Clinical trial NCT03154827
Conditions: Acute Myeloid Leukemia
Sponsor: BioLineRx, Ltd.
Start date: 2018-01-08; Completion date: 2020-04-01
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Phase Ib/II, Multicenter, Single Arm, Open-Label Study, To Evaluate the Safety, Tolerability and Efficacy of the BL-8040 and Atezolizumab Combination for Maintenance Treatment in Subjects with Acute Myeloid Leukemia- The BATTLE Study

The main goal of this clinical trial is to assess the safety and tolerability of the treatment combination of BL-8040 and Atezolizumab as Maintenance Treatment in Subjects with Acute Myeloid Leukemia.

Additional objectives are:

Assessment of the effect of combination of BL-8040 and Atezolizumab on relapse free survival (RFS) Assessment whether the treatment combination of BL-8040 and Atezolizumab can reduce the Minimal Residual Disease (MRD) as compared to baseline Assessment of the Overall Survival (OS) time in subjects treated with the combination of BL-8040 and Atezolizumab for maintenance Assessment of the Event Free Survival (EFS) time in subjects treated with the combination of BL-8040 and Atezolizumab for maintenance

Detailed description:
This study will assess the safety and effectiveness of a combination of BL-8040 and atezolizumab to find out what is the Safety, Tolerability and Efficacy of this treatment combination for maintenance treatment in subjects with acute myeloid leukemia.

This is a single arm, open label, Phase Ib/II study in which eligible subjects will receive maintenance treatment consisting of intravenous (IV) infusion of Atezolizumab on Day 2 of each 21-day cycle and subcutaneous (SC) injections of BL-8040 on Days 1, 2 and 3 of each 21-day cycle. Cycles will be repeated for up to 2 years (a maximum of 34 treatment cycles), until early discontinuation for any reason or until disease relapse, whichever comes first.

Approximately 60 patients will take part at multiple centers worldwide.

The duration of the treatment period of the study will be up to 2 years and will be followed by one year safety follow up. The study will consist of:

* a screening period of 21 days to allow your doctor to assess your suitability for enrollment into the study
* a treatment period of combination regimen of 21 day cycles for up to 2 years
* a follow-up period of up to 30 days after completion of combined treatment with BL-8040 + Atezolizumab
* an additional follow up period for up to one year after the completion of the treatment

Arms: arm 1: Combination Treatment of BL-8040 with Atezolizumab
Interventions: intervention 1: BL-8040 intervention 2: Atezolizumab
Intervention descriptions: intervention 1: Subjects will receive maintenance treatment consisting of subcutaneous (SC) injections of BL-8040 on Days 1, 2 and 3 of each 21-day cycle. Cycles will be repeated for up to 2 years (a maximum of 34 treatment cycles), until early discontinuation for any reason or until disease relapse, whichever comes first. intervention 2: Subjects will receive maintenance treatment consisting of intravenous (IV) infusion of Atezolizumab on Day 2 of each 21-day cycle. Cycles will be repeated for up to 2 years (a maximum of 34 treatment cycles), until early discontinuation for any reason or until disease relapse, whichever comes first.

Protocol documents:
Prot_SAP_000.pdf: 
BioLineRx.com
Israel Headquarters
Modi’in Technology Park
2 HaMa’ayan Street
Modi’in 7177871, Israel
Phone: +972.8.642.9100 
NCT Number:
NCT03154827 
Sponsor Study Number: 
BL-8040.AML.202 
Official Study Title: 
Phase Ib/II, Multicenter, Single Arm, Open-Label Study to 
Evaluate the Safety, Tolerability and Efficacy of the BL-8040 
and Atezolizumab Combination for Maintenance Treatment in 
Subjects with Acute Myeloid Leukemia - The BATTLE Study
Document Version and Date: 
Clinical Study Protocol, version 4.0, 27 January 2019  






PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 3 of 110
Version 4.0, 27 January 2019
Principal Investigator  
By signing below, I, the Investigator, approve the protocol and agree to conduct the clinical 
trial according to all stipulations of the protocol as specified in both the clinical and 
administrative sections, CRF and any protocol-related documents (subject to any amendments 
agreed to in writing between the Sponsor and Principal Investigator). I agree to comply with 
the ICH-GCP, World Medical Association Declaration of Helsinki (and relevant updates) and 
applicable local regulations. I agree to ensure that the confidential information contained in this 
document will not be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of BioLineRx Ltd. I understand that the study 
may be terminated, or enrollment suspended at any time by sponsor, or by me, at my center, if 
it becomes necessary in my opinion, to protect the best interests of the study subjects. 
Name
Investigator Signature
Date
Center’s Name
 City, Country 






PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 6 of 110
Version 4.0, 27 January 2019
Table of contents
Protocol Version History Page......................................................................................... 4
Protocol Synopsis........................................................................................................... 10
Glossary 24
1
Introduction.................................................................................................. 27
1.1
Therapeutic Indication............................................................................................ 27
1.1.1
The Prognostic and Therapeutic Relevance of Minimal Residual Disease ....................... 27
1.2
Investigational Therapy .......................................................................................... 28
1.2.1
BL-8040............................................................................................................................. 28
1.2.2
Atezolizumab..................................................................................................................... 29
1.3
Study Rationale....................................................................................................... 30
1.3.1
Intended study.................................................................................................................... 31
1.4
Dose Selection Rationale ......................................................................................... 32
1.4.1
Rationale for BL-8040 Dose Selection.............................................................................. 32
1.4.2
Rationale for Atezolizumab Dose Selection...................................................................... 33
2
Study Objectives and Endpoints................................................................... 34
2.1
Study Objectives ..................................................................................................... 34
2.2
Study Endpoints/Outcome Measures ...................................................................... 34
2.2.1
Safety and Tolerability Primary endpoints and Outcome Measures.................................. 34
2.2.2
Secondary Endpoints – Efficacy Measures........................................................................ 35
2.2.3
Exploratory Outcome Measures ........................................................................................ 35
2.2.4
Pharmacokinetic (PK) Assessment.................................................................................... 35
3
Study Design................................................................................................. 35
3.1
Dose-Limiting Toxicities and Ongoing Safety Assessment....................................... 36
3.2
Study Diagram:....................................................................................................... 38
4
Study Population .......................................................................................... 38
4.1
Inclusion Criteria.................................................................................................... 38
4.2
Exclusion Criteria................................................................................................... 39
4.3
Subject Identification.............................................................................................. 41
4.4
Screening Failures................................................................................................... 41
4.5
Removal, Replacement, or Early Withdrawal of Subjects from Therapy or 
Assessment ............................................................................................................ 41
4.6
Handling of Withdrawals........................................................................................ 42
4.7
Sponsor's Termination of Study.............................................................................. 43
5
Study Procedures and Assessments .............................................................. 43
5.1
Screening Period (Visit 1, Day -28 to Day -1)........................................................... 43
5.2
Baseline (Pre-Dose, Day 1 of Treatment Cycle 1) .................................................... 44
5.3
Treatment Period (Days 1, 2 and 3 of each treatment cycle).................................... 44
5.4
End of treatment visit (Treatment discontinuation) ................................................ 46
5.5
Follow-Up visit........................................................................................................ 46
5.6
Early Discontinuation Study Visit........................................................................... 46


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 7 of 110
Version 4.0, 27 January 2019
5.7
Unscheduled Visit ................................................................................................... 47
5.8
Safety Assessments.................................................................................................. 47
5.8.1
Adverse Events (AEs)........................................................................................................ 47
5.8.2
Concomitant Medications.................................................................................................. 47
5.8.3
Electrocardiogram.............................................................................................................. 47
5.8.4
Physical Examination ........................................................................................................ 48
5.8.5
Vital signs.......................................................................................................................... 48
5.8.6
Laboratory Safety Assessments......................................................................................... 48
5.8.7
Anti-drug antibody (ADA) Assessment ............................................................................ 49
5.9
Biomarker and Pharmacodynamic Assessments ..................................................... 49
5.9.1
MRD Status ....................................................................................................................... 49
5.9.2
Immuno-phenotyping ........................................................................................................ 49
5.9.3
DNA and RNA Collection................................................................................................. 49
5.9.4
PK Assessments................................................................................................................. 49
5.9.5
Blood Sampling and Processing ........................................................................................ 50
6
Investigational Product................................................................................. 50
6.1
Identity of Investigational Products ........................................................................ 50
6.1.1
BL-8040............................................................................................................................. 50
6.1.2
Atezolizumab..................................................................................................................... 50
6.2
Study Drug Administration and Dosage.................................................................. 50
6.2.1
BL-8040............................................................................................................................. 50
6.2.2
Atezolizumab..................................................................................................................... 50
6.2.3
Dose Limiting Toxicities................................................................................................... 51
6.2.4
BL-8040 Treatment Interruption Rules ............................................................................. 52
6.2.5
Atezolizumab Treatment Interruption Rules ..................................................................... 52
6.2.6
Atezolizumab Re-introduction........................................................................................... 53
6.2.7
Permanent Discontinuation of Atezolizumab.................................................................... 53
6.2.8
Atezolizumab Dose Reduction .......................................................................................... 53
6.2.9
Rescue medication............................................................................................................. 53
6.3
Manufacturing of Study Medication ....................................................................... 53
6.4
Packaging and Labeling of Study Medication ......................................................... 53
6.4.1
BL-8040............................................................................................................................. 53
6.4.2
Atezolizumab..................................................................................................................... 54
6.5
Distribution and Shipment of Study Medication ..................................................... 54
6.6
Storage, Dispensing and Return of the Investigational Medicinal Products ............ 54
6.7
Accountability and Compliance of Investigational Medicinal Product.................... 54
6.8
Concomitant Therapy ............................................................................................. 55
6.8.1
BL-8040 Adverse Event Management: ............................................................................. 56
6.8.2
Permitted Concomitant Medications ................................................................................. 56
6.8.3
Prohibited Concomitant Medications ................................................................................ 56
7
Safety and Pharmacovigilance...................................................................... 57
7.1
Adverse Event (AE)................................................................................................. 57
7.2
Serious Adverse Events (SAEs) ............................................................................... 60
7.3
Definition of an Unexpected Adverse Event ............................................................ 60
7.4
Exceptions in the Reporting of SAE ........................................................................ 60


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 8 of 110
Version 4.0, 27 January 2019
7.5
Notification of Serious Adverse Event (SAE)........................................................... 61
7.5.1
Initial notification of SAEs................................................................................................ 61
7.5.2
Follow-up of SAEs ............................................................................................................ 61
7.6
Adverse Events Associated with an Overdose or Error in Drug Administration..... 62
7.7
Guidelines for Management of Patients Who Experience Specific Adverse Events 
while being treated by Atezolizumab  BL-8040.................................................... 62
7.8
Injection-Related Reactions .................................................................................... 65
8
Statistical Methodology................................................................................. 65
8.1
Analysis Sets ........................................................................................................... 65
8.2
Sample Size Justification......................................................................................... 65
8.3
Significance Level and Multiplicity Adjustment...................................................... 65
8.4
Efficacy Endpoints and Analyses ............................................................................ 66
8.4.1
Relapse Free Survival as a Secondary Endpoint................................................................ 66
8.4.2
Changes in MRD status, measured from baseline to Cycles 3, 9, 18 and 34 using 
quantitative multi-color flow cytometry............................................................................ 66
8.4.3
Overall Survival (OS), measured as time from 1st study drug administration to death from 
any cause ........................................................................................................................... 66
8.4.4
Event Free Survival (EFS), measured as the earlier from 1st study drug administration to 
the date of primary refractory disease, or relapse from CR, or death from any cause from 
1st study drug administration ............................................................................................ 66
8.5
Safety and Tolerability Analyses............................................................................. 66
8.5.1
Adverse Events.................................................................................................................. 67
8.5.2
Dose-Limiting-Toxicity Assessment................................................................................. 67
8.5.3
Safety Laboratory Data...................................................................................................... 69
8.5.4
Vital Signs ......................................................................................................................... 69
8.5.5
Physical Examinations....................................................................................................... 69
8.5.6
12-Lead ECG..................................................................................................................... 69
8.5.7
Tolerability Assessment..................................................................................................... 70
8.6
Exploratory Outcome Measures.............................................................................. 70
8.7
Pharmacokinetics (PK) Assessment ........................................................................ 70
8.8
Statistical Analysis Plan (SAP)................................................................................ 70
8.9
Statistical Analysis Software ................................................................................... 70
9
Ethics ............................................................................................................ 70
9.1
Institutional Review Board or Independent Ethics Committee................................ 71
9.2
Ethical Conduct of the study................................................................................... 71
9.3
Subject Information and Consent ........................................................................... 71
9.4
Subject Insurance ................................................................................................... 72
9.5
Informing the General Practitioner......................................................................... 72
9.6
Personal Data Protection......................................................................................... 72
9.7
Data and Safety Monitoring.................................................................................... 72
9.8
Protocol Exceptions and Deviations ........................................................................ 72
9.9
Protocol Amendments............................................................................................. 73
10
Quality Control and Quality Assurance........................................................ 73
10.1
Audits and Inspections............................................................................................ 73
10.2
Study Monitoring.................................................................................................... 73


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 9 of 110
Version 4.0, 27 January 2019
10.3
Quality Laboratory Standards................................................................................ 74
11
Study Documentation ................................................................................... 75
11.1
Source Documents................................................................................................... 75
11.2
Recording of Data on Case Report Form (CRF) ..................................................... 75
11.3
Investigator Site File ............................................................................................... 76
12
Clinical Trial Supplies .................................................................................. 76
13
Data Management......................................................................................... 76
14
Study Administration ................................................................................... 76
14.1
Participating Centers .............................................................................................. 76
14.2
Required Documents Prior to Study Initiation........................................................ 77
14.3
Study Completion ................................................................................................... 77
14.4
Clinical Study Report.............................................................................................. 78
14.5
Retention of Study Records..................................................................................... 78
14.6
Confidentiality and Publication of Study Results .................................................... 78
14.6.1 General............................................................................................................................... 78
14.6.2 Published Data................................................................................................................... 79
15
References..................................................................................................... 81
16
Appendices.................................................................................................... 84
16.1
Appendix A Schedule of Assessments...................................................................... 85
16.2
Appendix B: PK and ADA Assessment ................................................................... 88
16.3
Appendix C AML Diagnosis Criteria...................................................................... 90
16.4
Appendix D Eastern Cooperative Oncology Group Performance Status................. 92
16.5
Appendix E Preexisting Autoimmune Diseases ....................................................... 93
16.6
Appendix F Anaphylaxis Precautions...................................................................... 94
16.7
Appendix G Response criteria in acute myeloid leukemia....................................... 95
16.8
Appendix H Outcome measures for clinical trials in acute myeloid leukemia.......... 97
16.9
Appendix I Management of Atezolizumab Therapy Further to Adverse Events ..... 98
List of Tables
Table 1
Administration of First and Subsequent Atezolizumab Infusions......................................... 51
Table 2
Severity of Adverse Events According to CTCAE (Version 4.03) ......................................... 58
Table 3
Relationship of Adverse Event to Treatment......................................................................... 59
Table 4
Management Guidelines for Pulmonary Events, Including Pneumonitis.............................. 98
Table 5
Management Guidelines for Hepatic Events.......................................................................... 99
Table 6
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis) ........................ 100
Table 7
Management Guidelines for Endocrine Events.................................................................... 101
Table 8
Management Guidelines for Ocular Events......................................................................... 103
Table 9
Management Guidelines for Immune-Related Myocarditis ................................................ 104
Table 10
Management Guidelines for Infusion-Related Reactions .................................................... 105
Table 11
Management Guidelines for Pancreatic Events, Including Pancreatitis ............................. 106
Table 12
Management Guidelines for Dermatologic Events............................................................... 107
Table 13
Management Guidelines for Neurologic Disorders.............................................................. 108
Table 14
Management Guidelines for Immune-Related Meningoencephalitis................................... 109
Table 15        Management Guidelines for Renal Events........................................................................... 109


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 10 of 110
Version 4.0, 27 January 2019
Protocol Synopsis 
Study Title
A Phase Ib/II, Multicenter, Single Arm, Open-Label Study, To Evaluate the 
Safety, Tolerability and Efficacy of the BL-8040 and Atezolizumab
Combination for Maintenance Treatment in Subjects with Acute Myeloid 
Leukemia– The BATTLE Study
Protocol No. 
BL-8040.AML.202
Clinical Sites
USA-5 sites, Israel-2 sites, EU-20 sites
Optional: Other countries and sites may be added  
Study Phase
Ib/II
Planned 
Sample Size
A total of up to 60 subjects will be enrolled in two study periods: 
x
Initial Risk-Benefit Period of 12 subjects
x
Expansion Period of up to 48 additional subjects
Therapeutic 
Indication 
Maintenance therapy in Acute Myeloid Leukemia (AML) subjects  in first 
Complete Remission (CR1), who are not planned for stem cell transplantation. 
Study 
Objectives
Primary Study Objective - Safety and Tolerability:
To demonstrate that the proposed combination is safe and tolerated. 
Secondary Study Objectives - Efficacy: 
x
To assess the relapse free survival (RFS) time in subjects treated with the 
combination of BL-8040 and Atezolizumab for maintenance. 
x
To demonstrate that the combination of BL-8040 and Atezolizumab
reduces the Minimal Residual Disease (MRD) as compared to baseline. 
x
To assess the Overall Survival (OS) time in subjects treated with the 
combination of BL-8040 and Atezolizumab for maintenance. 
x To assess the Event Free Survival (EFS) time in subjects treated with the 
combination of BL-8040 and Atezolizumab for maintenance. 
Study Design 
This is a single arm, open label, Phase Ib/II study in which eligible subjects 
will receive maintenance treatment consisting of intravenous (IV) infusion of 
1200 mg Atezolizumab on Day 2 of each 21-day cycle and subcutaneous (SC) 
injections of BL-8040 (1.25mg/kg) on Days 1, 2 and 3 of each 21-day cycle. 
Cycles will be repeated for up to 2 years (a maximum of 34 treatment cycles),
until early discontinuation for any reason or until disease relapse, whichever 
comes first.
Patients in CR1 will be recruited after induction, with 1-4 cycles of cytarabine-
based consolidation therapy, unless they have been deemed intolerant or,


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 11 of 110
Version 4.0, 27 January 2019
refused to receive consolidation therapy or they receive treatment with at least 
3 cycles of Hypomethylating agents (HMA).  
The study will recruit an initial Risk-Benefit period staggered cohort of up to
12 subjects in order to establish the safety, tolerability and efficacy of the 
combination treatment before opening enrollment to the full study population. 
Safety data will be reviewed by an independent Data Monitoring Committee 
(DMC).
Hematology (CBC) assessment will be performed before each dose of BL-
8040. BL-8040 injections will be skipped in case of a significant increase in 
white blood cells (WBCs)
:%&  60,000/μL) measured prior to 
administration of the next BL-8040 injection and/or evidence of leukostasis. 
When WBC is reduced below 60,000/μL Treatment can be resumed. Missed 
doses can be skipped until the WBC count has decreased to < 60,000/μL up to 
2 Cycles. Missed doses will not be made up if >72 h have passed. If the delay 
is beyond the 2 Cycles, the Medical Monitor should be consulted in order to 
assess the continuation of the study for the specific subject. The pre dosing 
monitoring of WBC should be continued until WBC is below 40,000 ȝ/
Dose Limiting Toxicities and Ongoing Safety Assessment
Adverse events (AEs) will be reported from the time of informed consent until 
30 days after the last dose of study drug. The period considered for dose-
limiting toxicity (DLT) assessment will be limited to the first cycle of therapy 
defined as the time from the first dose of BL-8040 up to and including the day 
when the first cycle of combination therapy ends (usually Day 21). Beyond the 
DLT assessment period, AE data will be collected on an ongoing basis and 
recorded within the CRF. However, these events will not be considered for 
DLT evaluation.
Dose-limiting toxicity (DLT) is defined as a clinically significant adverse 
event (AE) or abnormal laboratory value assessed as unrelated to disease 
progression, intercurrent illness or concomitant medications and occurring 
during the first treatment cycle that meets any of the following criteria (refer 
to Table 2 for CTCAE severity grading):
x
&7&$(JUDGH$676*27RU$/76*37RUELOLUXELQIRUGD\V
x
CTCAE grade 4 AST (SGOT) or ALT (SGPT) of any duration
x
All other clinically significant, non-hematological NCI common 
terminology criteria that are CTCAE grade 3 or 4
x
Change from baseline to Grade 4 neutropenia or thrombocytopenia 
lasting for >4 weeks in the absence of persistent Leukemia 
x
Symptomatic leukostasis 
To be considered a DLT the toxicity must be possibly, probably or definitely
related to either of the study drugs or the combination. 
An AE must be clinically significant to define DLT, e.g., nausea and vomiting, 
alopecia, study drug-UHODWHGIHYHURUHOHFWURO\WHDEQRUPDOLWLHVWKDWDUH Grade 
3 will not constitute DLT. For subjects who experience a DLT, the study 


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 12 of 110
Version 4.0, 27 January 2019
continuation should be discussed with the Medical Monitor. Subjects who 
experience AEs that are not considered DLT or are unrelated to BL-8040 or 
Atezolizumab may continue study participation at the discretion of the 
Investigator. 
BL-8040 injections may be skipped for any reason per Investigator judgment; 
KRZHYHUWKH\PXVWEHVNLSSHGLQWKHFDVHRID:%&!ȝ/PHDVXUHG
prior to administration of the next BL-8040 injection and/or evidence of 
leukostasis.  
Increase in WBC is not considered a DLT since it is a direct effect of CXCR4 
inhibition and reflects the drug’s mechanism of action.  
In case of HOHYDWHG:%&!ȝ/, daily WBC assessment should be done.
When WBC is reduced to or below ȝ/ treatment can be resumed. The
Pre-dosing monitoring of WBC should be continued until WBC is below 
ȝ/ DQG IXUWKHU DQDO\VLV VKRXOG EH GRQH EDVHG RQ WKH ,QYHVWLJDWRU¶V
judgment.  
The study will consist of two periods: 
x
Initial Risk-Benefit Period which will enroll a total of 12 subjects. The 
decision whether to continue to the extension phase will be made based on 
a risk-benefit analysis and data review by the DMC together with the 
Sponsor.
x
Expansion Period of additional up to 48 subjects.
Safety review of the accumulated data will be performed by an independent 
DMC after the first 6 subjects have completed the first cycle of combination therapy 
and again after 6 additional subjects have completed the first cycle of 
combination therapy. Guidelines to be used by the DMC for the review of the 
proposed combination toxicity are presented below:
x
If  out of 6 subjects experience a DLT during the first cycle of 
treatment, enrollment should be expended to include 6 additional 
subjects.
x
,I out of 6 subjects experiences a DLT, the DMC will assess the 
risk/benefit profile of the combination treatment and recommend one 
or more of the following: 1) Recruitment should continue to include 
additional 6 subjects, 2) the protocol should be modified, 3) the 
treatment schedule should be modified or 4) the study should be 
discontinued. 
x
If 2 out of 12 subjects experience a DLT the DMC will recommend 
the recruitment of additional 3 subjects for the completion of the pre-
planned Initial Risk-Benefit Period population size of 12 subjects. .   
x
If >2 out of 12 subjects experience a DLT, the DMC will recommend 
one or more of the following: 1) Recruitment should be continued to 
include 3 additional subjects for the completion of the pre-planned 


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 13 of 110
Version 4.0, 27 January 2019
Initial Risk-Benefit Period population size of 12 subjects, 2) the 
protocol should be modified, 3) the treatment schedule should be 
modified or 4) the study should be discontinued. 
Following the completion of the Initial Risk-Benefit Period which is planned 
to enroll a total of 12 subjects, an integrative analysis of risk-benefit of the 
proposed combination will be performed. Then, the DMC, in collaboration
with the Sponsor, based on an assessment of the integrated database will decide 
whether to continue to the Expansion Period and to enroll 48 additional 
subjects or to discontinue the study. 
The number of subjects planned for DLT assessment will be up to 12 subjects,
recruited in a staggered manner, not exceeding the potential for observing that
the proposed combination therapy would be considered unacceptably toxic
according to the criteria above.
In order to be evaluable for the DLT assessment period, a subject must 
complete the first cycle of treatment. If a subject is discontinued before 
completion of the first cycle (unless due to a DLT), he/she will be replaced by 
an additional subject ensuring that the pre-planned size of 12 subjects for DLT 
assessment is preserved. The subjects that are discontinued early will be 
included in all the other relevant analyses according to the population 
described in the statistical analysis section.
Clinical sites are required to contact the Sponsor within 24 hours in case 
subjects present suspected DLTs during the assessment period.  
After completion of the DLT assessment period, further DMC assessments will 
be continued according to the DMC charter to be finalized before study 
recruitment. 
Study 
Procedures,
Periods and 
Duration 
For a detailed description of the study procedures see schedule of assessments
(Appendix A). Study planned periods are displayed below: 
Study Period
Duration
Screening period
Up to 28 days
Treatment Period
21-day cycles for up to 24 months for a maximum of 34 
cycles
Post-Treatment Safety 
Follow-Up
At 30 days from last study drug cycle. May be extended 
for up to 90 days
Long-Term Survival Period
Every 3 months following Treatment Period during an 
additional period of the later of 5 years or till End of Study 
for AML status and survival
Screening Period: The purpose and procedures of the study will be fully 
explained to the participants. Those wishing to be enrolled in the study will 
sign a written informed consent prior to initiating any evaluations or study-
related procedures. Following the signing of informed consent, subjects will 
undergo screening period procedures during the period of up to 28 days and 
will be evaluated for study eligibility.


