Conditions: Acute Myeloid Leukemia
Keywords: AML Acute Myeloid Leukemia Relapsed Acute Myeloid Leukemia Refractory Acute Myeloid Leukemia
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 42
Healthy volunteers: no

Brief summary:
A study is designed to assess if BL-8040 in combination with cytarabine (Ara-C) can help controlling the disease in patients with Acute Myeloid Leukemia (AML) that have relapsed or did not respond adequately to previous treatment. The safety of the study drug combination will also be studied.

Detailed description:
Open-label, multicenter, Phase IIa, dose escalating study in subjects with relapsed/refractory AML, defined according to WHO criteria, including subjects who failed chemotherapy only and those who failed previous Autologous Stem Cell Transplantation (ASCT)/ Allogeneic Stem Cell Transplantation (AlloSCT), provided at least 6 months have passed from transplant.

Eligible subjects will receive subcutaneous (SC) injections of BL-8040 ("monotherapy period") over two days (one injection per day) followed by concurrent administration of BL-8040 with standard salvage chemotherapy ("combined period") over 5 days. During the "combined period," BL-8040 will be administered 4 hours prior to chemotherapy. The chemotherapy will consist of cytarabine (Ara-C) 1.5 or 3 g/m2/d per dose (based on age), administered intravenously (IV) over 3 hours, for 5 days and will not be escalated.

The first part of the study (Part 1) will include escalating dose groups and be considered the 'escalation phase'. Six potential dose levels will be investigated starting at dose level 1. Patients will be accrued in a conventional 3+3 design. Applying this study design, the first cohort of 3 patients will be treated at dose level 1 and evaluated for dose escalation.

At the discretion of the Sponsor, additional subjects may be enrolled into a selected dose group to confirm safety and efficacy for selected dose. the portion of this study is considered expansion phase.

Arms:
arm 1: Arm 1: Participants will be dosed with SC injections of BL-8040 over two days followed by concurrent administration of 0.5 mg/kg BL-8040 with cytarabine (Ara-C) 1.5 or 3 g/m2/d per dose (based on age) during 5 days. arm 2: Arm 2: Participants will be dosed with SC injections of BL-8040 over two days followed by concurrent administration of 0.75 mg/kg BL-8040 with cytarabine (Ara-C) 1.5 or 3 g/m2/d per dose (based on age) during 5 days. arm 3: Arm 3: Participants will be dosed with SC injections of BL-8040 over two days followed by concurrent administration of 1 mg/kg BL-8040 with cytarabine (Ara-C) 1.5 or 3 g/m2/d per dose (based on age) during 5 days. arm 4: Arm 4: Participants will be dosed with SC injections of BL-8040 over two days followed by concurrent administration of 1.25 mg/kg BL-8040 with cytarabine (Ara-C) 1.5 or 3 g/m2/d per dose (based on age) during 5 days. arm 5: Arm 5: Participants will be dosed with SC injections of BL-8040 over two days followed by concurrent administration of 1.5 mg/kg BL-8040 with cytarabine (Ara-C) 1.5 or 3 g/m2/d per dose (based on age) during 5 days. arm 6: Arm 6: Participants will be dosed with SC injections of BL-8040 over two days followed by concurrent administration of 2 mg/kg BL-8040 with cytarabine (Ara-C) 1.5 or 3 g/m2/d per dose (based on age) during 5 days.

Interventions: intervention 1: Ara-C intervention 2: BL-8040
Intervention descriptions: intervention 1: IV (intravenous administration) intervention 2: SC (subcutaneous injection)

Protocol document:
Prot_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: 
NCT01838395 
Sponsor Study Number: 
BL-8040.01 
Official Study Title: 
A Phase IIa, Multicenter, Open-Label Study Designed to 
Evaluate the Safety and Efficacy of Escalating Doses of BL-
8040 in Adult Subjects with Relapsed/Refractory Acute 
Myeloid Leukemia 
Document Version and Date: 
Clinical Study Protocol, version 7, 15 March 2015 
 


 
Investigational Product 
BL-8040 
Abbreviated Title: Phase IIa Study 
Evaluating Safety and Efficacy of BL-
8040 in Relapsed/Refractory AML 
Patients 
 
Protocol No.  
BL-8040.01 
Phase:  
IIa   
Version and Date 
Final Version 7,  
15 Mar 2015 
 
Protocol: BL-8040.01 
Page 1 of 81 
Final version 7, March 15, 2015 
CLINICAL STUDY PROTOCOL 
A PHASE IIA, MULTICENTER, OPEN-LABEL STUDY DESIGNED TO 
EVALUATE THE SAFETY AND EFFICACY OF ESCALATING DOSES 
OF BL-8040 IN ADULT SUBJECTS WITH RELAPSED/REFRACTORY 
ACUTE MYELOID LEUKEMIA  
Sponsors: 
BioLineRx, Ltd. 
 
  
  
IND No. 
 
Investigational Medicinal 
Product 
BL-8040 (previously BKT-140) 
Principal Investigator(s): 
 
 
Protocol Number: 
BL-8040.01 
Study Phase: 
IIa 
Contract Research 
Organization: 
 
Statistics and Data 
Management and 
Pharmacokinetic Analysis: 
 
Sponsor Contact: 
 
 
 
Study Safety Officer:  
 
Protocol Version and Date: 
Version 7, March 15, 2015 
 
 
 
Confidentiality Statement 
This protocol is a confidential communication document of BioLineRx, Ltd. The recipient of this document agrees not to 
disclose the information contained herein to others without prior written authorization of BioLineRx, Ltd. except that this 
document may be disclosed to appropriate Institutional Review Boards/Independent Ethics Committees or duly authorized 
representatives of Regulatory authorities, under the condition that they maintain confidentiality. 




 
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Protocol: BL-8040.01 
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Final version 7, March 15, 2015 
 
Protocol Version History Page 
 
Version 
Main Changes 
01 
Original 
02 
 
Clarification of 3+3 design in synopsis and protocol body 
 
Clarification of MTD definition 
 
Clarification of role of Data Monitoring Committee during dose escalation 
and expansion. 
 
Dose limiting toxicity definition amended in synopsis and protocol body. 
Stopping rules and dose limiting toxicity section moved to Study Design 
section in synopsis for clarity. 
 
