib/II multicenter open-label study of BGB324(bemcentinib) as a 
single agent and in combination with cytarabine or decitabine in patients with Acute 
Myeloid Leukemia (AML) or as a single agent in patients with myelodysplastic 
syndrome. Final protocol dated 04AUG2020 (Version 10.0).  
• Norway: A Phase Ib/II multicenter open-label study of bemcentinib (BGB324) as a 
single agent and in combination with cytarabine or decitabine in patients with acute 
myeloid leukemia (AML) or as a single agent in patients with myelodysplastic 
syndrome (MDS). Final protocol dated 04AUG2020 (Version 8.0). 
• United States: An open label, multicentre, phase I/Ib/II study of BGB324 (bemcentinib) 
administered as a single agent or in combination with cytarabine or decitabine in 
patients with acute myeloid leukemia (AML) or as a single agent in patients with 
myelodysplastic syndrome (MDS). Final protocol dated 04SEP2020 (Version 9.0) 
• Italy: An open label, multicentre, phase Ib/II study of BGB324(bemcentinib) 
administered as a single agent or in combination with cytarabine or decitabine in 
patients with acute myeloid leukemia or as a single agent in patients with 
myelodysplastic syndrome. Final protocol dated 23MAR2020 (Version 4.0) 
 
The SAP provides the description of the final analyses for all 4 protocols listed above. The data 
will be analysed together as a unique single study taken into account the individuality of each 
protocol. 
2 Study Objectives 
2.1 Primary objectives 
The primary objectives of this study are: 
Part A: 
• In Norway: To identify the maximum tolerated dose (MTD) and/or Recommande Phase 
2 dose (RP2D) of BGB324 (bemcentinib) in patients with relapsed or refractory AML 
or high risk MDS patients.  
• In US and Italy: To identify the maximum tolerated dose (MTD) of bemcentinib in 
AML patients who have received previous treatment with cytotoxic chemotherapy 
(with or without hematopoietic stem cell transplantation) or a targeted or biologic agent 
(e.g. hypomethylating agent, tyrosine kinase inhibitor, antibody), and have relapsed 
after or have been refractory to treatment with such prior therapy. 
• In Germany: To identify the maximum tolerated dose (MTD) of bemcentinib in AML 
patients who have received previous treatment with cytotoxic chemotherapy (with or 
without hematopoietic stem cell transplantation) or a gene expression modulator, such 
as a demethylating agent, and have relapsed after or have been refractory to treatment 
with that therapy. 
 


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Part B: 
• To identify the safety and tolerability of bemcentinib, as a single agent in patients with 
AML (Part B1) or MDS (Part B2) and in combination with low dose cytarabine (Part 
B2 and Part B5) or decitabine (Part B3),  
o In Norway, US and Germany: in patients with AML who are unsuitable for 
intensive chemotherapy as a result of advanced age or existing co-morbidities.  
o In Italy: in patients with AML who are unsuitable for intensive chemotherapy.  
2.2 Secondary objectives 
The secondary objectives of this study are: 
Part A: 
• To identify the dose limiting toxicity (DLT) profile of bemcentinib 
• To explore the safety, tolerability and efficacy of bemcentinib 
• To characterise the pharmacokinetic (PK) profile of bemcentinib 
Part B: 
• To explore the efficacy of bemcentinib as a single agent in patients with AML or MDS 
(part B1 and B4) 
• To explore the efficacy of bemcentinib in combination with low dose cytarabine (Part 
B2 and Part B5) or decitabine (Part B3) in patients with AML who are unsuitable for 
intensive chemotherapy as a result of advanced age or existing co-morbidities or not. 
• To evaluate bemcentinib PK (all Part B cohorts) 
2.3 Exploratory objectives 
The exploratory objectives of this study are: 
• To identify and evaluate potential predictive biomarkers, e.g. soluble AXL (sAXL) and 
other associated soluble biomarkers. Pre-treatment levels of biomarkers will be 
correlated with clinical endpoints 
• To establish the effects of bemcentinib on relevant biological endpoints in peripheral 
blood (including sAXL peripheral blood mononuclear cells [PBMC]) and BM samples 
• To assess pharmacodynamic biomarkers in tissue and blood to support the clinical 
development of bemcentinib 
• To evaluate other biomarkers relevant to the investigational agents for exploratory 
purposes  
3 Endpoints 
3.1 Safety endpoints 
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 


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• Vital signs including blood pressure (BP), heart rate (HR), respiration rate and 
temperature 
• Electrocardiogram (ECG) 
• Echocardiogram 
• Laboratory findings including clinical chemistry, hematology and urinalysis 
3.2 Efficacy endpoints 
In AML, efficacy endpoints will be measured using objective response criteria, in evaluable 
patients. 
• Objective Response (OR) or Stable Disease (SD) according to the revised 
recommendations of the International Working Group (IWG) in AML [Cheson, 
BGBC003 v8.0 (NO); 04 August 2020 CONFIDENTIAL Page 37 of 113 2003 and 
Döhner, 2017] (see Appendix 5 of the protocol). SD is defined as having unchanged 
disease for at least 3 treatment cycles. 
• Proportion of patients with an OR + SD as an estimate of clinical benefit. 
• Relapse Free Survival 
• Event Free Survival 
• Overall Survival 
• To explore the correlation between baseline biomarker levels and clinical endpoints 
In MDS, efficacy endpoints will be measured using the following response criteria. 
• OR or SD according to the revised recommendations of the IWG in MDS (see 
Appendix 6 of the protocol). SD is defined as failure to achieve at least PR but not 
evidence of PD for at least 3 treatment cycles. 
• Proportion of patients with an OR + SD as an estimate of clinical benefit. 
• Relapse Free Survival 
• Event Free Survival 
• Overall Survival 
• To explore the correlation between baseline biomarker levels and clinical endpoints 
3.3 Pharmacokinetic endpoints 
Pharmacokinetic analysis is not part of this SAP, it will be summarized in a separate document. 
3.4 Pharmacodynamic endpoints 
Pharmacodynamic analysis is not part of this SAP, it will be summarized in a separate 
document. 
4 Study Design 
4.1 Discussion of Study Design 
This is the general summary of the study design in the 4 protocols, detailed design can be found 
in the individual study protocol for each of the 4 countries.  


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The design is a Phase Ib/II, open-label, dose-escalation and cohort expansion study to obtain a 
preliminary assessment of the safety, tolerability and efficacy of bemcentinib, a small molecule 
inhibitor of Axl kinase in patients with acute AML or high/intermediate (int-2) risk MDS. The 
study will be conducted at up to approximately 20 sites in Europe and the US and will be 
performed in approximately 102 evaluable patients with AML or MDS. Additional countries 
and sites may be added as required to meet the enrolment needs of the study. 
Bemcentinib will be administered orally according to a daily schedule during continuous 21-
day treatment cycles. During Cycle 1, Week 1 ONLY the first 3 doses of bemcentinib may 
serve as a ‘loading’ dose. 
Dosing will consist of a loading dose of 200 mg administered on Days 1, 2 and 3 followed by 
a daily maintenance dose of 100 mg. This dose may be escalated as agreed by the SMC to a 
maximum daily loading dose of 400 mg on Days 1, 2 and 3 followed by a maximum daily 
maintenance dose of 200 mg. 
Patients will be instructed to take bemcentinib on an empty stomach at a similar time each 
morning when they wake, or more than 2 hours after a light meal, with water. To maintain a 
fasted state, patients should be told not eat or drink anything other than water for at least 1 hour 
after taking the drug. 
In Part A the study will follow a 3+3 design to explore the safety and tolerability of repeat 
dosing of bemcentinib, and to identify the MTD and/or RP2D. A minimum of 6-10 patients 
will be treated at the MTD and/or RP2D, as determined by the SMC. Depending upon the 
results of this phase of the study, the safety and efficacy of bemcentinib may be established in 
up to 4 disease-specific cohorts in Part B. 
Part B1 
Single agent bemcentinib will be administered to patients with AML who are unsuitable for 
intensive chemotherapy as a result of advanced age and or existing co-morbidities. In order to 
be eligible patients should have received at least one line of previous therapy. 
Part B2 
Bemcentinib will be administered in combination with cytarabine to patients with AML who 
are not suitable for intensive chemotherapy as a result of advanced age or existing co-
morbidities. 
Part B3 
Bemcentinib will be administered in combination with decitabine to patients with AML who 
are not suitable for intensive chemotherapy as a result of advanced age or existing co-
morbidities. 
Part B4 
Single agent bemcentinib will be administered to patients with intermediate (int-2) or high risk 
MDS according to the International Prognostic Scoring System (IPSS) Risk Stratification 
[Greenberg, 1997]. Patients must have received at least 1 prior treatment for their disease. 
Prior treatment may include those patients who have received hypomethylating agents, 
decitabine or other approved treatments for MDS. 
Part B5 
Bemcentinib will be administered in combination with cytarabine in patients with AML who 
are unsuitable for intensive chemotherapy as a result of advanced age or existing co-