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 14 of 110
Version 4.0, 27 January 2019
Treatment Period: Eligible subjects will receive maintenance treatment 
consisting of intravenous (IV) infusion of Atezolizumab on Day 2 of each 21-
day cycle and subcutaneous (SC) injections of BL-8040 on Days 1, 2 and 3 of 
each 21-day cycle. Cycles will be repeated for up to 2 years (a maximum of 34 
treatment cycles), until early discontinuation for any reason or until disease 
relapse, whichever comes first.
Post-Treatment Safety Follow-Up: Assessment will be performed at 30 days 
after the last dose of study drug. The period might be extended for up to 90 
days after the last dose of study drug for any SAEs considered to have a 
reasonable possibility of being related to BL-8040 and/or Atezolizumab. 
Long-Term Survival Follow-Up: Subjects will be contacted by phone every 
3 months after termination/early termination of the Treatment Period in order 
to follow survival and AML status. Follow up will be done for an additional 
period of 5 years or until End of Study, whichever comes later. 
Study Duration: The study will end no longer than 84 months after the last 
enrolled subject was administered with the 1st study drug, if the preliminary 
phase and extension will be enrolled. Assuming an enrolment period of 18 
months, the study is planned to be ended no longer than 102 months (8.5 years) 
after the 1st study drug administration of the first enrolled subject (hereafter, 
referred to as “End of Study”). 
Individual Subject Study Participation: The study duration for an individual 
subject depends on RFS duration. Treatment cycles will continue until the 
earlier of relapse, death, intolerable toxicity or any other reason for early 
discontinuation for up to 24 months for a maximum of 34 treatment cycles. 
Following Treatment Period, subjects who are RFS will continue to be 
followed-up every 3 months during the Long-Term Survival Period until End 
of Study. 
Inclusion Criteria
1.
$GXOWPHQDQGZRPHQDJHG 18 years.
2.
Confirmed diagnosis of AML (according to WHO criteria. See 
Appendix C) 
3.
Subjects with newly diagnosed AML who have achieved 
Complete Remission (CR or Cri), after 
a.
Up to two cycles of cytarabine based induction chemotherapy. 
b. A minimum of 3 cycles of hypomethylating agent (HMA) such 
as: azacytidine, decitabine, etc.
4.
Subjects with intermediate or adverse risk factors according to the 
ENL guidelines 2017a.
a Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. 
Döhner H. et al, Blood, 26 January 2017 X Volume 129, Number 4-Appendix F


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 15 of 110
Version 4.0, 27 January 2019
5.
CR (or CRi) must be confirmed by bone marrow aspirate up to 28
days prior to enrollment. 
6.
Subjects who have received 1-4 cycles of consolidation therapy
unless they have been deemed intolerant, or have refused 
consolidation therapy, or subjects that received at least 3 cycles of 
HMA.
7.
Subjects who prior to screening are MRD positive according to 
local laboratory or with an unknown MRD status; are to be 
confirmed or tested, respectively, for MRD by central laboratory 
prior to enrollment. 
8.
Subjects who were diagnosed with AML within 18 months prior 
to study enrollment.  
9.
Subjects should have received the last dose /of induction, 
consolidation or HMA, whichever comes later, within 6 months 
prior to study enrollment
10. Subjects who, at the time of enrollment, are not planned for 
allogeneic stem cell transplantation.
11. Female subjects must be post-menopausal or of non-childbearing 
potential defined as absence of menses for > 1 year or those who 
have had a bilateral tubal ligation or hysterectomy.
12. Male subjects with partners of childbearing potential must agree 
to use an adequate method of contraception starting with the first 
dose of study therapy through at least 5 months after the last dose 
of study therapy. Examples of adequate methods are: for males-
condom with or without spermicide, sexual abstinence or surgical 
sterility (vasectomy) or for female partners with childbearing 
potential- oral, transdermal patch, implanted contraceptives, 
intrauterine device, diaphragm. 
13. Subject is able and willing to comply with the requirements of the 
protocol. 
14. Subject is able to voluntarily provide written informed consent
prior to the initiation of any screening or study-related procedures


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 16 of 110
Version 4.0, 27 January 2019
Exclusion criteria 
1. Subjects diagnosed with acute promyelocytic leukemia. 
2. Subjects with extramedullary AML, including CNS involvement. 
3. Subjects who have achieved CR or CRi following treatment for 
relapsed or refractory AML after 2 inductions. 
4. Subjects in CR1 following allogeneic stem cell transplantation.
5. Subjects who are candidates for allogeneic stem cell transplantation 
and have a suitable donor. 
6. /LIHH[SHFWDQF\RIPRQWKV
7. Clinically significant abnormal laboratory safety test values 
including, but not limited to: 
o Total bilirubin > 2 times upper limit of normal (x ULN)  
o Aspartate Aminotransferase (AST/SGOT) or Alanine 
Aminotransferase (ALT/SGPT) > 2 x ULN 
o Creatinine > 1.5 x ULN or GFR < 30 mL/min. 
8. Low Performance Status (ECOG > 2; Appendix D) 
9. Treatment with systemic immunosuppressive medication (including, 
but not limited to, corticosteroids, cyclophosphamide, azathioprine, 
methotrexate, thalidomide, and antitumor necrosis factor alpha 
[antiTNF-D] agents) within 2 weeks prior to initiation of study 
treatment, or anticipation of need for systemic immunosuppressive 
medication during the course of the study, with the following 
exceptions:
o Patients 
who 
received 
acute, 
low-dose 
systemic 
immunosuppressant medication or a one-time pulse dose of 
systemic immunosuppressant medication (e.g., 48 hours of 
corticosteroids for a contact allergy) are eligible for the study 
after Medical Monitor approval has been obtained. 
o Patients 
who 
received 
mineralocorticoids 
(e.g., 
fludrocortisone), corticosteroids for chronic obstructive 
pulmonary disease or asthma, or low-dose corticosteroids for 
orthostatic hypotension or adrenal insufficiency are eligible for 
the study. 
o Requirement for use of denosumab during the study: Patients 
who are receiving denosumab for any reason (including 
hypercalcemia) must be willing and eligible to receive a 
bisphosphonate instead while in the study. 
10. Treatment with systemic immunostimulatory agents (including, but 
not limited to, interferon and interleukin 2) within 4 weeks or five 


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 17 of 110
Version 4.0, 27 January 2019
half-lives of the drug (whichever is longer) prior to initiation of study 
treatment.
11. Treatment with a live, attenuated vaccine within 4 weeks prior to 
initiation of study treatment, or anticipation of need for such a 
vaccine during treatment with Atezolizumab or within 5 months after 
the last dose of Atezolizumab
12. Prior treatment with immune checkpoint blockade therapies 
DQWLí&7/$- DQWLí3'- RU DQWLí3'-L1) or immune agonists 
(anti-CD137, anti-CD40, anti-OX40).
13. Known allergy or hypersensitivity to any of the test compounds, 
materials or contraindication to test product, including: 
o
History of severe allergic anaphylactic reactions to chimeric, 
human or humanized antibodies or fusion proteins 
o
Known hypersensitivity to Chinese hamster ovary (CHO) cell 
products or any component of the Atezolizumab formulation. 
14. Use of investigational device or drug within 2 weeks or five half-
lives, whichever is longer, prior to the enrolment date.
15. Past or current history of autoimmune disease or immune deficiency, 
including, but not limited to, myasthenia gravis, myositis, 
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid 
arthritis, inflammatory bowel disease, autoimmune myocarditis,
antiphospholipid antibody syndrome, Wegener granulomatosis, 
Sjögren’s syndrome, Guillain-Barré syndrome, or multiple sclerosis 
(see Appendix E for a more comprehensive list of autoimmune 
diseases and immune deficiencies), with the following exceptions: 
o Patients with a history of autoimmune-related hypothyroidism 
who are on thyroid replacement hormone are eligible for the 
study.
o Patients with controlled Type 1 diabetes mellitus who are on a 
stable insulin regimen are eligible for the study. 
o Patients with eczema, psoriasis, lichen simplex chronicus, or 
vitiligo with dermatologic manifestations only (e.g., patients 
with psoriatic arthritis are excluded) are eligible for the study 
provided all of following conditions are met: 

Rash must cover <10% of body surface area

The disease is well controlled at baseline and requires 
only low-potency topical corticosteroids 

No occurrence of acute exacerbations of the 
underlying 
condition 
requiring 
psoralen 
plus 
ultraviolet A radiation, methotrexate, retinoids, 


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 18 of 110
Version 4.0, 27 January 2019
biologic agents, oral calcineurin inhibitors, or high 
potency or oral corticosteroids within the previous 12 
months. 
16. History of idiopathic pulmonary fibrosis, organizing pneumonia 
(e.g., 
bronchiolitis 
obliterans), 
drug-induced 
or 
idiopathic 
pneumonitis, or evidence of active pneumonitis on screening chest 
computed tomography (CT) scan. History of radiation pneumonitis 
in the radiation field (fibrosis) is permitted.
17. Serious infection requiring oral or IV antibiotics, antifungals, antivirals, 
and/or hospitalization within 14 days prior to Cycle 1, Day 1  

Patients who receive prophylactic oral antibiotics, antifungals, and 
antivirals as a result of prolonged neutropenia in the absence of 
documented infection are eligible.

Patients being treated for non-serious, infectious complications (e.g., 
oral candidiasis or uncomplicated urinary tract infection) with oral 
and/or topical antimicrobials may be eligible for study treatment 
(antimicrobials must be completed, prior to Cycle 1, Day 1 and all cases 
must be discussed with and approved by the Medical Monitor). 
18. Subjects with history of organ or stem cell transplantation. 
19. Known clinically significant liver disease, including alcoholic 
hepatitis, cirrhosis, fatty liver disease and inherited liver disease.
20. Active tuberculosis. 
21. Significant cardiovascular disease (such as New York Heart 
Association Class II or greater cardiac disease, myocardial 
infarction, or cerebrovascular accident) within 12 months prior to 
initiation of study treatment, or unstable arrhythmia or unstable 
angina within 3 months prior to initiation of study treatment.
22. *UDGH KHPRUUKDJH RU bleeding event within 28 days prior to 
initiation of study treatment.
23. Positive HIV test at screening or at any time prior to screening. 
24. Active hepatitis B virus (HBV) infection (chronic or acute), defined 
as having a positive hepatitis B surface antigen (HBsAg) test at 
screening. Patients with a past or resolved HBV infection, defined as 
having a negative HBsAg test and a positive total hepatitis B core 
antibody (HBcAb) test at screening, are eligible for the study.
25. Active hepatitis C virus (HCV) infection, defined as having a 
positive HCV antibody test followed by a positive HCV RNA test at 
screening. The HCV RNA test will be performed only for patients 
who have a positive HCV antibody test. 


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 19 of 110
Version 4.0, 27 January 2019
26. Subjects with concurrent, uncontrolled medical condition, laboratory 
abnormality, or psychiatric illness which could place him/her at 
unacceptable risk, including, but not limited to: 
o History of malignancy other than AML within 2 years prior to 
screening, with the exception of those with a negligible risk of 
metastasis or death (e.g., 5-year OS of > 90%), such as adequately 
treated carcinoma in situ of the cervix, non-melanoma skin 
carcinoma, localized prostate cancer, ductal carcinoma in situ, or 
Stage I uterine cancer
o Any other disease, metabolic dysfunction, physical examination 
finding, or clinical laboratory finding that contraindicates the use 
of an investigational drug, may affect the interpretation of the 
results, or may render the patient at high risk from treatment 
complications.
o Unable to comply with study requirements in the opinion of the 
Investigator. 
Investigational 
Product Route 
and Dosage Form
BL-8040 (formerly named BKT140)
A highly selective CXC chemokine 4 receptor (CXCR4) antagonist 
developed by BioLineRx, Ltd. as a novel therapy for treatment of cancer.  
BL-8040 is a white to off-white powder comprised of synthetic 
polypeptide, which is freely soluble in water.  
Subjects will receive once daily SC injections of 1.25 mg/kg of BL-8040 
after CBC assessment on Days 1, 2 and 3 of each 21-day cycle. On Day 
2, BL-8040 will be administered 1 h (± 30 min) after the end of the 
Atezolizumab infusion. 
The BL-8040 injection site will be rotated daily, to minimize the severity 
of any local injection site reactions. When the reconstitution volume is > 
2 mL, the injection should be split in order to have less than 2 ml per 
injection and administered into more than one site (e.g. hand and leg). At 
the discretion of the Investigator, lower volumes may be split and injected 
into more than one site.  
Atezolizumab
The Atezolizumab drug product will be supplied by the Sponsor in a 
single-use, 20 mL USP/Ph. Eur. Type 1 glass vial as a colorless to slightly 
yellow, sterile, preservative-free, clear liquid solution intended for IV 
administration. For information on the formulation and handling of 
Atezolizumab, see the pharmacy manual and the Atezolizumab
Investigator's Brochure. 
Subjects will receive Atezolizumab 1200 mg IV on Day 2 of every cycle.
The first infusion of Atezolizumab should be administered over 60 mins. 
If well tolerated, subsequent infusions may be performed over 30 mins. 


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 20 of 110
Version 4.0, 27 January 2019
Concomitant 
Medications
All treatments that the Investigator considers necessary for a subject’s 
welfare may be administered at the discretion of the Investigator in 
keeping with the community standards of medical care. 
All concomitant medications received within 30 days prior to the 
screening visit and 30 days after the last dose of study treatment should 
be recorded. Concomitant medications administered more than 30 days 
after the last dose of study treatment will be recorded when related to 
SAEs. All concomitant medication will be recorded on the CRF 
including all prescription, over-the-counter (OTC), herbal supplements, 
and IV medications and fluids. If changes occur during the trial period, 
documentation of drug dosage, frequency, route, and date should also be 
included in the CRF. 
Transient hypotension, due to vaso-vagal episodes, was witnessed in 
several cases following the first treatment with BL-8040. Therefore, 
caution should be taken with the use of negative chronotropic drugs such 
as beta blockers. When appropriate, negative chronotropes should be 
replaced by non-chronotropic alternatives. 
Pre-medication and allowed medication for BL-8040 adverse event 
management:
x
Premedication prior to BL-8040 injection with antihistamines 
(e.g. diphenhydramine, promethazine, etc.) in order to minimize 
the occurrence of BL-8040 related systemic reactions is highly 
recommended.  
x
Systemic steroids are allowed for the treatment of systemic 
reaction but not as regular pre-medication of these reactions.  
x
Clinically appropriate measures in case of BL-8040-related local 
injection site reactions e.g., local corticosteroids, systemic and 
local painkillers, antihistamines, local treatments etc. are allowed.
Permitted Concomitant Medications
x
Antiemetic drugs (e.g., ondansetron) as required clinically based 
on local guidelines for subjects experiencing nausea.
x
Prophylactic antibiotics (e.g., quinolone or cephalosporin), anti-
fungals (e.g., voriconazole) and antivirals (e.g., valacyclovir) 
when appropriate. 
x
Blood products that are commonly required in oncology subjects.
x
Low-dose steroids are allowed as pre-medication for blood 
transfusion or with IV anti-fungals. 
x
Vitamins, nutritional supplements, herbal supplements and over 
the counter medications are permitted per PI’s judgement.


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 21 of 110
Version 4.0, 27 January 2019
x
Vitamin D therapy.
x
Polyphenols in green tea/supplements
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the 
screening period and treatment phase of this trial:
x
Antineoplastic systemic chemotherapy or biological therapy.
x
Immunotherapy or other therapy not specified in this protocol. 
x
Investigational agents other than BL-8040 and Atezolizumab. 
x
Live vaccines within 30 days prior to the first dose of trial 
treatment and while participating in the trial and 5 months after 
the last dose of Atezolizumab. Examples of live vaccines include, 
but are not limited to, the following: measles, mumps, rubella, 
chickenpox, yellow fever, BCG, and typhoid (oral) vaccine. 
Seasonal influenza vaccines for injection are generally killed 
viruses and are allowed. However, intranasal influenza vaccines 
(e.g. Flu-Mist®) are live attenuated vaccines and are not allowed.
x
Lodonal 
x
Systemic glucocorticoids for any purpose other than to modulate 
symptoms from an event of suspected immunologic etiology or 
for systemic and local reactions secondary to BL-8040 and/or 
Atezolizumab treatment. The use of physiologic doses of 
corticosteroids may be approved after consultation with the 
Sponsor.  Note: Inhaled steroids are allowed for management of 
asthma, and dermatological formulations are allowed to reduce 
the intensity of injection site reactions.
x
Medications or vaccinations specifically prohibited in the 
Exclusion Criteria are not allowed during the ongoing trial. If 
there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation of trial 
therapy may be required. The Investigator should discuss any 
questions regarding this with the Sponsor’s Medical Monitor. The 
final decision on any supportive therapy or vaccination rests with 
the Investigator and/or the subject's primary physician. However, 
the decision to continue the subject’s trial therapy requires mutual
agreement of the Investigator, the Sponsor, and the subject. 
Subjects who, in the assessment of the Investigator, require the use of any 
of the aforementioned treatments for clinical management should be 
removed from the trial. Subjects may receive other medications that the 
Investigator deems to be medically necessary.
No live attenuated vaccines can be given up to 5 months post last dose. 


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 22 of 110
Version 4.0, 27 January 2019
Study Endpoints
Primary Safety and Tolerability Endpoints and Outcome Measures:
x
Dose Limiting Toxicity (DLT).
x
Adverse Events and serious adverse events.
x
12-Lead ECG.
x
Vital Signs.
x
Safety laboratory tests.
x
Early discontinuations; reasons and time to event. 
Secondary Efficacy Endpoints
x
Time from CR to the occurrence of earlier relapse or death from any 
cause (RFS).
x
Change from baseline to Cycles 3, 9, 18 and 34 in MRD status 
measured using quantitative, multi-color, flow cytometry. 
x
Time from 1st study drug administration to death from any cause 
(OS). 
x
Event Free Survival (EFS) measured as the earlier from 1st study drug 
administration to the date of primary refractory disease, or relapse 
from CR, or death from any cause from 1st study drug administration.
Pharmacokinetics
Characterize the PK profile of BL-8040 and Atezolizumab.  
Exploratory Outcome Measures
x
Biomarkers that may serve as surrogates or predictors of clinical 
efficacy (PD-L1 expression, CXCR4 expression, and presence of 
immune cells).  
x
Immune response to BL-8040 and Atezolizumab.  
x
Presence of ADAs during the study relative to the presence of ADAs 
at baseline.  
x
Pharmacodynamic endpoints. 
x
Measurement of mast cell activation
x
Molecular tests may be assessed following emerging public domain 
literature and other clinical trials with BL-8040.
Statistical 
Analysis  
Sample Size Justification:
This is a single arm, open-label, phase Ib/II study designed to evaluate the 
safety, tolerability and to initially assess the effectiveness of the proposed 
combination therapy. Therefore, neither power assessment, nor formal 
hypothesis testing are currently planned for study outcome measures.  
The study will consist of two periods: 
x
Initial Risk-Benefit Period which will enroll up to a total of 12
subjects. The decision whether to continue to the extension phase will 


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 23 of 110
Version 4.0, 27 January 2019
be made based on a risk-benefit analysis and data review by the DMC 
together with the Sponsor. Within this study period, the 12 initially 
recruited patients are considered appropriate for the evaluation of the 
DLT rate of the proposed combination. 
x
Expansion Period of additional up to 48 subjects.
The total planned sample size of up to 60 subjects is considered clinically 
appropriate for further characterization of the safety, tolerability and 
preliminary efficacy of the proposed combination maintenance therapy in 
subjects with acute myeloid leukemia. 
Comprehensive interim reports of accumulated safety, tolerability and 
preliminary available efficacy data will be presented to the independent 
Data Monitoring Committee (DMC) periodically in line with the DMC 
charter. 
All measured variables and derived parameters will be listed individually 
and if appropriate, presented in summary tables by potential study 
population subgroups and overall, providing sample size, absolute and 
relative frequency for categorical variables, or sample size, arithmetic 
mean, standard deviation, median, minimum and maximum for 
continuous variables. Confidence intervals will be presented for the 
efficacy endpoints for exploratory purposes only. 
Statistical Analysis Plan (SAP):
A detailed Statistical Analysis Plan (SAP) will be developed following 
the recruitment of the 40th subject.


PRIVILEGED &
CONFIDENTIAL
Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 24 of 110
Version 4.0, 27 January 2019
GLOSSARY
Subject and patient will be used interchangeably throughout this document. 
Abbreviation/Term
Definition
Ȝz
Elimination rate constant
μL
Microliter
ADA
Anti-drug Antibody
AE
Adverse Event
ALP
Alkaline Phosphatase
ALT/SGPT
Alanine Transaminase/Serum Glutamic Pyruvic Transaminase
AML
Acute Myeloid Leukemia
aPTT
Activated Partial Thromboplastin Time
Ara-C
Arabinofuranosyl Cytidine / Cytarabine / Cytosine Arabinoside
AST/SGOT
Aspartate 
Aminotransferase/Serum 
Glutamic 
Oxaloacetic 
Transaminase
AUC
Area under the curve
BM
Bone Marrow
Cmax
Maximum plasma concentration
CBC
Complete Blood Count
CFR
Code of Federal Regulations
CHO
Chinese Hamster Ovary
CI
Confidence Interval
CR
Complete Remission
CR1
First Complete Remission
CRF
Case Report Form
Cri
Complete Response with Incomplete Hematological Recovery
CRO
Contract Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
CXCR4
CXC Chemokine Receptor Type 4
DFS
Disease Free Survival
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
FACS
Fluorescence-activated cell sorting


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Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 25 of 110
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Abbreviation/Term
Definition
FDA
Food and Drug Administration
GCP
Good Clinical Practice
G-CSF
Granulocyte Colony-Stimulating Factor 
GFR
Glomerular Filtration Rate
GLP
Good Laboratory Practice
GMP
Good Manufacturing Practice
h
Hour
HBcAb
Hepatitis B Core Antibody
HBsAg
Hepatitis B Surface Antigen
HBV
Hepatitis B Virus
HCT
Hematocrit
HCV
Hepatitis C Virus
HGB
Hemoglobin
HIV
Human Immunodeficiency Virus
HMA
Hypomethylating agent
HPLC
High Performance Liquid Chromatography
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IgG1
IMP
Immunoglobulin G1
Investigational Medicinal Product
INR
International Normalized Ratio (for blood coagulation tests)
IRB/IEC
Institutional Review Board / Independent Ethics Committee
ITT
Intention-to-treat
IV
Intravenous
kg
Kilogram
L
Liter
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
MDR
Multi Drug Resistance
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
min
Minute
mL
Milliliter
MM
Multiple Myeloma
MRD
Minimal Residual Disease


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Investigational Product
BL-8040 & Atezolizumab
A Phase Ib/II, Multicenter, Single Arm, 
Open-Label Study, To Evaluate the Safety,
Tolerability and Efficacy of the BL-8040 and 
Atezolizumab Combination for Maintenance 
Treatment in Subjects with Acute Myeloid 
Leukemia - The BATTLE Study
Protocol No. 
BL-8040.AML.202
Phase:
Ib/II
Version 4.0
27 January 2019
Protocol: BL-8040.AML.202
Page 26 of 110
Version 4.0, 27 January 2019
Abbreviation/Term
Definition
NCI 
National Cancer Institute 
NK
Natural Killer
OS
Overall Survival
PD
Pharmacodynamic
PD-1
Programmed cell death protein-1
PD-L1
Programmed cell death-ligand 1
PK
Pharmacokinetic
PT
Prothrombin Time 
QA
Quality Assurance
RBC
Red Blood Cell
RFS
Relapse Free Survival
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard Deviation
SE
Standard Error
SEER
Surveillance, Epidemiology and End Results
SOC
System Organ Class
SOP
Standard Operation Procedures
SUSAR
Suspected Unexpected Serious Adverse Reaction
t1/2
Terminal Elimination Half-/LIH'HILQHGDVȜz
Tmax
Time to Reach the Maximum Plasma Concentration
TTR
Time to Relapse
ULN
Upper Limit of Normal
US
United States
USP
United State Pharmacopeia
WBC
White Blood Cell
WHO
World Health Organization


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1
INTRODUCTION
1.1
Therapeutic Indication
Acute myeloid leukemia (AML) represents a group of clonal hematopoietic stem cell disorders 
in which both failure to differentiate and over proliferation in the stem cell compartment result 
in accumulation of non-functional cells termed myeloblasts (Stone RM, et al. 2004). The 
annual age-adjusted incidence of AML in the US is 3.6 cases per 100,000 people (2005 - 2009), 
with a median age at diagnosis of 66 years. The five-year relative survival in US patients 
diagnosed over the period 2002-2008 was 23.4% (SEER [Surveillance, Epidemiology and End 
Results] Cancer Statistics Review 2005-2009). 
Standard AML induction therapy consists of 7-day treatment with cytarabine (Ara-C) and 3-
day treatment with daunorubicin or idarubicin (7+3 schedule). The goal of induction therapy
is to achieve a complete hematological remission (CR), correlating to a reduction of blasts by 
3 log-levels, and reflected in a normalized cellularity of the bone marrow with less than 5% 
blasts and normalization of the peripheral blood count, with neutrophils > 1x109/L and platelets 
> 100x109/L. Additional defining characteristics of CR are the absence of blasts with Auer 
rods, absence of extramedullary disease and independence from red cell transfusions. Complete 
Remission with incomplete haematological recovery (CRi) has the same characteristics with 
the exception of residual neutropenia (< 1x109/L) or thrombocytopenia (< 100x109/L). 
After complete remission (CR) is achieved, consolidation therapy should optimally lead to 
further reduction of residual leukemic load and reduction of relapse risk. Consolidation therapy 
is generally performed according to a relapse-risk stratification approach in order to balance 
therapeutic risks and benefits. Low risk patients receive high-dose Ara-C or high-dose Ara-C
plus autologous stem cell transplantation (Byrd JC et al., 2004). Intermediate-risk patients 
receive high-dose Ara-C or allogeneic stem cell transplantation. High risk patients receive 
allogeneic stem cell transplantation, preferentially a treatment within a clinical trial or high-
dose Ara-C.  
Given the available treatment options for AML patients that are not candidates for allogeneic 
stem cell transplant, there is a clear unmet need for improved therapies to improve patient 
outcomes.  
1.1.1
The Prognostic and Therapeutic Relevance of Minimal Residual Disease
The recent availability of sensitive assays with the ability to detect residual, sub-microscopic 
leukemia on the basis of leukemia-specific features such as aberrant immune phenotypes and 
abnormal molecular markers have rekindled the interest in minimal residual disease (MRD). 
Achieving MRD-negative status according to multiparameter flow cytometry is associated with 
a highly significant improvement in the outcomes of younger patients with AML receiving 
Ara-C plus idarubicin-based induction and consolidation regimens (Ravandi F et al., 2016).  
Another work found that the long-term outcome of AML patients is strongly influenced by 
their pre-allogeneic stem cell transplant MRD results as assessed by 10-color multi-parametric 
FACS (fluorescence-activated cell sorting) analysis on BM aspirates. Three-year relapse 
estimates were 67% in patients in MRD-positive morphologic remission, 65% in patients with 
active AML compared to 22% of patients in MRD-negative remission. Three-year OS 
estimates were 26%, 23% and 73% in these three groups (Araki D et al., 2016). Moreover, the 
negative impact of pre-transplant MRD is similar for AML in first and second complete 
remission and associated with adverse outcome (Walter RB et al., 2013).  


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Elderly patients reached post-consolidation MRD negative status less frequently than younger 
patients (11 vs 28%, p=0.009) (Buccisano F et al., 2015). However, in elderly patients, MRD 
negativity resulted in a longer 5-year disease-free survival (DFS) (57 vs 13%, p=0.0197), 
compared to younger patients (56 vs 31%, p=0.0017). These results underline the importance 
of MRD negativity for disease outcome in both young and older AML patients. 
1.2
Investigational Therapy 
1.2.1
BL-8040 
BL-8040 is a 14-residue, cyclic, synthetic peptide capped with an aromatic ring. BL-8040 binds 
and inhibits the CXCR4 chemokine receptor with high affinity (IC50 0.54 - 4.5 nM). It was 
shown in vitro and in vivo to be a specific antagonist of CXCR4, and to have a slow dissociation 
rate from the receptor. The chemokine CXCL12 (SDF-1-stromal-derived-factor-1) and its 
receptor, CXCR4, play a pivotal role in the trafficking of hematopoietic stem cells to the bone 
marrow (BM). In in-vivo animal studies, as well as in the clinical setting, BL-8040 has 
demonstrated accelerated mobilization of adult WBCs (neutrophils, monocytes, lymphocytes) 
and normal stem-cells. In addition to its activity as a mobilizer of WBCs, BL-8040 exhibits a 
CXCR4-dependent selective cytotoxicity toward malignant cells of hematopoietic origin. BL-
8040 significantly and preferentially stimulated apoptotic cell death of cells from AML patients 
(Beider K et al., 2011).  
1.2.1.1
Nonclinical Studies of BL-8040 
The nonclinical development of BL-8040 has encompassed a large number of 
pharmacodynamic (PD), pharmacokinetic (PK), safety pharmacology, and single and repeated 
dose toxicity studiesa.
BL-8040 exhibits CXCR4-dependent selective cytotoxicity toward malignant cells both in vivo 
and in vitro and induces apoptotic cell death in cancer cells (Beider K et al., 2011, Beider K et 
al., 2014, Tavor S et al., 2013).  BL-8040 leads to phospharidylserine externalization, decreased 
mitochondrial membrane potential, caspase activation, subsequent sub-G1 arrest and DNA 
double-stranded breaks in leukemic and multiple myeloma (MM) cells (Beider K et al., 2011). 
These effects were shown to be specific; BL-8040 did not affect the viability of human 
keratinocytes and normal human hematopoietic cells (Beider K et al., 2011). These direct 
apoptotic effects in addition to the mobilization capacity, distinguishes BL-8040 from other 
CXCR4 antagonists such as mozobil/plerixafor (Beider K et al., 2011). Furthermore,
administration of BL-8040 induces the mobilization of natural killer (NK) cells, T cells and B 
cells from the bone marrow (BM) and lymph nodes into the periphery. Using a syngeneic 
cancer model in mice it was demonstrated that BL-8040 may eliminate the immunological 
barrier and allow the accumulation of immune cells within the tumor microenvironment 
(unpublished data).
BL-8040 exhibited very high binding to human plasma proteins (99.2%) and high binding to 
the proteins in rat and dog plasma (94.9-96.9%) in the range of tested concentrations.  
The subcutaneous injection (SC) of BL-8040 was tested in GLP toxicology studies in dogs, 
and rats with the main identified AE’s being a transient and local erythema at the injection site 
and peripheral edema. These reactions were noticed from a few minutes up to approximately 2 
hours following the injection. There were no significant changes in terms of histopathology, 
a The active peptide doses referred to in the "Nonclinical Studies" section are 80.63±1.18% of the indicated dose 
in the text. The indicated doses were calculated based on total content (including active peptide, peptide 
impurities, acetic acid and water content).


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electrocardiogram (ECG), ophthalmological findings, blood chemistry or hematologic 
variables. No target organ for toxicity could be identified.  
For detailed information refer to the BL-8040 Investigator’s Brochure (IB).
1.2.1.2
Clinical Studies and Safety profile BL-8040 
BL-8040 has demonstrated safety and initial clinical efficacy in three completed Phase I and II 
studies: 
x
A Phase IIa, open-label, single ascending dose, safety study of BL-8040 in combination 
with granulocyte colony-stimulating factor (G-CSF) in MM subjects (BKTSC001).  
x
A Phase IIa, multicenter, open-label study to evaluate the safety and efficacy of 
escalating doses of BL-8040 in subjects with relapsed/refractory AML (NCT01838395; 
BL-8040.01). 
x
A Phase I, two-part study exploring safety, tolerability, PD and PK effect of ascending 
doses of BL-8040 in healthy subjects (BL-8040.02). 
The most frequent AEs seen in these studies were injection site reactions, including: pain, 
erythema, pruritus and inflammation, and systemic reactions including among others: hives, 
pruritus (not at the injection site), flushing, chills, rash and urticaria. Other isolated AEs 
reported among others were paresthesia, musculoskeletal pain, headache, constipation, tingling 
and elevated liver function tests. 
For details concerning these studies please refer to the BL-8040 IB. 
1.2.2
Atezolizumab
Atezolizumab is a humanized immunoglobulin G (IgG) 1 monoclonal antibody that targets 
PD-L1 and inhibits the interaction between PD-L1 and its receptors, PD-1 and B7-1 (also 
known as CD80), both of which function as inhibitory receptors expressed on T cells.  
Therapeutic blockade of PD-L1 binding by Atezolizumab has been shown to enhance the 
magnitude and quality of tumor-specific T-cell responses, resulting in improved anti-tumor 
activity (Fehrenbacher et al. 2016; Rosenberg et al. 2016).  Atezolizumab has minimal binding 
to Fc receptors, thus eliminating detectable Fc-effector function and associated antibody-
mediated clearance of activated effector T cells.
Atezolizumab shows anti-tumor activity in both nonclinical models and cancer patients and is 
being investigated as a potential therapy in a wide variety of malignancies.  Atezolizumab is 
being studied as a single agent in the advanced cancer and adjuvant therapy settings, as well as 
in combination with chemotherapy, targeted therapy, and cancer immunotherapy. 
Atezolizumab is approved in the United States for the treatment of locally advanced or 
metastatic urothelial carcinoma and for the treatment of metastatic nonsmall cell lung cancer
(NSCLC). 
1.2.2.1
Summary of Clinical Studies for Atezolizumab. 
As of 10 May 2016, an estimated total of 6053 patients with solid tumor and hematologic 
malignancies have received Atezolizumab in clinical trial participation as a single agent or in 
combination with cytotoxic chemotherapy and/or targeted therapy.   