Study procedures separated from study design in synopsis and introduced 
into self-contained section. 
03 
 
Removed reference to specific CD markers to be used in characterization of 
leukemic blast cells by FACS analysis in "Study Procedures" section of 
synopsis, Sections 5.2 and 5.7.4 
 
Reinstated footnote on page 12 which was accidentally removed during 
previous amendment. 
 
Removed all references to Day 7 pre-dose sampling for FACS and FISH 
analyses throughout. 
 
Secondary objectives amended because BL-8040 effect on leukemic cell 
mobilization and apoptosis when combined with high-dose Ara-C will not 
be possible following removal of Day 7 FACS and FISH analyses. 
 
References to white cell and blast counts amended throughout the 
document to correct the unit from "/mL" to "/µL." 
 
Reference to approximately 3 US sites 
 
 
 
Deleted check marks from Appendix A, Schedule of Assessments, for 
coagulation sampling on Day 2 and Day 7 pre-dose sampling for FACS and 
FISH analyses.  
 
Edited faulty hyperlinks within document. 
04 
 
 replaces 
 as VP Medical Affairs. 
 
Replace TUNEL assay with caspase-3 staining – deletion of reference 30. 
 
Addition of FACS analysis to Day 30 bone marrow aspirate. 


 
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05 
 
Synopsis Study Design and Investigational Product – Eligible subjects may 
receive one or more injections during the daily administration in case the 
dose is split and injected into more than one site at the discretion of the 
investigator. 
 
Section 6 – In addition to the division of injections, reconstitution and 
administration instructions will be provided in a separate study manual. 
06 
 
Addition of sixth dose level (2.0 mg/kg) with corresponding increase in 
potential patient recruitment to “escalation phase” to 36 patients.  
 
Increase in total patient recruitment to 70 patients. 
 
Removal of restriction on concomitant treatment with high dose steroids. 
07 
 
Update number of participating sites.  
 
Inclusion criteria amended to only include patients in first relapse. 
 
Clarifications provided to inclusion criteria for relapse/refractory patients. 
 
Addition of exclusion criteria – extramedullary AML. 
 
Protocol amended to allow Investigator’s to administer a second treatment 
cycle to subjects in the expansion phase. 
 
Study procedures and Schedule of assessments adjusted accordingly. 
 
Increase in screening window for performing baseline BM biopsy from 72 
hours to 7 days. 
 
Addition of anti-drug antibody assessments. 
 
Addition of telephonic long-term follow up to monitor AML status and 
survival. 
 
Addition of time windows for post-dose safety, efficacy and PK 
assessments. 
 
Addition of flexibility to discontinue PK collections during the expansion 
phase at the Sponsor’s discretion.  
 
Addition of efficacy endpoints – CRc and OS during the long-term follow-
up. 
 
Minor change to concomitant medication section specifically relating to 
BL-8040 injection site and systemic reactions. 


 
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TABLE OF CONTENTS 
Page 
PROTOCOL SYNOPSIS ......................................................................................................................................................... 8 
GLOSSARY ............................................................................................................................................................................ 21 
1 
INTRODUCTION........................................................................................................................................................... 24 
1.1 
THERAPEUTIC INDICATION .................................................................................................................................. 24 
1.2 
INVESTIGATIONAL THERAPY ............................................................................................................................... 24 
1.2.1 
Nonclinical Studies .............................................................................................................................. 24 
1.2.2 
Clinical Studies.................................................................................................................................... 26 
1.3 
STUDY RATIONALE ............................................................................................................................................. 26 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................................................. 28 
2.1 
STUDY OBJECTIVES ............................................................................................................................................. 28 
2.2 
STUDY ENDPOINTS/OUTCOMES ........................................................................................................................... 28 
2.2.1 
Safety Outcomes .................................................................................................................................. 28 
2.2.2 
Efficacy Endpoints .............................................................................................................................. 28 
2.2.3 
Pharmacokinetic Endpoint ................................................................................................................... 29 
2.2.4 
Exploratory Endpoints ......................................................................................................................... 29 
3 
STUDY DESIGN ............................................................................................................................................................. 29 
4 
STUDY POPULATION ................................................................................................................................................. 33 
4.1 
INCLUSION CRITERIA .......................................................................................................................................... 33 
4.2 
EXCLUSION CRITERIA ......................................................................................................................................... 34 
4.3 
SUBJECT IDENTIFICATION .................................................................................................................................... 35 
4.4 
SCREENING FAILURES ......................................................................................................................................... 35 
4.5 
REMOVAL, REPLACEMENT, OR EARLY WITHDRAWAL OF SUBJECTS FROM THERAPY OR ASSESSMENT .................. 35 
4.6 
HANDLING OF WITHDRAWALS ............................................................................................................................ 35 
4.7 
SPONSOR'S TERMINATION OF STUDY ................................................................................................................... 36 
5 
STUDY PROCEDURES AND ASSESSMENTS .......................................................................................................... 36 
5.1 
SCREENING PERIOD (VISIT 1, DAY -7 TO DAY 0) ................................................................................................. 36 
5.2 
TREATMENT PERIOD (VISITS 2-8 AND 10-16, DAY 1 TO DAY 7) ........................................................................... 37 
5.3 
FOLLOW-UP PERIOD (VISITS 9 AND 17) ............................................................................................................... 39 
5.4 
LONG-TERM FOLLOW-UP ................................................................................................................................... 40 
5.5 
EARLY DISCONTINUATION STUDY VISIT .............................................................................................................. 40 
5.6 
UNSCHEDULED VISIT .......................................................................................................................................... 40 
5.7 
SAFETY ASSESSMENTS ........................................................................................................................................ 40 
5.7.1 
Adverse Events (AEs) ......................................................................................................................... 41 
5.7.2 
Concomitant Medications .................................................................................................................... 41 
5.7.3 
Vital Signs ........................................................................................................................................... 41 
5.7.4 
Electrocardiogram ............................................................................................................................... 41 
5.7.5 
Physical Examination .......................................................................................................................... 41 
5.7.6 
Laboratory Safety Assessments ........................................................................................................... 42 
5.7.7 
Anti-drug antibody (ADA) assessment ................................................................................................ 43 
5.7.8 
Leukostasis and Tumor Lysis Syndrome (TLS) .................................................................................. 43 
5.8 
EFFICACY ASSESSMENTS ..................................................................................................................................... 43 