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morbidities. Patients must have received at least one prior treatment for AML. Please refer to 
Figure 1 for an outline of the overall study design. 
 
 
Figure 1: BGBC003 Study Design 
 
 
Phase I DLT Assessment Period 
During the dose-escalation phase (Part A), safety, tolerability, PK, and preliminary clinical 
activity of BGB324 will be assessed, and the MTD established, in patients with AML who 
have received previous treatment with cytotoxic chemotherapy or a targeted or biologic agent 
(e.g. hypomethyllating agent, tyrosine kinase inhibitor, antibody) or a gene expression 
modulator, such as a demethylating agent and have relapsed after or have been refractory to 
treatment with such prior therapy or in high risk MDS.  Patients suitable for intensive 
chemotherapy should be in second or subsequent relapse or be refractory to at least two 
induction regimens.  Patients receiving an allograft in first remission would be eligible at the 
time of relapse. 
A loading dose (Cohort 1) of 200 mg administered on Cycle 1, Days 1, 2 and 3 followed by a 
daily maintenance dose of 100 mg during continuous 21-day treatment cycles will be evaluated. 
This dose may be escalated as agreed by the SMC to a maximum daily loading dose of 400 mg 
on Days 1, 2 and 3 followed by a maximum daily maintenance dose of 200 mg. At least three 
evaluable patients will be entered per cohort.(see Section 9 of the individuals protocols).  At 
least three evaluable patients will be entered per cohort. 
 
 


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Dose Escalation Scheme 
Initially three patients will be recruited into Cohort 1 and will complete 1 cycle of treatment 
before a dose-escalation evaluation is made. A patient must receive all loading doses and miss 
no more than 3 standard doses in Cycle 1 in order to be considered as informative to support 
dose escalation, unless the missed doses are due to bemcentinib toxicity. 
The decision to dose-escalate (or not) will be made by the SMC comprising a representative 
from each actively recruiting investigational site and a representative of the BerGenBio AS 
study team. Minutes of the SMC meeting will be recorded and circulated for final approval 
before being placed in the Trial Master File (TMF). The decision to dose escalate will be based 
upon the tolerability of bemcentinib observed at the previous dose level. Dose escalation will 
range between 25% and 50% of the previous dose according to the nature and severity of the 
toxicity observed.  
Where dose escalation occurs, three patients will be recruited to the next Cohort (dose level) 
and will complete 1 cycle of treatment before a dose-escalation evaluation is made, as outlined 
above. 
If one patient in a cohort experiences a DLT during Cycle 1, the cohort will be expanded to six 
patients. If two of three or two of six patients in a cohort experience DLT no further dose-
escalation will take place and the dose below will be nominated as the MTD. If the starting 
dose exceeds the MTD, a lower dose may be explored if recommended by the SMC. Provided 
treatment with the starting dose is considered safe by the SMC according to DLT evaluation, 
dose escalation may proceed.  
The maximum daily dose that may be explored in this study will be 400 mg.  
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.  
Dose Limiting Toxicity 
DLT will be assessed during the first 3 weeks of treatment (Cycle 1) with bemcentinib, 
according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) version 4, considered unrelated to leukemia progression or intercurrent 
illness, and defined as any of the following: 
• CTCAE Grade 3 or 4 nausea, vomiting, or diarrhea that persists despite maximum 
prophylactic and supportive care 
• Any other CTCAE Grade 3 or 4 non-hematological toxicity that is considered to be 
clinically significant and causally related to BGB324, excluding isolated changes in 
laboratory results if no clinical significance or no clinical sequelae and adequately 
improve within 7 days. 
• Prolonged neutropenia with ANC < 500 and platelet count < 75000 after Day 42 from 
the start of treatment in the absence of residual leukemia  
• Treatment discontinuation, inability to administer one or more BGB324 loading dose, 
or inability to administer three BGB324 maintenance doses as result of BGB324-related 
toxicity 
• Any Ventricular Arrhythmia 
 


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Part B: Following SMC review of all treatment emergent safety and efficacy data from Part 
A, up to 14 evaluable patients (up to 20 evaluable patients in Part B5)  will be recruited into 
four cohorts . 
Depending upon the safety profile of BGB324 observed in Part A the initial starting dose in 
combination with cytarabine (Part B2) or decitabine (Part B3), may be reduced by a single 
dose level (i.e. MTD -1) which will be evaluated in at least three subjects before introduction 
of the MTD or RP2D identified in Part A. The bemcentinib dose level to be investigated in 
Part B2 and Part B3 will be dependent upon the MTD confirmed in Part A. A dose lower than 
100 mg daily is not available. The Part B5 dose is based on the combination dose that was 
identified as safe and well tolerated in Part B2. 
4.2 Study Treatment 
Every patient enrolled in the study will receive bemcentinib. Patients enrolled in Part B2 and 
B5 will receive bemcentinib in combination with low dose cytarabine. Patients enrolled in Part 
B3 will receive bemcentinib in combination with decitabine. More detailed information for the 
treatment scheduled and administration are provided in section 12.1 of the individual protocols. 
4.2.1 Bemcentinib 
In Part A, the starting dose of bemcentinib (Cohort 1) will be 200 mg on Cycle 1, Days 1, 2 
and 3 (loading dose), followed by a daily maintenance dose of 100 mg. In Part B depending 
upon the safety profile of bemcentinib observed in Part A the initial starting dose in 
combination with cytarabine (Part B2) or decitabine (Part B3) may be reduced by a single dose 
level (i.e. MTD -1) which will be evaluated in at least three patients in each cohort before the 
introduction of the MTD identified in Part A. The bemcentinib dose level to be investigated in 
Parts B2 and B3 will be dependent upon the MTD confirmed in Part A. A dose lower than 100 
mg daily is not available. 
The bemcentinib dose in Part B5 (combination with low dose cytarabine) will be 400 mg orally 
daily for the first 3 days of treatment (loading dose) and 200 mg orally daily thereafter 
(maintenance dose). 
Patients receiving Formulation 2 will be instructed to take bemcentinib on an empty stomach 
at a similar time each morning when they wake, or more than 2 hours after a light meal, with 
water. To maintain a fasted state patients should be told not eat or drink anything other than 
water for at least 1 hour after taking the drug. 
Patients will record their dosing at home in a dosing diary that will be reviewed regularly 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 bemcentinib 
bottles, including unused and empty bottles, with them to each study visit. The site staff will 
record the amount of used and unused bemcentinib capsules at selected study visits. 
4.2.2 Cytarabine (Part B2 and Part B5) 
For Part B2, cytarabine will be administered subcutaneously according to standard practice (i.e. 
20 mg/m2 twice daily for 10 days followed by a rest period of <1 month according to persisting 
myelosuppression). Cytarabine should be administered approximately 30 minutes after the 
bemcentinib dose. 
For Part B5, cytarabine will be administered at a dose of 20 mg subcutaneously twice daily for 
10 days every 28 days. Cytarabine should be administered approximately 30 minutes after the 
bemcentinib dose. 