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Safety findings of single-agent Atezolizumab across multiple tumor types in the clinical 
development program are consistent with the known mechanism of action of Atezolizumab
and the underlying disease. Overall, treatment with Atezolizumab is well tolerated, with a 
manageable adverse event profile. Currently, no maximum tolerated dose, no dose-limiting 
toxicities, and no clear dose-related trends in the incidence of adverse events have been 
determined. As of 15 December 2015, safety information was available for 629 safety-
evaluable patients in Study PCD4989g, an ongoing Phase Ia trial evaluating the safety and 
pharmacokinetics of single-agent Atezolizumab in patients with locally advanced or metastatic 
solid tumors including NSCLC, urothelial carcinoma, renal cell carcinoma, triple negative 
breast cancer, and small-cell lung cancer and hematologic malignancies. Across all studies and 
tumor types, the most commonly reported adverse events with single-agent Atezolizumab
include fatigue, nausea, decreased appetite, diarrhea, constipation, and cough.   
The adverse events observed with Atezolizumab in combination with chemotherapy and/or 
targeted therapies are consistent with the known risks of each study treatment. Systemic 
immune activation, characterized by an excessive immune response, is a potential risk 
associated with Atezolizumab when used in combination with another immunomodulating 
compound. 
Immune-related adverse events are consistent with the role of the PD-L1/PD-1 pathway in 
regulating peripheral tolerance. Given the mechanism of action of Atezolizumab, events 
associated with inflammation and/or immune-related adverse events are closely monitored 
during the Atezolizumab clinical program.  To date immune-related adverse events associated 
with Atezolizumab include hepatitis, pneumonitis, colitis, pancreatitis, diabetes mellitus, 
hypothyroidism, hyperthyroidism, adrenal insufficiency, Guillain-Barré syndrome, myasthenic 
syndrome/myasthenia gravis, and meningoencephalitis.  Overall most of the immune-related
adverse events observed with Atezolizumab have been mild and self-limiting.  Immune-related 
adverse events should be recognized early and treated promptly to avoid potential major 
complications.  Discontinuation of Atezolizumab may not have an immediate therapeutic 
effect, and in severe cases, immune-related toxicities may require acute management with 
topical corticosteroids, systemic corticosteroids, or other immunosuppressive agents.  
The data on development of graft-versus-host disease (GVHD) following anti-PD-L1 therapy 
like Atezolizumab and subsequent bone marrow transplant are limited.  Given the mechanism 
of action of anti-PD-L1 agents as modulators of the immune system, the potential exists for 
acute GVHD in a patient who received treatment with Atezolizumab and then proceeded to 
allogeneic stem cell transplant (allo SCT).  
For details concerning previous nonclinical and clinical experience, please refer to the 
Atezolizumab IB.
1.3
Study Rationale 
The rationale to use BL-8040 is provided by data obtained by administration of growth factors 
in the treatment of AML. Sensitization of leukemic cells with hematopoietic growth factors, 
such as G-CSF and granulocyte macrophage (GM)-CSF, led to increased cytotoxicity of 
chemotherapy (Estey EH et al., 2001). The large study groups (HOVON and SAKK) showed 
that priming with G-CSF resulted in a significantly better DFS, and in the intermediate-risk 
group also a significantly better OS (Löwenberg B et al., 2003).  


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Emerging data have highlighted the importance of the BM niche for AML growth (Giles FJ et 
al., 2002, Mayani H, 1996, Bradstock KF et al., 1995, Liesveld JL et al., 1994). The interaction 
of malignant blasts with the BM micro-environment, mediated through the chemokine receptor 
CXCR4 and various adhesion molecules including VLA-4 and CD44, is postulated to function 
as a “tumor survival factor,” promoting tumor growth and protecting malignant cells from 
chemotherapy-induced apoptosis (Bradstock KF et al., 1995, Liesveld JL et al., 1994, 
Matsunaga T et al., 2003, Becker PS, 2012, Bendall LJ et al., 1998). A recent clinical trial 
investigating AMD3100 (plerixafor) in combination with chemotherapy in patients with 
relapsed AML, observed leukemic cell mobilization, resulting in an overall response rate 
higher than expected in patients with advanced AML (Uy GL et al., 2012).  
In our study BL-8040.01, the combination of BL-8040 with high dose Ara-C in patients with 
relapsed/refractory AML was explored. Robust mobilization of AML cells from the BM to the 
peripheral blood was observed, thereby sensitizing these cells to the Ara-C chemotherapy. In 
addition, BL-8040 had a direct apoptotic effect on the leukemia cells in the BM and induced 
leukemia progenitor cells towards differentiation, as evidenced by a decrease in the number of 
these progenitor cells. Taken together, the addition of BL-8040 resulted in an overall response 
rate greater than those historically expected with Ara-C alone (manuscript in preparation).  
Animal studies have demonstrated that the PD-1/PD-L1 pathway plays an important role in 
limiting the host immune response against hematologic malignancy (Zhang L et al., 2009). PD-
1–expressing T cells found in the liver of AML-bearing mice at a late stage of tumor 
progression have been shown to be functionally impaired and disruption of the interaction 
between PD-1 and PD-L1 reduced immunosuppression and restored T cell function (Zhou Q 
et al., 2010). Furthermore, PD-L1 has been identified as an immunoescape molecule in blast 
cells from patients with AML. Expression of PD-L1 increases on leukemic blast cells with 
relapse, therefore increased expression may be targeted to facilitate T-cell-mediated killing 
(Berthon C et al., 2010).  
Clinical trials with PD-1 inhibitors in patients with hematologic malignancies are ongoing with 
promising clinical responses (Sehgal A et al., 2015). In this context, co-expression of multiple 
inhibitory receptors on hematopoietic cells offers the opportunity for combined blockade of 
specific targets/pathways to increase therapeutic efficacy. More specifically, the chemotherapy 
induced upregulation of PD-1 on T-cells after conventional leukemia therapy creates a solid 
rationale for using checkpoint inhibitors as maintenance therapy after initial chemotherapy.
The pro-apoptotic activity of BL-8040 combined with its ability to mobilize cancerous blasts 
from the BM to the periphery, together with Atezolizumab-induced blockade of the interaction 
between PD-L1 with PD-1 and CD80, might have a beneficial effect on MRD status. 
Specifically, this combined approach could conceivably convert a patient with MRD positive 
status to MRD negative status, with a positive effect on disease outcome in AML patients in 
CR1 that are not candidates for allogeneic stem cell transplantation. Our study regimen, 
offering a maintenance approach in this variable outcome group, aims at further prolonging the 
period of CR and thereby prolonging relapse free survival RFS.
1.3.1
Intended study
According to the above-mentioned rationale, the proposed study is planned to combine BL-
8040 and Atezolizumab maintenance therapy in AML patients who are >18 years old in CR1 
and with positive MRD. The study will assess safety, tolerability and preliminary efficacy of a 
treatment combination comprising BL-8040 administration on Days 1, 2 and 3 of each 21-day 
cycle and IV administration of Atezolizumab on Day 2 of each cycle. Treatment duration will 
be 2 years (a maximum of 34 cycles), until early discontinuation for any reason or until relapse,
whichever comes first. Patients must be older than 18 years, diagnosed with AML (except 


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AML M3), and be in CR1 (including CRi, confirmed by BM) with MRD positive status.
Patients will be included after a maximum of 2 cycles induction chemotherapy containing at a
minimum Ara-C (may also include an anthracycline or mitoxantrone) and one or up to four 
cycles of Ara-C based consolidation treatment. The primary study endpoint will be safety and 
tolerability of the combination treatment, Atezolizumab and BL-8040. The secondary study 
endpoints will be RFS, assessed from CR to the occurrence of the earlier relapse or death from 
any cause, change in MRD, OS, and EFS. Exploratory endpoints will include among others: 
evaluation of the biomarkers that may serve as surrogates or predictors for clinical efficacy 
(analyses may include PD-L1 expression, CXCR4 expression, and presence of immune cells);
evaluation of the immune response to the study drugs; analysis of presence of ADAs during 
the study relative to the presence of ADAs at baseline, measurement of mast cell activation. 
Additional molecular tests may be assessed by emerging literature and other clinical trials. 
1.4
Dose Selection Rationale 
1.4.1
Rationale for BL-8040 Dose Selection
In the Phase I/IIa study BKTSC001 (NCT01010880), a dose escalation study to assess the 
safety of BL-8040 for induction of mobilization of progenitor and stem cells from the BM to 
the PB in subjects with multiple myeloma, a total of 18 subjects were exposed to escalating 
doses according to the following scheme:
Group dose
BL-8040 mg/kg [free base]
N
1
0.006 [0.0048]
2
2
0.03 [0.024]
4
3
0.1 [0.08]
4
4
0.3 [0.24]
4
5
0.9 [0.72]
4
In Phase I study, BL-8040.02 (NCT02073019), the safety, tolerability, pharmacodynamic and 
PK effect of ascending doses of BL-8040 were assessed in healthy subjects. The study had two 
phases, escalation and expansion. A total of 26 subjects were exposed to escalating doses of 
BL-8040 according to the following scheme:
Group dose
BL-8040 mg/kg (free 
base)
N
(escalation)
N
(expansion)
1
0.5
8 (6 active)
-
2
0.75
8 (6 active)
-
3
1.0
8 (6 active)
8
In addition, ascending doses of BL-8040 were assessed in the BL-8040.01 (NCT01838395) 
study, a phase IIa study to assess the safety and efficacy of BL-8040 in subjects with 
relapsed/refractory acute myeloid leukemia. A total of 25 subjects were exposed to seven days 
of BL-8040 according to the protocol’s escalation scheme and three additional subjects 
received compassionate use therapy according to the scheme below. All doses were found to 
be safe and well tolerated and the 1.5 mg/kg was selected for the currently ongoing expansion 
phase.  
Group dose
BL-8040 mg/kg (free N (escalation)
Compassionate 
1
0.5
3
-
2
0.75
3
-
3
1.0
6
-


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4
1.25
4
2
5
1.5
6
1
6
2.0
3
-
The MTD in humans for BL-8040 has not been reached. A similar PK profile was observed 
across different clinical studies showing similar exposure between healthy volunteers, multiple 
myeloma subjects and AML subjects. Adequate receptor occupancy was confirmed from the 
1.0 mg/kg dose and higher. The rationale for the suggested combination relies on the ability of 
BL-8040 as a CXCR4 antagonist to mobilize immune cells from the BM and the lymph nodes 
to the PB. Rapid and dose-dependent mobilization of WBCs was seen in both, preclinical 
studies (mice) and humans treated with BL-8040. BL-8040 induces rapid (2-4 hrs), dose-
dependent and transient mobilization of WBCs, including monocytes, B cells, T cells and NK 
cells. The mobilization effect of BL-8040 was observed at doses of 0.5-2.0mg/kg in all 
conducted clinical trials. In addition, immune suppression by the tumor microenvironment 
involves the production of the chemokine, CXCL12 the ligand of CXCR4, by the fibroblastic 
stromal cells. Binding of CXCL12 by T cells results in their exclusion from the vicinity of the 
cancer cells. T cell exclusion occurs in several types of human adenocarcinomas, causes 
antagonists of T cell checkpoints to be ineffective, despite the presence of cancer-specific 
CD8+ T cells. This immune suppression may be interrupted by administering BL-8040, an 
inhibitor of CXCR4, the receptor for CXCL12, which leads to the rapid accumulation of T cells 
among cancer cells, thereby uncovering the efficacy of the anti-PD-1 and eliminating cancer 
cells. The effect was seen in mice at a dose range of 10-20 mg/kg, equivalent to 0.83-1.66 
mg/kg, respectively, in humans. 
Although the higher dose tested in the BL-8040.01 study (escalation to 2 mg/kg and expansion 
of 1.5 mg/kg) in combination with cytarabine was found to be safe and well tolerated and MTD 
was not achieved, our policy with new combinations is to leave safety margins and use a dose 
lower than the highest tested exposure in humans. In general, BL-8040 at the dose of 1.25 
mg/kg was observed to be associated with a favorable safety profile with the most common 
AEs being injection site irritation, flushing, and itching, and systemic reactions that were 
successfully managed with pre-medication. Based on the above safety and mobilization the 
1.25 mg/kg dose was selected for the combination study. After treatment of 6 patients in the 
study, the DMC will review data and advise whether to continue with the current combination, 
expand the DLT period revision to assess 12 patients or whether findings suggest that changes 
to the dose regimen are warranted. In case 5 out of the 6 of the first patients do not experience 
a DLT the recruitment will not stop (as two DLT in the first 6 patients will not have been 
reached) and the DMC will review the safety data without stopping recruitment.
1.4.2
Rationale for Atezolizumab Dose Selection
The dose of Atezolizumab is the same across studies as a single agent and in several 
combinations. Atezolizumab will be administered at a fixed dose of 1200 mg every 3 weeks 
(Q3W) (1200 mg on Day 2 of each 21-day cycle), which is the approved dosage for 
Atezolizumab (Tecentriq£ U.S. Package Insert).  Anti-tumor activity has been observed 
across doses ranging from 1 mg/kg to 20 mg/kg Q3W.  In Study PCD4989g, the maximum 
tolerated dose of Atezolizumab was not reached and no dose-limiting toxicities were 
observed at any dose.  The fixed dose of 1200 mg Q3W (equivalent to an average body 
weightbased dose of 15 mg/kg Q3W) was selected on the basis of both nonclinical studies 
(Deng et al. 2016) and available clinical pharmacokinetic, efficacy, and safety data (refer to 
the Atezolizumab Investigator's Brochure for details).


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2
STUDY OBJECTIVES AND ENDPOINTS
2.1
Study Objectives
Primary Study Objective - Safety and tolerability: 
To demonstrate that the proposed combination is safe and tolerable.  
Secondary Study Objectives: 
x
To assess the relapse free survival (RFS) time in patients treated with the combination of 
BL-8040 and Atezolizumab. 
x
To demonstrate that the combination of BL-8040 and Atezolizumab reduces the Minimal 
Residual Disease (MRD) as compared to baseline. 
x
To assess the Overall Survival (OS) time in patients treated with the combination of BL-
8040 and Atezolizumab for maintenance. 
x
To assess the Event Free Survival (EFS) time in patients treated with the combination of 
BL-8040 and Atezolizumab for maintenance. 
x
To assess the time to first relapse in patients treated with the combination of BL-8040 and 
Atezolizumab for maintenance. 
2.2
Study Endpoints/Outcome Measures
2.2.1
Safety and Tolerability Primary endpoints and Outcome Measures   
x
Dose Limiting Toxicity (DLT).
•
Adverse Events and serious adverse events. 
•
12-Lead ECG. 
•
Vital Signs. 
•
Safety laboratory tests. 
•     Early discontinuations; reasons and time to event. 


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2.2.2
Secondary Endpoints – Efficacy Measures 
x
Time from CR to the occurrence of earlier relapse or death from any cause (RFS). 
x
Change from baseline to Cycles 3, 9, 18 and 34 in MRD status measured using 
quantitative, multi-color, flow cytometry. 
x
Time from 1st study drug administration to death from any cause (OS).  
x
Event Free Survival (EFS) measured as the earlier from 1st study drug administration to 
the date of primary refractory disease, or relapse from CR, or death from any cause from 
1st study drug administration.
x
Relapse Free Survival (RFS). 
2.2.3
Exploratory Outcome Measures
x
Biomarkers that may serve as surrogates or predictors of clinical efficacy (PD-L1 
expression, CXCR4 expression, and presence of immune cells).  
x
Immune response to BL-8040 and Atezolizumab.  
x
Presence of ADAs during the study relative to the presence of ADAs at baseline.  
x
Pharmacodynamic endpoints. 
x
Measurement of mast cell activation
x
Molecular tests may be assessed following emerging public domain literature and other 
clinical trials with BL-8040. 
2.2.4
Pharmacokinetic (PK) Assessment.  
Sparse samples will be collected for PK analysis and to compare exposure in this study with 
that attained in previous studies. Serum concentrations of Atezolizumab and plasma 
concentrations of BL-8040 will be reported as individual values and summarized (mean, SD, 
coefficient of variation [%CV], median, range, geometric mean, and geometric mean CV 
[%CV]) by cycle, when appropriate and as data allow. Atezolizumab or BL-8040 concentration 
data may be pooled with data from other studies using an established population PK model to 
derive PK parameters such as clearance, volume of distribution and AUC, as warranted by the 
data. 
3
STUDY DESIGN
This is a single arm, open label, Phase Ib/II study in which eligible subjects will receive 
maintenance treatment consisting of intravenous (IV) infusion of 1200 mg Atezolizumab on 
Day 2 of each 21-day cycle and subcutaneous (SC) injections of BL-8040 (1.25mg/kg) on Days 
1, 2 and 3 of each 21-day cycle. Cycles will be repeated for up to 2 years (a maximum of 34 
treatment cycles), until early discontinuation for any reason or disease relapse, whichever 
comes first.
Patients in CR1 will be recruited after induction, with 1-4 cycles of subsequent cytarabine-
based consolidation therapy, unless they have been deemed intolerant or refused to receive 
consolidation therapy or they received treatment with at least 3 cycles of HMA
The study will recruit an initial Risk-Benefit period staggered cohort for up to 12 subjects in 
order to establish the safety tolerability and efficacy of the combination treatment before 
opening enrollment to the full study population. Safety data will be reviewed by an independent 
Data Monitoring Committee (DMC) (see below for more details).
Hematology (CBC) assessment will be performed before each dose of BL-8040. BL-8040 
injections will be skipped in case of a significant increase in white blood cells (WBCs) (WBC 


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/PHDVXUHGSULRUWRDGPLQLVWUDWion of the next BL-8040 injection and/or evidence 
of leukostasis. Dosing will resume when the WBC count is < 60,000/μL measured before 
administration of BL-8040. Missed doses can be skipped until the WBC count has decreased 
to < 60,000/μL. up to 2 Cycles. Missed doses will not be made up if >72 h have passed. If the 
delay is beyond the 2 Cycles, the Medical Monitor should be consulted in order to assess the 
continuation of the study for the specific subject.  Pre-dosing WBC monitoring should continue 
as lonJDVWKH:%&FRXQWLVȝ/. 
3.1
Dose-Limiting Toxicities and Ongoing Safety Assessment 
Adverse events (AEs) will be reported from the time of informed consent until 30 days after 
the last dose of study drug. The period considered for dose-limiting toxicity (DLT) assessment 
will be limited to the first cycle of therapy defined as the time from the first dose of BL-8040 
up to and including the day when the first cycle of combination therapy ends (usually Day 21). 
Beyond the DLT assessment period, AE data will be collected on an ongoing basis and recorded 
within the CRF. However, these events will not be considered for DLT evaluation. 
Dose-limiting toxicity (DLT) is defined as a clinically significant adverse event (AE) or 
abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness or 
concomitant medications and occurring during the first treatment cycle that meets any of the 
following criteria (refer to Table 2 for CTCAE severity grading):
x
&7&$(JUDGH$676*27RU$/76*37RUELOLUXELQIRUGD\V
x
CTCAE grade 4 AST (SGOT) or ALT (SGPT) of any duration
x
All other clinically significant, non-hematological NCI common terminology criteria 
that are CTCAE Grade 3 or 4 
x
Change from baseline to Grade 4 neutropenia or thrombocytopenia lasting for >4 weeks 
in the absence of persistent leukemia. 
x
Symptomatic leukostasis
To be considered a DLT the toxicity must be possibly, probably or definitely related to either of 
the study drugs or the combination.
An AE must be clinically significant to define a DLT, e.g., nausea and vomiting, alopecia, study 
drug-UHODWHGIHYHURUHOHFWURO\WHDEQRUPDOLWLHVWKDWDUHJUDGHZLOOQRWFRQVWLWXWH'/7 For 
subjects who experience a DLT, the study continuation should be discussed with the Medical 
Monitor. Subjects who experience AEs that are not considered DLT or are unrelated to BL-8040 
or Atezolizumab may continue study participation at the discretion of the Investigator.
BL-8040 injections may be skipped for any reason per Investigator judgment; however, they 
PXVWEHVNLSSHGLQWKHFDVHRID:%&!ȝ/PHDVXUHGSULRUWRDGPLQLVWUDWLRQRIWKHQH[W
BL-8040 injection and/or evidence of leukostasis.  
Increase in WBC is not considered a DLT since it is a direct effect of CXCR4 inhibition and 
reflects the drug’s mechanism of action.
In case of HOHYDWHG:%&!ȝ/, daily WBC assessment should be done, and BL-8040 
WUHDWPHQWFDQEHUHVXPHGSURYLGHGWKDWWKH:%&FRXQWVGHFUHDVHWRȝ/3UH-dosing 
:%& PRQLWRULQJ VKRXOG FRQWLQXH DV ORQJ DV WKH :%& FRXQW LV ȝ/ )RU YDOXHV
ȝ/GDLO\:%&PRQLWRULQJPDy be stopped and further analysis should be done based 
on the Investigator’s judgment.  


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The study will consist of two periods: 
x
Initial Risk-Benefit period which will enroll a total of 12 subjects. The decision whether 
to continue the extension phase will be made based on a risk-benefit analysis and data 
review by the DMC together with the Sponsor. 
x
Expansion period of up to 48 additional patients.
Safety review of the accumulated data will be performed by an independent DMC after the first 
6 patients have completed the first cycle of combination therapy and further again after 6 
additional patients have completed the first cycle of combination therapy. Guidelines to be used 
by the DMC for the review of the proposed combination toxicity are presented below: 
x
If  out of 6 subjects experiences a DLT during the first cycle of treatment, enrolment 
should be continued to include 6 additional patients.
x
,IRXWRIVXEMHFWVH[SHULHQFHD'/7WKH'0&ZLOODVVHVVWKHULVN/benefit profile 
of the combination treatment and recommend one or more of the following: 1) 
Recruitment should be continued to include 6 additional patients 2) the protocol should 
be modified 3) the treatment schedule should be modified 4) the study should be 
discontinued. 
x
If < 2 out of 12 subjects experience a DLT the DMC will recommend a recruitment of 
additional 3 subjects for the completion of the pre-planned Initial Risk-Benefit Period 
population size of 12 subjects., the DMC will recommend one or more of the following:   
x
If > 2 out of 12 subjects experience a DLT the DMC will recommend one or more of 
the following: 1) Recruitment should be continued to include 3 additional  patients for 
the completion of the pre-planned Initial Risk-Benefit Period population size of 12 
subjects, 2) the protocol should be modified, 3) the treatment schedule should be 
modified or 4) the study should be discontinued. Following the completion of this initial 
risk-benefit period which is planned to enrol a total of 12 patients, an integrative 
analysis of risk-benefit of the proposed combination will be performed. Then the DMC, 
jointly with the sponsor, based on an assessment of the integrated database will decide 
whether to continue to the expansion period and to enrol additional 48 patients or to 
early discontinue the study. 
The number of patients planned for DLT assessment will be up to 12, recruited in a staggered 
manner not exceeding the potential for observing that the proposed combination therapy would 
be considered unacceptably toxic according to the criteria above. In order to be evaluable for 
the DLT assessment period, a subject must complete the first cycle of treatment. If a subject is 
discontinued before completion of the first cycle (unless due to a DLT), an additional subject 
will be recruited and included in the Safety DLT Cohort to ensure a total of six evaluable 
subjects. Similar rules will be applied in the expanded 12 subject cohort. 
Clinical sites are required to contact the Sponsor within 24 hrs in case subjects present 
suspected DLTs during the assessment period.  
After completion of the DLT assessment period, further DMC assessments will be performed 
biannually. Standard therapy event rates and toxicity measurements for these findings will be 
obtained from historical data reviews. Any CI that no longer covers the historical event rate or 
the historical mean of a continuous toxicity measurement will represent a possible increase in 
the risk/benefit profile for the subjects. These data will be presented to the DMC for review. 
The DMC will be charged with monitoring the performance and safety profile of the protocol 
for the subjects. 


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3.2
Study Diagram: 
4
STUDY POPULATION
This study will be conducted in AML patients, DJHG18 years, who are in CR1 and not planned
for stem cell transplantation. Up to 60 patients are planned to be enrolled in the study. 
4.1
Inclusion Criteria
1.
$GXOWPHQDQGZRPHQDJHG 18 years.
2.
Confirmed diagnosis of AML (according to WHO criteria. See Appendix C) 
3.
Subjects with newly diagnosed AML who have achieved complete remission (CR or 
CRi/), after 
a. Up to two cycles of cytarabine based induction chemotherapy. 
b. A minimum of 3 cycles of HMA, such as azacytidine, decitabine, etc.
4.
Subjects with intermediate or adverse risk factors according to the ENL guidelines 
2017a.
5.
CR (or CRi) must be confirmed by bone marrow aspirate up to 28 days prior to 
enrollment.
6.
Subjects who have received 1-4 cycles of consolidation therapy unless they have been 
deemed intolerant, or have refused consolidation or, for patients that received at least 3 
cycles of HMA.
7.
Subjects who prior to screening are MRD positive according to the local laboratory or 
with an unknown MRD status; are to be confirmed or tested, respectively, for MRD by 
central laboratory prior to enrollment. 
8.
Subjects who were diagnosed with AML within 18 months prior to study enrollment. 
9.
Subjects should have received the last dose of the induction or consolidation or HMA, 
whichever comes later, therapy within 6 months prior to study enrollment. 
10. Subjects who, at the time of enrollment, are not planned for allogeneic stem cell 
transplantation.
11. Female subjects must be post-menopausal or of non-childbearing potential defined as 
the absence of menses for > 1 year or those who have had a bilateral tubal ligation or 
hysterectomy.
12. Male subjects with partners of childbearing potential must agree to use an adequate 
method of contraception starting with the first dose of the study therapy through at least 5 
months after the last dose of the study therapy. Examples of adequate methods are: for 
males- condom with or without spermicide, sexual abstinence or surgical sterility 
a Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. 
Döhner H. et al, Blood, 26 January 2017 X Volume 129, Number 4-Appendix F


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(vasectomy) or for female partners of childbearing potential-oral, transdermal patch, 
implanted contraceptives, intrauterine device, diaphragm.  
13. Subject is able and willing to comply with the requirements of the protocol. 
14. Subject is able to voluntarily provide written informed consent prior to initiation of any 
study-related procedure. 
4.2
Exclusion Criteria
1.
Subjects diagnosed with acute promyelocytic leukemia. 
2.
Subjects with extramedullary AML, including CNS involvement. 
3.
Subjects who have achieved CR or CRi following treatment for relapsed or refractory 
AML after 2 inductions. 
4.
Subjects in CR1 following allogeneic stem cell transplantation.
5.
Subjects who are candidates for allogeneic stem cell transplantation and have a suitable 
donor. 
6.
/LIHH[SHFWDQF\RIPRQWKV
7.
Clinically significant abnormal laboratory safety test values including, but not limited 
to: 
x Total bilirubin > 2 times upper limit of normal (x ULN)  
x
Aspartate Aminotransferase (AST/SGOT) or Alanine Aminotransferase (ALT/SGPT) 
> 2 x ULN 
x Creatinine > 1.5 x ULN or GFR < 30 mL/min. 
8.
Low Performance Status (ECOG > 2; Appendix D).
9.
Treatment with systemic immunosuppressive medication (including, but not limited to, 
corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-
tumor necrosis factor alpha [antiTNF-D] agents) within 2 weeks prior to initiation of 
study treatment, or anticipation of need for systemic immunosuppressive medication 
during the course of the study, with the following exceptions: 
x Patients who received acute, low-dose systemic immunosuppressant medication 
or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 
hours of corticosteroids for a contact allergy) are eligible for the study after 
Medical Monitor approval has been obtained. 
x Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids 
for chronic obstructive pulmonary disease or asthma, or low-dose 
corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible 
for the study. 
x Requirement for use of denosumab during the study: Patients who are receiving 
denosumab for any reason (including hypercalcemia) must be willing and 
eligible to receive a bisphosphonate instead while in the study. 
10. Treatment with systemic immunostimulatory agents (including, but not limited to, 
interferon and interleukin 2) within 4 weeks or five half-lives of the drug (whichever is 
longer) prior to initiation of study treatment.
11. Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study 
treatment, or anticipation of need for such a vaccine during treatment with 
Atezolizumab or within 5 months after the last dose of Atezolizumab
12. 3UHYLRXV WUHDWPHQW ZLWK LPPXQH FKHFNSRLQW EORFNDGH WKHUDSLHV DQWLí&7/$-4, 
DQWLí3'-RUDQWLí3'-L1) or immune agonists (anti-CD137, anti-CD40, anti-OX40).