 
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5.8.1 
Response rate ....................................................................................................................................... 43 
5.8.2 
Leukemic cells apoptosis in PB ........................................................................................................... 43 
5.8.3 
Leukemic cells apoptosis in BM.......................................................................................................... 43 
5.8.4 
Leukemic blast counts in PB ............................................................................................................... 44 
5.8.5 
Assessment of Chromosomal Abnormalities by FISH ........................................................................ 44 
5.8.6 
CXCR4 receptor occupancy in PB ...................................................................................................... 44 
5.9 
PK ASSESSMENTS ............................................................................................................................................... 44 
5.10 BLOOD SAMPLING AND PROCESSING ................................................................................................................... 44 
5.11 TIME WINDOWS FOR SAFETY, PK AND EFFICACY ASSESSMENTS ......................................................................... 44 
6 
INVESTIGATIONAL PRODUCT ................................................................................................................................ 45 
6.1 
IDENTITY OF INVESTIGATIONAL PRODUCT ........................................................................................................... 45 
6.2 
STUDY DRUG ADMINISTRATION AND DOSAGE ..................................................................................................... 45 
6.2.1 
BL-8040 .............................................................................................................................................. 45 
6.2.2 
Chemotherapy ..................................................................................................................................... 46 
6.2.3 
Stopping Rules and Dose Limiting Toxicities ..................................................................................... 46 
6.2.4 
Rescue medication ............................................................................................................................... 47 
6.3 
MANUFACTURING OF STUDY MEDICATION .......................................................................................................... 48 
6.4 
PACKAGING AND LABELING OF STUDY MEDICATION ........................................................................................... 48 
6.5 
DISTRIBUTION AND SHIPMENT OF STUDY MEDICATION ....................................................................................... 48 
6.6 
STORAGE, DISPENSING AND RETURN OF THE INVESTIGATIONAL MEDICINAL PRODUCT ........................................ 48 
6.7 
ACCOUNTABILITY AND COMPLIANCE OF INVESTIGATIONAL MEDICINAL PRODUCT .............................................. 49 
6.8 
CONCOMITANT THERAPY .................................................................................................................................... 49 
6.8.1 
Allowed Medications........................................................................................................................... 49 
7 
SAFETY AND PHARMACOVIGILANCE.................................................................................................................. 50 
7.1 
ADVERSE EVENT (AE) ........................................................................................................................................ 50 
7.2 
SERIOUS ADVERSE EVENTS (SAES) .................................................................................................................... 53 
7.3 
DEFINITION OF AN UNEXPECTED ADVERSE EVENT .............................................................................................. 53 
7.4 
EXCEPTIONS IN THE REPORTING OF SAE ............................................................................................................. 54 
7.5 
NOTIFICATION OF SERIOUS ADVERSE EVENT (SAE) ............................................................................................ 54 
8 
STATISTICAL ANALYSIS ........................................................................................................................................... 55 
8.1 
SAMPLE SIZE CONSIDERATION ............................................................................................................................ 55 
8.2 
ANALYSIS SETS................................................................................................................................................... 55 
8.3 
STATISTICAL METHODS ...................................................................................................................................... 55 
8.3.1 
Safety Analysis .................................................................................................................................... 56 
8.3.2 
Efficacy Analysis ................................................................................................................................ 56 
8.3.3 
PK Analysis ......................................................................................................................................... 56 
9 
ETHICS ........................................................................................................................................................................... 56 
9.1 
INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE ............................................................... 56 
9.2 
ETHICAL CONDUCT OF THE STUDY ...................................................................................................................... 57 
9.3 
SUBJECT INFORMATION AND CONSENT ................................................................................................................ 57 
9.4 
SUBJECT INSURANCE ........................................................................................................................................... 57 
9.5 
INFORMING THE GENERAL PRACTITIONER ........................................................................................................... 58 
9.6 
PERSONAL DATA PROTECTION ............................................................................................................................ 58 
9.7 
DATA AND SAFETY MONITORING ........................................................................................................................ 58 


 
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9.8 
PROTOCOL EXCEPTIONS AND DEVIATIONS ........................................................................................................... 58 
9.9 
PROTOCOL AMENDMENTS ................................................................................................................................... 58 
10 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................................................................... 58 
10.1 AUDITS AND INSPECTIONS ................................................................................................................................... 59 
10.2 STUDY MONITORING ........................................................................................................................................... 59 
10.3 QUALITY LABORATORY STANDARDS................................................................................................................... 60 
10.4 STUDY DOCUMENTATION .................................................................................................................................... 60 
10.4.1 Source Document ................................................................................................................................ 60 
10.4.2 Recording of Data on Case Report Form (CRF).................................................................................. 60 
10.4.3 Investigator Site File............................................................................................................................ 61 
10.5 CLINICAL TRIAL SUPPLIES .................................................................................................................................. 61 
10.6 DATA MANAGEMENT .......................................................................................................................................... 61 
11 
STUDY ADMINISTRATION ..................................................................................................................................... 62 
11.1 PARTICIPATING CENTERS .................................................................................................................................... 62 
11.2 REQUIRED DOCUMENTS PRIOR TO STUDY INITIATION .......................................................................................... 62 
11.3 STUDY COMPLETION ........................................................................................................................................... 63 
11.4 CLINICAL STUDY REPORT ................................................................................................................................... 63 
11.5 RETENTION OF STUDY RECORDS ......................................................................................................................... 63 
11.6 CONFIDENTIALITY AND PUBLICATION OF STUDY RESULTS ................................................................................... 64 
11.6.1 General ................................................................................................................................................ 64 
11.6.2 Published Data ..................................................................................................................................... 64 
12 
REFERENCES ............................................................................................................................................................. 66 
13 
APPENDICES .............................................................................................................................................................. 69 
APPENDIX A-SCHEDULE OF ASSESSMENTS ..................................................................................................................... 69 
APPENDIX B-AML DIAGNOSIS CRITERIA ....................................................................................................................... 72 
APPENDIX C-AML RESPONSE DEFINITION FOR CLINICAL TRIALS .................................................................................. 73 
APPENDIX D-CAIRO-BISHOP CRITERIA FOR DIAGNOSIS OF TUMOR LYSIS SYNDROME (TLS) .......................................... 74 
APPENDIX E-EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS ......................................................... 75 
APPENDIX F-DECLARATION OF HELSINKI (2008) ........................................................................................................... 76 
APPENDIX G-CORTICOSTEROID COMPARISON CHART..................................................................................................... 81 
 