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If toxicity presents, then the cytarabine dose may be modified in accordance with the approved 
prescribing information or Summary of Product Characteristics (SmPC) and in accordance 
with local treatment guidelines. 
4.2.3 Decitabine 
Decitabine will be administered per standard local practice up to a maximum dose of 20 mg/m2 
body surface area by intravenous infusion over one hour, repeated daily for five consecutive 
days (i.e. a total of five doses per treatment cycle). 
The total daily dose must not exceed 20 mg/m2 and the total dose per treatment cycle must not 
exceed 100 mg/m2. The cycle should be repeated every four weeks depending on the patient's 
clinical response and observed toxicity. Decitabine should be administered within 
approximately 30 minutes of bemcentinib dose.  
If toxicity presents, then the dose may be modified in accordance with the approved prescribing 
information or SmPC and in accordance with local treatment guidelines. 
Both cytarabine and decitabine are considered to be standard of care for these patients and will 
not be supplied or reimbursed by BerGenBio ASA. 
4.3 Study Schedule 
The study period will consist of screening, treatment, Final Study Visit, and follow-up. The 
Final Study Visit will occur 28 days after the patient has discontinued study treatment. A 
detailed Schedule of Events can be found in the section 9.3 of the Norway, US and German 
study protocols and 9.2 of the Italian study protocol. 
4.3.1 Screening 
Patient eligibility for the study will be determined within 14 days prior to the first dose of 
BGB324. Screening assessment will be conducted according to the schedule of events in 
section 11 of the protocol.  
4.3.2 Treatment  
Eligible patients will visit the study site to receive study treatment and protocol-specified 
procedures according to the relevant Schedule of Events in the study protocol, Section 11. The 
treatment period will consist of continuous 21-day treatment cycles. 
Patients will be intensively monitored throughout Day 1 to Day 4 inclusive of Cycle 1, and in 
addition will attend the clinic on Day 8, and Day 15.  
Patients will attend the clinic once per week during Cycle 2 and then once per cycle thereafter. 
All patients will continue to receive bemcentinib or the combination for as long as, in the 
opinion of the investigator, they continue to derive clinical benefit. When there is unacceptable 
toxicity, confirmed disease progression in the absence of clinical benefit, death or withdrawal 
of consent, bemcentinib or combination treatment must be discontinued. 
For patients in the combination arms (Part B2, B3 or B5), if treatment-related toxicity requires 
discontinuation, and the toxicity can be clearly assigned to one of the study treatments, the 
other study drug in the combination can be continued if it is safe to do so (investigator 
discretion) in the absence of disease progression or intolerable toxicity. The investigator may 
also decide to discontinue both study treatments at this time. 
Patients with AML who are receiving bemcentinib monotherapy and who do not achieve an 
objective response after two cycles of treatment may start additional therapy with oral anti-
metabolites (e.g. 6-mercaptopurine, hydroxyurea), or low dose cytarabine, or melphalan 


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administered at 50% of the institution’s starting dose, which may be escalated in subsequent 
cycles according to tolerability.  
4.3.3 Final Study Visit 
Patients will return to the study site for the Final Study Visit 28 days after permanent 
discontinuation of all study treatments. 
4.3.4 Follow Up 
An AE will be monitored for 28 days after the last dose of BGB324, although only events 
considered to be related to treatment need to be recorded in the electronic Case Report Form 
(eCRF) between the last administration of BGB324 and the end of the 28 day follow up period. 
If BGB324-related toxicities continue beyond the follow up period, patients will be followed 
until all BGB324-related toxicities have resolved to ≤Grade 1, stabilised or returned to baseline. 
If necessary, follow up monitoring for AEs may be conducted over the telephone.  
SAEs with a suspected relationship to BGB324 will be collected beyond the 28-day follow-up 
period until the event is resolved to ≤ Grade 1, stabilized or returned to baseline.  
All patients that have permanently discontinued study treatment for whatever reason must be 
followed for survival. The investigator or designee must confirm with the patient at the time of 
the Final Study Visit how the patient will be followed for survival (e.g. contact with family or 
health care provider). Survival follow-up must be conducted at least every 3 months by the 
investigator or designee and the date-of-death reported in the eCRF. 
All subsequent anticancer therapy for AML or MDS must be reported in the eCRF.  
4.3.5 End of Study 
Except in the case of early termination (Section 9.4), the end of the study is defined as the date 
when all patients have an OS event, unless the Sponsor terminates OS follow-up once all 
patients have discontinued study treatment. Should the last patient enrolled to the study be 
continuing to receive bemcentinib 52 weeks from their Cycle 1 Day 1, the Sponsor may choose 
to lock the data base to that point and prepare the clinical study report (CSR). Data collected 
as part of this study after this point, will be reported as an addendum to the CSR.  
A final clinical study report will be prepared when the last patient has completed their Final 
Study Visit and the database is locked. The Statistical Analysis Plan (SAP) will be finalized 
and signed before database lock. 
Patients will continue to be followed for suspected SAEs until these are resolved to ≤ Grade 1, 
stabilized or returned to baseline. Refer to Section 15.2.2 for SAE reporting after the end of 
study.  
4.4 Concomitant Medication and Procedures 
All prescription, non-prescription, or over-the-counter medications including herbal remedies 
given to, or 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 bemcentinib in Part A. Patients who have evidence of 
treatment benefit after >1 cycle of treatment in Part B may receive hematopoietic growth 
factors to maintain bemcentinib dosing. 


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Concurrent treatment with any agent known to cause QT prolongation and have a risk for 
Torsades de pointes is an exclusion criterion for the study. A comprehensive list of these 
prohibited medications is provided in the study protocol Appendix 3.  
Treatment with any medication which is predominantly metabolized by CYP3A4 and has a 
narrow therapeutic index is also excluded (see Appendix 4 in study protocol for details of 
CYP3A4 substrates).  Patients being treated with antacid histamine receptor 2 inhibitors or 
proton pump inhibitors within 3 days of administration of bemcentinib will be excluded.  The 
Investigator may initiate rescue treatment with these medications in the evening for 
symptomatic relief following one week’s treatment with bemcentinib.  
4.5 Study Analysis Populations 
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 Analysis Population  
The Safety analysis population will be defined as all enrolled patients who receive at least one 
dose of bemcentinib. The Safety analysis population will be analysed by dose group or 
combination in Part B.  
Patients enrolled to Part A who meet the eligibility criteria for Part B1 and who receive the 
MTD and/or RP2D, may contribute to the Part B1 analysis. 
4.5.3 Efficacy Analysis Population  
The Efficacy Analysis Population will include all from Safety Analysis Population that,   
✓ Meet key eligibility criteria, have assessable disease at baseline and have at least one 
post-baseline response assessment 
✓ Have received >1 dose of bemcentinib (and combination agent in Part B2, B3 and B5) 
Any patient who continues treatment with bemcentinib beyond confirmed disease progression 
will be followed for the same safety and efficacy assessments as for all other patients enrolled 
into the study until they are withdrawn from the study as defined in protocol section 13. 
 