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13. Known allergy or hypersensitivity to any of the test compounds, materials or 
contraindication to test product, including: 
x History of severe allergic anaphylactic reactions to chimeric, human or 
humanized antibodies or fusion proteins 
x Known hypersensitivity to Chinese hamster ovary (CHO) cell products or any 
component of the Atezolizumab formulation. 
14. Use of investigational device or drug within 2 weeks or five half-lives, whichever is 
longer, prior to the enrolment date. 
15. Past or current history of autoimmune disease or immune deficiency, including, but not 
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus 
erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune 
myocarditis, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren’s 
syndrome, Guillain-Barré syndrome, or multiple sclerosis (see Appendix E for a more 
comprehensive list of autoimmune diseases and immune deficiencies), with the 
following exceptions: 
x Patients with a history of autoimmune-related hypothyroidism who are on 
thyroid replacement hormone are eligible for the study. 
x Patients with controlled Type 1 diabetes mellitus who are on a stable insulin 
regimen are eligible for the study.
x Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with 
dermatologic manifestations only (e.g., patients with psoriatic arthritis are 
excluded) are eligible for the study provided all of following conditions are met:
x
Rash must cover <10% of body surface area 
x
The disease is well controlled at baseline and requires only low-
potency topical corticosteroids 
x
No occurrence of acute exacerbations of the underlying condition 
requiring psoralen plus ultraviolet A radiation, methotrexate, 
retinoids, biologic agents, oral calcineurin inhibitors, or high potency 
or oral corticosteroids within the previous 12 months. 
16. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis 
obliterans), drug-induced or idiopathic pneumonitis, or evidence of active pneumonitis 
on screening chest computed tomography (CT) scan. History of radiation pneumonitis 
in the radiation field (fibrosis) is permitted.
17. Serious infection requiring oral or IV antibiotics, antifungals, antivirals, and/or 
hospitalization within 14 days prior to Cycle 1, Day 1 
x
Patients who receive prophylactic oral antibiotics, antifungals, and antivirals as a 
result of prolonged neutropenia in the absence of documented infection are eligible.
x
Patients being treated for non-serious, infectious complications (e.g., oral 
candidiasis or uncomplicated urinary tract infection) with oral and/or topical 
antimicrobials may be eligible for study treatment (antimicrobials must be 
completed, prior to Cycle 1, Day 1 and all cases must be discussed with and 
approved by the Medical Monitor). 
18. Subjects with a history of organ or stem cell transplantation. 
19. Known clinically significant liver disease, including alcoholic hepatitis, cirrhosis, fatty 
liver disease and inherited liver disease.
20. Active tuberculosis. 


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21. Significant cardiovascular disease (such as New York Heart Association Class II or 
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 12 
months prior to initiation of study treatment, or unstable arrhythmia or unstable angina 
within 3 months prior to initiation of study treatment.
22. *UDGHKHPRUUKDJHRUEOHHGLQJHYHQWZLWKLQGD\VSULRUWRLQLWLDWLRQRIVWXG\
treatment.
23. Positive HIV test at screening or at any time prior to screening. 
24. Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive 
hepatitis B surface antigen (HBsAg) test at screening. Patients with a past or resolved 
HBV infection, defined as having a negative HBsAg test and a positive total hepatitis 
B core antibody (HBcAb) test at screening, are eligible for the study.
25. Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody 
test followed by a positive HCV RNA test at screening. The HCV RNA test will be 
performed only for patients who have a positive HCV antibody test.
26. Subjects with concurrent, uncontrolled medical condition, laboratory abnormality, or 
psychiatric illness which could place him/her at unacceptable risk, including, but not 
limited to:
x History of malignancy other than AML within 2 years prior to screening, with 
the exception of those with a negligible risk of metastasis or death (e.g., 5-year 
OS of > 90%), such as adequately treated carcinoma in situ of the cervix, non-
melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, 
or Stage I uterine cancer. 
x Any other disease, metabolic dysfunction, physical examination finding, or 
clinical laboratory finding that contraindicates the use of an investigational drug, 
may affect the interpretation of the results, or may render the patient at high risk 
from treatment complications.
x Unable to comply with study requirements in the opinion of the Investigator. 
4.3
Subject Identification
At screening, all subjects who signed informed consent will be identified by a subject number, 
initials and birth date; the subject number will be used throughout the study. Screening failures 
numbers will not be re-assigned. Subject numbers will not be re-used for different subjects. 
4.4
Screening Failures
Subjects who fail to meet the entrance criteria at any stage during the screening period are 
defined as screen failures. All screen failures will be documented on the screening log, which 
documents the subject number, subject’s initials, birth date and reason(s) for screen failure. 
The screening log will be kept in the Investigator's Site File. 
Screen failure subjects will be withdrawn from the study and receive standard of care 
performed at the site. Subjects may be rescreened after consultation with the Sponsor. 
Rescreening should include all screening procedures, listed in the protocol flow chart, 
including re-consent signature 
4.5
Removal, Replacement, or Early Withdrawal of Subjects from Therapy or 
Assessment
Subjects are free to discontinue their participation in the study at any time and without prejudice 
to further treatment. The Investigator must withdraw any subject from the study if that subject 


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requests to be withdrawn, or if it is determined that continuing in the study would result in a 
significant safety risk to the subject.
Subjects withdrawn from the study prior to first BL-8040 injection will be replaced by the 
Investigator to achieve the appropriate number of subjects, regardless of the reason for 
withdrawal.
Subjects must complete the first cycle of treatment in order to be evaluable for the DLT 
assessment period. If a subject is discontinued before completion of the first cycle for any 
reason other than a DLT, an additional subject will be recruited and included in the Safety DLT 
Cohort to ensure a total of six evaluable subjects. Similar rules will be applied in case the Safety 
DLT Cohort is expanded to 12 subjects. 
The subject's participation in this study may be discontinued due to the following reasons: 
x
Request of regulatory agency or Sponsor or primary care physician or Investigator 
x
Withdrawal of consent by subject 
x
Any subject who develops intolerance to treatment 
x
Any subject who requires concomitant medication which could confound evaluation of 
the study drug 
x
The subject is unwilling or unable to continue the study or is lost to follow-up 
x
The subject is non-compliant with study procedures / study protocol 
x
Investigator decides that withdrawal from the study is in the best interest of the subject
x
Subject meets one of the stopping/dosing interruption rules criteria during the study 
(see Sections 6.2.4 and 6.2.5).
4.6
Handling of Withdrawals
If a subject is withdrawn from the study, either at his/her request or at the Investigator’s 
discretion or if requested by the Sponsor, primary care physician or regulatory agency, or fails 
to return, every effort should be made to determine the reason. This information will be 
recorded on the subject’s case report form (CRF). All subjects who withdraw from the study 
prematurely, regardless of cause, should undergo all Early Discontinuation Study Visit 
assessments (see Section 5.6). It is vital to obtain follow-up data for any subject withdrawn 
because of an AE or abnormal laboratory test finding. In any case, every effort must be made 
to undertake safety follow-up procedures. 


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Premature withdrawal may occur for any of the following reasons: 
1.
Death
2.
Disease progression/relapse
3.
AE 
4.
Subject request
5.
Investigator request
6.
Sponsor request 
7.
Other party’s request
8.
Any other reason
If withdrawal is caused by an AE that the Investigator considers may be related to the study 
drug, it will be reported to the DMC, institutional review board/independent ethics committee 
(IRB/IEC) and Sponsor. 
Any serious AE (SAE) must be reported to the Sponsor or Sponsor's designee within 24 hours 
of becoming aware of the event and to the IRB/IEC according to local regulations (for SAE 
notification procedures, refer to Section 7.5). 
In the event of any AEs considered to be clinically significant by the Investigator, subjects will 
be followed up with appropriate medical management until the outcome is determined or 
stabilized, according to the Investigator’s clinical judgment. All follow-up information will be 
recorded in the subject's CRF until resolution of the AE. Subsequent follow-up will be 
documented in the subject's personal file. 
4.7
Sponsor's Termination of Study 
The Sponsor reserves the right to discontinue the study at any time at the participating centers 
for any reason included in the applicable law.  
Regulatory Authorities also have the right to terminate the study for any reason. 
5
STUDY PROCEDURES AND ASSESSMENTS
The schedule of events for this study is shown in Appendix A. No protocol related procedures 
should be performed before subjects provide written informed consent. Study related events 
and activities including specific instructions, procedures, concomitant medications, dispensing 
of study medication, and descriptions of AEs should be recorded in the appropriate source 
documents and CRF.  
5.1
Screening Period (Visit 1, Day -28 to Day -1) 
At Visit 1, the purpose and procedures of the study will be fully explained to participants. Those 
wishing to enroll in the study will sign a written informed consent prior to initiating any 
evaluations or study-related procedures. Following the signing of informed consent, adult male 
and post-menopausal IHPDOHVXEMHFWVDJHG 18 years will be screened for study eligibility by 
assessment of inclusion and exclusion criteria.  
The following assessments will be performed at screening (visit 1): 
x
Collection of demographic data and medical history. 
x
Prior and concomitant medication review. 
x
Full physical examination (including weight measurement).


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x
Vital signs (blood pressure, pulse rate, oral temperature, O2 saturation and respiratory 
rate).
x
ECOG performance status (Appendix D). 
x
12-lead electrocardiogram (ECG). 
x
Safety laboratory assessments including hematology, biochemistry, thyroid function 
tests (T3, T4 and TSH) and coagulation (PT/INR and aPTT), HCV and HBV serology.
x
HIV serology, unless not permitted per local regulations 
x
CT scan chest (within 28 days prior to treatment). 
x
Fresh BM biopsy taken during the screening visit (following approval of provisional 
enrollment package) to confirm AML status (CR or CRi) and ENL prognostic factors.  
x
BM aspirate to confirm positive MRD status by central laboratory assessment and for 
DNA and RNA for the correlative studies (optional for Israel).  
x
Blood sampling for biomarker assessment including DNA and RNA for the correlative 
studies (optional for Israel).
x
Review of inclusion and exclusion criteria. 
5.2
Baseline (Pre-Dose, Day 1 of Treatment Cycle 1) 
The following assessments will be performed at baseline:
x
AE and concomitant medication review
x
Directed physical examination (including weight measurement). 
x
Vital signs. 
x
ECOG performance status.
x
12-lead electrocardiogram (ECG).
x
Safety laboratory assessments including hematology and biochemistry
x
Review of inclusion/exclusion criteria and confirmation of eligibility. 
x
Pre-dose BL-8040 PK sample. 
x
Pre-dose sample for anti-BL-8040 antibodies, complement activation and biomarkers. 
5.3
Treatment Period (Days 1, 2 and 3 of each treatment cycle) 
During the treatment period, eligible subjects will receive study drug on Days 1, 2 and 3 of 
each 21-day cycle. Cycles will be repeated for up to 2 years (a maximum of 34 treatment 
cycles), until early discontinuation for any reason or disease relapse, whichever comes first.
There will be a ± 3-day window for the start of each treatment cycle.
Subjects will receive once daily SC injections of 1.25 mg/kg of BL-8040 on Days 1, 2 and 3 
of each 21-day cycle. Subjects will receive Atezolizumab 1200 mg IV on Day 2 of every cycle. 
The first infusion of Atezolizumab should be administered over 60 mins. If well tolerated, 
subsequent infusions may be performed over 30 mins. On Day 2, BL-8040 will be administered 
1 h (± 30 min) after the end of the Atezolizumab infusion.  
Hematology (CBC) assessment will be performed before each dose of BL-8040. BL-8040 
LQMHFWLRQV ZLOO EH VNLSSHG LQ FDVH RI D VLJQLILFDQW LQFUHDVH LQ :%&V :%&  /
measured prior to administration of the next BL-8040 injection and/or evidence of leukostasis. 
Dosing will resume when the WBC count is < 60,000/μL measured before administration of 
BL-8040. Missed doses can be skipped until the WBC count has decreased to < 60,000/μL, up 
to 2 cycles. Missed doses will not be made up if >72 h have passed.  


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If the delay is beyond the 2 Cycles, the Medical Monitor should be consulted in order to assess 
the continuation of the study for the specific subject. Pre-dosing WBC monitoring should 
continuHDVORQJDVWKH:%&FRXQWLVȝ/
The following assessments will be performed throughout the treatment period at the time points
indicated in the schedule of assessments (see Appendix A):
o
Clinical Evaluations:
x
AE and concomitant medication review will be performed on every treatment day 
throughout the study.  
x
ECOG performance status will be determined pre-dose on Day 1 of every cycle. 
x
Directed physical examination will be performed pre-dose on Day 1 of every treatment 
cycle.
x
Subject weight will be measured pre-dose on Day 1 of every treatment cycle to 
determine the correct dose of BL-8040.  
o
Vital signs will be assessed on: 
x
Days 1, 2 and 3 at pre-dose and 4 ± 2 h post-BL-8040 administration during the first 
cycle. 
x
In the following cycles pre-dose and 4±2h post BL-8040 administration on day 1 only.  
x
Additional assessments may be performed at the discretion of the Investigator or upon 
Sponsor's request. 
o
12-lead ECGs:
x
12-lead ECGs will be recorded on Day 1 and 2 of treatment cycle 1 at pre-dose and 4 ± 
2 h post-BL-8040 administration.
x
Additional ECGs may be performed at the discretion of the Investigator or upon 
Sponsor's request. 
o
Laboratory safety evaluations:
x
Hematology (CBC) and differential counts will be performed before each dose of BL-
8040 throughout the study (see above). During treatment cycle 1, samples will also be 
collected at 4 ± 2 h post-BL-8040 administration on day 1, 2 and 3. 
x
Biochemistry samples will be collected pre-dose on Day 1 and 3 on cycle 1 and on day 
1 and 3 pre-dose every cycle. 
x
Thyroid function tests and coagulation will be tested pre-dose on Day 1 of every other 
treatment cycle starting from treatment cycle 2.  
x
Additional hematology, biochemistry and coagulation samples may be collected at the 
discretion of the Investigator or upon Sponsor's request. 
o
BM Aspirate/Flow Cytometry Analysis:
x
BM aspirate samples for determination of MRD status by Flow Cytometry will be 
collected post dose on Day 3 of treatment cycles 3, 9, 18, end of cycle 34/end of 
treatment (whichever comes first).
x
Peripheral blood and BM aspirate samples for immune-phenotyping by Flow 
Cytometry including measuring CXCR4, PD-1 and PD-L1 as well as DNA and RNA 
for the correlative studies (optional for Israel) will be collected post dose on Day 3 of 
treatment cycles 3, 9, end of cycle 18, end of cycle 34/end of treatment (whichever 
comes first).
o
PK Sampling: See Appendix B.
o
Anti-drug Antibody (ADA) and Complement Activation 


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x
Blood samples for assessment of BL-8040 ADA and complement activation will be 
collected according to timepoints listed in Appendix B.
x
Blood samples for assessment of Atezolizumab ADA and complement activation will 
be collected according to timepoints listed in Appendix B.
o
Blood Sampling for biomarkers 
x Cycles 1, 3, 9 and 18. Day 1 pre-dose and day 3 2 hours post dose. 
x End of treatment or discontinuation visit.
5.4
End of treatment visit (Treatment discontinuation)
An end of treatment visit will be performed at the time of treatment discontinuation. The 
following assessments will be performed:
x
AE and concomitant medication review. 
x
ECOG performance status.
x
Full physical examination.
x
Vital signs. 
x
12-lead Electrocardiogram (ECG). 
x
Safety laboratory assessments including haematology, biochemistry, thyroid function 
tests (T3, T4 and TSH) and coagulation (PT/INR and aPTT). 
x
Blood sample for anti-BL-8040 antibodies and complement activation and anti-
Atezolizumab antibodies  
x
Peripheral blood and BM aspirate samples for DNA and RNA for correlative studies 
(optional for Israel).
x
Post-study anticancer therapy status.
5.5
Follow-Up visit
Follow-up is divided into 2 parts:  
x
A safety follow-up for 30 days after treatment discontinuation, or within 7 days prior 
to initiation of a new anti-cancer treatment, whichever comes first. The safety follow-
up period may be extended up to 90 days after the last dose of study drug for any SAEs 
considered reasonable possibly related to BL-8040 and/or Atezolizumab.
x
Long term survival follow-up every 3 months (± 1 month) and up to 5 years. 
During both the survival follow-up, the following assessments will be performed: 
x
Post-study anticancer therapy status
x
Relapse and survival status (patients who discontinue the study for any reason e.g. 
relapse, personal decision.  
5.6
Early Discontinuation Study Visit 
An early discontinuation study visit will be performed for subjects who withdraw from the 
study for the reasons specified in Section 4.5.
All reasons for treatment discontinuation will be documented in the source documents as well 
as in the CRF. Only one reason (the most severe) for early discontinuation should be recorded 
in the CRF. If one of the reasons for discontinuation is an AE, this should be chosen as the 
reason. Every effort should be made to follow-up these subjects for resolution of the AE. 


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This visit may be performed on the same day as an originally scheduled visit or could be 
conducted separately. The data collected at this visit should be as listed in Section 5.6.
5.7
Unscheduled Visit 
An unscheduled visit may be performed at any time during the study at the subject's request or 
as deemed necessary by the Investigator. The date and reason for the unscheduled visit will be 
recorded. AE monitoring and concomitant medication recording will be performed by the 
Investigator. Other procedures and evaluations will be completed as deemed necessary by the 
Investigator and may include (but not be limited to) laboratory safety tests, vital signs and 
physical examination.
5.8
Safety Assessments
Safety assessments will be based on changes from baseline of clinical signs and symptoms 
reported by the subject or observed by the Investigator, including AEs, concomitant medication 
use, treatment compliance, tolerability (e.g., dropouts due to AEs), vital signs, ECGs, physical 
examination and laboratory safety assessments.
5.8.1
Adverse Events (AEs)
Adverse Events will be assessed at all study visits from the date of informed consent and
throughout the entire study until the end of the safety follow up. 
Any new systemic AE that occurs between scheduled assessment visits should be brought to 
the attention of the Investigator and recorded in the subject’s medical file and on the appropriate 
CRF page.
AEs will be reported and graded in accordance with the latest NCI-CTCAE version (currently 
version 4.03) and coded by Data Management using the latest version of MedDRA (currently 
version 19.0) (see Section 7.1 for more details).
5.8.2
Concomitant Medications
Concomitant medication use will be recorded from baseline (visit 2) through all study visits. 
All concomitant medication will be recorded on the CRF including all prescription, over-the-
counter (OTC), herbal supplements, and IV medications and fluids. If changes occur during 
the trial period, documentation of drug dosage, frequency, route, and date should also be 
included in the CRF. 
Vital signs will be measured at the time points indicated in the schedule of assessments (see 
Appendix A). Vital signs will include blood pressure, pulse rate, oral temperature, oxygen 
saturation and respiration rate after at least 5 min rest as per standard practice at the 
investigational site. Significant findings noticed after the start of study drug which meet the 
definition of an AE must be recorded on the AE CRF module.  
5.8.3
Electrocardiogram
Electrocardiograms will be performed at the time points indicated in the schedule of 
assessments (Appendix A). Additional 12-lead ECGs may be performed at the discretion of the 
Investigator or upon Sponsor request. The subject should rest for at least 10 minutes before 
measurements are taken.
ECG printouts will be evaluated by the Investigator or designee, signed and dated and filed in 
the source documentation file. When potentially clinically significant findings are detected by 
the Investigator or designee, a cardiologist should be consulted for a definitive interpretation 
and appropriate treatment, if required. All communications and diagnoses should be filed in 


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the source documentation file and clinically significant findings should be reported within the 
CRF. The Investigator/Investigator’s designee/local cardiologist is responsible for determining 
whether the ECG findings are of clinical significance. All abnormalities will be closely 
monitored until stabilized or resolved. 
5.8.4
Physical Examination 
A full physical examination will be conducted at screening (visit 1), and at the end of treatment 
visit.
Physical examination will include weight measurement, assessment of head, lungs, 
cardiovascular system, abdomen, musculoskeletal system, skin, lymph nodes, neurological 
system and, where appropriate, other body systems as indicated in the study schedule.  
A directed physical examination will be performed on Day 1 of each treatment cycle.
Information about the physical examination must be present in the source documentation at the 
study site. Significant findings that are present prior to the signature of the informed consent 
must be included in the Relevant Medical History/ Current Medical Conditions CRF. 
Significant findings made after the signature of the informed consent which meet the definition 
of an AE must be recorded on the AE CRF module. 
5.8.5
Vital signs
Vital signs will be measured at the time points indicated in the schedule of assessments 
(Appendix A).
Vital signs will include blood pressure, pulse rate, oral temperature, oxygen saturation and 
respiration rate after at least 5 min rest as per standard practice at the investigational site. 
Significant findings noticed after the start of study drug which meet the definition of an AE 
must be recorded on the AE CRF module.  
5.8.6
Laboratory Safety Assessments  
Laboratory safety sampling will include the parameters listed below. The exact time-points for 
each one of the tests are specified in the schedule of assessments (Appendix A). 
Evaluations
Parameters
Hematology
Red blood cell (RBC) count, hemoglobin (HGB), hematocrit (HCT), mean 
cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC), 
mean corpuscular volume (MCV), white blood cell (WBC) count and 
differential (including number of blasts, neutrophils and lymphocytes) and 
platelet count.
Biochemistry Electrolytes: sodium, chloride, potassium, calcium and phosphorus 
Liver function tests: AST (not mandatory and only upon ALT elevation),
ALT, ALP, total bilirubin, direct bilirubin, total protein, albumin  
Kidney function tests: creatinine, BUN  
Other: glucose, uric acid
Coagulation
Pro-thrombin time (PT)/INR and activated partial thromboplastin time 
(aPTT)
Serologya
HIV antibodies (HIV1 and HIV2), Hepatitis B surface antigen (HBsAg) 
and Hepatitis C antibody (Hep C Ab).
Other
Thyroid function tests (T3, T4 and TSH)
a To be collected at screening only.


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Laboratory safety test abnormalities, which arise after study drug administration, will be 
repeated as clinically indicated until the values return to normal or until the etiology has been 
determined and the condition considered stable. Abnormal laboratory test results that are 
considered to be clinically important by the Investigator will be reported as an AE in the AE 
CRF module.  
A laboratory abnormality will not be considered an AE unless: 
x
Intervention is required 
x
Changes in dose are required (decrease, discontinued, interrupted) 
x
Other treatment/therapy is required
x
Associated with other diagnoses 
x
Is considered clinically significant by the investigator
Laboratory results will be reported to the Investigator or designee who will review, sign and 
date abnormal laboratory findings for clinical significance. The Investigator will note any 
laboratory test results of clinical concern or values that were outside normal ranges and provide 
details of the relationship to investigational product and the action taken. If a change in a 
laboratory value represents a medical condition, the medical condition will be listed in the AE 
record. If no correlation is possible, the direction of change (increase or decrease) in addition 
to the actual value will be recorded.
5.8.7
Anti-drug antibody (ADA) Assessment
Blood sampling for assessment of ADA formation and complement activation will be 
performed at the time points indicated in the schedule of assessments (Appendix A).
5.9
Biomarker and Pharmacodynamic Assessments
5.9.1
MRD Status
MRD status will be determined by flow cytometry analysis of BM aspirates collected at the 
time points indicated in the schedule of assessments (Appendix A). MRD assessments will be 
performed at a central laboratory. According to the assay used, any level of detectable MRD is 
considered positive.  
5.9.2
Immuno-phenotyping
Immuno-phenotyping and PD-1/PD-L1 and CXCR4 expression will be performed on 
peripheral blood and BM aspirates collected at the time points indicated in the schedule of 
assessments (Appendix A).  
5.9.3
DNA and RNA Collection
DNA and RNA collection will be performed on peripheral blood and BM aspirates collected 
at the time points indicated in the schedule of assessments (optional for Israel) (Appendix A).
5.9.4
PK Assessments
PK sampling schedule is listed in Appendix B.
PK analysis of BL-8040 will be conducted by BioLineRx using a validated High-Performance
Liquid Chromatography (HPLC) method. Serum concentration of Atezolizumab will be 
analyzed with a validated ELISA assay. 