List of Tables 
TABLE 1            PLANNED BL-8040 DOSE ESCALATION SCHEDULE .............................................................................................. 9 
TABLE 2            SEVERITY OF ADVERSE EVENTS ACCORDING TO CTCAE (VERSION 4.03) .............................................. 51 
TABLE 3           RELATIONSHIP OF ADVERSE EVENT TO TREATMENT ........................................................................................ 52 
 
 


 
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PROTOCOL SYNOPSIS 
Study Title 
A Phase IIa, Multicenter, Open-label Study Designed to Evaluate the Safety and 
Efficacy 
of 
Escalating 
Doses 
of 
BL-8040 
in 
Adult 
Subjects 
with 
Relapsed/Refractory Acute Myeloid Leukemia  
Protocol No. 
BL-8040.01 
Clinical Sites 
Approximately 5 sites in the USA and 5 sites in Israel are planned.  
Additional sites may be added in the event of slow recruitment. 
Study Phase 
IIa 
Therapeutic 
Indication 
Treatment of Acute Myeloid Leukemia (AML) in relapsed/refractory adult 
subjects  
Study Objectives 
Primary 
 
To assess the safety and tolerability of escalating repeated doses of BL-
8040 administered as monotherapy for two days, followed by five days of 
combined administration with high-dose Ara-C in AML adult subjects 
with relapsed or refractory disease 
Secondary 
 
To assess the clinical efficacy (response rates) of escalating repeated 
doses of BL-8040 administered as monotherapy for two days, followed by 
five days of combined administration with high-dose Ara-C in AML adult 
subjects 
 
To assess the apoptotic effect of BL-8040 on leukemic blasts when 
administered as monotherapy  
 
To assess the effect of BL-8040 on mobilization of AML blasts to 
peripheral blood (PB) when administered as monotherapy  
 
To assess the single and multiple dose pharmacokinetic profile of BL-
8040 
Exploratory 
 
To assess additional pharmacodynamic parameters relevant to CXCR4 
inhibition 
Study Design  
This will be an open-label, multicenter, phase IIa, dose escalating study in subjects 
with relapsed/refractory AML, defined according to WHO criteria (1), including 
subjects who failed chemotherapy only and those who failed previous Autologous 
Stem Cell Transplantation (ASCT) / Allogeneic Stem Cell Transplantation 
(AlloSCT), provided at least 6 months have passed from transplant.  
Eligible subjects will receive subcutaneous (SC) injections of BL-8040 
(“monotherapy period”) over two days (one dose per day that may be administered 
into one or more injection sites) followed by concurrent administration of BL-
8040 with standard salvage chemotherapy (“combined period”) over 5 days. BL-
8040 administration during the “combined period” will also be one dose per day 
into one or more injection sites, at the discretion of the Investigator. During the 
“combined period,” BL-8040 will be administered 4 hours prior to chemotherapy. 


 
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The chemotherapy will consist of cytarabine (Ara-C) 1.5 or 3 g/m2/d per dose 
(based on age), administered intravenously (IV) over 3 hours, for 5 daysa and will 
not be escalated.  
The first part of the study (Part 1) will include escalating dose groups and be 
considered the ‘escalation phase’. Six potential dose levels (see Table 1) will be 
investigated starting at dose level 1. Patients will be accrued in a conventional 3+3 
design. Applying this study design, the first cohort of 3 patients will be treated at 
dose level 1 and evaluated for dose escalation.  
 
Table 1            Planned BL-8040 dose escalation schedule 
Dose Level 
BL-8040 dose (free base) 
per SC injection 
Sample size (N) 
1 
0.5 mg/kg 
3 
2 
0.75 mg/kg 
3 
3 
1.0 mg/kg 
3 
4 
1.25 mg/kg 
3 
5 
1.5 mg/kg 
3 
6 
2.0 mg/kg 
3 
 
If at dose level 1 and beyond, 0 out of 3 patients experience dose-limiting toxicity 
(DLT), then the next cohort of 3 patients will be treated at the next dose level.  If 1 
out of 3 patients develop DLT, an additional 3 patients will be treated at the same 
dose level. If no more DLT develops at that dose, i.e. 1 out of a total of 6 patients 
develops DLT, the dose escalation continues to the next dose level. At any given 
dose, if greater than 1 out of 3 patients or 1 out of 6 patients experience DLT, the 
dose level exceeds the maximum tolerated dose (MTD). In this situation, 3 more 
patients will be treated at the next lower dose if there are less than 6 patients 
already treated at that dose. MTD is defined as the highest dose level in which 6 
patients have been treated with less than 2 instances of DLT. 
The decision to proceed to the next higher dose level will be made by an 
independent Data Monitoring Committee (DMC)b after review of relevant safety 
data collected up to and including Day 30 (± 2 days; Day 28 ± 2 of chemotherapy) 
of the last subject of the previous dose group. The DMC may recommend 
evaluation of intermediate doses (or doses lower than the starting dose of 0.5 
mg/kg) of BL-8040 in combination with Ara-C. 
Dose escalation will be permitted until the MTD is established and protocol 
specific stopping rules for toxicity are met. If no MTD is reached, dose escalation 
will continue up to dose level 6 (2.0 mg/kg). It is anticipated that up to 36 eligible 
patients will be required for the dose escalation. 
At the discretion of the Sponsor, additional subjects may be enrolled into a 
selected dose group to confirm safety, efficacy and pharmacokinetic (PK) profile 
for the selected dose, bringing the study up to approximately 70 subjects in total. 
This portion of the study will be considered the ‘expansion phase’ (Part 2). The 
DMC, in consultation with the Sponsor and Investigators, will decide on the 
selected dose level for expansion based on safety data, MTD, other relevant 
toxicity considerations, and all available pharmacokinetic (PK) and correlative 
                                                 
a  Subjects ≤ 60 years will receive Ara-C 3 g/m2/d, and those > 60 years will receive Ara-C 1.5 g/m2/d  
b Data Monitoring Committee will be comprised of 3 members appointed by the Sponsor including at least one 
clinician, and persons knowledgeable of the investigational drug. 