4.5.1 Per protocol Analysis Population  
No per protocol population will be analysed in this study.  
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. In addition, 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 
• Patient experiences an unacceptable toxicity that precludes them from continuing in  
the study e.g. patient experiences a ventricular arrhythmia (see study protocol Section 
12.2), as agreed by the investigator and the sponsor 


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• Lack of adequate recovery from a DLT, see Section 9.2.1.2 in study protocol 
• Failure of toxicity to adequately resolve, as outlined in Section 12.2 in study protocol 
• Female patient becomes pregnant 
• Patient experiences clinical disease progression 
• Patient and/or investigator decision 
AEs resulting in discontinuation will be followed as outlined in study protocol Section 9.3.4.  
Patients who discontinue during the DLT assessment period (Part A), for any reason other than 
a DLT, will be replaced. All other patients who discontinue study treatment will not be 
replaced. 
If a patient discontinues treatment prior to study completion, and for reasons other than 
progression or non-tolerability, every effort should be made to conduct the Final Study Visit 
assessments as outlined in Section 11.5 of the protocol. The reason for the patient’s withdrawal 
from the study must be recorded in the eCRF. 
 
4.7 Randomisation 
This is a non-randomized study. All patients will receive treatment with orally administered 
BGB324. All patients enrolled in Part B2 will also receive intravenously administered 
cytarabine and patients enrolled in Part B3 will receive decitabine in addition to BGB324. 
 
4.8 Blinding 
This is an open-label study and consequently there are no blinding procedures in operation.  
4.9 Sample Size 
Part A of the study follows a conventional algorithm (3+3 patients per dose level) to identify 
the MTD, escalating on 0/3 or 1/6 patients experiencing 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 1.  
Table 1: 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 
The total sample size of Part A depends 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 MTD. A minimum of 6-10 patients will be treated at the MTD. 
The sample size of up to 14 evaluable patients for Parts B1, B2, B3 and B4 and up to 20 
evaluable patients in Part B5 in this study has been calculated on the basis of the following 
assumptions for a one-sided, within-group test of proportions, comparing an anticipated ORR 
of >20% against the null hypothesis rate of 5%, with power 80% for a test of size 0.2. This 


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calculation is based on statistical significance at the 0.2 level, since this will be taken as 
evidence of a trend worthy of further study. Although this is offered as a formal sample size 
calculation, it is acknowledged that for this early-stage study the analyses will be exploratory 
in nature, and that no account has been taken of multiplicity inherent in the assessment of 
several, presumably non-independent criteria, for ORR. 
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 Analysis Set. Safety 
analyses will be carried out using the Safety Analysis Set. Efficacy analyses will be carried out 
using the Efficacy Analysis 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 or treatment groups will be performed. Percentages will be calculated using the 
total patients per dose cohort in the given population unless otherwise noted.  
All data from this study will be presented in data listings.  All listings will be sorted by dose 
level or treatment group and patient. 
Baseline will be defined as the last assessment prior to study drug administration. Typically 
this will be Cycle 1 Day 1. 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 in Part A and by treatment group (AML (B1: 
BGB324 400/200 mg Single agent; B2: BGB324 400/200 mg + Cytarabine; B3: BGB324 
400/200 mg + Decitabine; B5: BGB324 400/200 mg + Cytarabine) and  MDS (B4: BGB324 
400/200 mg) ) and overall in Part B. 
Where appropriate, the data for patients who received the MTD during Part A will be combined 
with that for patients who received the MTD in Part B for the purpose of data summarisation. 
A clear distinction will be made in the relevant Tables to differentiate between the cohort who 
received the MTD during the dose escalation phase of Part A, the MTD cohort from the cohort 
expansion phase in Part A, and the combined MTD cohort. 
Any patient treated with bemcentinib beyond disease progression will be followed for the same 
safety and efficacy assessments as for all other patients enrolled into the study. The data for 
patients treated beyond progression will be presented in both a combined output (with all 
patients) and a separate output (reflecting a new period of analysis with the data collected in 
this period). All data collected will be included in the study CSR and may be presented at 
congress/symposia.  
For subjects in Part B a new period (treated beyond disease progression) will be created if the 
date of progression < date of any intake of the bemcentinib, to identify patient treated with 
bemcentinib beyond disease progression and also the visit cycle where the data are collected 
beyond the disease progression. The data collected during this period will be identified to be 
added in this analysis.   
For Part B analysis, some outputs such as disposition, demographic and baseline 
characteristics,  cancer history, ORR, AE and ECG(QtCF), the data for cohort B2 and B5 will 
be summarized together.  


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5.2 Interim Analysis 
No formal statistical interim analyses are planned, however data will be monitored by the 
Safety Monitoring Committee (SMC), in an on-going manner, to assess patient safety. 
 
5.3 Disposition of Subjects 
The number of patients receiving study treatment in each analysis population and the reasons 
for any discontinuation from the study will be presented. 
 
5.4 Baseline and Demographic Characteristics 
All baseline and demographic characteristics will be summarised. This will include age, age 
group, sex, height, weight, and Eastern Cooperative Oncology Group (ECOG) performance 
status at screening. Cancer history (time since initial diagnosis, type of cancer), medical history 
by system organ class and preferred term, and prior cancer therapies (chemotherapy, hormonal 
therapy, immunotherapy, monoclonal therapy, radiotherapy, other therapy) will also be 
summarized. 
The following parameters may be used for defining and comparing the various subtypes of 
AML patients: 
• Age Groups are defined as: <75  years and ≥=75  years of age. 
• AML Disease status: Relapsed and Refractory.  
• AML Disease Type: Primary and Secondary 
• AML Disease Cytogenetic profile: Favorable, Intermediate, Adverse and Not Done 
Medical history will be coded according to Medical Dictionary for Regulatory Activities 
(MdDRA) version 17.0 or higher. 
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 by therapeutic area and preferred drug 
name. Prior medications will be listed only. 
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 higher. 
 
5.6 Exposure and Compliance 
BGB324 exposure will be summarized by the number of cycles started on BGB324 and 
duration of administration by dose cohort. Duration of BGB324 administration will be defined 
in days as: 
(Date of Last Drug Administration – Date of First Drug Administration + 1 day). 
Duration of BGB324 administration will also be summarized in weeks and defined as: 
Duration of administration (in days) / 7 


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Total treatment exposure to BGB324 will also be characterized by total cumulative dose over 
the whole study and summarized by dose cohort.  
For subjects in part B2, total administrations of cytarabine will be summarized by the number 
of cycles started, the total number of infusions (total number of days cytarabine has been 
administered), and total cumulative dose administered over the study. The same analysis will 
be performed for decitabine (part B3). 
Study drug percent compliance for BGB324 will be calculated as: 
((Actual Duration) / Expected number of doses) * 100 
Actual Duration is the sum of each treatment duration by cycle when Dose is not missing or 
null. 
Expected Number of Doses is defined as duration of study drug administration in days (number 
of cycles received * 21 days). 
Overall percent compliance will be summarized by frequency count and percentage of subjects 
with compliance <80%, 80 to 100%, and > 120%. Overall percent compliance will also be 
summarized as a continuous variable using descriptive statistics. 
Number and percentage of dose reductions per cycle and overall will also be tabulated for part 
A and Part B. 
Number and percentage of dose interruptions per cycle and overall will also be tabulated for 
part A and Part B. Duration of dose interruptions will also be summarised. 
 