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5.9.5
Blood Sampling and Processing 
Samples will be collected for safety and efficacy analysis, ADA titers and determination of 
BL-8040 plasma concentrations at the time-points indicated in Appendix A.
Instructions for the collection, processing, storage and shipment of samples are detailed in the 
Laboratory Manual provided by the Sponsor. 
6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Products 
6.1.1
BL-8040 
BL-8040 is a highly selective CXCR4 antagonist co-developed by 
.
and BioLineRx Ltd. as a novel investigational therapy for the treatment of cancer. 
BL-8040 drug product is formulated as a sterile and non-pyrogenic lyophilized powder for 
reconstitution in a vial containing 73mg BL-8040 free base peptide, on dry basis. BL-8040 
administrated SC upon reconstitution with 2mL 0.45% Sodium Chloride for Injection (Half 
Normal Saline). BL-8040 is filled and packed in clear Type I glass vials (DIN 6R) with 20mm 
rubber stoppers and sealed with 20mm aluminum caps.
6.1.2
Atezolizumab
The Atezolizumab drug product will be supplied by the Sponsor in a single-use, 20-mL 
USP/Ph. Eur. Type 1 glass vial as a colorless to slightly yellow, sterile, preservative-free clear 
liquid solution intended for IV administration. The vial is designed to deliver 20 mL (1200 mg) 
of Atezolizumab solution but may contain more than the stated volume to enable delivery of the 
entire 20 mL volume. 
6.2
Study Drug Administration and Dosage
6.2.1
BL-8040 
Subjects will receive once daily SC injections of 1.25 mg/kg of BL-8040 on Days 1, 2 and 3 
of each 21 day-cycle. 
The BL-8040 injection site will be rotated daily, to minimize the severity of local injection site 
reactions. When volume after reconstitution is greater than 2 mL the injection should be split. 
At the discretion of the Investigator, lower volumes may be split and injected into more than 
one site. When the dose is split, the injection should be applied at various parts of the body, 
e.g. arm and leg 
Hematology (CBC) assessment will be performed before each dose of BL-8040. BL-8040 
injections will be skipped in case of a significant increase in WBCs (WBC  /
measured prior to administration of the next BL-8040 injection and/or evidence of leukostasis. 
Dosing will resume when the WBC count is < 60,000/μL measured before administration of 
BL-8040. Missed doses can be skipped until the WBC count has decreased to < 60,000/μL, up 
to 2 cycles. Missed doses will not be made up if > 72 h have passed. If the delay is beyond the 
2 Cycles, the medical monitor should be consulted in order to assess the continuation of the 
study for the specific patient.   Pre-dosing WBC monitoring should continue as long as the 
:%&FRXQWLVȝ/
6.2.2
Atezolizumab
Subjects will receive Atezolizumab 1200 mg IV on Day 2 of every cycle. The first infusion of 
Atezolizumab should be administered over 60 mins. If well tolerated, subsequent infusions 


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may be performed over 30 mins. On Day 2, BL-8040 will be administered 1 h (± 30 min) after 
the end of the Atezolizumab infusion.  
Administration of Atezolizumab will be performed in a monitored setting where there is 
immediate access to trained personnel and adequate equipment and medicine to manage 
potentially serious reactions.  For anaphylaxis precautions, see Appendix F. Atezolizumab
infusions will be administered per the instructions outlined in Table 1.
Table 1
Administration of First and Subsequent Atezolizumab Infusions
First Infusion
Subsequent Infusions
x
No premedication is permitted prior to the 
first Atezolizumab administration.
x
Vital signs (heart rate, respiratory rate, 
blood pressure, and temperature) should 
be recorded within 60 minutes prior to the 
infusion. 
x
Atezolizumab should be infused over 
60 (r 15) minutes. 
x
If clinically indicated, vital signs should 
be recorded during the infusion at 15, 30, 
45, and 60 minutes (r 5 minutes for all 
timepoints) during the infusion and at 
30 (r 10) minutes after the infusion. 
x
Patients should be informed about the 
possibility of delayed post-infusion 
symptoms and instructed to contact their 
study physician if they develop such 
symptoms.
x
If the patient experienced an infusion-
related reaction with any previous 
infusion, premedication with 
antihistamines, antipyretics, and/or 
analgesics may be administered for 
subsequent doses at the discretion of the 
investigator.
x
Vital signs should be recorded within 
60 minutes prior to the infusion. 
x
Atezolizumab should be infused over 
30 (r 10) minutes if the previous 
infusion was tolerated without an 
infusion-related reaction, or 60 (r 15) 
minutes if the patient experienced an 
infusion-related reaction with the 
previous infusion. 
x
If the patient experienced an infusion-
related reaction with the previous 
infusion or if clinically indicated, vital 
signs should be recorded during the 
infusion and at 30 (r 5) minutes after 
the infusion. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration.
Guidelines for medical management of infusion-related reactions (IRRs) are provided in 
Appendix F.
No dose modification for Atezolizumab is allowed. Guidelines for treatment interruption or 
discontinuation are provided in sections 6.2.4-6.2.7. 
6.2.3
Dose Limiting Toxicities
Dose-limiting toxicity (DLT) is defined as a clinically significant AE or abnormal laboratory 
value assessed as unrelated to disease progression, intercurrent illness or concomitant 
medications and occurring during the first treatment cycle that meets any of the following 
criteria (refer to Table 2 for CTCAE severity grading):
x
&7&$(JUDGH$676*27RU$/76*37RUELOLUXELQIRUGD\V
x
CTCAE grade 4 AST (SGOT) or ALT (SGPT) of any duration
x
All other clinically significant, non-hematologic NCI common terminology criteria that 
are CTCAE grade 3 or 4


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x
Change from baseline to Grade 4 neutropenia or thrombocytopenia lasting for >4 weeks 
in the absence of persistent leukemia. 
x
Symptomatic leukostasis
To be considered a DLT the toxicity must be possibly, probably or definitely related to either 
of the study drugs or the combination. 
An AE must be clinically significant to define DLT, e.g., nausea and vomiting, alopecia, study 
drug-related fever or electrolyte DEQRUPDOLWLHVWKDWDUHJUDGHZLOOQRWFRQVWLWXWH'/7For 
subjects who experience a DLT, the study continuation should be discussed with the Medical 
Monitor. Subjects who experience AEs that are not considered DLT or are unrelated to BL-
8040 or Atezolizumab may continue study participation at the discretion of the Investigator. 
BL-8040 injections may be skipped for any reason as per Investigator judgment; however, they 
PXVWEHVNLSSHGLQWKHFDVHRID:%&!ȝ/PHDVXUHGSULRUWRDGPLQLVWUDWLRQRI the 
next BL-8040 injection and/or evidence of leukostasis.  
Increase in WBC is not considered a DLT since it is a direct effect of CXCR4 inhibition and 
reflects the drug’s mechanism of action. 
In case of HOHYDWHG:%&!ȝ/, daily WBC assessment should be done, and BL-8040 
WUHDWPHQWFDQEHUHVXPHGSURYLGHGWKDWWKH:%&FRXQWVGHFUHDVHWRȝ/3UH-dosing 
:%& PRQLWRULQJ VKRXOG FRQWLQXH DV ORQJ DV WKH :%& FRXQW LV ȝ/ )RU YDOXHV
ȝ/GDLO\:%&PRQLWRULQJPD\EHVWRSSHGDQGIXUWKHUanalysis should be done based 
on the Investigator’s judgment.  
6.2.4
BL-8040 Treatment Interruption Rules 
For sXEMHFWVH[SHULHQFLQJJUDGH%/-8040 related toxicity, the study continuation will be 
discussed with a Medical Monitor. Patients who discontinue from a study due to any AE, will 
be followed for until resolution or stabilization of toxicity. Subjects who experience any 
toxicity, which is not related to BL-8040 will be allowed to continue BL-8040 treatment at the 
Investigator's discretion.  
BL-8040 injections will be stopped in case of a persistent, significant increase in WBC (WBC 
μL) measured prior to administration of the next BL-8040 injection and/or evidence 
of leukostasis or grade 3-4 allergic reaction. These subjects will be withdrawn from the study 
and will be followed-up for safety for up to 90 days.  
6.2.5
Atezolizumab Treatment Interruption Rules 
Atezolizumab IV infusions must be withheld in the event of for any of the following events: 
x
Grade 2 pneumonitis  
x
AST or ALT > DQG 5 times ULN, or total bilirubin > DQG 3 times ULN
x
Grade 2 or 3 diarrhea or colitis 
x
Symptomatic hypophysitis, adrenal insufficiency, hypothyroidism, hyperthyroidism, or 
grade 3 or 4 hyperglycemia 
x
Grade 2 ocular inflammatory toxicity 
x
Grade 2 or 3 pancreatitis, or grade 3 or 4 increases in amylase or lipase levels (> 2 times 
ULN) 
x
Grade 3 or 4 infection  
x
Grade 2 infusion-related reactions
x
Grade 3 rash.  
x
Grade 2 Immune related myocarditis and neuropathy 


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6.2.6
Atezolizumab Re-introduction
Atezolizumab IV infusions may be resumed in patients whose AEs recover to grade .  
6.2.7
Permanent Discontinuation of Atezolizumab
Atezolizumab IV infusions must be permanently discontinued in the event of any of the 
following events: 
x
Grade 3 or 4 pneumonitis 
x
AST or ALT > 5 times ULN or total bilirubin > 3 times ULN 
x
Grade 4 diarrhea or colitis  
x
Grade 4 hypophysitis  
x
Myasthenic syndrome/myasthenia gravis, Guillain-Barré, or meningoencephalitis (all 
grades)
x
Grade 3 or 4 ocular inflammatory toxicity
x
Grade 4 or any grade of recurrent pancreatitis 
x
Grade 3 or 4 infusion-related reactions 
x
Grade 4 rash 
x
Grade 3 or 4 Immune related myocarditis and neuropathy
6.2.8
Atezolizumab Dose Reduction
No Atezolizumab dose reductions are recommended.
6.2.9
Rescue medication
Rescue medication regimens will be applied according to the respective clinical conditions at 
the discretion of the Investigator. 
6.3
Manufacturing of Study Medication
6.3.1 BL-8040 
BL-8040 drug substance (4F-benzoyl-TN14003 peptide) is a white or off-white powder 
synthetic polypeptide, freely soluble in water and in 0.45% Sodium Chloride (half normal 
saline). It is manufactured in accordance with current good manufacturing practice (cGMP) 
requirements by 
Reconstitution and administration instructions will be provided in the Pharmacy Manual. 
6.3.2 Atezolizumab
The Atezolizumab drug product is provided in a single-use, 20-cc USP or European 
Pharmacopoeia Type 1 glass vial as a colorless-to-slightly-yellow, sterile, preservative-free 
clear liquid solution intended for IV administration. Atezolizumab must be refrigerated at 
&í&)í)XSRQUHFHLSWXQWLOXVHAtezolizumab vials should not be used beyond 
the expiration date provided by the manufacturer. No preservative is used in the 
Atezolizumab drug product; therefore, each vial is intended for single use only. Vial contents 
should not be frozen or shaken and should be protected from direct sunlight.  
6.4
Packaging and Labeling of Study Medication 
6.4.1
BL-8040 
The study drug is packaged in a USP Type 1 clear glass, single-use, 6 mL vial. The packaging 
and labeling will be performed by: 




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documentation of study drug distribution will be maintained by the pharmacy and the study 
staff of the investigational site which may include confirmation of receipts of clinical supply, 
drug accountability logs and other forms.  
The medical center pharmacist (or authorized study team member responsible for the 
investigational medicinal product) is responsible for ensuring the supervision of the storage 
and allocation of these supplies, which will be forwarded to the Investigator at the appropriate 
time before administration. The Investigator may dispense investigational drug only to subjects 
enrolled in the study.  
Drug accountability records must be maintained by the clinical investigation site at all times. 
At the last study visit, all used and unused investigational drug will be collected and drug 
accountability performed by the study staff.  The study monitor will check these regularly 
during monitoring visits.  
The subject number, the date, batch number/pack number and quantity of study drug used by 
the subject will be checked for correctness and recorded on the appropriate accountability 
forms. Unused drug supplies will be returned to the Sponsor. At the end of the study, all clinical 
supplies and the corresponding accountability forms must be returned to the Sponsor, the study 
monitor, or designee for reconciliation or destruction. A photocopy of these records must be 
kept at the clinical investigation site.
The inventory will be made available to the study monitor who will verify accountability and 
verify dose during the course of the study. 
Study drug orders, records of study drug receipts, dispensing records and inventory forms 
located at the site will be examined and reconciled by the study monitor periodically during 
and at the end of the study.   
Compliance: 
For subjects that will have to skip two consecutive cycles due to any reason the decision to 
continue the participation in the study should be discussed with the Medical Monitor. 
6.8
Concomitant Therapy
At the screening visit, relevant treatments currently received by the subject will be recorded in 
the subject’s CRF including treatment's name, indication, dose, total daily dose and start and 
stop dates.   
Any medications (including prescription, over-the-counter, herbal supplements and other 
health store-type products) to be taken during the study must be approved by the Investigator.  
All concomitant medications received within 30 days prior to the screening visit and 30 days 
after the last dose of trial treatment should be recorded. The following information should be 
recorded: treatment's name (generic, if possible), indication, dose and start and stop dates. All 
concomitant medication will be recorded on the CRF including all prescription, over-the-
counter (OTC), herbal supplements, and IV medications and fluids. If changes occur during 
the trial period, documentation of drug dosage, frequency, route, and date should also be 
included in the CRF. All treatments that the Investigator considers necessary for a subject’s 
welfare may be administered at the discretion of the Investigator in keeping with the 
community standards of medical care. Concomitant medications administered more than 30 
days after the last dose of trial treatment should be recorded when related to SAEs.
Transient hypotension was witnessed in several cases following the initial treatment with BL-
8040.  Therefore, caution should be taken with the use of negative chronotropic drugs such as 


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beta blockers. When appropriate, beta blocker should be replaced by non-negative chronotropic 
alternatives. 
6.8.1
BL-8040 Adverse Event Management: 
x
Premedication prior to BL-8040 injection with antihistamines (e.g. diphenhydramine, 
promethazine, etc.) in order to minimize the occurrence of BL-8040 related systemic 
reactions is highly recommended.  
x
Systemic steroids are allowed for the treatment of systemic reaction but not as regular 
pre-medication of these reactions.  
x
Clinically appropriate measures in case of BL-8040-related local injection site 
reactions e.g., local corticosteroids, systemic and local painkillers, antihistamines, local 
treatments etc.
6.8.2
Permitted Concomitant Medications
The following concomitant medications/therapies will be allowed during the treatment period:
x
Antiemetic drugs (e.g., Ondansetron) as required clinically based on local guidelines 
for subjects experiencing nausea.
x
Prophylactic antibiotics (e.g., quinolone or cephalosporin), anti-fungals (e.g., 
voriconazole) and antivirals (e.g., valacyclovir) when appropriate. 
x
Blood products, commonly required in oncology subjects. 
x
Low-dose steroids are allowed as pre-medication for blood transfusion or with IV 
anti-fungals.
x
Vitamins, nutritional supplements, herbal supplements and over the counter 
medications are permitted per PI’s judgement. 
x
Vitamin D therapy.
x
Polyphenols in green tea/supplements. 
Additional medications/therapies to manage treatment or disease emergent conditions will be 
allowed at the discretion of the Investigator in consultation with the Sponsor, in advance when 
possible. In case there is a change in therapy related to an AE, the Sponsor or Investigator may 
decide to withdraw the subject (refer to Section 4.6).
6.8.3
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the screening period and 
treatment phase of this trial:
x
Other treatment for their AML
x
Antineoplastic systemic chemotherapy or biological therapy.
x
Immunotherapy or other therapy not specified in this protocol. 
x
Investigational agents other than BL-8040 and Atezolizumab. 
x
Lodonal 
x
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial and 5 months after the last dose of Atezolizumab. Examples 
of live vaccines include, but are not limited to, the following: measles, mumps, rubella,
chickenpox, yellow fever, BCG, and typhoid (oral) vaccine. Seasonal influenza 
vaccines for injection are generally killed virus and are allowed. However, intranasal 


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influenza vaccines (e.g. Flu - Mist®) are live attenuated vaccines and are not allowed.
No live attenuated vaccines can be given up to 5 months post last dose. 
x
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of suspected immunologic etiology or for systemic and local reactions secondary 
to BL-8040 and/or Atezolizumab treatment. The use of physiologic doses of 
corticosteroids 
may 
be 
approved 
after 
consultation 
with 
the 
Sponsor. 
Note: Inhaled steroids are allowed for management of asthma, and dermatological 
formulations are allowed to reduce the intensity of injection site reactions.
x
Medications or vaccinations specifically prohibited in the Exclusion Criteria are not 
allowed during the ongoing trial. If there is a clinical indication for any medication or 
vaccination specifically prohibited during the trial, discontinuation of trial therapy may 
be required. The Investigator should discuss any questions regarding this with the 
Sponsor’s Medical Monitor. The final decision on any supportive therapy or 
vaccination rests with the Investigator and/or the subject's primary physician. 
However, the decision to continue the subject’s trial therapy requires the mutual 
agreement of the Investigator, the Sponsor, and the subject. 
Subjects who, in the assessment of the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
7
SAFETY AND PHARMACOVIGILANCE
7.1
Adverse Event (AE)
An AE is defined in ICH E6 as “any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.” 
An abnormal result of diagnostic procedures including abnormal laboratory findings will be 
considered an AE if it fulfills one or more of the following:  
x
Results in subject's withdrawal by the Investigator
x
Is associated with an SAE
x
Is associated with clinical signs or symptoms
x
Is considered by the physician to be of clinical significance
x
A new condition or the worsening of a pre-existing condition will be considered an AE. 
x
AEs do not include the following: 
x
Medical/surgical procedures are not AEs (e.g., surgery, endoscopy, tooth extraction, 
transfusion). The condition that leads to the procedure is an AE if the procedure was 
not planned at screening visit.
x
Overdose of concomitant medication without any signs or symptoms unless the subject 
is hospitalized for observation.  
x
Hospitalization for elective surgery planned prior to study (situation where an untoward 
medical occurrence has not occurred). 
x
Disease progression


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All AEs, whether observed by the Investigator or designee or volunteered by or elicited from 
the subject, should be recorded individually on an AE CRF page with the following 
information: the specific event or condition, whether the event was present pre-baseline or not, 
the dates and times (using the 24 hour clock, where midnight is 00:00 and noon is 12:00) of 
occurrence, duration, severity, relationship to study medication, action taken to study drug, 
outcome, and whether considered non-serious or serious, drug-related or not.
Once the subject has signed the Informed Consent Form (ICF), AEs will be recorded until the 
end of the Follow-up period. The severity of the AE will be assessed by the investigating 
physician in accordance with the definitions below. A Serious AE must fulfill the requirements 
listed in Section 7.2.
Adverse Event severity (Table 2) will be recorded and graded according to the latest version 
of the NCI-CTCAE (currently version 4.03) and coded into the database according to the latest 
version of MedDRA (currently version 19.0). 
Table 2
Severity of Adverse Events According to CTCAE (Version 4.03)
Grade
Description
0
No AE or within normal limits
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL)
3
Severe or medically significant but
not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL
4
Life-threatening consequences; urgent intervention indicated
5
Death related to AE
A semi-colon indicates ‘or’ within the description of the grade. 
A single dash (-) indicates a grade is not available
The following definitions should be used for toxicities/AEs that are not defined in the CTCAE:
x
Mild (Grade 1): The AE is noticeable to the subject but does not interfere with routine 
activity, no medical intervention is required;   
x
Moderate (Grade 2): The AE interferes with routine activity but responds to 
symptomatic therapy or rest;
x
Severe (Grade 3): The AE significantly limits the subject’s ability to perform routine
activities despite symptomatic therapy;
x
Life-threatening (Grade 4): The subject is at immediate risk of death.
The Investigator will document his opinion of the relationship of the AE to treatment with 
investigational product using the criteria outlined in Table 3.
Outcome to Date are classified as follows:
x
Recovered: The subject has fully recovered from the AE with no residual effects 
observable 
x
Recovered with sequelae: The subject has recovered from the AE with residual effects 
observable 
x
Improved: the subject status improved but has not been fully recovered 


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x
Ongoing: AE is not recovered 
x
Fatal
x
Unknown 
AEs will be coded by Data Management using the latest version of MedDRA (currently version 
19.0) AE dictionary. 
All AEs, serious and not serious, will be recorded on the AE Case Report Form, and if relevant, 
the Concomitant Medications Record in the CRF will be updated. Severity and relationship to 
study drug will be assessed by the Investigator as described in Table 3. Particular attention 
should be made to ensure no discrepancies between the AE and the SAE form (i.e. outcome, 
severity, relationship must be consistent).   
Treatment emergent AEs (TEAEs) are defined as AEs observed after 1st dose of study drug.
Table 3
Relationship of Adverse Event to Treatment
Term
Definition
Clarification
No 
reasonable 
possibility
(not 
related)
This category applies to 
adverse events which, after 
careful consideration, are 
clearly due to extraneous 
causes (disease, 
environment, etc.) or to 
adverse events, which, after 
careful medical 
consideration at the time 
they are evaluated, are 
judged to be unrelated to the 
study drug. 
The relationship of an adverse event may be 
considered “no reasonable possibility” if it is 
clearly due to extraneous causes or if at least 
2 of the following apply: 
x
It does not follow a reasonable temporal 
sequence from the administration of the 
test drug. 
x
It could readily have been produced by 
the patient’s clinical state, environmental 
or toxic factors, or other modes of 
therapy administered to the patient.
x
It does not follow a known pattern of 
response to the test drug.  
x
It does not reappear or worsen when the 
drug is re-administered.
Reasonable 
possibility
(related)
This category applies to 
adverse events for which, 
after careful medical 
consideration at the time 
they are evaluated, a 
connection with the test drug 
administration cannot be 
ruled out with certainty nor 
felt with a high degree of 
certainty to be related to the 
study drug. 
The relationship of an adverse event may be 
considered “reasonable possibility” if at least 
2 of the following apply: 
x
It follows a reasonable temporal sequence 
from administration of the drug. 
x
It cannot be reasonably explained by the 
known characteristics of the patient’s 
clinical state, environmental or toxic 
factors, or other modes of therapy 
administered to the patient.
x
It disappears or decreases on cessation or 
reduction in dose. There are important 
exceptions when an adverse event does 
not disappear upon discontinuation of the 
drug, yet drug-relatedness clearly exists.
x
It follows a known pattern of response to 
the test drug.


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7.2
Serious Adverse Events (SAEs)
An SAE is any AE occurring at any dose that suggest a significant hazard or side effect, 
regardless of the Investigator or Sponsor's opinion on the relationship to the investigational 
medicinal product and that results in, but may not be limited to, any of the following outcomes:
x
death (regardless of the cause)
x
a life-threatening experience
x
inpatient hospitalization or prolongation of existing hospitalization (any inpatient 
hospital admission that includes a minimum of an overnight stay in a health care 
facility) 
x
a persistent or significant disability/incapacity
x
a congenital anomaly or birth defect
x
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be serious when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed above. 
Inpatient hospitalization or prolongation of existing hospitalization means that hospital 
inpatient admission and/or prolongation of hospital stay were required for treatment of AE, or 
that they occurred as a consequence of the event.
Hospitalization for elective treatment of a pre-study condition (pre-baseline) that did not 
worsen while on study and optional hospitalizations not associated with a clinical AE (e.g. 
elective cosmetic surgery) are not considered SAEs. 
Significant medical events are those which may not be immediately life-threatening, but may 
jeopardize the subject and may require intervention to prevent one of the other serious 
outcomes listed above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization; such an AE will normally be considered serious by this criterion. 
A life-threatening adverse drug experience is any AE that places the subject, in the view of
the Investigator, at immediate risk of death from the reaction as it occurred, i.e., it does not 
include a reaction that, had it occurred in a more severe form, might have caused death.  
Any newly emergent SAEs, after treatment is discontinued or the subject has completed the 
study and is considered to be related to the study drug or study participation, should be recorded 
and reported immediately to Sponsor or delegate.   
7.3
Definition of an Unexpected Adverse Event
An unexpected adverse drug event is any AE, the specificity or severity of which is not 
consistent with information in the current Investigator’s Brochure for an unapproved 
investigational product. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) is a SAE assessed as unexpected 
by the Sponsor and that is judged by either the reporting Investigator or the Sponsor to have a 
reasonable causal relationship to the investigational medicinal product. 
7.4
Exceptions in the Reporting of SAE
According to EU and FDA detailed guidance on the collection, verification and presentation of 
adverse reaction reports arising from clinical trials on medicinal products for human use, 
regarding clinical trials in high morbidity or mortality diseases, it is acceptable to define some 
exceptions in the immediate reporting of specific SAEs. Refer to EU guidance ENTR/CT3, 




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As for the initial SAE report, once sent, the Follow-up SAE report and accompanying 
documentation should be placed in the SAE section of the Investigator’s site file.  
7.6
Adverse Events Associated with an Overdose or Error in Drug Administration
An overdose is the accidental or intentional use of a drug in an amount higher than the dose 
being studied.  An overdose or incorrect administration of study treatment is not itself an 
adverse event, but it may result in an adverse event.  All adverse events associated with an 
overdose or incorrect administration of study treatment should be recorded on the Adverse 
Event eCRF.  If the associated adverse event fulfills seriousness criteria, the event should be 
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 7.5). No safety data related to overdosing of Atezolizumab or BL-8040 are 
available.  
7.7
Guidelines for Management of Patients Who Experience Specific Adverse Events 
while being treated by Atezolizumab  BL-8040 
Guidelines for the management of patients who experience specific adverse events are provided 
in the Atezolizumab Investigator's Brochure, Appendix I and are outlined below: 
•
The Atezolizumab Investigator's Brochure and Appendix I provides guidelines for the 
management of patients who experience Atezolizumab-associated IRRs and immune-related 
pulmonary, hepatic, gastrointestinal, endocrine, ocular, pancreatic, dermatologic, neurologic, 
and meningoencephalitis events.  It is recommended that Atezolizumab be withheld or 
discontinued per the guidelines in the Atezolizumab Investigator's Brochure and that BL-8040 
be withheld or discontinued per the guidelines in this section.
•
For cases in which management guidelines are not covered in this section, Appendix I
or the Atezolizumab Investigator's Brochure, patients should be managed, and treatments 
should be withheld or discontinued as deemed appropriate by the investigator according to best 
medical judgment.
Event
Action to Be Taken
IRRs and anaphylaxis
x Guidelines for management of IRRs are provided in the 
Atezolizumab Investigator's Brochure for Atezolizumab.
x For anaphylaxis precautions, see Appendix F. 
x For severe hypersensitivity reactions, permanently 
discontinue Atezolizumab and BL-8040. 
Injection-site reactions
x Clinically appropriate measures (according to 
institutional guidelines) should be considered in case of 
BL-8040related local reactions at the injection site 
(e.g., local treatments with steroids and or 
antihistamines) or systemic reactions (e.g., systemic 
antihistamines and steroids) or for preventive treatment 
before subsequent doses. 
Overdose of BL-8040
(dose t 3.75 mg/kg) 
x Observe patient for any signs of toxicity and provide 
appropriate supportive treatment as indicated.
x Patients with low blood counts should have blood counts 
monitored until recovery.  
Pulmonary events


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Event
Action to Be Taken
Pulmonary event, Grade 1
x Follow guidelines provided in the Atezolizumab
Investigator's Brochure. 
x Continue BL-8040. 
x For recurrent pneumonitis, treat as a Grade 3 or 4 event. 
Pulmonary event, Grade 2
x Follow guidelines provided in the Atezolizumab
Investigator's Brochure. 
x Withhold BL-8040.
x Monitor WBC count. 
x If event resolves to Grade 1 or better and WBC count is 
d 60 u 109/L (60,000/PL) within 21 days, resume BL-
8040.  If not, permanently discontinue BL-8040. 
x For recurrent events, treat as a Grade 3 or 4 event.
Pulmonary event, Grade 3 or 
4
x Follow guidelines provided in the Atezolizumab
Investigator's Brochure. 
x Permanently discontinue BL-8040. 
Gastrointestinal toxicity
Diarrhea or colitis, Grade 1
x Follow guidelines provided in the Atezolizumab
Investigator's Brochure. 
x Continue BL-8040. 
Diarrhea or colitis, Grade 2 
or 3
x Follow guidelines provided in the Atezolizumab
Investigator's Brochure. 
x Withhold BL-8040. 
x If event resolves to Grade 1 or better within 21 days, 
resume BL-8040.  If not, permanently discontinue BL-
8040.
Diarrhea or colitis, Grade 4
x Follow guidelines provided in the Atezolizumab
Investigator's Brochure. 
x Permanently discontinue BL-8040. 
Dermatologic toxicity
Rash, Grade 1 or 2
x Follow guidelines provided in the Atezolizumab
Investigator's Brochure. 
x Continue BL-8040. 
Rash, Grade 3
x Follow guidelines provided in the Atezolizumab
Investigator's Brochure. 
x Withhold BL-8040. 
x If event resolves to Grade 1 or better within 21 days, 
resume BL-8040.  If not, permanently discontinue BL-
8040.
Rash, Grade 4
x Follow guidelines provided in the Atezolizumab
Investigator's Brochure. 
x Permanently discontinue BL-8040. 
Leukostasis


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Event
Action to Be Taken
Clinical evidence of 
leukostasis or WBC count 
! 60 u 109/L (60,000/PL)
x Withhold BL-8040 and Atezolizumab.
x Consider leukapheresis.
x At the discretion of the investigator and according to 
each site’s institutional guidelines the patients may be 
treated with chemotherapy, leukapheresis, hydroxyurea 
or any other treatment accepted at the specific site.
x Monitor patients with shortness of breath and administer 
oxygen to patients with reduced oxygen saturation.   
x Monitor WBC count daily.
x If WBC count improves to d 60 u 109/L (60,000/PL) and 
there are no signs of leukostasis within 21 days, resume 
BL-8040.  If not, permanently discontinue BL-8040. 
x Monitor WBC count prior to dosing at least until WBC 
count has recovered to t 40 u 109/L (40,000/PL).
BL-8040related toxicities not described above
Grade 3
x Withhold BL-8040.  Continue Atezolizumab.
x If event resolves to Grade 2 within 21 days and Medical 
Monitor agrees that BL-8040 should be continued, 
resume BL-8040 with a different schedule of SC 
injections.  If not, permanently discontinue BL-8040. 
x If event resolves to Grade 1 or better within 21 days, 
resume BL-8040.  If not, permanently discontinue 
BL-8040. 
BL-8040related toxicities not described above
Grade 4
x Withhold BL-8040 and Atezolizumab.
x If event resolves to Grade 2 or better within 21 days and 
Medical Monitor agrees that BL-8040 should be 
continued, resume BL-8040 with a different schedule of 
SC injections.  If not, permanently discontinue BL-8040. 
x If event improves and Medical Monitor agrees that 
Atezolizumab should be continued, resume 
Atezolizumab.  If not, permanently discontinue 
Atezolizumab. 
Atezolizumab-related toxicities not described above
Grade 3
x Follow guidelines provided in the Atezolizumab
Investigator's Brochure. 
x Withhold BL-8040. 
x If event resolves to Grade 2 within 21 days and Medical 
Monitor agrees that BL-8040 should be continued, 
resume BL-8040 with a different schedule of SC 
injections.  If not, permanently discontinue BL-8040. 
x If event resolves to Grade 1 or better within 21 days, 
resume BL-8040.  If not, permanently discontinue 
BL-8040. 