 
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pharmacodynamic (PD) data. 
During Part 2 of the study, at the Investigator’s discretion and after discussion 
with the Sponsor, subjects may be treated with a second cycle of BL-8040 in 
combination with Ara-C if they are considered to have had clinical benefit during 
the first treatment cycle, but failed to achieve complete remission (CR or CRi). In 
the event that subjects receive a second treatment cycle, the dosing regimen will 
be identical to that in the first treatment cycle. The second treatment cycle will 
start after clinical response assessment has been completed for the first treatment 
cycle, i.e., no sooner than Day 30 (± 2 days; Day 28 ± 2 of chemotherapy).  
During Part 2 of the study, any DLT occurring at a frequency of > 30% will stop 
accrual. In this situation, the DMC, in consultation with the Sponsor and 
Investigators, may recommend a lower dose level for the expanded cohort. 
Stopping Rules and Dose Limiting Toxicities 
Dose-limiting toxicity (DLT)a is defined as a clinically significant adverse event 
or abnormal laboratory value assessed as unrelated to disease progression, 
intercurrent illness or concomitant medications and occurring during the safety 
period (30 days)b that meets any of the following criteria (refer to Table 2 for 
CTCAE severity grading): 
  
 CTCAE grade 3 AST (SGOT) or ALT (SGPT) or bilirubin for ≥ 7 days 
 CTCAE grade 4 AST (SGOT) or ALT (SGPT) of any duration 
 All other clinically significant, non-hematological NCI common terminology 
criteria that are CTCAE grade 3 or 4 
 
To be considered a DLT such toxicity must be possibly, probably or definitely 
related to BL-8040. 
An adverse event must be clinically significant to define DLT e.g. nausea and 
vomiting, alopecia, study drug-related fever, electrolyte abnormalities (including 
K, Na, Cl, HCO3, Mg, Ca, bilirubin) that are ≤ grade 3 will not constitute DLT.  
Myelosuppression and cytopenias are expected outcomes of leukemia treatment 
and per se will not constitute DLT. Only prolonged myelosuppression, as defined 
by the NCI criteria specific for leukemia, i.e. marrow cellularity < 5% on Day 42 
or later (6 weeks) from start of therapy without evidence of leukemia, will be 
considered in defining MTD and DLT.   
Subjects experiencing ≥ grade 3 BL-8040-related toxicity, either in the 
monotherapy or combined treatment period (excluding hematological toxicity), 
will be withdrawn from the study, but followed for toxicity. Subjects who 
experience toxicity, which is not related to BL-8040, either during monotherapy or 
within the combination therapy period, will be allowed to continue BL-8040 
treatment at the Investigator's discretion.  
BL-8040 injections will be stopped in case of a significant increase in WBC 
and/or blasts (WBC ≥ 60,000/µL and/or blasts ≥ 50,000/µL, respectively) 
measured prior to administration of the next BL-8040 injection and/or evidence of 
leukostasis, TLS or grade 3-4 allergic reaction. These subjects will be withdrawn 
                                                 
a Only drug related or possibly related grade 3-4 define DLT. For example, bone pain at grade 3/4 will not 
necessarily be defined as DLT, based on physician's decision and accounting for other administered drugs. 
b In case of prolonged BM recovery it will be evaluated again at 6 weeks and considered part of the DLT 
assessment. The safety period for subjects who receive a second treatment cycle in the expansion phase will be 
30 days after the start of the second treatment cycle or up to 6 weeks in the event of delay in BM recovery. 


 
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from the study and will be followed-up for safety for up to 6 weeks. In addition, 
during the escalation phase, subjects with blast values of ≥ 30,000 and < 
50,000/µL and/or WBC counts of ≥ 50,000 and < 60,000/µL 24 hrs following BL-
8040 injection on Days 1-6, will be withdrawn from the study and replaced. 
During the expansion phase of the study, subjects with blast values of ≥ 30,000 
and < 50,000/µL and/or WBC counts of ≥ 50,000 and < 60,000/µL, 24 hrs 
following the first BL-8040 injection, will not receive the second injection. 
Provided there are no signs of leukostasis on detailed physical examination, they 
will proceed directly to the combination therapy stage (protocol Day 3). In this 
situation, subjects will not receive BL-8040 prior to the first dose of Ara-Ca, but 
will receive BL-8040 prior to Ara-C on subsequent days provided blast count is < 
30,000/µL and WBC count is < 50,000/µL. 
Similarly, subjects with blast values of ≥ 30,000 and < 50,000/µL and/or WBC 
counts of ≥ 50,000 and < 60,000/µL 24 hrs following the second BL-8040 
injection will be given the first dose of Ara-C without receiving BL-8040b, 
provided there are no signs of leukostasis on detailed physical examination, but 
will receive BL-8040 prior to Ara-C on subsequent days provided blast count is < 
30,000/µL and WBC count is < 50,000/µL. 
Subjects who do not receive BL-8040 on Days 2 and/or 3, will not provide the full 
data set required for assessment of secondary endpoints relating to leukemic blast 
apoptosis and mobilization. However, they will be considered eligible for 
assessment of the secondary efficacy endpoint relating to response rate.  
During the combination therapy, if blast values are ≥ 30,000/µL, BL-8040 
administration will be discontinued. 
Study Procedures 
The study will comprise a screening period, a treatment period (monotherapy and 
combined treatment) and a follow-up period. For each dose group, visit scheduling 
and assessments will be similar. During the expansion phase, at the Investigator’s 
discretion and after discussion with the Sponsor, subjects may be treated with a 
second cycle of BL-8040 in combination with Ara-C if they are considered to 
have had clinical benefit during the first treatment cycle, but failed to achieve CR 
or CRi. 
Screening Period (Day -3 to Day 0) 
After signing informed consent, adult men and women subjects aged 18-75 years 
will be screened for study eligibility by assessment of inclusion and exclusion 
criteria.  
Screening procedures will include  
 