5.7 Efficacy Analysis 
The endpoints to be analysed in the efficacy analysis are:   
Objective response rate [ORR] : Proportion of patients with a best objective response such 
as, CR (Complete Remission), Cri (Complete Remission with Incomplete hematologic 
Recovery), CRp (Complete Remission with Incomplete Platelet Recovery), CRh and 
PR(Partial Remission) for AML patients and CR, PR, MR(Marrow Response), PMR(Partial 
Marrow Response) for MDS patients; 
CRh is defined as, CR (<5% myelobasts and 0% blasts in the peripheral blood) with partial 
hematologic recovery, defined as meeting CR criteria but with ANC > 0.5 10^9/L and platelets 
> 50 10^9/L responses for patients with AML. 
Best Objective Response (BOR) = Best response obtain during the study participation for a 
patient;  
Disease control Rate (Objective Response + SD) [DCR]: Proportion of patients with a best 
objective response such as, CR, CRi, CRp, CRh and PR for AML patients and CR, PR, MR, 
PMR for MDS patients,  + SD (stable disease) as an estimate of clinical benefit; 
The ORR will be summarized by;  
➢ Age group (<75 years, >= 75); 
➢ AML Disease Cytogenetic Profile (Favourable, Intermediate, Adverse and not done);  
Relapse Free Survival [RFS] 
Relapse free survival [RFS]: defined as the months from the date of response until the date of 
relapse as confirmed by blast counts assessment (date of the disease progression will be used 
since disease progression is based in blast count assessment) .  


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Relapse Free Survival is defined only for subjects with a best objective response of 
CR/CRi/CRp/PR for AML patients or CR, PR, MR, PMR for MDS patients. Subjects who do 
not achieve CR/CRi/CRp/PR will be excluded from this analysis.  
Duration of RFS is calculated as (days):  
- 
Date of disease relapse, patient death, or censoring - Date of first Response evaluation 
+ 1. 
- 
Subjects without an objective disease relapse who die for any reason will be considered 
to have an event on the date of death. Otherwise subjects will be censored at the date 
of last objective response assessment showing no relapse has occurred. 
Reason for censoring 
Rule 
Early death 
Date of death 
Disease 
progression 
leading 
to 
discontinuation 
Date of last OR with no relapse 
New anticancer treatment started before 
documentation of disease progression or death 
Date of last radiological assessment prior to 
the start of non-protocol anticancer treatment 
RFS will be summarized with (Mean (SD), median, min and max). 
RFS will be presented graphically using Kaplan-Meier method.  
Event Free Survival [EFS] 
Event is defined as death or progression.  
Duration of EFS is calculated as (days):  
- 
Date of onset of Event, patient death or censoring - Date of first intake of study 
treatment (BGB324) + 1. 
 
EFS will be summarized with (Mean (SD), median, min and max). 
EFS will be presented graphically using Kaplan-Meier method.  
 
Overall Survival [OS]: 
OS is defined as the months from the first day of treatment until date of death for any cause. 
Patients who were alive at the time of the final analysis will be censored at the date the patients 
was known to be alive.   
Situation 
Date of Progression or Censoring 
Outcome 
New anticancer treatment 
started before documentation of 
disease progression or death 
Date of last radiological assessment 
prior to the start of non-protocol 
anticancer treatment 
Censored 
Alive and without 
documentation of disease 
progression 
Date of last radiological assessment 
Censored 


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Patient who do not die during the study will be followed up until date of death collected in the 
Survival Follow up CRF form or will be censored with the last Date of Follow-up when the 
patient was still alive. 
Date of last known to be alive is the last date with available information for a subject in the 
study. 
Duration of OS is calculated as (days):  
- 
Date of death or censoring (date of last known to be alive) - Date of first intake of study 
treatment (BGB324) + 1. 
OS will be summarized using Kaplan-Meier estimates (number of subjects who died, number 
of subjects censored, min, max, median, 95%CI of median). 
 
5.8 Safety Analysis 
No formal statistical analysis will be performed. The safety endpoints will consist of treatment-
emergent adverse events, physical examinations, vital signs, ECOG, ECG, Echocardiograms, 
and laboratory tests (clinical chemistry, hematology and urinalysis). Change from baseline will 
be presented where appropriate. 
 
5.8.1 Adverse events 
The number and percentage of patients reporting TEAEs will be tabulated by MedDRA 
preferred term and system organ class, and summarized by CTCAE grade also. 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. 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 definitely, possibly or probably related to study 
medication or with an unknown relationship. 
Treatment-Emergent AEs are any AEs that start or worsen after first dose of study drug until 
28 days following the last dose. 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 
BGB324. 
 
5.8.1.1 Subsets 
• Non-serious adverse events will be presented by dose level (part A) or treatment group 
(parts B), system organ class and preferred term 


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• Related (BGB324) adverse events will be presented by dose level or treatment group, 
system organ class and preferred term. 
• Related (Cytarabine) adverse events will be presented by system organ class and 
preferred term. (Part B2 only) 
• Related (Decitabine) adverse events will be presented by system organ class and 
preferred term. (Part B3 only) 
• Related (Other Anti-Cancer Medications) adverse events will be presented by dose 
level or treatment group, system organ class and preferred term. 
• Serious adverse events will be presented by dose level or treatment group, system organ 
class and preferred term 
• Related (BGB324) serious adverse events will be presented by dose level or treatment 
group, system organ class and preferred term. 
• 
Related (Cytarabine) serious adverse events will be presented by system organ class 
and preferred term. (Part B2 only) 
• 
Related (Decitabine) serious adverse events will be presented by system organ class 
and preferred term. (Part B3 only) 
• 
Related (Other Anti-Cancer Medications) serious adverse events will be presented 
by dose level or treatment group, system organ class and preferred term. 
• 
Serious adverse events will be presented by dose level or treatment group, system 
organ class, preferred term, and maximum CTCAE grade. 
• Adverse events leading to discontinuation will be presented by dose level or treatment 
group, system organ class and preferred term. 
• Adverse events ≥ Grade 3 will be presented by dose level or treatment group, system 
organ class and preferred term. 
• 
Related (BGB324) adverse events ≥ Grade 3 will be presented by dose level or 
treatment group, system organ class and preferred term. 
• 
Related (Cytarabine) adverse events ≥ Grade 3 will be presented by system organ 
class and preferred term. (Part B2 only) 
• 
Related (Decitabine) adverse events ≥ Grade 3 will be presented by system organ 
class and preferred term. (Part B3 only) 
• The most frequent MedDRA preferred terms (≥10% subjects in the overall safety 
population restricted to each part) will be presented by dose level or treatment group.  
• Separate listings will be produced for DLTs, SAEs, related (all 3 types) AEs, 
discontinuations due to AEs, and events of ≥ Grade 3 severity. 
• A listing of death occurring during the study with time interval between first/last intake 
date and death date, as well as a flag for only Early Death during the first 4-week period 
after C1D1will also be presented. 
All other information collected (e.g. action taken) will be listed as appropriate.  
Notes: 
• AEs coded using MedDRA version 17.0 or higher 


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5.8.2 Physical Examination 
Any new or worsened post-baseline 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 weight (kg), systolic and diastolic blood pressure (mmHg), pulse rate (BPM), 
respiration rate (BREATHS/MIN), and temperature (°C) will be summarised by dose cohort 
and scheduled visit, as well as Change from Baseline. Height (cm) at screening will be 
summarized with the demographics, but presented with other vital signs in the listing. 
 
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 
The quantitative ECG assessments (PR interval, RR interval, QRS Duration, QT interval, and 
QTcF interval) will be summarised 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 dose cohort and scheduled visit. 
 
5.8.6 Echocardiograms 
Any new or worsened post-baseline 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 results will be presented in a data listing. 
 