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Event
Action to Be Taken
Grade 4
x Follow guidelines provided in the Atezolizumab
Investigator's Brochure. 
x Withhold BL-8040. 
x If event resolves to Grade 2 or better within 21 days and 
Medical Monitor agrees that BL-8040 should be 
continued, resume BL-8040 with a different schedule of 
SC injections.  If not, permanently discontinue BL-8040. 
BAL = bronchoscopic alveolar lavage; IVIG = intravenous immunoglobulin 
a ,IFRUWLFRVWHURLGVKDYHEHHQLQLWLDWHGWKH\PXVWEHWDSHUHGRYHUPRQWKWRPJGD\RUDOSrednisone or 
equivalent before Atezolizumab can be resumed. 
b Atezolizumab may be withheld for a period of time beyond 12 weeks to allow for corticosteroids to be reduced 
WRPJGD\RUDOSUHGQLVRQHRUHTXLYDOHQW7KHDFFHSWDEOHOHQJWKRIWKHH[WHQGHGSHULRGRIWLPHPXVWEH
agreed upon by the investigator and the Medical Monitor. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and have fully recovered 
from the immune-related event. Patients can be rechallenged with Atezolizumab only after approval has been 
documented by both the investigator (or an appropriate delegate) and the Medical Monitor.
7.8
Injection-Related Reactions
Adverse events that occur during or within 24 hours after study treatment administration and 
are judged to be related to study treatment injection should be captured as a diagnosis (e.g., 
"injection-related reaction") on the Adverse Event eCRF. If possible, avoid ambiguous terms 
such as "systemic reaction." Associated signs and symptoms should be recorded on the 
dedicated Injection-Related Reaction eCRF. Separation should be made between “injection 
site reaction” and “systemic reaction”. If a patient experiences both a local and systemic 
reaction to the same dose of study treatment, each reaction should be recorded separately on 
the Adverse Event eCRF, with signs and symptoms also recorded separately on the dedicated 
Injection-Related Reaction eCRF.
8
STATISTICAL METHODOLOGY  
This section describes the statistical methods that will be used to analyze data from the 
BATTLE study. A more detailed SAP will be developed following the recruitment of the 20th
subject and the receipt of study database. Should the methods of the SAP differ from the 
methods in this section, the methods of the SAP will prevail. 
8.1
Analysis Sets 
x
Intention-To-Treat (ITT) Analysis Set: All enrolled subjects. 
x
Modified Intention-To-Treat (mITT) Analysis Set: Enrolled subjects who were treated at least once
with both BL-8040 and with Atezolizumab. 
8.2
Sample Size Justification
The planned sample size of 60 subjects is considered clinically appropriate for further 
characterization of the safety, tolerability and preliminary efficacy of the proposed combination 
therapy in subjects with Acute Myeloid Leukemia.
8.3
Significance Level and Multiplicity Adjustment
The overall alpha level for this study is 
. Confidence interval will be calculated for the 
efficacy endpoint in order to potentially explore the effectiveness of the proposed combination 
therapy: 1-sided 95% VI's for survival analysis derived metrics and 2-sided 95% CI's for 
change from baseline. 


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8.4
Efficacy Endpoints and Analyses 
All efficacy endpoints are secondary and exploratory endpoints. 
8.4.1
Relapse Free Survival as a Secondary Endpoint
The time from CR to occurrence of earlier relapse or death from any cause (RFS). In case of 
death following relapse, the relapse will be considered as study event. Subjects who were lost 
to follow-up for whatever reason and the attempt to obtain missing data on deaths/relapses 
failed will be right censored at the time of early study discontinuation. 
This endpoint will be presented using a Kaplan-Meier plot and a 1-sided lower 95% CI for the 
observed median time to event [
] will be calculated. 
Any estimate quoted from the Kaplan-Meier plot will have the estimate and the standard error 
(SE) of the estimate provided.  Greenwood’s formula will be used to calculate the SE.
8.4.2
Changes in MRD status, measured from baseline to Cycles 3, 9, 18 and 34 using 
quantitative multi-color flow cytometry
A repeated measures model (
) 
including the categorical month in trial and baseline MRD status as one degree of freedom 
covariate and an unstructured covariance matrix for repeated observations within subjects will 
be used.  
To drive the Least Square Means (LSM) of the changes from baseline to each time point and 
two-sided 95% confidence interval.  
8.4.3
Overall Survival (OS), measured as time from 1st study drug administration to 
death from any cause 
Subjects not known to have died at last follow-up will be right-censored on the date they were 
last known to be alive. 
This endpoint will be presented using a Kaplan-Meier plot and a 1-sided lower 95% CI for the 
observed median to event [
] will be calculated.  
Any estimate quoted from the Kaplan-Meier plot will have the estimate and the standard error 
(SE) of the estimate provided.  Greenwood’s formula will be used to calculate the SE.
8.4.4
Event Free Survival (EFS), measured as the earlier from 1st study drug 
administration to the date of primary refractory disease, or relapse from CR, or 
death from any cause from 1st study drug administration 
Subjects not known to have any of these events will be right-censored on the date they were 
last examined.
This endpoint will be presented using a Kaplan-Meier plot and a 1-sided lower 95% CI for the 
observed median time to event [
] will be calculated.  
Any estimate quoted from the Kaplan-Meier plot will have the estimate and the standard error 
(SE) of the estimate provided.  Greenwood’s formula will be used to calculate the SE. 
8.5
Safety and Tolerability Analyses  
All safety assessments will use the ITT and mITT analyses sets. 


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8.5.1
Adverse Events
Adverse events will be recorded from the time a subject has signed the Informed Consent Form. 
The MedDRA dictionary will be used to standardize the terms used by the investigator to 
describe the Adverse Events (AEs). Adverse events analyses will include only the Treatment 
Emergent Adverse Events (TEAEs), namely, those events which started at the time of first 
study IP administration or afterwards.
The following analyses are pre-planned for adverse events:
x
The incidence (no. of patients) and frequency (no. of events) of most frequent TEAEs 
(>5%) by Preferred Term (PT).
x
The incidence (no. of patients) and frequency (no. of events) of TEAEs broken down 
by System Organ Class (SOC) and PT.
x
The incidence (no. of patients) and frequency (no. of events) of TEAEs broken down 
by SOC, High Level Term (HLT) and PT.
x
The incidence (no. of patients) and frequency (no. of events) of TEAEs by SOC and PT 
in Subjects Early Discontinued from Study/Treatment.
x
The incidence (no. of patients) and frequency (no. of events) of serious TEAEs by SOC 
and PT.
x
The incidence (no. of patients) and frequency (no. of events) of serious TEAEs by SOC, 
HLT and PT.
x
The incidence (no. of patients) and frequency (no. of events) of TEAEs when broken 
down by severity.
x
The incidence (no. of patients) and frequency (no. of events) of injection site reactions 
TEAEs.
x
The incidence (no. of patients) and frequency (no. of events) of TEAEs broken down 
by relationship to study IMP.
x
The incidence (no. of patients) and frequency (no. of events) of TEAEs when broken 
down by action taken with study IMP. 
x
The incidence (no. of patients) and frequency (no. of events) of TEAEs when broken 
down by event outcome.
Adverse Events dictionary used to code Investigator’s verbatim terms will be provided. 
Individual subject listings of all SAEs, treatment emergent SAEs, TEAEs and non-TEAEs.
8.5.2
Dose-Limiting-Toxicity Assessment
Dose-limiting toxicity (DLT) is defined as a clinically significant adverse event (AE) or 
abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness or 
concomitant medications and occurring during the first treatment cycle that meets any of the 
following criteria (refer to Table 2 for CTCAE severity grading):
x
&7&$(JUDGH$676*27RU$/76*37RUELOLUXELQIRUGD\V
x
CTCAE grade 4 AST (SGOT) or ALT (SGPT) of any duration
x
All other clinically significant, non-hematological NCI common terminology criteria 
that are CTCAE grade 3 or 4
x
Change from baseline to Grade 4 neutropenia or thrombocytopenia lasting for >4 weeks 
in the absence of persistent Leukemia. 
x
Symptomatic leukostasis
To be considered a DLT the toxicity must be possibly, probably or definitely related to either 
of the study drugs or the combination. 


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An AE must be clinically significant to define DLT, e.g., nausea and vomiting, alopecia, study 
drug-UHODWHGIHYHURUHOHFWURO\WHDEQRUPDOLWLHVWKDWDUHJUDGHZLOOQRWFRQVWLWXWH'/7For 
subjects who experience a DLT, the study continuation should be discussed with the Medical 
Monitor. Subjects who experience AEs that are not considered DLT or are unrelated to BL-
8040 or Atezolizumab may continue study participation at the discretion of the Investigator.
BL-8040 injections may be skipped for any reason as per Investigator judgment; however, they 
PXVWEHVNLSSHGLQWKHFDVHRID:%&!ȝ/PHDVXUHGSULRUWRDGPLQLVWUDWLRQRIWKH
next BL-8040 injection and/or evidence of leukostasis.  
Increase in WBCs will not be considered as a DLT since is a direct effect of CXCR4 inhibition 
and reflects the drug’s mechanism of action.  
In case of HOHYDWHG:%&!ȝ/, daily WBC assessment should be done, and BL-8040 
WUHDWPHQWFDQEHUHVXPHGSURYLGHGWKDWWKH:%&FRXQWVGHFUHDVHWRȝ/3UH-dosing 
:%& PRQLWRULQJ VKRXOG FRQWLQXH DV ORQJ DV WKH :%& FRXQW LV ȝ/ )RU YDOXHV
ȝ/GDLO\:%&PRQLWRULQJPDy be stopped and further analysis should be done based 
on the Investigator’s judgment. 
Safety review of the accumulated data will be performed by an independent DMC after the first 
6 subjects have completed the first cycle of combination therapy and again after 6 additional 
subjects have completed the first cycle of combination therapy. The number of active subjects 
in the DLT assessment period will not exceed the potential for observing that the combination 
would be considered unacceptably toxic according to the criteria above. The DMC will 
evaluate the safety data of the first 6 subjects and further after the first 12 subjects if needed. 
In case 5 out of the 6 of the first patients do not experience a DLT the recruitment will not stop 
(as two DLT in the first 6 patients will not have been reached) and the DMC will review the 
safety data without stopping recruitment. In case of expansion of the Safety DLT Cohort to 12 
patients, the same rules will apply. In case we have > 1 DLT out of 5 patients (or >3 out of 11), 
they study recruitment will stop for DMC assessment and recommendations before study 
continuation. In order to be evaluable for the DLT assessment period, a subject must complete 
the first cycle of treatment. If a subject is discontinued before completion of the first cycle 
(unless due to a DLT), an additional subject will be recruited and included in the Safety DLT 
Cohort to ensure a total of six evaluable subjects. Similar rules will be applied in case the Safety 
DLT Cohort is expanded to 12 subjects. The subjects that are discontinued early will be 
included in all the other relevant analyses according to the population described in the statistical 
analysis section.
DMC recommendations will thereafter be presented to the Sponsor. The guidelines to be used 
by the DMC for the review of the Safety DLT Cohort are presented below: 
x
If  out of 6 subjects experience a DLT during the first cycle of treatment, the 
combination treatment will be considered as eligible for further evaluation and 
recruitment will continue without a pause.   
x
,IRXWRIVXEMHFWVH[SHULHQFHD'/7WKH'0&ZLOODVVHVVWKHULVNEHQHILWSURILOH
of the combination treatment and recommend one or more of the following: 1) Safety 
DLT Cohort should be expanded to 12 subjects, 2) the protocol should be modified, 3) 
the treatment schedule should be changed, or 4) the study should be discontinued. 
x
If  2 out of 12 subjects experience a DLT in the expanded Safety DLT Cohort, 
recruitment will continue to the full proposed study size.   
x
If >2 out of 12 subjects experience a DLT in the expanded Safety DLT Cohort, the 
DMC will determine whether recruitment will be stopped, or recruitment can be 
continued with or without a protocol modification. 


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8.5.3
Safety Laboratory Data 
Analyses of safety central laboratory data will be performed in the following manner: 
x
Quantitative laboratory measurements will be categorized with reference to the normal 
ranges as Low, Normal or High. The incidence (no. of subjects) of abnormal values at 
any time post initiation of the 1st study IMP administration, calculated for subjects with 
normal values at baseline will be provided. Analysis will include, per tested parameter, 
those subjects with normal baseline and at least one post-treatment measurement. 
Summary table will display the number and relative percentage of subjects with at least 
one abnormal value (above upper or below the lower normal range) at any time post 
initiation of the 1st study IMP administration.
x
Quantitative laboratory measurements will be categorized with reference to the normal 
ranges as Low, Normal or High. Shift analysis of the categorical change from baseline 
to each scheduled visit and to the last observed value will be provided. 
x
Box-Plots of measurements done and figures of mean values ±SEs as well as descriptive 
statistics for all laboratory quantitative parameters and changes from baseline will be 
provided by scheduled visits.  
8.5.4
Vital Signs
Analyses of vital signs data will be performed in the following manner: 
x
The more detailed SAP will provide the quantitative criteria used to define the 
potentially clinically significant (PCS) abnormal vital signs values. Measurements to 
be used in the analysis are those taken immediately following the first administration 
of the study IMP and onwards. The incidence tables of PCS values as well as the 
individual subject listing will be provided. The denominator to be used for calculating 
percentages is the number of subjects with at least one observation post 1st study IMP
administration.
x
Box-Plots of measurements done, figures of mean values ±SEs as well as descriptive 
statistics for all parameters and changes from baseline (derived) will be provided by 
scheduled visits and treatment groups.  
8.5.5
Physical Examinations 
Analyses of physical examinations will be performed in the following manner: 
x
Distribution of number of subjects by body system examined and result assessments 
made will be presented at baseline and at termination.
x
Shift analysis of categorical change by body system will also be performed.
x
Incidence and listings of individual subject’s findings of Abnormal Clinically 
Significant following 1st study IMP administration and onwards will also be provided. 
8.5.6
12-Lead ECG
12-lead ECG will be recorded on Days 1 and 2 of treatment cycle 1 at pre-dose and 4 ± 2 h 
post-BL-8040 administration. Additional ECGs may be performed at the discretion of the 
Investigator. Analyses of ECG evaluations are presented in the report in the following manner:
x
Descriptive statistics and Box-Plots of quantitative 12-Lead ECG parameters measured 
by scheduled timepoints (Pre-Dose/Post-Dose) as well as their changes from baseline.
x
Distribution of the number of subjects by the interpretation (Normal/Abnormal) at each 
scheduled timepoint. 


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x
Listing of QTC Interval Fridericia (msec) Measurements > 450 msec AND changes 
from baseline > 60 msec will be listed along with baseline value and change from 
baseline. 
8.5.7
Tolerability Assessment
Tolerability and drop-out assessments will be performed for the ITT and mITT analyses sets. 
Tolerability analysis will be based on the number and percent (%) of subjects who failed to 
complete the study IMP dosing period and will be presented by withdrawal reason.  
The time to withdrawal will be presented using a Kaplan-Meier Plots. Any estimate quoted 
from these plots will have the estimate and the standard error (SE) of the estimate provided. 
Greenwood’s formula will be used to calculate the SE.  
8.6
Exploratory Outcome Measures
x
Biomarkers that may serve as surrogates or predictors of clinical efficacy (PD-L1 
expression, CXCR4 expression, and presence of immune cells). 
x
Immune response to BL-8040 and Atezolizumab.
x
Presence of ADAs during the study relative to the presence of ADAs at baseline.  
x
Pharmacodynamic endpoints. 
x
Measurement of mast cell activation
x
Molecular tests may be assessed following emerging public domain literature and other 
clinical trials with BL-8040.
Univariate statistics will be presented using Box Plots. Any analysis adjustments to the data 
analysis will be accomplished using Mixed Model Analysis of Variance. Significant findings 
in the model will be presented by providing the estimate and its calculated SE.
8.7
Pharmacokinetics (PK) Assessment
Sparse samples will be collected for PK analysis and to compare exposure in this study with 
that attained in previous studies. Serum concentrations of Atezolizumab and plasma 
concentrations of BL-8040 will be reported as individual values and summarized (mean, SD, 
coefficient of variation [%CV], median, range, geometric mean, and geometric mean CV 
[%CV]) by cycle, when appropriate and as data allow. Atezolizumab or BL-8040 concentration 
data may be pooled with data from other studies using an established population PK model to 
derive PK parameters such as clearance, volume of distribution and AUC, as warranted by the 
data. 
8.8
Statistical Analysis Plan (SAP) 
A detailed SAP will be developed following the recruitment of the 40th subject.
Any deviation from this Statistical Analysis Plan (SAP) will be reported in the Clinical Study 
Report.  
8.9
Statistical Analysis Software 
All data listings, summary tables and statistical analyses will be generated using SAS® Version 
9.4 or higher (SAS is a registered trademark of the SAS Institute Inc., Cary, NC, USA).   
9
ETHICS 


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9.1
Institutional Review Board or Independent Ethics Committee
Prior to initiation of the study, the Investigator will submit the study protocol and amendments, 
Investigator’s Brochure and amendments, ICF and any other documents that may be provided 
to the subject or any other documents requested by the IRB/IEC for review and approval. 
The names and affiliations of all members of the IRB/IEC must be provided to the Principal 
Investigator and BioLineRx. In lieu of this, the IRB/IEC must certify that it has been officially 
authorized/recognized according to the national legislation.
The IRB/IEC must provide written approval of the study to keep in the Investigator’s file. 
Records of approval of all documents pertaining to this study, including the local regulatory 
authority, should be filed as such. The Investigator will not begin the study until the protocol,
ICF and any other document provided to the subject have been approved by the IRB/IEC. The 
Investigator must agree to make any required progress reports to the IRB/IEC, as well as reports 
of SAEs, life-threatening conditions or death. The IRB/IEC will also be notified of Part 1 
preliminary results. 
9.2
Ethical Conduct of the study
All clinical work conducted under this protocol is subject to ICH GCP (E6) guidelines. This 
includes an inspection by Sponsor or its designee, health authority or IRB/IEC representatives 
at any time. The Investigator must agree to the inspection of study-related records by health 
authority representatives and/or Sponsor or its designee.  
The study will be conducted in accordance with Sponsor and/or designee’s standards operating 
procedures and the following guidelines: 
GCP: Consolidated Guideline (International Conference on Harmonization of Technical 
Requirements for the Registration of Pharmaceuticals for Human Use, May 1996). 
Declaration of Helsinki: Seoul, 2008.  
US Code of Federal Regulations (Title 21, CFR Part 11, 50, 54, 56 and 312) and/or EU 
Directives; and/or local country regulations and guidelines.  
9.3
Subject Information and Consent
Prior to screening for the study each subject will be informed in detail about the study drugs to 
be administered and the nature of the clinical investigation with its risks and discomforts to be 
expected. The basic elements of informed consent as specified by the FDA (21 CFR 50.25) and 
ICH-GCP will be followed. The subjects will also be instructed that they are free to withdraw 
their consent and discontinue their participation in the study at any time without prejudice. 
Written consent will be obtained from each subject to be involved in the clinical trial by using 
the IRB/IEC-approved ICF prior to the conduct of any study-related activity. A copy of the 
ICF will be submitted together with this protocol and must be approved by the IRB/IEC prior 
to study commencement. Each subject will be given a copy of the written ICF, and each 
subject’s chart will include the signed ICF for study participation. The original subject signed 
and dated ICFs will be maintained per ICH record retention requirements. The consent form 
will also be signed by the person administering the informed consent. An entry should be made 
in the subject’s dated source documents to confirm that the informed consent was obtained 
prior to administering any study related procedures. The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial. The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 


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by the subject’s legally acceptable representative’s dated signature. Regulatory authorities may 
check the existence of the signed ICF in this central study folder if not having performed so 
during the study.   
9.4
Subject Insurance
A product liability to cover against injury and damages arising from the use of investigational 
products in this project is provided by the Sponsor for the total duration of the study covering 
the subjects and Investigators in respect of the risks involved in conducting this study according 
to this protocol. The insurance policy will be filed in the Investigator’s site file or can be made 
available to the Investigator and to the IRB/IEC upon request. 
Subjects will be insured through contract between an insurance company and the Sponsor. 
9.5
Informing the General Practitioner
When required by location regulation, the Investigator will inform the subject's primary care 
physician of his/her participation in the study, by sending a letter to the physician.
9.6
Personal Data Protection 
The Sponsor will comply with local regulations and with the principle of subject’s right to 
protection against invasion of privacy. Throughout this trial, all subject data will be identified 
only by a subject identification number and subject initials and date of birth. The data will be 
blinded in all data analyses. The subject must be informed and consent to authorized personnel 
of the Sponsor, such as study monitor, auditor, etc. and relevant health regulatory agencies 
having direct access to personal medical data to assure a high-quality standard of the study. At 
the subject's request, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her welfare.   
9.7
Data and Safety Monitoring  
A DMC will be assigned by the Sponsor prior to the beginning of the study. The committee 
will be comprised of 3 members appointed by the Sponsor including at least one clinician and 
persons knowledgeable of the investigational drug. 
After treatment of 6 patients, the DMC will review the safety data to assess the progress of the 
clinical trial and will recommend to the Sponsor and to the Investigator whether to continue
with the current combination, expand the DLT period revision to assess 12 patients, modify the 
dose regimen or stop the trial. In case 5 out of the 6 of the first patients do not experience a 
DLT the recruitment will not stop (as two DLT in the first 6 patients will not have been reached) 
and the DMC will review the safety data without stopping recruitment. DMC activities and 
procedures will be described in detail within the DMC charter. 
9.8
Protocol Exceptions and Deviations 
Departures from the protocol should be avoided, unless required for the safety of the subject. 
Protocol deviations, and if possible the reason for occurrence, will be documented by the study 
monitor for visit reports and will be included in the final clinical study report. The Investigator 
must report any protocol deviations to the Sponsor or the Sponsor's designee, should they 
occur. If required, the Investigator should also report deviations to the IRB/IEC in accordance 
with local regulations and within a reasonable time. No prospective waivers will be allowed 
for patients who do not fulfill the inclusion/exclusion criteria.   


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9.9
Protocol Amendments
Changes to the protocol may be made only by the Sponsor (with or without consultation with 
the Investigator). All protocol modifications must be submitted to the site IRB/IEC in 
accordance with local requirements and, if required, to the Regulatory Authority, either as an 
amendment or a notification. Approval for amendments must be received before any changes 
can be implemented, except for changes necessary to eliminate an immediate hazard to trial 
subjects, or when the changes involve only logistical or administrative aspects of the trial. No 
approval is required for notifications. 
10 QUALITY CONTROL AND QUALITY ASSURANCE 
The study will be conducted according to GCP as outlined by ICH Topic E6 step 5 guidelines. 
The CRO’s SOPs will be followed to ensure that clinical trials are conducted, and data are 
generated, documented and reported in compliance with the protocol, GCP and applicable 
regulatory requirements. 
10.1 Audits and Inspections
The study may be audited according to the Sponsor's or its designee's QA inspection program. 
The purpose of the audit is to determine whether or not the study is being conducted and 
monitored in compliance with the study protocol and ICH GCP guidelines. Audit visit(s) will 
be arranged in advance with site personnel at a mutually acceptable time.
The Investigator should understand that source documents for this trial should be made 
available to appropriately qualified personnel from the Sponsor or its designees or the 
regulatory authority inspectors after appropriate notification. The verification of the CRF data 
must be made by direct inspection of source documents. The auditor may ask to visit the 
facilities where laboratory samples are collected, where the investigational product is stored 
and prepared and any other facility used during the study. These audits or inspections may take 
place at any time, during or after the study, and are based on the national regulations, as well 
as ICH guidelines. 
10.2 Study Monitoring
Monitoring of the study is the responsibility of the Sponsor and may be delegated to a CRO. 
The study monitor will advise the Investigator regarding the practical conduct of the study and 
maintaining compliance with the protocol, GCP and all applicable regulatory requirements.   
Before study initiation, at the site initiation visit or at an Investigator’s meeting, a Sponsor or 
CRO representative will review the protocol and CRFs with the Investigator and his staff. The 
Sponsor/CRO will also be responsible for training study personnel in the study specific 
procedures.    
Throughout the course of the study, the study monitor will oversee the conduct and the progress 
of the study by frequent contacts with the Investigator and his staff. This will include telephone 
calls and on-site visits. During the on-site visits, the CRF will be reviewed for completeness 
and accuracy with corresponding source documents. As part of the data audit, source 
documents will be made available for review by the study monitor. The study monitor will also 
perform drug accountability checks and will periodically review the Investigator study file to 
ensure completeness of documentation in all respects of clinical study conduct.  
Periodically, some or all of the facilities used in the study (e.g., local laboratory, pharmacy) 
may be reviewed. Monitoring visits will be arranged in advance with site personnel at a 


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mutually acceptable time. Sufficient time must be allowed by the site personnel for the monitor 
to review CRFs and relevant source documents. The Investigator should be available to answer 
questions or resolve data clarifications. The Investigator or appointed delegate will receive the 
study monitor during these on-site visits, cooperate in providing the documents for inspection 
and respond to enquiries.   
The Investigator will ensure that the study participants are aware of and consent to their 
personal information being scrutinized during the data verification process, as part of study-
related monitoring, inspection and/or auditing, by properly authorized persons associated with 
Sponsor or by domestic and/or foreign regulatory authorities. However, the subject’s 
participation and personal information will be treated as strictly confidential to the extent that 
the applicable law permits and will not be made publicly available.  
Upon completion of the study, the study monitor will arrange for a final review of the study 
files after which the files should be secured for the appropriate time period.  The details of the 
monitoring procedures are listed in the study-specific Monitoring Plan. 
10.3 Quality Laboratory Standards 
Laboratory tests or evaluations described in this protocol will be conducted in accordance with 
quality laboratory standards as described in the SOPs of the central and local institution 
laboratories.
Before the study begins, the laboratories to be used in the study will provide a list of the 
reference ranges for all laboratory tests to be undertaken and details of the method used for 
quality control. These will be held in the Investigator Site File and the Trial Master File. The 
methods employed for each assay should be available on request. Any change in the laboratory, 
its procedures, references, values, etc. during the study must be notified promptly to the 
Sponsor. 


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11 STUDY DOCUMENTATION
Study documents will include the following:
Signed ICFs
Source documents (e.g. subject files, medical notes) 
Investigator copies of the CRFs and SAE reports 
Investigator site file + contents
Study manual (if applicable) 
Study Pharmacy manual (includes instructions for use) 
Investigator meeting binder, laboratory manuals and/or other training materials
Upon completion of the study, the study monitor will arrange for a final review of the study 
files after which the files should be secured for the appropriate time period.   
11.1 Source Documents 
The Investigator will permit study-related monitoring, audits by or on behalf of the Sponsor, 
IRB/IEC review and regulatory inspections providing direct access to source data documents. 
Source documents are original records in which raw data are first recorded. These may be 
office/clinic/hospital records, charts, diaries, x-rays, laboratory results, printouts, pharmacy 
records, care records or completed scales for each study participant. Source documents should 
be kept in a secure and limited access area. All source documents must be accurate, clear, 
unambiguous, permanent and capable of being audited. They should be made using a 
permanent form of recording (ink, typing, printing, optical disc etc.). They should not be 
obscured by correcting fluid or have temporary attachments (such as removable self-stick 
notes). Source documents that are computer generated and stored electronically must be 
printed, signed and dated by the Investigator.  
Source data for subjects registered to the study should indicate the date the ICF was signed, 
participation in a clinical trial with the clinical protocol number and title, treatment number and 
evidence that inclusion/exclusion criteria have been met.
11.2 Recording of Data on Case Report Form (CRF)
The development of the CRF will be the responsibility of the Sponsor or its designee. 
All eCRFs will be completed in English and will be reviewed by study monitors for accuracy 
and completeness.   All data pertaining to the visit should be recorded in the eCRF no later than 
five days after the completion of the visit. The Investigator is responsible for verifying that all 
data entries in the eCRFs are accurate and correct. The PI must sign the completed CRF prior 
to its submission to the Sponsor. 
A representative of the Sponsor or designee will instruct the Investigator and his/her staff prior 
to the enrollment of the first patient and will train them on recording the findings into the 
electronic data capture (EDC) system. 
After the enrollment of the first patient, a study monitor will periodically monitor the progress 
of the study by conducting onsite visits. The study monitor will also have the ability to review 
query statuses remotely which may warrant more frequent contact with the Investigator and 
his/her staff. The Investigator will make available to the study monitor the computer that 
accesses the eCRFs, source documents, signed consent forms and all other study related 
documents. The Investigator will be responsible for reviewing eCRFs, providing resolution to 
data queries generated by the study monitor via the EDC system, providing missing or 
corrected data, and approving all changes performed on his/her data, and endorsing the patient 


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data within the EDC system. This approval method will include applying an electronic 
signature, a uniquely assigned username and a password, that together would represent a 
traditional handwritten signature.
The Investigator will agree to the inspection of study-related records by the Sponsor, external 
auditor and/or health authority representatives. 
11.3 Investigator Site File 
All documents required for the conduct of the study as specified in the ICH-GCP guidelines 
will be maintained by the Investigator in an orderly manner and made available for monitoring 
and/or auditing by the Sponsor/or designee and regulatory agencies. 
12 CLINICAL TRIAL SUPPLIES 
The Sponsor or designee will be responsible for supplying clinical trial supplies to the sites. 
The Principal Investigator will be responsible for the administration, inventory and 
accountability of all clinical trial supplies provided to the site, exercising accepted medical and 
pharmaceutical practices. An accurate and timely record of the disposition of all clinical 
supplies must be maintained. The supplies and inventory record must be made available for 
inspection upon request. Upon completion or termination of the study, the Investigator will 
return the remaining clinical supplies along with a copy of the inventory record and a record of 
the clinical supplies returned. A copy of these records should be maintained in the site study 
files. Under no circumstances will the Investigator allow the study drugs to be used other 
than as directed by this protocol.
13 DATA MANAGEMENT
Data Management services will be provided by the Sponsor or designee. The data management 
system will be specified in the Data Management Plan.   
After the data have been entered and verified, various edit checks will be performed for the 
purpose of ensuring the accuracy, integrity and validity of the database. These edit checks may 
include: 
x
Missing value checks
x
Range checks
x
Consistency checks
x
Sequence checks
x
Protocol adherence checks
Queries generated from these checks will be sent to the investigational site for resolution, and 
the database will be updated to reflect query resolutions as appropriate.  
Adverse events will be coded using the latest version of MedDRA (currently version 19.0). 
Prior and concomitant medications will be coded according to the World Health Organization 
(WHO) Drug Dictionary.
14
STUDY ADMINISTRATION
14.1 Participating Centers
Centers in the USA-5 sites , Europe-15 sites  and Israel-2 sites. Optional centers can be 
opened in other countries.. 