Collection of demographic data, medical history, physical examination 
(including height, weight and assessment of cerebellar function), vital 
signs (blood pressure, pulse rate, oral temperature, O2 saturation levels 
                                                 
a Subjects who skip Day 2 due to blast counts ≥ 30,000 and < 50,000 and or WBC counts ≥ 50,000 and < 
60,000/mL 24 hrs following the 1st dose of BL-8040, will proceed directly to protocol Day 3. All Day 3 
assessments and procedures will be performed with the exception of BL-8040 administration and the following 
post-dose assessments: PK profiling, ECG measurements, WBC count (differential and leukemic cells), partial 
biochemistry and assessment of CXCR4 receptor occupancy, leukemic blast apoptosis and mobilization 
(FACS and FISH). BM biopsy and/or aspiration must be performed prior to Ara-C administration. 
b Subjects with blast counts ≥ 30,000 and < 50,000 and/or WBC counts ≥ 50,000 and < 60,000/mL 24 hrs 
following the 2nd dose of BL-8040, will undergo all Day 3 assessments and procedures with the exception of 
BL-8040 administration and the following post-dose assessments: PK profiling, ECG measurements, WBC 
count (differential and leukemic cells), partial biochemistry and assessment of CXCR4 receptor occupancy, 
leukemic blast apoptosis and mobilization (FACS and FISH). BM biopsy and/or aspiration must be performed 
prior to Ara-C administration. 


 
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and respiration rate), Eastern Cooperative Oncology Group (ECOG) 
performance status, 12-lead electrocardiogram (ECG), Echocardiogram 
(ECHO)/Multiple Gated Acquisition (MUGA), chest x-ray and safety 
laboratory evaluations (hematology, biochemistry, coagulation [PT and 
aPTT] and a serum pregnancy test for women of childbearing potential).  
 
Screening for HIV, HCV, HBV serology. 
 
Clinical evaluation of leukostasis (2) related symptoms (visual symptoms, 
shortness of breath and decreased oxygen saturation in blood measured by 
pulse oximetry) and tumor lysis syndrome (TLS, according to Cairo–
Bishop criteria (3); Appendix D). 
 
Bone marrow (BM) biopsy and aspirate will be conducted within 7 days 
prior to commencement of the treatment for baseline assessment of 
leukemic cell numbers and apoptosis in BM. 
 
CXCR4 levels and other relevant parameters will be assessed by 
immunohistochemistry (IHC) and/or other techniques in pre- BL-8040 
BM biopsy samples and will be analyzed for correlation to efficacy. 
Treatment Period (Day 1 to Day 7) 
Monotherapy period – On Day 1 (Baseline, enrollment day) and Day 2, eligible 
subjects will receive BL-8040 monotherapy administered by SC injection(s), once 
daily in the morning.  
Subjects considered suitable for a second treatment cycle during the expansion 
phase will receive BL-8040 monotherapy on Days 1 and 2 of the additional cycle 
as described above. 
Combined therapy period – On Days 3-7, subjects will be treated once daily in the 
morning with BL-8040 SC injection(s) followed by chemotherapy 4 (± 0.5) hours 
later. The chemotherapy will consist of Ara-C 1.5 or 3 g/m2/d administered IV 
over 3 hoursa. 
Subjects considered suitable for a second treatment cycle during the expansion 
phase will receive BL-8040 in combination with Ara-C on Days 3-7 of the 
additional cycle as described above. 
The following assessments will be conducted during the treatment period: 
 Laboratory safety evaluationsb: 
o Hematology (CBC) and biochemistry samples will be collected 
daily on Days 1-7 prior to administration of BL-8040. 
o Coagulation (PT and aPTT) will be evaluated on Day 1 pre-dose 
and 24 hrs post-dose, and on Day 7 at 24 hrs post-dose.  
o WBC counts, including differential and leukemic cell count, will 
be measured on Days 1, 2, 3 and 7 at 4 and 8 hrs post BL-8040 
injection.  
o Partial biochemistry samples (electrolytes and kidney function) 
will be collected on Days 1, 2, 3 and 7 at 4 and 8 hrs post BL-
8040 injection.  
o Additional hematology, biochemistry and coagulation samples 
may be collected at the discretion of the Investigator or upon 
                                                 
a Subjects ≤ 60 years will receive Ara-C 3 g/m2/d, and those > 60 years will receive Ara-C 1.5 g/m2/d  
b Subjects considered suitable for a second treatment cycle during the expansion phase will undergo the same 
laboratory safety evaluations during the second cycle with the exception of coagulation and partial 
biochemistry evaluation. 


 
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Sponsor's request. 
 Anti-drug antibody (ADA) and complement activation: 
o Blood samples for assessment of ADA and complement activation 
will be collected pre-dose and at 4 hrs post BL-8040 
administration on Days 1 and 7. On Day 3 an ADA sample will be 
collected pre-dose only. 
 Pharmacokinetic (PK) samplinga: 
o Blood samples for BL-8040 PK analysis will be collected on Days 
1, 3 and 7 at pre-dose, 0.25, 0.5, 1, 2, 4, 8 and 24 hrs post BL-
8040 administration.  
o Samples will also be collected on Day 5 at pre-dose and 0.5 hr 
post BL-8040 administration.  
o PK sampling may be discontinued during the expansion phase at 
the discretion of the Sponsor. The Sponsor will notify sites when 
PK sample collection can be halted. 
 12-lead ECGs: 
o 12-lead ECGs will be recorded on Days 1, 3 and 7 at pre-dose, 
0.5, 1, 2, 4, 8 and 24 hrs post BL-8040 administration. For 
subjects receiving a second treatment cycle during the expansion 
phase, ECGs will only be recorded on Days 1 and 7 of the second 
cycle at pre-dose and 4 hrs post BL-8040 administration. 
o Additional ECGs may be recorded at the discretion of the 
Investigator or upon Sponsor's request. 
 BM biopsy and/or aspirateb: 
o Bone marrow biopsy and/or aspiration will be performed on Day 
3 (prior to BL-8040 injection) for quantitative assessment of 
leukemic blast number and apoptosis of leukemic cells in the BMc 
using caspase-3 staining. 
 Fluorescence-activated cell sorting (FACS) analysisd: 
o Leukemic blasts in peripheral blood (PB) will be assessed by 
analysis of surface markers on Days 1 and 3 at pre-dose, 4e and 24 
hrs post BL-8040 injection. Additional signaling pathway proteins 
may be assessed at the discretion of the Sponsor. 
o Leukemic cell apoptosis in PB will be assessed by Annexin V and 
Propidium iodide (PI) analysis on Days 1 and 3 at pre-dose, 4e 
and 24 hrs post BL-8040 injection.  
o CXCR4 occupancy will be measured in the PB of dose escalation 
phase subjects, using the CXCR4 antibodies 12G5 and 1D9, on 
Days 1 and 3 at pre-dose, 4e and 24 hrs post BL-8040 injection. 
 Fluorescent In Situ Hybridization (FISH) analysisf: 
                                                 