5.8.7 Laboratory findings 
Results from the following laboratory parameters, recorded at scheduled visits, will be 
presented in listings:  
Hematology: 
 
Hemoglobin, Hematocrit, Red Blood Cells (RBC), Mean Corpuscular Hemoglobin (MCH), 
Mean Corpuscular Hemoglobin Concentration (MCHC), White Blood Cells (WBC), 
Neutrophils, Eosinophils, Basophils, Lymphocytes, Monocytes, Platelets, and Blasts (in 
percent). 
Clinical Chemistry: 
Sodium, Potassium, Calcium, Chloride, Magnesium, Inorganic Phosphate, Creatine 
phosphokinase, Serum Creatinine, CK-Myocardial B, Total Protein, Total Bilirubin, Direct 
Bilirubin, Indirect Bilirubin, Albumin, Alkaline Phosphatase (ALP), Alanine Aminotransferase 
(ALT), Aspartate Aminotransferase (AST), Glucose, Uric Acid, and Blood Urea Nitrogen 
(BUN). 


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Urine: 
pH, Specific Gravity; semi-quantitative "dipstick" evaluation of Proteins, Glucose, Ketones, 
Blood, Bilirubin, Nitrite, Leukocytes, and Urobilinogen, and a microscopic examination 
including Casts, Crystals, RBC, and WBC. 
Coagulation: 
Prothrombin Time (PT), Activated Partial Thromboplastin Time (APTT), International 
Normalized Ratio (INR), and Quick Test. 
 
Numeric Hematology and Clinical Chemistry parameters will be summarised along with each 
corresponding Change from Baseline for all scheduled visit by dose level or treatment group. 
The incidence of laboratory test results outside the normal range will be listed by dose cohort 
and time point. 
The following shift tables from baseline to all the cycles of hematology CTCAE grades will 
also be displayed by dose level or treatment group: 
- 
All post baseline grades according to all baseline grades 
- 
Number of patients with at least CTCAE Grade 2 according to all baseline grades 
Finally, number of patients with at least CTCAE Grade 3 at each visit will be summarized. 
 
Clinically significant treatment-emergent laboratory findings will be summarised 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.  
• Any other laboratory results will be listed only.  
 
5.9 Pharmacokinetic Analysis 
The Pharmacokinetic Analysis will be conducted separate from this analysis. Details will be 
found in a specific analysis plan. 
 
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, while the protocol deviations are being reviewed, the project 
manager will forward all relevant documentation highlighting protocol deviations to the study 


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statistician. These deviations will be included in the protocol violation document for agreement 
and will be listed with the protocol violations in the CSR. 
 
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. 
In case of missing or partially missing dates for initial diagnosis, the following rules will be 
applied: 
- If initial diagnosis date=../mmm/yyyy (= missing day), then it will be substituted by 
01/mmm/yyyy 
- If initial diagnosis date=.../.../yyyy (= missing day and month), then it will be substituted 
by 01/JAN/yyyy 
- If initial diagnosis date=.../.../…. (= completely missing), then it won’t be substituted. 
 
5.13 Deviations from SAP 
Any deviations from the statistical plan will be described and justified in the final clinical study 
report. 
 
5.14 Changes in Conduct or Planned Analyses from the Protocol 
Following are the changes in analyses from those defined in the protocol: 
- 
Population of analysis is updated to match with the usual definition in clinical trials. In 
the protocol, safety population and efficacy population have the same definition and 
per protocol population definition is the typically definition of efficacy population. 
Then, the efficacy population is updated with definition of per protocol and it is decided 
that no per protocol analysis will be handled.  
- 
The exploratory objective “To explore the correlation between baseline biomarker 
levels and clinical endpoints". Biomarker data will be analyzed in exploratory analyses 
not in scope of this SAP so this analysis will be presented within biomarker analysis.  
 
 
 
 
 


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5.15 Algorithms/SAS Codes 
• Tables that need 95% CIs within group for binomial proportions: 
PROC FREQ DATA=dset; 
  
BY byvar; (optional) 
   TABLES var1/binomial (exact p=.05) alpha=0.05; 
  
EXACT BINOMIAL; 
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; 
 
 


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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 
dose level or treatment group, subject and visit and have the source data received by data 


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management referenced in a footnote. All tables and listings will be converted into Microsoft 
Word documents and collated into two complete documents.  
 
6.3 Tables 
 
6.3.1 Section 14.1: Demographic and baseline 
 
Table 14.1.1.1 
Subject Disposition – Part A (Enrolled Population) 
Table 14.1.1.2 
Subject Disposition – Part B (Enrolled Population) 
Table 14.1.1.3  
Important Protocol Violations – Part A 
(Enrolled Population) 
Table 14.1.1.4 
Important Protocol Violations – Part B 
(Enrolled Population) 
Table 14.1.2.1 
Demographics  – Part A (Safety Population)  
Table 14.1.2.2 
Demographics  – Part B (Safety Population)  
Table 14.1.3.1 
Medical History  – Part A (Safety Population)  
Table 14.1.3.2 
Medical History  – Part B (Safety Population)  
Table 14.1.4.1 
Cancer History – Part A (Safety Population)  
Table 14.1.4.2 
Cancer History – Part B (Safety Population)  
Table 14.1.5.1 
Prior Cancer Therapies – Part A (Safety Population)  
Table 14.1.5.2 
Prior Cancer Therapies – Part B (Safety Population)  
Table 14.1.6.1 
Concomitant Medications – Part A (Safety Population)  
Table 14.1.6.2 
Concomitant Medications – Part B (Safety Population)  
Table 14.1.7.1 
Other Anti-Cancer Medications – Part A (Safety Population)  
Table 14.1.7.2 
Other Anti-Cancer Medications – Part B (Safety Population)  
Table 14.1.8.1.1 
Summary of Exposure to BGB324 – Part A (Safety Population)  
Table 14.1.8.1.2 
Summary of Exposure to BGB324 – Part B (Safety Population)  
Table 14.1.8.2 
Summary of Exposure to Cytarabine – Part B (Safety Population)  
Table 14.1.8.3 
Summary of Exposure to Decitabine – Part B (Safety Population)  
Table 14.1.9.1.1 
Compliance – Part A (Safety Population)  
Table 14.1.9.1.2 
Compliance – Part B (Safety Population)  
Table 14.1.9.2.1 
Summary of BGB324 dose reduction and dose interruption – Part A  
(Safety Population) 
Table 14.1.9.2.2 
Summary of BGB324 dose reduction and dose interruption – Part B 
(Safety Population) 
Table 14.1.10.1.1 Summary of BGB324 Dose Modification during the Study – Part A 
(Safety Population) 
Table 14.1.10.1.2 Summary of BGB324 Dose Modification during the Study – Part B 
(Safety Population) 
 
 
6.3.2 Section 14.2: Efficacy Analysis 
Table 14.2.1.1 
Objective Response Rate – Part A (Efficacy Population)  
Table 14.2.1.2 
Objective Response Rate – Part B (Efficacy Population)  
Table 14.2.2.1 
Relapse Free Survival – Summary – Part B (Efficacy Population)  
Table 14.2.3.1 
Event Free Survival – Summary – Part B (Efficacy Population)  
Table 14.2.4.1 
Overall Survival – Kaplan Meier Analysis – Part B (Efficacy 
Population) 


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Table 14.2.5.1.1 
Objective Response Rate by Age Group – Part A (Efficacy 
Population) 
Table 14.2.5.1.2 
Objective Response Rate by Age Group – Part B (Efficacy Population) 
Table 14.2.5.1.3 
Objective Response Rate by AML Disease Cytogenetic profile – Part 
A (Efficacy Population) 
Table 14.2.5.1.4 
Objective Response Rate by AML Disease Cytogenetic profile – Part 
B (Efficacy Population) 
6.3.3 Section 14.3: Safety Analysis 
6.3.3.1 Adverse events  
 