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14.2 Required Documents Prior to Study Initiation
Prior to the start of this study, all pre-investigational requirements must be met by the 
Investigator and study site. These may include:
Appropriate local health authority documentation properly signed and dated by the required 
Investigator (i.e., documents required for submission to the local IRB/IECs or applicable 
regulatory authorities).  
Signed copy (original) of the approved protocol 
Acknowledgement of receipt of the approved Investigator Brochure 
Completed and signed statement of Investigator 
A signed Clinical Trial Agreement
Curriculum vitae for the Investigator and sub-Investigator (can be collected at site initiation 
visit)
Financial Disclosure Forms for the Principal Investigator and Sub-Investigators 
IRB/IEC name and address; and membership list (can be collected at site initiation visit)
Letter of approval from the IRB/IEC for both protocol (identified by protocol title and number) 
and ICF (identified by protocol title and number) 
Copy of the IRB/IEC-approved written ICF to be used in the study (that has also been approved 
by the Sponsor) 
Provisions for direct access to source/data documents, if necessary, for trial-related monitoring, 
audits, IRB/IEC review and regulatory inspection 
Name and location of the laboratory utilized for laboratory assays and other facilities 
conducting tests, as well as a copy of the laboratory certificate and list of normal laboratory
values (can be collected at site initiation visit)
In case a laboratory certification is not available, a written statement as to how the laboratory 
complies with quality assurance should be provided.   
Upon satisfactory receipt of all required regulatory documents, the Sponsor will arrange for 
study drugs to be delivered to the study site. Supply of all other study materials will be the 
responsibility of the Sponsor and/or designee. Subject entry should not begin until after the 
required regulatory documents are confirmed as received and the Investigator 
Meeting/Initiation Meeting has occurred. All personnel expected to be involved in the conduct 
of the study will undergo study initiation to include review of study protocol, instructions for 
CRF completion, AE reporting and overall responsibilities including those for drug 
accountability and study file maintenance.
The Investigator and/or designee (study monitor) will be provided with an Investigator's File.  
This file should be used for all trial related documents. The Investigator will be responsible for 
keeping the Investigator's file updated and ensuring that all required documents are filed. The 
file will be inspected during monitoring visits.
14.3 Study Completion
This study is expected to end when all required subjects have been enrolled and the last subject 
has completed the study and all query resolutions have been completed. 
Data and materials that are required before the study can be considered complete and/or 
terminated include, but are not limited to:


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Laboratory findings, clinical data and all special test results from screening through the end of 
the follow-up period 
CRF properly completed by appropriate study personnel and electronically signed by the 
Investigator 
Completed Drug Accountability Records 
Statement of outcome for each SAE reported
Copies of protocol amendments and IRB/IEC as well as relevant health authority 
approval/notification (if applicable) 
Retention of Study Documents Statement
14.4 Clinical Study Report
A clinical study report will be developed by the Sponsor on completion of data analysis. This 
report will be a clinical and statistical integrated report, according to the ICH E3 guidelines.
14.5 Retention of Study Records
The Investigator will retain copies of the approved protocol, completed CRF, signed ICFs, 
relevant source documents and all other supporting documentation related to the project as 
defined in ICH-E6 section 8 related to the project per ICH-E6 record retention requirements 
for at least 2 years after the last approval of a marketing application in an ICH region and until 
there are no pending or contemplated marketing applications in an ICH region or at least 2 
years have elapsed since the formal discontinuation of clinical development of the 
investigational product in a secure and safe facility with limited access. If the Investigator is 
unable to retain the study documents for the required amount of time, the Sponsor or designee 
must be informed of the individual who will be assuming this responsibility. 
The Sponsor will notify, in writing, the Investigator when the clinical study data may be 
discarded. The Investigator will take measures to prevent accidental or premature destruction 
of these documents.  
These files must be made available for inspection upon reasonable request by authorized 
representatives of the Sponsor and/or the relevant regulatory agencies.
14.6 Confidentiality and Publication of Study Results
14.6.1 General
All data and information supplied by or on behalf of the Sponsor or otherwise acquired or 
obtained by any Research Institution, the Principal Investigator and other Investigators 
("Recipients") in any manner, in connection with or in performance of this study, is considered 
"Confidential Information". This Confidential Information includes, but is not limited to, the 
Investigator’s brochure, this protocol and any information relating thereto, CRFs and other 
scientific data, information relating to Sponsor's Investigational Product and treatment 
methodology and information relating to Sponsor's (or its affiliates') commercial, technical and 
financial information, research technology, products, inventions, trade secrets and research and 
development. The results produced in performance of the study and any data, information or 
other material collected, developed, generated or prepared during and in the course of 
performing the study shall be promptly disclosed to Sponsor in full in writing, and are also 
considered Confidential Information. This Confidential Information shall be and remain the 
sole property of the Sponsor. Except for Publishable Results (defined below) to the extent it 
may be published under Section 14.6.2, throughout the duration of the study and after its 


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completion, Recipients shall not disclose Confidential Information to others without the written 
consent of the Sponsor, except to those of its employees who have a need to know the 
Confidential Information in order to Recipients' obligations hereunder, and where such 
employees are bound by written contractual obligations covering Confidential Information that 
are no less restrictive or protective than those contained herein, provided that Recipients shall 
remain liable for any disclosure or use of Confidential Information by such employees, (ii) use 
the same degree of care to preserve confidentiality of Confidential Information as they use for 
their own information of like nature, which shall not be less than reasonable degree of care, 
and (iii) not use Confidential Information for any purpose except in the performance of this 
study. Promptly at Sponsor's request, or upon completion of the study, Recipients will 
discontinue use and return to Sponsor or destroy, in accordance with Sponsor’s instructions, 
all copies or other manifestations of Confidential Information that may be in their possession 
or control, except to the extent expressly required hereunder and to comply with Applicable 
Laws (defined below). Should a Recipient be required to disclose Confidential Information 
pursuant to law, regulation, judicial or administrative order or request by a governmental or 
other entity authorized by law to make such request, Recipient shall (i) promptly notify Sponsor 
prior to such disclosure, (ii) cooperate with Sponsor and provide assistance in seeking a 
protective order or other suitable protection with respect to the Confidential Information, and 
(iii) only disclose such Confidential Information to the extent pursuant to said law, regulation, 
judicial or administrative order, or request by a governmental or other authorized entity. 
At the subject's request, medical information may be given to his or her personal physician or 
other appropriate medical personnel responsible for his or her welfare. The personal physician 
will be notified by site personnel of subject participation in the study.
14.6.2 Published Data
The object of the study will be to publish the results of the complete study ("Publishable 
Results") in an appropriate peer-reviewed journal after the conclusion of the study 
("Publication").  A formal Publication of the Publishable Results is planned and will be 
considered a joint publication by the Principal Investigator, other Investigators, Sponsor and 
the appropriate Sponsor personnel (and Research Institutions) (Subject to internal review).
Publication must be undertaken in a responsible and ethical manner, taking into account 
relevant external standards regarding the manner and content of scientific, technical and 
medical publications and in subject to applicable laws, rules, regulations, policies and 
guidelines ("Applicable Laws"). Authorship will be determined by mutual agreement between 
Sponsor and Principal Investigator.  Sponsor shall be mentioned in all Publications unless 
contrary instruction is given by Sponsor. Review and comment by Sponsor authorized 
personnel on draft abstracts and manuscripts for Publication or presentation is required prior to 
publication or presentation.  Authors shall submit a copy of any abstracts, manuscripts or other 
material proposed for publication or presentation ("Draft Publications") to the Sponsor for its 
approval no fewer than sixty (60) days prior to the intended date of submission of such Draft 
Publications to any journal, publisher, and/or third party. The Sponsor has the right, at its 
discretion (a) to evaluate Draft Publications for accuracy and concurrence regarding data, 
evaluations, and conclusions, (b) to provide an opportunity for Sponsor to share with the 
Investigator(s) any new or unpublished information of which he or she may be unaware, (c) to 
ensure that no Confidential Information or other Sponsor proprietary information is being 
utilized and has been included, and (d) evaluate Draft Publications to determine if patent 
applications need to be filed on any information disclosed therein.   
If the Sponsor determines that such Draft Publication contains Confidential Information or 
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effects on its business, and notifies Principal Investigator of its determination, the Principal 
Investigator, Research Institutions and other Investigators/authors shall remove such 
Confidential Information from the Draft Publication or at Sponsor's election, modify it to 
remove language that is detrimental to Sponsor's intellectual property or other interests,  and 
refrain from submitting such Draft Publication to a journal, publisher and/or other third party 
for additional ninety (90) days from Sponsor's notification to allow for filing of patent 
applications or the taking of such other measures as Sponsor deems appropriate to establish, 
preserve and protect its intellectual property or other interests. Principal Investigator, other 
Investigators and Research Institutions further agree to redact or modify those sections of the 
draft Publication in which Sponsor in good faith determines falls within (a) to (d) above. 


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15
REFERENCES
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Leukemia: Time to Move Toward a Minimal Residual Disease-Based Definition of Complete 
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Becker PS. Dependence of acute myeloid leukemia on adhesion within the bone marrow 
microenvironment. Scientific World Journal 2012; 2012. 
Beider K, Begin M, Abraham M, Wald H, Weiss ID, Wald O, Pikarsky E, Zeira E, Eizenberg 
O, Galun E, Hardan I, Engelhard D, Nagler A, Peled A. CXCR4 antagonist 4F-benzoyl-
TN14003 inhibits leukemia and multiple myeloma tumor growth. Experimental Hematology 
2011; 39(3): 282-292. 
Beider K, Darash-Yahana M, Blaier O, Koren-Michowitz M, Abraham M, Wald H, et al. 
Combination of imatinib with CXCR4 antagonist BKT140 overcomes the protective effect of 
stroma and targets CML in vitro and in vivo. Mol Cancer Ther 2014; 13: 1155–69.  
Bendall LJ, Makrynikola V, Hutchinson A, Bianchi AC, Bradstock KF, Gottlieb DJ. Stem cell 
factor enhances the adhesion of AML cells to fibronectin and augments fibronectin-mediated 
anti-apoptotic and proliferative signals. Leukemia 1998; 12(9): 1375-1382.  
Berthon C, Driss V, Liu J, Kuranda K, Leleu X, Jouy N, Hetuin D, Quesnel B. In acute myeloid 
leukemia, B7-H1 (PD-L1) protection of blasts from cytotoxic T cells is induced by TLR ligands 
and interferon-gamma and can be reversed using MEK inhibitors. Cancer Immunol 
Immunother. 2010 Dec; 59(12):1839-49. 
Bradstock KF, Gottlieb DJ. Interaction of acute leukemia cells with the bone marrow 
microenvironment: implications for control of minimal residual disease. Leukemia Lymphoma 
1995; 18(1-2): 1-16.  
Buccisano F, Maurillo L, Piciocchi A, Del Principe MI, Sarlo C, Cefalo M, Ditto C, Di Veroli 
A, De Santis G, Irno Consalvo M, Fraboni D, Panetta P, Palomba P, Attrotto C, Del Poeta G, 
Sconocchia G, Lo-Coco F, Amadori S, Venditti A. Minimal residual disease negativity in 
elderly patients with acute myeloid leukemia may indicate different post-remission strategies 
than in younger patients. Ann Hematol. 2015 Aug; 94(8):1319-26 
Byrd JC, Ruppert AS, Mrózek K, Carroll AJ, Edwards CG, Arthur DC, Pettenati MJ, Stamberg 
J, Koduru PR, Moore JO, Mayer RJ, Davey FR, Larson RA, Bloomfield CD. Repetitive cycles 
of high-dose cytarabine benefit patients with acute myeloid leukemia and inv(16) (p13q22) or 
t(16;16)(p13;q22): results from CALGB 8461. J Clin Oncol. 2004 Mar 15; 22(6):1087-94.  
Döhner H, Estey EH, Amadori S, Appelbaum FR, Büchner T, Burnett AK, Dombret H, Fenaux 
P, Grimwade D, Larson RA, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz MA, 
Sierra J, Tallman MS, Löwenberg B, Bloomfield CD; European LeukemiaNet. Diagnosis and 
management of acute myeloid leukemia in adults: recommendations from an international 
expert panel, on behalf of the European LeukemiaNet. Blood. 2017 Jan 26; 129(4):424-447.  
Estey EH. Growth factors in acute myeloid leukaemia. Best Pract Res Clin Haematol. 2001 
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Giles FJ, Keating A, Goldstone AH, Avivi I, Willman CL, Kantarjian HM. Acute myeloid 
leukemia. American Society of Hematology Education Program 2002: 73-110.  
Kantarjian H, O'Brien S, Cortes J, Giles F, Faderl S, Jabbour E, Garcia-Manero G, Wierda W, 
Pierce S, Shan J, Estey E. Results of intensive chemotherapy in 998 patients age 65 years or 
older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive 
prognostic models for outcome. Cancer. 2006 Mar 1; 106(5):1090-8.  
Liesveld JL, Dipersio JF, Abboud CN. Integrins and adhesive receptors in normal and leukemic 
CD34+ progenitor cells: potential regulatory checkpoints for cellular traffic. Leukemia 
Lymphoma 1994; 14(1-2): 19-28.  
Löwenberg B, van Putten W, Theobald M, Gmür J, Verdonck L, Sonneveld P, Fey M, Schouten 
H, de Greef G, Ferrant A, Kovacsovics T, Gratwohl A, Daenen S, Huijgens  P, Boogaerts M; 
Dutch-Belgian Hemato-Oncology Cooperative Group; Swiss Group for  Clinical Cancer 
Research. Effect of priming with granulocyte colony-stimulating factor on the outcome of 
chemotherapy for acute myeloid leukemia. N Engl J Med. 2003 Aug 21; 349(8):743-52.  
Matsunaga T, Takemoto N, Sato T, Takimoto R, Tanaka I, Fujimi A, Akiyama T, Kuroda H, 
Kawano Y, Kobune M, Kato J, Hirayama Y, Sakamaki S, Kohda K, Miyake K, Niitsu Y. 
Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for 
minimal residual disease of acute myelogenous leukemia. Nature Medicine 2003; 9(9): 1158-
1165.
Mayani H. Composition and function of the hemopoietic microenvironment in human myeloid 
leukemia. Leukemia 1996; 10(6): 1041-1047.  
Menzin J, Lang K, Earle CC, Kerney D, Mallick R. The outcomes and costs of acute myeloid 
leukemia among the elderly. Arch Intern Med. 2002 Jul 22; 162(14):1597-603.  
Ravandi F, Jorgensen J, Borthakur G, Jabbour E, Kadia T, Pierce S, Brandt M, Wang S, 
Konoplev S, Wang X, Huang X, Daver N, DiNardo C, Andreeff M, Konopleva M, Estrov Z, 
Garcia-Manero G, Cortes J, Kantarjian H. Persistence of minimal residual disease assessed by 
multiparameter flow cytometry is highly prognostic in younger patients with acute myeloid
leukemia. Cancer. 2016 Sep 22; [Epub ahead of print]. 
Rollig et al, Long-Term Prognosis of Acute Myeloid Leukemia According to the New Genetic 
Risk Classification of the European LeukemiaNet Recommendations: Evaluation of 
the Proposed Reporting System. J Clin Oncol 29:2758-2765 
SEER Cancer
Statistics Review 2005-2009. HYPERLINK "http://seer.cancer.gov"   
http://seer.cancer.gov . (Accessed November 2012). 
Sehgal A, Whiteside TL, Boyiadzis M. Programmed death-1 checkpoint blockade in acute 
myeloid leukemia. Expert Opin Biol Ther. 2015; 15(8):1191-203.  
Stone RM, O'Donnell MR, Sekeres MA. Acute myeloid leukemia. American Society of 
Hematology Education Program 2004: 98-117. 
Tavor S, Weiss I, Beider K, Wald H, Eizenberg O, Pereg Y, et al. The CXCR4 Antagonist BL-
8040 Efficiently Induces Apoptosis and Inhibits the Survival of AML Cells. Blood ASH Annu. 
Meet. Abstr., 2013, p. 122: 3939. 
Uy GL, Rettig MP, Motabi IH, McFarland K, Trinkaus KM, Hladnik LM, Kulkarni S, Abboud 
CN, Cashen AF, Stockerl-Goldstein KE, Vij R, Westervelt P, DiPersio JF. A phase 1/2 study 


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of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or refractory acute 
myeloid leukemia. Blood 2012; 119(17): 3917-3924. 
Walter RB, Buckley SA, Pagel JM, Wood BL, Storer BE, Sandmaier BM, Fang M, Gyurkocza 
B, Delaney C, Radich JP, Estey EH, Appelbaum FR. Significance of minimal residual disease 
before myeloablative allogeneic hematopoietic cell transplantation for AML in first and second 
complete remission. Blood. 2013 Sep 5; 122(10):1813-21.  
Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses 
in a murine acute myeloid leukemia model. Blood. 2009 Aug 20; 114(8):1545-52. 
Zhou Q, Munger ME, Highfill SL, Tolar J, Weigel BJ, Riddle M, Sharpe AH, Vallera DA, 
Azuma M, Levine BL, June CH, Murphy WJ, Munn DH, Blazar BR. Program death-1
signaling and regulatory T cells collaborate to resist the function of adoptively transferred 
cytotoxic T lymphocytes in advanced acute myeloid leukemia. Blood. 2010; 116(14):2484-93. 


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16
APPENDICES


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16.1 Appendix A 
Schedule of Assessments
Study Day
Study Procedure  
Screening 
Period
Baseline
Treatment Period
End of 
Treatment / 
Early 
Discontinua
tion
Follow-up
Pre-dose 
Day 1 
Treatme
nt Cycle 
1
21-day treatment cycles for up 
2 years 
(a maximum of 34 cycles)
Safety 
Follow-
up
Survival 
Follow-
up
Day -28 to
Day -1 
Day 11
Day 2 
Day 3 
30 days 
post 
study 
drug2
Every 3 
months 
(± 1 
month)
Informed consent
X
Inclusion/exclusion criteria
X
X3
Demographic & medical history 
X
Physical examination4
X
X
X
X
Weight
X
X
X5
Vital signs6
X
X
X
X
X
X
ECOG Performance Status
X
X
X7
X
12-lead ECG8
X
X
X
X
X
Hematology9
X
X
X
X
X
X
1 Day 1 of each treatment cycle will have a ± 3-day window.
2 The safety follow-up period may be extended up to 90 days after the last dose of study drug for any SAEs considered reasonable possibly related to BL-8040 and/or Atezolizumab. 
3 Review inclusion/exclusion criteria to confirm eligibility.
4 Full physical examination at screening and End of Treatment visit. Directed physical examination to be performed at baseline and pre-dose on Day 1 of every subsequent treatment cycle.
5 Weight will be measured pre-dose on Day 1 of every treatment cycle to determine the correct dose of BL-8040.
6 Vital signs will include blood pressure, pulse rate, oral temperature, O2 saturation levels and respiration rate. To be performed on. Days 1, 2 and 3 at pre-dose and 4 ± 2 h post-BL-8040 administration during the 
first cycle. In the following cycles pre-dose and 4±2h post BL-8040 administration on day 1 only. 
7 ECOG performance status will be determined pre-dose on Day 1 of every cycle.
8 12-lead ECG will be recorded on Days 1 and 2 of treatment cycle 1 at pre-dose and 4 ± 2 h post-BL-8040 administration. Additional ECGs may be performed at the discretion of the Investigator.
9 Haematology and differential counts will be performed before each dose of BL-8040 throughout the study. During treatment cycle 1, samples will also be collected at 4 ± 2 h post-BL-8040 administration on 
Days 1, 2 and 3. 


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Study Day
Study Procedure  
Screening 
Period
Baseline
Treatment Period
End of 
Treatment / 
Early 
Discontinua
tion
Follow-up
Pre-dose 
Day 1 
Treatme
nt Cycle 
1
21-day treatment cycles for up 
2 years 
(a maximum of 34 cycles)
Safety 
Follow-
up
Survival 
Follow-
up
Day -28 to
Day -1 
Day 11
Day 2 
Day 3 
30 days 
post 
study 
drug2
Every 3 
months 
(± 1 
month)
Biochemistry10
X
X
X
X
X
Thyroid Function Tests11
X
X
X
Coagulation10
X
X
X
HIV, HBV, HCV serology
X17
CT scan chest (within 28 days prior to 
treatment)
X
Bone Marrow (BM) biopsy
X12
Bone Marrow (BM) aspirate including 
MRD assessment, biomarker assessments
and DNA/RNA for correlative studies
X13
X13
X13
Peripheral blood immune-phenotyping,
biomarker assessments and DNA/ RNA for 
correlative studies
X13
X13
X13
BL-8040 SC injections
X
X14
X
Atezolizumab IV infusion
X15
10 Biochemistry samples will be collected pre-dose on Days 1 and 3 of each treatment cycle.
11 Thyroid function tests and coagulation will be performed pre-dose on Day 1 of every other treatment cycle starting from treatment cycle 2.
12 Screening BM biopsy and aspirate only to be performed after Sponsor approval of provisional enrolment package. 
13 Bone marrow aspirate samples to be collected during the screening and post-dose on Day 3 of treatment cycles 3, 9, 18 and end of cycle 34 (or EOT, whichever comes first). Sample will be used for immune-
phenotyping, and to measure CXCR4, PD-1 and PD-L1 expression.
14 BL-8040 to be administered 1h (± 30 min) after completion of Atezolizumab infusion.
15 Atezolizumab IV infusion during treatment cycle 1 to be administered over 1 h. If well tolerated, subsequent infusions to be administered over 30 min.




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16.2 Appendix B: PK and ADA Assessment  
Visit
Time
Sample
Cycle 1 Day 1
Prior to first BL-8040 dose 
x BL-8040 PK (plasma)
x BL-8040 ADA (serum)
x BL-8040 CA (serum) 
x Tryptase (plasma)
1-hour post- BL-8040 dose 
x BL-8040 CA (serum)
x Tryptase (plasma)
Post BL-8040 dose Full Profile
x BL-8040 PK (plasma) FP
Cycle 1 Day 2
Prior to the atezo infusion 
x Atezolizumab PK (serum)
x Atezolizumab ADA (serum)
x BL-8040 PK (plasma) 
x Tryptase (plasma)
30 (+/-10) minutes after Atezolizumab
infusion
x Atezolizumab PK (serum)
Cycle 2 Day 1
Prior to BL-8040 dose
x BL-8040 ADA (serum)
x Tryptase (plasma)
1-hour post BL-8040 dose
x Tryptase (plasma)
Cycle 2 Day 2
Prior to the atezo infusion
x Atezolizumab PK (serum)
x Atezolizumab ADA(serum)
x Tryptase (plasma)
Cycle 3 Day 1 
Prior to BL-8040 dose 
x BL-8040 PK (serum)
x BL-8040 ADA (serum) 
x BL-8040 CA (serum) 
x Tryptase (plasma)
Cycle 3 Day 1
1-hour post BL-8040 dose 
x BL-8040 PK (plasma) FP
x BL-8040 CA (serum) 
x Tryptase (plasma)
Cycle 3 Day 2
Prior to the atezo infusion
x Atezolizumab PK (serum)
x Atezolizumab ADA (serum)
x BL-8040 PK (plasma)
x Tryptase (plasma)
30 (+/- 10) minutes after Atezolizumab
infusion
x Atezolizumab PK (serum)
Cycle 4 Day 1
Prior to BL-8040 dose 
x BL-8040 ADA (serum)
x Tryptase (plasma)
Cycle 4 Day 1
1-hour post BL-8040 dose
x Tryptase (plasma)
Cycle 4 Day 2
Prior to the atezo infusion 
x Atezolizumab PK (serum)
x Atezolizumab ADA (serum)
x Tryptase (plasma)
Cycle 8 Day 1
Prior to BL-8040 dose 
x BL-8040 PK (plasma)
x BL-8040 ADA (serum) 
x BL-8040 CA (serum) 
x Tryptase (plasma)
Cycle 8 Day 2
Prior to the atezo infusion 
x Atezolizumab PK (serum)
x Atezolizumab ADA (serum)
x BL-8040 PK (plasma)


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Visit
Time
Sample
Cycle 12 Day 2
Prior to the atezo infusion 
x Atezolizumab PK (serum)
x Atezolizumab ADA (serum)
Cycle 16 Day 1  
Prior to BL-8040 dose 
x BL-8040 ADA (serum)
x Tryptase (plasma)
Cycle 16 Day 1
1-hour post BL-8040 dose
x Tryptase (plasma)
Cycle 16 Day 2
Prior to the atezo infusion 
x Atezolizumab PK (serum)
x Atezolizumab ADA (serum)
x Tryptase (plasma)
30 days after last 
dose study drug 
(end or 
discontinuation of 
treatment)
Anytime At visit
x Atezolizumab PK (serum)
x Atezolizumab ADA (serum)
x BL-8040 PK (plasma)
x BL-8040 ADA (serum) 
ATA = anti-therapeutic antibody; PBMC = peripheral blood mononuclear cell; PK =pharmacokinetic;
FP= Full Profile 
PK Full Profile: 15 mins; 30 mins; 1 hr; 2 hrs; 4 hrs; 8 hrs)


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16.3 Appendix C 
AML Diagnosis Criteria
AML diagnosis is based on WHO classification of myeloid neoplasm and acute.  


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16.4 Appendix D Eastern Cooperative Oncology Group Performance Status
Eastern Cooperative Oncology Group
(Zubrod-ECOG)1,2 
Description
Grade
Fully active, able to carry on all 
pre-disease activities without restriction.
0
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. 
1
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50%  
of waking hours. 
2
Capable of only limited self-care, 
confirmed to bed or chair more than 50% of waking hours. 
3
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
4
1Zubrod, C.G., et al. Appraisal of Methods for the Study of Chemotherapy of Cancer in 
Man. Journal of Chronic Diseases, 11:7-33, 1960. 
2 Oken, M.M., et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol (CCT) 5: 649-655, 1982 


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16.5 Appendix E
Preexisting Autoimmune Diseases
Patients should be carefully questioned with regard to their history of acquired or 
congenital immune deficiencies or autoimmune disease. Patients with any history of 
immune deficiencies or autoimmune disease listed in the table below will be excluded
from participation in the study. Possible exceptions to this exclusion could be patients 
with a medical history of such entities as atopic disease or childhood arthralgias where 
the clinical suspicion of autoimmune disease is low. Patients with a history of
autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone 
may be eligible for this study. In addition, transient autoimmune manifestations of an
acute infectious disease that resolved upon treatment of the infectious agent are not 
excluded (e.g., acute Lyme arthritis). Contact the Medical Monitor with regard to any 
uncertainty over autoimmune exclusions. 


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16.6 Appendix F 
Anaphylaxis Precautions 
EQUIPMENT NEEDED: 
• Tourniquet 
• Oxygen 
• Epinephrine for subcutaneous, intravenous, and/or endotracheal use in accordance 
with standard practice
• Antihistamines
• Corticosteroids 
• Intravenous infusion solutions, tubing, catheters, and tape 
PROCEDURES: 
In the event of a suspected anaphylactic reaction during study drug infusion, 
the following procedures should be performed: 
1. Stop the study drug infusion. 
2. Apply a tourniquet proximal to the injection site to slow systemic absorption of study 
drug. Do not obstruct arterial flow in the limb. 
3. Maintain an adequate airway.
4. Administer antihistamines, epinephrine, or other medications as required by patient 
status and directed by the physician in charge.
Continue to observe the patient and document observations. Use of a tourniquet is not 
applicable for patients receiving IV infusion via a central line.