a PK sampling will only be performed during the first treatment cycle for subjects in the expansion phase.  
b Day 3 BM sampling will only be performed during the first treatment cycle for subjects in the expansion 
phase. 
c Subjects who do not undergo BM evaluation on Day 3 will still be included in the safety and efficacy 
evaluation.  
d FACS analysis will only be performed during the first treatment cycle for subjects in the expansion phase. 
e 4 hr post-dose samples on Day 3 to be taken prior to administration of Ara-C. 
f FISH analysis will only be performed during the first treatment cycle for subjects in the expansion phase. 


 
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o In the expansion phase of the study, subjects with identifiable 
chromosomal abnormalities will be assessed by FISH in PB 
and/or BM aspirate collected on Days 1 and 3 at pre-dose, 4a and 
24 hrs post BL-8040 injection.  
 Clinical evaluations: 
o Vital signs, physical examination, including assessment of 
cerebellar function and recording of adverse events (AEs) and 
concomitant medications will be performed daily on Days 1-7 
prior to administration of BL-8040. For expansion phase subjects 
receiving a second treatment cycle, the same assessments will be 
performed daily on Days 1-7 prior to administration of BL-8040.  
o Clinical evaluation of leukostasis (2) related symptoms (visual 
symptoms, shortness of breath and decreased oxygen saturation in 
blood measured by pulse oximetry) and tumor lysis syndrome 
(TLS, according to Cairo–Bishop criteria (3)) will be assessed on 
Day 1 and upon commencement of such symptoms or when WBC 
≥ 30,000/µL. 
 
Follow-up period  
The follow-up period will start after completion of Ara-C chemotherapy and 
continue for up to 6 weeks after initiation of salvage chemotherapy with Ara-C, 
i.e., up to Day 44. Expansion phase subjects who receive a second treatment cycle 
will also be followed for up to 6 weeks after initiation of Ara-C during the second 
cycle, i.e., up to Day 44 of the second cycle. 
Bone marrow biopsy and aspiration will be performed on Day 30 (± 2 days; 28 ± 2 
days from initiation of salvage chemotherapy) unless, in the opinion of the 
Investigator, earlier biopsy/aspiration is indicated based on early appearance of 
blast cells in PB. The follow-up period will end when a BM biopsy and/or 
aspirate, performed between Day 20 – 44, provides definite assessment of 
response to therapy. Bone marrow aspirate collected during this time frame will be 
examined by FACS analysis for final assessment of leukemic cell numbers. 
In subjects who do not show sufficient BM recovery by Day 30 (in the absence of 
leukemic cells), BM biopsy and aspiration will be repeated 2 weeks later (Day 44) 
to exclude aplasia. Additional bone marrow aspirations may be performed at the 
Investigator’s discretion to assess response.   
Haematology and biochemistry tests will be performed twice a week for the 
duration of the follow up period. Follow-up assessments will also include time to 
recovery of WBC and platelets, recording of AEs and concomitant medications 
and collection of an ADA sample at the end of the follow-up period.  
For expansion phase subjects receiving a second treatment cycle, bone marrow 
biopsy/aspiration and follow-up assessments following the second treatment cycle 
will be performed as described above. However, ADA sample collection will only 
take place at the end of the follow-up period following the first treatment cycle. 
Long-term Follow-up 
Subjects participating in the expansion phase will be followed for up to 5 years 
after completion of the Follow-up period. Sites will contact subjects by telephone 
at approximately 3 month intervals (± 1 month) after the end of the follow-up 
period to determine AML status and survival. 
                                                 
a 4 hr post-dose samples on Day 3 to be taken prior to administration of Ara-C. 


 
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Study Duration 
The study duration for each subject will be up to 7 weeks as followsa: 
Study Period 
Duration 
Screening period 
7 days 
Treatment Period: 
 
    Monotherapy period 
2 days 
    Combined therapy period   
5 days 
Follow up period 
up to 5 weeks (measured from end of 
salvage chemotherapy with Ara-C) 
Planned Sample 
Size 
The exact number of subjects enrolled will depend on the toxicity observed in 
each dose group and the number of dose groups required to reach MTD. If all six 
dose groups are required and if each dose group is expanded to 6 subjects (see 
stopping rules below), then a total of 36 subjects will be enrolled into the dose 
escalation part of the study. 
Once a dose has been selected for the expansion phase, additional subjects may 
be enrolled in that dose group up to a total of approximately 70 subjects in the 
study. 
Inclusion Criteria 
1. Adult men and women subjects aged 18 to 75, inclusive. 
2. Confirmed diagnosis of relapsed/refractory AML (WHO criteria (1); Appendix 
B). 
 Refractory subjects after up to 2 cycles of induction therapyb or first 
complete response (CR1) duration ≤ 90 days. 
 Relapse occurring > 90 days and ≤ 24 months since CR1c.  
3. AML relapse > 6 months since autologous or allogeneic stem cell 
transplantation, provided they are in first relapse and:  
 No active graft-versus-host disease (GVHD > grade 1). 
 No treatment with high dose steroids for GVHD (up to 20 mg 
Prednisolone or equivalent, Appendix G). 
 No treatment with immunosuppressive drugs with the exception of low 
dose cyclosporine and tacrolimus (blood levels of 0.5-0.6 µg/mL). 
4. Clinical laboratory values should be as follows: 
 WBC < 30,000/µL 
 Blasts in PB ≤ 20,000. Treatment with Hydroxyurea is permitted up to 
24 hrs prior to BL-8040 administration to achieve blast counts < 20,000 
prior to enrollment. 
 Creatinine < 1.3 mg/dL; if Creatinine is > 1 mg/dL the Creatinine 
clearance should be > 40 mL/min as calculated using the Cockcroft-
                                                 
a The study duration for subjects participating in the expansion phase who receive a second treatment cycle 
will be up to approximately 13 weeks. 
b Subjects who have failed to respond to up to 2 prior induction treatment regimens will be considered eligible. 
Prior induction therapy must include at least 1 cycle of an anthracycline (e.g., at least 45 mg/m2/dose 
daunorubicin or at least 9 mg/m2/dose idarubicin) or anthracenedione (e.g., at least 10 mg/m2/dose 
mitoxantrone) and cytarabine-based regimen. 
c Relapsed subjects must have achieved a CR or CRi lasting > 90 days, resulting from no more than 2 cycles of 
induction cytotoxic chemotherapy including at least 1 cycle of an anthracycline (e.g., at least 45 mg/m2/dose 
daunorubicin or at least 9 mg/m2/dose idarubicin) or anthracenedione (e.g., at least 10 mg/m2/dose 
mitoxantrone) and cytarabine-based regimen. An unlimited number of consolidation cycles following CR1 are 
allowed. 