Table 14.3.1.1.1 
Summary of Adverse Events – Part A (Safety Population) 
Table 14.3.1.1.2 
Summary of Adverse Events – Part B (Safety Population) 
Table 14.3.1.2.1.1 
Adverse Events by System Organ Class and Preferred Term – Part 
A (Safety Population) 
Table 14.3.1.2.1.2 
Adverse Events by System Organ Class and Preferred Term – Part 
B (Safety Population) 
Table 14.3.1.2.2.1 
Adverse Events by System Organ Class, Preferred Term, and 
CTCAE Grade – Part A (Safety Population) 
Table 14.3.1.2.2.2 
Adverse Events by System Organ Class, Preferred Term, and 
CTCAE Grade – Part B (Safety Population) 
Table 14.3.1.2.3.1 
Adverse Events Related to BGB324 by System Organ Class and 
Preferred Term – Part A (Safety Population) 
Table 14.3.1.2.3.2 
Adverse Events Related to BGB324 by System Organ Class and 
Preferred Term – Part B (Safety Population) 
Table 14.3.1.2.4 
 
Adverse Events Related to Cytarabine by System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.2.5 
 
Adverse Events Related to Decitabine by System Organ Class and 
Preferred Term (Safety Population) 
Table 14.3.1.2.6.1 
Adverse Events Related to Other Anti-Cancer Medications by 
System Organ Class and Preferred Term – Part A (Safety 
Population) 
Table 14.3.1.2.6.2 
Adverse Events Related to Other Anti-Cancer Medications by 
System Organ Class and Preferred Term – Part B (Safety 
Population) 
Table 14.3.1.2.7.1 
Adverse Events by System Organ Class, Preferred Term and 
Frequency CTCAE Grade – Part A (Safety Population) 
Table 14.3.1.2.7.2 
Adverse Events by System Organ Class, Preferred Term and 
Frequency CTCAE Grade – Part B (Safety Population) 
Table 14.3.1.3.1.1 
Serious Adverse Events by System Organ Class and Preferred 
Term – Part A (Safety Population) 
Table 14.3.1.3.1.2 
Serious Adverse Events by System Organ Class and Preferred 
Term – Part B (Safety Population) 
Table 14.3.1.3.2.1 
Serious Adverse Events by System Organ Class, Preferred Term, 
and CTCAE Grade – Part A (Safety Population) 
Table 14.3.1.3.2.2 
Serious Adverse Events by System Organ Class, Preferred Term, 
and CTCAE Grade – Part B (Safety Population) 
Table 14.3.1.3.3.1 
Serious Adverse Events Related to BGB324 by System Organ 
Class and Preferred Term – Part A (Safety Population) 


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Table 14.3.1.3.3.2 
Serious Adverse Events Related to BGB324 by System Organ 
Class and Preferred Term – Part B (Safety Population) 
Table 14.3.1.3.4 
Serious Adverse Events Related to Cytarabine by System Organ 
Class and Preferred Term (Safety Population) 
Table 14.3.1.3.5 
Serious Adverse Events Related to Decitabine by System Organ 
Class and Preferred Term (Safety Population) 
Table 14.3.1.3.6.1 
Serious Adverse Events Related to Other Anti-Cancer Medications 
by System Organ Class and Preferred Term – Part A (Safety 
Population) 
Table 14.3.1.3.6.2 
Serious Adverse Events Related to Other Anti-Cancer Medications 
by System Organ Class and Preferred Term – Part B (Safety 
Population) 
Table 14.3.1.4.1.1 
Adverse Events Leading to Discontinuation by System Organ 
Class and Preferred Term – Part A (Safety Population) 
Table 14.3.1.4.1.2 
Adverse Events Leading to Discontinuation by System Organ 
Class and Preferred Term – Part B (Safety Population) 
Table 14.3.1.5.1.1 
Adverse Events >= Grade 3 by System Organ Class and Preferred 
Term – Part A (Safety Population) 
Table 14.3.1.5.1.2 
Adverse Events >= Grade 3 by System Organ Class and Preferred 
Term – Part B (Safety Population) 
Table 14.3.1.5.2.1 
Adverse Events >= Grade 3 Related to BGB324 by System Organ 
Class and Preferred Term – Part A (Safety Population) 
Table 14.3.1.5.2.2 
Adverse Events >= Grade 3 Related to BGB324 by System Organ 
Class and Preferred Term – Part B (Safety Population) 
Table 14.3.1.5.3 
Adverse Events >= Grade 3 Related to Cytarabine by System 
Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.5.4 
Adverse Events >= Grade 3 Related to Decitabine by System 
Organ Class and Preferred Term (Safety Population) 
Table 14.3.1.6.1 
Adverse Events Occurring >= 10% by Preferred Term – Part A 
(Safety Population) 
Table 14.3.1.6.2 
Adverse Events Occurring >= 10% by Preferred Term – Part B 
(Safety Population) 
Table 14.3.1.7.1 
Non-Serious Adverse Events by System Organ Class and Preferred 
Term – Part A (Safety Population) 
Table 14.3.1.7.2 
Non-Serious Adverse Events by System Organ Class and Preferred 
Term – Part B (Safety Population) 
Table 14.3.1.8.1 
Adverse Events leading to death by System Organ Class and 
Preferred Term – Part A (Safety Population) 
Table 14.3.1.8.2 
Adverse Events leading to death by System Organ Class and 
Preferred Term – Part B (Safety Population) 
Table 14.3.1.9.1 
Summary of DLTs occurring during the study – Part A (Safety 
Population) 
Table 14.3.1.10.1 
Adverse Events beyond disease progression by System Organ 
Class and Preferred Term – Part B (Safety Population)  
Table 14.3.1.10.2 
Serious Adverse Events beyond disease progression by System 
Organ Class and Preferred Term – Part B (Safety Population)  
 
6.3.3.2 Laboratory results 
 


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Table 14.3.5.1.1.1 
Laboratory Results – Hematology – Summary and Change from 
Baseline – Part A (Safety Population) 
Table 14.3.5.1.1.2 
Laboratory Results – Hematology – Summary and Change from 
Baseline – Part B (Safety Population) 
Table 14.3.5.1.2.1 
Hematology Results: Shifts from Baseline to all the cycle by 
CTCAE Grade – Part A (Safety Population) 
Table 14.3.5.1.2.2 
Hematology Results: Shifts from Baseline to all the cycle by 
CTCAE Grade – Part B (Safety Population) 
Table 14.3.5.1.3.1 
Hematology Results: Shifts for patients with 2+ CTCAE Grade 
from Baseline – Part A (Safety Population) 
Table 14.3.5.1.3.2 
Hematology Results: Shifts for patients with 2+ CTCAE Grade 
from Baseline – Part B (Safety Population) 
Table 14.3.5.1.4.1 
Laboratory Results for patients with CTCAE >= Grade 3 – Part A 
(Safety Population) 
Table 14.3.5.1.4.2 
Laboratory Results for patients with CTCAE >= Grade 3 – Part B 
(Safety Population) 
Table 14.3.5.2.1.1 
Laboratory Results – Coagulation – Summary and Change from 
Baseline – Part A (Safety Population) 
Table 14.3.5.2.1.2 
Laboratory Results – Coagulation – Summary and Change from 
Baseline – Part B (Safety Population) 
Table 14.3.5.3.1.1 
Laboratory Results – Chemistry – Summary and Change from 
Baseline – Part A (Safety Population) 
Table 14.3.5.3.1.2 
Laboratory Results – Chemistry – Summary and Change from 
Baseline – Part B (Safety Population) 
Table 14.3.5.4.1.1 
Laboratory Results CTCAE >= Grade 3 – Part A (Safety 
Population) 
Table 14.3.5.4.1.2 
Laboratory Results CTCAE >= Grade 3 – Part B (Safety 
Population) 
 
6.3.3.3 Vital signs  
 
Table 14.3.5.5.1.1 
Vital Signs – Summary and Change from Baseline – Part A (Safety 
Population) 
Table 14.3.5.5.1.2 
Vital Signs – Summary and Change from Baseline – Part B (Safety 
Population) 
 