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16.7 Appendix G
Response criteria in acute myeloid leukemia


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16.8 Appendix H
Outcome measures for clinical trials in acute myeloid leukemia


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16.9 Appendix I
Management of Atezolizumab Therapy Further to Adverse Events
Pulmonary Events 
Dyspnea, cough, fatigue, hypoxia, pneumonitis, and pulmonary infiltrates have been 
associated with the administration of Atezolizumab. Patients will be assessed for pulmonary 
signs and symptoms throughout the study and will also have CT scans of the chest 
performed at every tumor assessment. 
All pulmonary events should be thoroughly evaluated for other commonly reported etiologies 
such as pneumonia or other infection, lymphangitic carcinomatosis, pulmonary embolism, 
heart failure, chronic obstructive pulmonary disease, or pulmonary hypertension. Management 
guidelines for pulmonary events are provided in Table 4. 
Table 4
Management Guidelines for Pulmonary Events, Including Pneumonitis
Event 
Management 
Pulmonary event, Grade 1 
x
Continue Atezolizumab and monitor closely. 
x
Re-evaluate on serial imaging. 
x
Consider patient referral to pulmonary specialist. 
Pulmonary event, Grade 2 
x
Withhold Atezolizumab for up to 12 weeks after event 
onset. a  
x
Refer patient to pulmonary and infectious disease 
specialists and consider bronchoscopy or BAL. 
x
Initiate treatment with 1-2 mg/kg/day oral prednisone or 
equivalent. 
x
If event resolves to Grade 1 or better, resume 
Atezolizumab. b 
x
If event does not resolve to Grade 1 or better while 
withholding Atezolizumab, permanently discontinue 
Atezolizumab and contact Medical Monitor. c  
x
For recurrent events, treat as a Grade 3 or 4 event. 
Pulmonary event, Grade 3 or 4 
x
Permanently discontinue Atezolizumab and contact 
Medical Monitor. c  
x
Bronchoscopy or BAL is recommended. 
x
Initiate treatment with 1-2 mg/kg/day oral prednisone or 
equivalent. 
x
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
x
If event resolves to Grade 1 or better, taper 
corticosteroids over - 1 month. 
BAL = bronchoscopic alveolar lavage; IVIG = intravenous immunoglobulin 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to < 10 mg/day oral prednisone or equivalent. 
The acceptable length of the extended period of time must be agreed upon by the investigator 
and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over > 1 month to < 10 mg/day oral 
prednisone or equivalent before Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be re-challenged with Atezolizumab
only after approval has been documented by both the investigator (or an appropriate delegate) 
and the Medical Monitor. 


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Hepatic Events 
Immune-related hepatitis has been associated with the administration of Atezolizumab. Eligible 
patients must have adequate liver function, as manifested by measurements of total bilirubin 
and hepatic transaminases, and liver function will be monitored throughout study treatment. 
Management guidelines for hepatic events are provided in Table 5.
Patients with right upper-quadrant abdominal pain and/or unexplained nausea or vomiting 
should have LFTs performed immediately and reviewed before administration of the next 
dose of study drug. 
For patients with elevated LFTs, concurrent medication, viral hepatitis, and toxic or neoplastic 
etiologies should be considered and addressed, as appropriate.
Table 5
Management Guidelines for Hepatic Events
Event 
Management 
Hepatic event, Grade 1 
x
Continue Atezolizumab.
x
Monitor LFTs until values resolve to within normal limits. 
Hepatic event, Grade 2 
x
All events: 
x
Monitor LFTs more frequently until return to baseline values. 
x
Events of > 5 days’ duration: 
x
Withhold Atezolizumab for up to 12 weeks after event onset. 
a  
x
Initiate treatment with 1-2 mg/kg/day oral prednisone or 
equivalent. 
x
If event resolves to Grade 1 or better, resume Atezolizumab.
b 
x
If event does not resolve to Grade 1 or better while 
withholding Atezolizumab, permanently discontinue 
Atezolizumab and contact Medical Monitor. c  
Hepatic event, Grade 3 or 4 
x
Permanently discontinue Atezolizumab and contact Medical 
Monitor. c  
x
Consider patient referral to gastrointestinal specialist for 
evaluation and liver biopsy to establish etiology of hepatic 
injury. 
x
Initiate treatment with 1-2 mg/kg/day oral prednisone or 
equivalent. 
x
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
x
If event resolves to Grade 1 or better, taper corticosteroids 
over > 1 month. 
LFTs = liver function tests. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to 
allow for corticosteroids (if initiated) to be reduced to < 10 mg/day oral prednisone or equivalent. 
The acceptable length of the extended period of time must be agreed upon by the investigator and 
the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over > 1 month to < 10 mg/day oral 
prednisone or equivalent before Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and have 
fully recovered from the immune-related event. Patients can be rechallenged with Atezolizumab
only after approval has been documented by both the investigator (or an appropriate delegate) and 
the Medical Monitor. 


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Gastrointestinal Events 
Immune-related colitis has been associated with the administration of Atezolizumab. Management 
guidelines for diarrhea or colitis are provided in Table 6.
All events of diarrhea or colitis should be thoroughly evaluated for other more common etiologies. For 
events of significant duration or magnitude or associated with signs of systemic inflammation or acute-
phase reactants (e.g., increased CRP, platelet count, or bandemia): Perform sigmoidoscopy (or 
colonoscopy, if appropriate) with colonic biopsy, with 3 to 5 specimens for standard paraffin block to 
check for inflammation and lymphocytic infiltrates to confirm colitis diagnosis.
Table 6
Management Guidelines for Gastrointestinal Events (Diarrhea or Colitis)
Event 
Management 
Diarrhea or colitis, Grade 1 
x
Continue Atezolizumab.
x
Initiate symptomatic treatment. 
x
Endoscopy is recommended if symptoms persist for > 7 
days. 
x
Monitor closely. 
Diarrhea or colitis, Grade 2 
x
Withhold Atezolizumab for up to 12 weeks after event 
onset. a 
x
Initiate symptomatic treatment. 
x
Patient referral to GI specialist is recommended. 
x
For recurrent events or events that persist > 5 days, 
initiate treatment with 1-2 mg/kg/day oral prednisone or 
equivalent. 
x
If event resolves to Grade 1 or better, resume 
Atezolizumab. b 
x
If event does not resolve to Grade 1 or better while 
withholding Atezolizumab, permanently discontinue 
Atezolizumab and contact Medical Monitor. c  
Diarrhea or colitis, Grade 3 
x
Withhold Atezolizumab for up to 12 weeks after event 
onset. a 
x
Refer patient to gastrointestinal specialist for evaluation 
and confirmatory biopsy. 
x
Initiate treatment with 1-2 mg/kg/day IV 
methylprednisolone or equivalent and convert to 1-2
mg/kg/day oral prednisone or equivalent upon 
improvement. 
x
If event resolves to Grade 1 or better, resume 
Atezolizumab. b 
x
If event does not resolve to Grade 1 or better while 
withholding Atezolizumab, permanently discontinue 
Atezolizumab and contact Medical Monitor. c  
Diarrhea or colitis, Grade 4 
x
Permanently discontinue Atezolizumab and contact 
Medical Monitor. c  
x
Refer patient to gastrointestinal specialist for evaluation 
and confirmation biopsy. 
x
Initiate treatment with 1-2 mg/kg/day IV 
methylprednisolone or equivalent and convert to 1-2
mg/kg/day oral prednisone or equivalent upon 
improvement. 
x
If event does not improve within 48 hours after initiating 
corticosteroids, consider adding an immunosuppressive 
agent. 
x
If event resolves to Grade 1 or better, taper 
corticosteroids over > 1 month. 
IV = intravenous 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to < 10 mg/day oral prednisone or equivalent. The 


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acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over > 1 month to < 10 mg/day oral 
prednisone or equivalent before Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with Atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
Endocrine Events 
Thyroid disorders, adrenal insufficiency, diabetes mellitus and pituitary disorders have been 
associated with the administration of Atezolizumab. Management guidelines for endocrine events are 
provided in Table 7.
Patients with unexplained symptoms such as headache, fatigue, myalgias, impotence, constipation, or 
mental status changes should be investigated for the presence of thyroid, pituitary, or adrenal 
endocrinopathies. The patient should be referred to an endocrinologist if an endocrinopathy is 
suspected. Thyroid-stimulating hormone (TSH) and free T3 and T4 levels should be measured to 
determine whether thyroid abnormalities are present. Pituitary hormone levels and function tests (e.g. 
TSH, growth hormone, luteinizing hormone, follicle-stimulating hormone, testosterone, prolactin, 
adrenocorticotropic hormone [ACTH] levels and ACTH stimulation test) and magnetic resonance 
imaging (MRI) of the brain (with detailed pituitary sections) may help to differentiate primary pituitary 
insufficiency from primary adrenal insufficiency.
Table 7
Management Guidelines for Endocrine Events
Event 
Management 
Asymptomatic hypothyroidism 
x
Continue Atezolizumab.
x
Initiate treatment with thyroid replacement hormone. 
x
Monitor TSH weekly. 
Symptomatic hypothyroidism 
x
Withhold Atezolizumab.
x
Initiate treatment with thyroid replacement hormone. 
x
Monitor TSH weekly. 
x
Consider patient referral to endocrinologist. 
x
Resume Atezolizumab when symptoms are controlled,
and thyroid function is improving. 
Asymptomatic hyperthyroidism 
x
TSH > 0.1 mU/L and < 0.5 mU/L: 
x
Continue Atezolizumab.
x
Monitor TSH every 4 weeks. 
x
TSH < 0.1 mU/L: 
x
Follow guidelines for symptomatic hyperthyroidism. 
Symptomatic hyperthyroidism 
x
Withhold Atezolizumab.
x
Initiate treatment with anti-thyroid drug such as 
methimazole or carbimazole as needed. 
x
Consider patient referral to endocrinologist. 
x
Resume Atezolizumab when symptoms are controlled,
and thyroid function is improving. 
x
Permanently discontinue Atezolizumab and contact 
Medical Monitor for life-threatening immune-related 
hyperthyroidism. c
Symptomatic adrenal insufficiency, 
Grade 2-4
x
Withhold Atezolizumab for up to 12 weeks after event 
onset. a
x
Refer patient to endocrinologist. 
x
Perform appropriate imaging. 
x
Initiate treatment with 1-2 mg/kg/day IV 
methylprednisolone or equivalent and convert to 1-2
mg/kg/day oral prednisone or equivalent upon 
improvement. 


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Event 
Management 
x
If event resolves to Grade 1 or better and patient is 
stable on replacement therapy, resume Atezolizumab. b  
x
If event does not resolve to Grade 1 or better or patient 
is not stable on replacement therapy while withholding 
Atezolizumab, permanently discontinue Atezolizumab
and contact Medical Monitor. c
Hyperglycemia 
Grade 1 or 2 
x
Continue Atezolizumab.
x
Initiate treatment with insulin if needed. 
x
Monitor for glucose control. 
Hyperglycemia, Grade 3 or 4 
x
Withhold Atezolizumab.
x
Initiate treatment with insulin. 
x
Monitor for glucose control. 
x
Resume Atezolizumab when symptoms resolve, and 
glucose levels are stable. 
Hypophysitis 
pan-hypopituitarism), Grade 2-3
x
Withhold Atezolizumab for up to 12 weeks after event 
onset. a 
x
Refer patient to endocrinologist. 
x
Perform brain MRI (pituitary protocol). 
x
Initiate treatment with 1-2 mg/kg/day IV 
methylprednisolone or equivalent and convert to 12
mg/kg/day oral prednisone or equivalent upon 
improvement. a  
x
Initiate hormone replacement therapy if clinically 
indicated. 
x
If event resolves to Grade 1 or better, resume 
Atezolizumab. b  
x
If event does not resolve to Grade 1 or better while 
withholding Atezolizumab, permanently discontinue 
Atezolizumab and contact Medical Monitor. c  
x
For recurrent hypophysitis, treat as a Grade 4 event. 
Hypophysitis 
(pan-hypopituitarism), Grade 4 
x
Permanently discontinue Atezolizumab and contact 
Medical Monitor. c  
x
Refer patient to endocrinologist. 
x
Perform brain MRI (pituitary protocol). 
x
Initiate treatment with 1-2 mg/kg/day IV 
methylprednisolone or equivalent and convert to 1-2
mg/kg/day oral prednisone or equivalent upon 
improvement. a  
x
Initiate hormone replacement therapy if clinically 
indicated. 
MRI = magnetic resonance imaging; TSH = thyroid-stimulating hormone, IV = intravenous 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to < 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
If corticosteroids have been initiated, they must be tapered over > 1 month to < 10 mg/day oral 
prednisone or equivalent before Atezolizumab can be resumed. 
Resumption of Atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with Atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical
Monitor. 


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Ocular Events 
An ophthalmologist should evaluate visual complaints (e.g., uveitis, retinal events). Management 
guidelines for ocular events are provided in Table 8. 
Table 8
Management Guidelines for Ocular Events
Event 
Management 
Ocular event, Grade 1 
x
Continue Atezolizumab.
x
Patient referral to ophthalmologist is strongly recommended. 
x
Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy. 
x
If symptoms persist, treat as a Grade 2 event. 
Ocular event, Grade 2 
x
Withhold Atezolizumab for up to 12 weeks after event onset. a  
x
Patient referral to ophthalmologist is strongly recommended. 
x
Initiate treatment with topical corticosteroid eye drops and 
topical immunosuppressive therapy. 
x
If event resolves to Grade 1 or better, resume Atezolizumab. b
x
If event does not resolve to Grade 1 or better while 
withholding Atezolizumab, permanently discontinue 
Atezolizumab and contact Medical Monitor. c  
Ocular event, Grade 3 or 4 
x
Permanently discontinue Atezolizumab and contact Medical 
Monitor. c  
x
Refer patient to ophthalmologist. 
x
Initiate treatment with 1-2 mg/kg/day oral prednisone or 
equivalent. 
x
If event resolves to Grade 1 or better, taper corticosteroids 
over > 1 month. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to < 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over > 1 month to < 10 mg/day oral 
prednisone or equivalent before Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with Atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
Immune-Related Myocarditis 
Immune-related myocarditis has been associated with the administration of Atezolizumab. Immune-
related myocarditis should be suspected in any patient presenting with signs or symptoms suggestive 
of myocarditis, including, but not limited to, dyspnea, chest pain, palpitations, fatigue, decreased 
exercise tolerance, or syncope. Immune-related myocarditis needs to be distinguished from myocarditis 
resulting from infection (commonly viral, e.g. in a patient who reports a recent history of gastrointestinal 
illness), ischemic events, underlying arrhythmias, exacerbation of pre-existing cardiac conditions, or 
progression of malignancy.
All patients with possible myocarditis should be urgently evaluated by performing cardiac enzyme 
assessment, an ECG, a chest X-ray, an echocardiogram, and a cardiac MRI as appropriate per 
institutional guidelines. A cardiologist should be consulted. An endomyocardial biopsy may be 
considered to enable a definitive diagnosis and appropriate treatment, if clinically indicated. 
Patients with signs and symptoms of myocarditis, in the absence of an identified alternate etiology, 
should be treated according to the guidelines in Table 9. 


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Table 9
Management Guidelines for Immune-Related Myocarditis
Event 
Management 
Immune-related myocarditis, Grade 1 
x
Refer patient to cardiologist 
x
Initiate treatment as per institutional guidelines. 
Immune-related myocarditis, Grade 2 
x
Withhold Atezolizumab for up to 12 weeks after 
event onset a and contact Medical Monitor. 
x
Refer patient to cardiologist 
x
Initiate treatment as per institutional guidelines and 
consider antiarrhythmic drugs, temporary 
pacemaker, ECMO, or VAD as appropriate. 
x
Consider treatment with 1-2 mg/kg/day IV 
methylprednisolone or equivalent and convert to 1-
2 mg/kg/day oral prednisone or equivalent upon 
improvement. a 
x
If event resolves to Grade 1 or better, resume 
Atezolizumab. b  
x
If event does not resolve to Grade 1 or better while 
withholding Atezolizumab, permanently discontinue 
Atezolizumab and contact Medical Monitor. c  
Immune-related myocarditis, Grade 3-4
x
Permanently discontinue Atezolizumab and contact 
Medical Monitor. c  
x
Refer patient to cardiologist 
x
Initiate treatment as per institutional guidelines and 
consider antiarrhythmic drugs, temporary 
pacemaker, ECMO, or VAD as appropriate. 
x
Initiate treatment with 1-2 mg/kg/day IV 
methylprednisolone or equivalent and convert to 1-
2 mg/kg/day oral prednisone or equivalent upon 
improvement. a, b
x
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
x
If event resolves to Grade 1 or better, taper 
corticosteroids over > 1 month. 
ECMO = extracorporeal membrane oxygenation; VAD = ventricular assist device; IV = intravenous. 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to < 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over > 1 month to < 10 mg/day oral 
prednisone or equivalent before Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with Atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 


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Infusion Related Reactions 
No premedication is indicated for the administration of Cycle 1 of Atezolizumab. However, patients 
who experience an infusion-related reaction with Cycle 1 of 
Atezolizumab
may receive premedication with antihistamines or antipyretics/analgesics (e.g., 
acetaminophen) for subsequent infusions. Metamizole (dipyrone) is prohibited in treating Atezolizumab
associated infusion-related reactions, due to its potential for causing agranulocytosis.
Guidelines for medical management of infusion-related reactions during Cycle 1 are provided in Table 
10. For subsequent cycles, infusion-related reactions should be managed according to institutional 
guidelines.
Table 10
Management Guidelines for Infusion-Related Reactions
Event 
Management 
IRR, Grade 1 
x
Reduce infusion rate to half the rate being given at 
the time of event onset. 
x
After the event has resolved, the investigator should 
wait for 30 minutes while delivering the infusion at 
the reduced rate. 
x
If the infusion is tolerated at the reduced rate for 30 
minutes after symptoms have resolved, the infusion 
rate may be increased to the original rate. 
IRR, Grade 2 
x
Interrupt Atezolizumab infusion. 
x
Administer aggressive symptomatic treatment (e.g., 
oral or IV antihistamine, anti-pyretic, glucocorticoids, 
epinephrine, bronchodilators, oxygen). 
x
After symptoms have resolved to baseline, resume 
infusion at half the rate being given at the time of 
event onset. 
x
For subsequent infusions, consider administration of 
oral premedication with antihistamines, anti-pyretics, 
and/or analgesics and monitor closely for IRRs. 
IRR, Grade 3 or 4 
x
Stop infusion. 
x
Administer aggressive symptomatic treatment (e.g., 
oral or IV antihistamine, anti-pyretic, glucocorticoids, 
epinephrine, bronchodilators, oxygen). 
x
Permanently discontinue Atezolizumab and contact 
Medical Monitor. a 
IRR = infusion-related reaction; IV = intravenous. 
a Resumption of Atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with Atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 


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Pancreatic Events 
Symptoms of abdominal pain associated with elevations of amylase and lipase, suggestive of 
pancreatitis, have been associated with the administration of Atezolizumab. The differential diagnosis 
of acute abdominal pain should include pancreatitis. Appropriate work-up should include an evaluation 
for ductal obstruction, as well as 
serum amylase and lipase tests. Management guidelines for pancreatic events, including pancreatitis, 
are provided in Table 11. 
Table 11
Management Guidelines for Pancreatic Events, Including Pancreatitis
Event 
Management
Amylase and/or lipase elevation, Grade 2 
x
Continue Atezolizumab.
x
Monitor amylase and lipase weekly. 
x
For prolonged elevation (e.g., > 3 weeks), consider 
treatment with 10 mg/day oral prednisone or 
equivalent. 
Amylase and/or lipase elevation, Grade 3 
or 4 
x
Withhold Atezolizumab for up to 12 weeks after event 
onset. a 
x
Refer patient to gastrointestinal specialist. 
x
Monitor amylase and lipase every other day. 
x
If no improvement, consider treatment with 1-2
mg/kg/day oral prednisone or equivalent. 
x
If event resolves to Grade 1 or better, resume 
Atezolizumab. b 
x
If event does not resolve to Grade 1 or better while 
withholding Atezolizumab, permanently discontinue 
Atezolizumab and contact Medical Monitor. c  
x
For recurrent events, permanently discontinue 
Atezolizumab and contact Medical Monitor. c 
Immune-related pancreatitis, Grade 2 or 3 
x
Withhold Atezolizumab for up to 12 weeks after event 
onset. a 
x
Refer patient to gastrointestinal specialist. 
x
Initiate treatment with 1-2 mg/kg/day IV 
methylprednisolone or equivalent and convert to 1-2
mg/kg/day oral prednisone or equivalent upon 
improvement. 
x
If event resolves to Grade 1 or better, resume 
Atezolizumab.
x
If event does not resolve to Grade 1 or better while 
withholding Atezolizumab, permanently discontinue 
Atezolizumab and contact Medical Monitor. c  
x
For recurrent events, permanently discontinue 
Atezolizumab and contact Medical Monitor. c  
Immune-related pancreatitis, Grade 4 
x
Permanently discontinue Atezolizumab and contact 
Medical Monitor. c 
x
Refer patient to gastrointestinal specialist. 
x
Initiate treatment with 1-2 mg/kg/day IV 
methylprednisolone or equivalent and convert to 1-2
mg/kg/day oral prednisone or equivalent upon 
improvement. 
x
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
x
If event resolves to Grade 1 or better, taper 
corticosteroids over > 1 month.
IV = intravenous 


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a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to 10 mg/day oral prednisone or equivalent. The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over > 1 month to < 10 mg/day oral 
prednisone or equivalent before Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with Atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
Dermatologic Events 
Treatment-emergent rash has been associated with Atezolizumab. The majority of cases of rash were 
mild in severity and self-limited, with or without pruritus. A dermatologist should evaluate persistent 
and/or severe rash or pruritus. A biopsy should be considered unless contraindicated. Management 
guidelines for dermatologic events are provided in Table 12. 
Table 12 
Management Guidelines for Dermatologic Events
Event
Management
Dermatologic event, Grade 1 
x
Continue Atezolizumab.
x
Consider treatment with topical corticosteroids and/or other 
symptomatic therapy (e.g., antihistamines). 
Dermatologic event, Grade 2 
x
Continue Atezolizumab.
x
Consider patient referral to dermatologist. 
x
Initiate treatment with topical corticosteroids. 
x
Consider treatment with higher-potency topical corticosteroids if 
event does not improve 
Dermatologic event, Grade 3 
x
Withhold Atezolizumab for up to 12 weeks after event onset. a 
x
Refer patient to dermatologist. 
x
Initiate treatment with 10 mg/day oral prednisone or equivalent, 
increasing dose to 1-2 mg/kg/day if event does not improve 
within 48-72 hours. 
x
If event resolves to Grade 1 or better, resume Atezolizumab. b 
x
If event does not resolve to Grade 1 or better while withholding 
Atezolizumab, permanently discontinue Atezolizumab and
contact Medical Monitor. c 
Dermatologic event, Grade 4 
x
Permanently discontinue Atezolizumab and contact Medical 
Monitor. c  
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow for 
corticosteroids (if initiated) to be reduced to < 10 mg/day oral prednisone or equivalent. The acceptable 
length of the extended period of time must be agreed upon by the investigator and the Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over > 1 month to < 10 mg/day oral 
prednisone or equivalent before Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with Atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 


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Neurologic Disorders 
Myasthenia gravis and Guillain-Barré syndrome have been observed with single-agent Atezolizumab.
Patients may present with signs and symptoms of sensory and/or motor neuropathy. Diagnostic work-
up is essential for an accurate characterization to differentiate between alternative etiologies. 
Management guidelines for neurologic disorders are provided in Table 13. 
Table 13
Management Guidelines for Neurologic Disorders
Event 
Management 
Immune-related neuropathy, Grade 1 
x
Continue Atezolizumab.
x
Investigate etiology. 
Immune-related neuropathy, Grade 2 
x
Withhold Atezolizumab for up to 12 weeks after event 
onset. a 
x
Investigate etiology. 
x
Initiate treatment as per institutional guidelines. 
x
If event resolves to Grade 1 or better, resume 
Atezolizumab. b 
x
If event does not resolve to Grade 1 or better while 
withholding Atezolizumab, permanently discontinue 
Atezolizumab and contact Medical Monitor. c  
Immune-related neuropathy, Grade 3 
or 4 
x
Permanently discontinue Atezolizumab and contact 
Medical Monitor. c  
x
Initiate treatment as per institutional guidelines. 
Myasthenia gravis and Guillain-Barré 
syndrome (any grade) 
x
Permanently discontinue Atezolizumab and contact 
Medical Monitor. c  
x
Refer patient to neurologist. 
x
Initiate treatment as per institutional guidelines. 
x
Consider initiation of 1-2 mg/kg/day oral or IV prednisone 
or equivalent. 
IV = intravenous 
a Atezolizumab may be withheld for a longer period of time (i.e., > 12 weeks after event onset) to allow 
for corticosteroids (if initiated) to be reduced to < 10 mg/day oral prednisone or equivalent. The 
acceptable length of the extended period of time must be agreed upon by the investigator and the 
Medical Monitor. 
b If corticosteroids have been initiated, they must be tapered over > 1 month to < 10 mg/day oral 
prednisone or equivalent before Atezolizumab can be resumed. 
c Resumption of Atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with Atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
Immune-Related Meningoencephalitis 
Immune-related meningoencephalitis is an identified risk associated with the administration of 
Atezolizumab. Immune-related meningoencephalitis should be suspected in any patient presenting with 
signs or symptoms suggestive of meningitis or encephalitis, including, but not limited to, headache, neck 
pain, confusion, seizure, motor or sensory dysfunction, and altered or depressed level of consciousness. 
Encephalopathy from metabolic or electrolyte imbalances needs to be distinguished from potential 
meningoencephalitis resulting from infection (bacterial, viral, or fungal) or progression of malignancy, or 
secondary to a paraneoplastic process.
All patients being considered for meningoencephalitis should be urgently evaluated with a CT scan 
and/or MRI scan of the brain to evaluate for metastasis, inflammation, or edema. If deemed safe by the 
treating physician, a lumbar puncture should be performed, and a neurologist should be consulted.
Patients with signs and symptoms of meningoencephalitis, in the absence of an identified alternate 
etiology, should be treated according to the guidelines in Table 14.


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Table 14
Management Guidelines for Immune-Related Meningoencephalitis
Event 
Management 
Immune-related meningoencephalitis, all 
grades 
x
Permanently discontinue Atezolizumab and contact 
Medical Monitor. a 
x
Refer patient to neurologist. 
x
Initiate treatment with 1-2 mg/kg/day IV 
methylprednisolone or equivalent and convert to 1-2
mg/kg/day oral prednisone or equivalent upon 
improvement. 
x
If event does not improve within 48 hours after 
initiating corticosteroids, consider adding an 
immunosuppressive agent. 
x
If event resolves to Grade 1 or better, taper 
corticosteroids over > 1 month. 
IV = intravenous. 
a Resumption of Atezolizumab may be considered in patients who are deriving benefit and have fully 
recovered from the immune-related event. Patients can be rechallenged with Atezolizumab only after 
approval has been documented by both the investigator (or an appropriate delegate) and the Medical 
Monitor. 
Immune related Nephritis
Immune-related nephritis has been associated with the administration of atezolizumab. Eligible patients 
must have adequate renal function, and renal function, including serum creatinine, should be monitored 
throughout study treatment. Patients with abnormal renal function should be evaluated and treated for 
other more common etiologies (including prerenal and postrenal causes, and concomitant medications 
such as nonsteroidal anti-inflammatory drugs). Refer the patient to a renal specialist if clinically 
indicated. A renal biopsy may be required to enable a definitive diagnosis and appropriate treatment. If 
no alternative cause of acute kidney injury is identified, patients with signs and symptoms of acute kidney 
injury, in the absence of an identified alternate etiology, should be treated according to the management 
guidelines for immune-related renal events in the table below.
Table 15
Management Guidelines for Renal Events
Event
Management
Renal event,
Grade 1
x Continue atezolizumab.
xMonitor kidney function, including creatinine, closely until
values resolve to within normal limits or to baseline values.
Renal event,
Grade 2
x Withhold atezolizumab for up to 12 weeks after event onset. a 
xRefer patient to renal specialist.
xInitiate treatment with corticosteroids equivalent to
12 mg/kg/day oral prednisone.
xIf event resolves to Grade 1 or better, resume atezolizumab. b 
xIf event does not resolve to Grade 1 or better while withholding
atezolizumab, permanently discontinue atezolizumab and
contact Medical Monitor. c
Renal event,
Grade 3 or 4
x Permanently discontinue atezolizumab and contact Medical
Monitor.
xRefer patient to renal specialist and consider renal biopsy.
xInitiate treatment with corticosteroids equivalent to
12 mg/kg/day oral prednisone.
xIf event does not improve within 48 hours after initiating
corticosteroids, consider adding an immunosuppressive agent.
xIf event resolves to Grade 1 or better, taper corticosteroids over
t 1 month.
Note: Management guidelines are presented by adverse event severity based on NCI CTCAE and are 
applicable to both CTCAE Version 4.0 and CTCAE Version 5.0. a) Atezolizumab may be withheld for a 


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longer period of time (i.e., 12 weeks after event onset) to allow for corticosteroids (if initiated) to be 
reduced to the equivalent of 10 mg/day oral prednisone. The acceptable length of the extended period 
of time must be agreed upon by the investigator and the Medical Monitor. b) If corticosteroids have 
been initiated, they must be tapered over 1 month to the equivalent of 10 mg/day oral prednisone 
before atezolizumab can be resumed. c) Resumption of atezolizumab may be considered in patients 
who are deriving benefit and have fully recovered from the immune-related event. Patients can be re-
challenged with atezolizumab only after approval has been documented by both the investigator (or an 
appropriate delegate) and the Medical Monitor.
Immune related Myositis
Cases of immune related myositis, including biopsy-confirmed cases, were identified in patients that 
received Atezolizumab. The incidence of myositis observed across the Atezolizumab monotherapy 
clinical program was <0.1%. There were 4 cases of myositis with a fatal outcome with some cases 
suggestive of cardiac involvement (myocarditis or AV block). Immune related myositis is considered an 
important identified risk for Atezolizumab.