6.3.3.4 ECG 
 
Table 14.3.5.6.1.1 
ECG Results – Summary and Change from Baseline – Part A (Safety 
Population) 
Table 14.3.5.6.1.2 
ECG Results – Summary and Change from Baseline – Part B (Safety 
Population) 
Table 14.3.5.6.2.1 
ECG Results – Overall Interpretation – Part A (Safety Population) 
Table 14.3.5.6.2.2 
ECG Results – Overall Interpretation – Part B (Safety Population) 
Table 14.3.5.6.3.1 
QTcF, by CTCAE Grade and Dose – Part A (Safety Population) 
Table 14.3.5.6.3.2 
QTcF, by CTCAE Grade and Dose – Part B (Safety Population) 
Table 14.3.5.6.4.1 
Maximum QTcF Increase from Baseline - Part A (Safety Population) 
Table 14.3.5.6.4.2 
Maximum QTcF Increase from Baseline - Part B (Safety Population) 
 
 


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6.3.3.5 ECOG Performance Status 
 
Table 14.3.5.7.1.1 
Eastern Cooperative Oncology Group (ECOG) Performance Status – 
Part A (Safety Population) 
Table 14.3.5.7.1.2 
Eastern Cooperative Oncology Group (ECOG) Performance Status – 
Part B (Safety Population) 
 
All safety tables will be produced using the Safety Population. 
 
6.4 Listings 
 
Listing 14.3.2    
Listing of Deaths (Enrolled Patients) 
Listing 16.1.7    
Dose Escalation Cohort Assignment (Enrolled Patients) 
Listing 16.2.1.1 
Subject Disposition (Safety Population) 
Listing 16.2.1.2   
Inclusion/Exclusion Descriptions (Safety Population) 
Listing 16.2.1.3   
Inclusion/Exclusion Criteria Not Met (Safety Population) 
Listing 16.2.2.1 
Important Protocol Deviation (Safety Population) 
Listing 16.2.3 
Patients excluded from the efficacy analysis (Enrolled Patients) 
Listing 16.2.4.1   
Demographics (Safety Population) 
Listing 16.2.4.2   
Medical History (Safety Population) 
Listing 16.2.4.3   
Cancer History (Safety Population) 
Listing 16.2.4.4.1   
Prior Cancer Therapy (Safety Population) 
Listing 16.2.4.4.2   
Prior Cancer Therapy – Radiotherapy Details (Safety Population) 
Listing 16.2.4.5   
Previous Transfusions (Safety Population) 
Listing 16.2.4.6 
Prior and Concomitant Medications (Safety Population) 
Listing 16.2.4.7 
Other Anti-Cancer 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 16.2.5.1 
BGB324 Exposure (Safety Population) 
Listing 16.2.5.2 
Cytarabine  / Decitabine 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 
Cytarabine / Decitabine Administration (Safety Population) 
Listing 16.2.5.6 
BGB324 Accountability (Safety Population) 
Listing 16.2.5.7 
AML Treatment in Follow-Up (Safety Population) 
Listing 16.2.6.1.1 
Response Assessment (Efficacy Population) 
Listing 16.2.6.1.2 
Response Assessment (Details) (Efficacy Population) 
Listing 16.2.6.2 
Relapse Free Survival (Efficacy Population) 
Listing 16.2.6.3 
Overall Survival (Efficacy Population) 
Listing 16.2.6.4 
Event Free Survival (Efficacy Population) 
Listing 16.2.6.5 
Survival Follow Up (Details) (Safety Population) 
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 BGB324 (Safety Population) 
Listing 16.2.7.4 
Adverse Events Related to Cytarabine (Safety Population) 
Listing 16.2.7.5 
Adverse Events Related to Decitabine (Safety Population) 


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Listing 16.2.7.6 
Adverse Events Related to Other Anti-Cancer Medications (Safety 
Population) 
Listing 16.2.7.7 
Adverse Events Leading to Discontinuation (Safety Population) 
Listing 16.2.7.8 
Adverse Events – Dose Limiting Toxicities (Safety Population) 
Listing 16.2.7.9 
Adverse Events >= Grade 3 (Safety Population) 
Listing 16.2.7.10     Adverse Events beyond disease progression (Safety Population) 
Listing 16.2.8.1 
Laboratory Results: Hematology (Safety Population) 
Listing 16.2.8.2 
Laboratory Results: Coagulation (Safety Population) 
Listing 16.2.8.3 
Laboratory Results: Chemistry (Safety Population) 
Listing 16.2.8.4 
Laboratory Results: Urinalysis (Safety Population) 
Listing 16.2.8.5 
Clinically Significant Laboratory Results (Safety Population) 
Listing 16.2.8.6 
Laboratory Results: Serum Pregnancy Test (Safety Population) 
Listing 16.2.8.7   
Vital Signs (Safety Population) 
Listing 16.2.8.8 
ECG Results (Safety Population) 
Listing 16.2.8.9 
Echocardiogram/Muga Scan (Safety Population) 
Listing 16.2.8.10 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
(Safety Population) 
Listing 16.2.8.11 
Ancillary Procedures (Safety Population) 
Listing 16.2.8.12 
Transfusions (Safety Population) 
Listing 16.2.8.13.1 
Bone Marrow Aspiration/Biopsy-Histology (Safety Population) 
Listing 16.2.8.13.2 
Bone Marrow Aspiration/Biopsy-Cytogenetics (Safety Population) 
 
6.5 Figures 
 
Figure 14.2.2.1.1 Relapse Free Survival – Kaplan Meier Survival Curves – Part B 
(Efficacy Population) 
Figure 14.2.2.2.1 Event Free Survival – Kaplan Meier Survival Curves – Part B  
(Efficacy Population)  
Figure 14.2.2.2.2 Event Free Survival – Kaplan Meier Survival Curves by Age Group – 
Part B (Efficacy Population) 
Figure 14.2.2.2.3 Event Free Survival – Kaplan Meier Survival Curves by AML Disease 
Cytogenetic profile – Part B  (Efficacy Population) 
Figure 14.2.2.3.1 Overall Survival – Kaplan Meier Survival Curves - Part B (Efficacy 
Population) 
Figure 14.2.2.3.2 Overall Survival – Kaplan Meier Survival Curves by Age Group – Part 
B (Efficacy Population) 
Figure 14.2.2.3.3 Overall Survival – Kaplan Meier Survival Curves by AML Disease 
Cytogenetic profile – Part B (Efficacy Population) 
Tables, Listings, and Figures will follow the format of: 
BGBC003_SAP_Shells_Version1_Final_06Sep2022.rtf 
 
6.6 References 
 
Cheson BD, Bennett JM, Kopecky KJ, et al., Revised Recommendations of the International 
Working Group for Diagnosis, Standardisation of Response Criteria, treatment Outcomes and 
Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J ClinOncol (2003) 
21 (24): 4642 – 4649 
 


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Cheson BD, Greenberg PL, Bennett JM et al., Clinical Application and Proposal for 
Modification of the International Working Group (IWG) Response Criteria in Myelodysplasia. 
Blood (2006) 108 (2): 419 – 425 


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6.7 Appendix 
6.7.1 Definitions of End Points for Clinical Trials in AML by Cheson & all 2003. 
Outcome  
Response 
Category  
Point 
of 
Measurement  
Definition 
Overall survival  
All patients  
Entry onto trial  Death from any cause 
Relapse-free 
survival  
CR  
Leukemia-free 
state  
Disease relapse or patient death from 
any cause 
NOTE. Complete blood counts should be evaluated at least monthly, or more often if clinically 
indicated, to establish the durability of responses. 
Abbreviations: AML, acute myelogenous leukemia; CR, complete remission.