 
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Gault formula.  
5. Women of childbearing potential and all men must agree to use an approved 
form of contraception (e.g. oral, transdermal patch, implanted contraceptives, 
intrauterine device, diaphragm, condom, abstinence or surgical sterility) prior 
to study entry and for the duration of study participation through 30 days after 
the last dose of BL-8040. Confirmation that female subjects are not pregnant 
must be established by a negative serum β-human chorionic gonadotropin (β-
hCG) pregnancy test result obtained during screening. Pregnancy testing is not 
required for post-menopausal or surgically sterilized women. 
6. Subject is able and willing to comply with the requirements of the protocol. 
7. Subject is able to voluntarily provide written informed consent. 
Exclusion criteria 
1. Administration of conventional chemotherapy within 2 weeks of enrollment 
date. In the event that subjects have received chemotherapy > 2 weeks from 
the date of enrollment, they may be included provided they have recovered 
from the associated non-hematological toxicities to ≤ grade 1.  
2. Life expectancy of ≤ 2 months.  
3. Known allergy or hypersensitivity to any of the test compounds, materials or 
contraindication to test product. 
4. Use of investigational device or agents within 2 weeks of enrollment date. 
5. Low Performance Status (ECOG > 2; Appendix E). 
6. O2 saturation < 92% (on room air), evidence of TLS > grade 2 (according to 
the Cairo-Bishop criteria (3)) or leukostasis (2). 
7. Abnormal liver function tests: 
o Serum 
aspartate 
transaminase 
(AST/SGOT) 
or 
alanine 
transaminase (ALT/SGPT) 2 x upper limit of normal (ULN). 
o Serum bilirubin. Total bilirubin > 2.0 mg/dL (34 µmol/L), 
conjugated bilirubin > 0.8 mg/dL. 
8. Left ventricular ejection fraction < 40 %. 
9. History of myocardial infarction or cerebrovascular accident within 6 months 
of enrollment date. 
10. Presence of active, uncontrolled infection. 
11. Known central nervous system disease (e.g., Alzheimer’s disease). 
12. Acute promyelocytic leukemia.  
13. Exposure to high dose Ara-C within 6 months of enrollment. 
14. Subject has 
concurrent, 
uncontrolled 
medical 
condition, 
laboratory 
abnormality, or psychiatric illness which could place him/her at unacceptable 
risk, including, but not limited to: 
o Subject has been diagnosed or treated for another malignancy 
within 3 years of enrolment, except in situ malignancy, or low-
risk prostate, skin or cervix cancer after curative therapy 
o A co-morbid condition which, in the view of the Investigators, 
renders the subject at high risk from treatment complications. 
15. Female subjects who are pregnant or breastfeeding. 
16. Prior clinically significant grade 3-4 non-hematological toxicity to high dose 
Ara-C or grade ≥ 2 of neurological toxicity.  
17. Seropositive for HIV antibodies (HIV1 and HIV2), Hepatitis C antibody (Hep 
C Ab) or a Hepatitis B carrier (positive for Hepatitis B surface antigen 
[HBsAg]). 
18. Unable to comply with study requirements in the opinion of the Investigator. 


 
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19. Extramedullary AML involvement (including CNS involvement). 
Investigational 
Product Route and 
Dosage Form 
BL-8040 (formally named BKT140) is a highly selective CXC chemokine 
receptor 4 (CXCR4) antagonist co-developed by 
 and 
BioLineRx, Ltd. as a novel therapy for treatment of cancer.   
BL-8040, a white to off-white powder synthetic polypeptide, is freely soluble in 
water. It is manufactured in accordance with cGMP by 
 
 
 
On Days 1 and 2, subjects will receive once daily SC injections of BL-8040 in the 
morning according to the dose group to which they are assigned.  
Between Days 3 and 7, BL-8040 will be administered once daily 4 (+/- 0.5) hrs 
prior to administration of standard chemotherapy (chemotherapy will be initiated 
on Day 3). The same instructions are applicable for expansion phase subjects who 
receive a second treatment cycle.  
 
The BL-8040 injection site will be rotated on Days 1-7, to minimize the severity 
of any local injection site reactions. At the discretion of the Investigator, a single 
dose administration may be split and injected into more than one site. The same 
instructions are applicable for expansion phase subjects who receive a second 
treatment cycle. 
 
During the expansion phase of the study, subjects with blast values of ≥ 30,000 
and < 50,000/µL and/or WBC counts of ≥ 50,000 and < 60,000/µL, 24 hrs 
following the first BL-8040 injection, will not receive the second injection. 
Provided there are no signs of leukostasis on detailed physical examination, they 
will proceed directly to the combination therapy stage (protocol Day 3). In this 
situation, subjects will not receive BL-8040 prior to the first dose of Ara-C, but 
will receive BL-8040 prior to Ara-C on subsequent days provided blast count is < 
30,000/µL and WBC counts is < 50,000/µL. 
 
Similarly, subjects with blast values of ≥ 30,000 and < 50,000/µL and/or WBC 
counts of ≥ 50,000 and < 60,000/µL 24 hrs following the second BL-8040 
injection will be given the first dose of Ara-C without receiving BL-8040, 
provided there are no signs of leukostasis on detailed physical examination, but 
will receive BL-8040 prior to Ara-C on subsequent days provided blast count is < 
30,000/µL and WBC counts is < 50,000/µL. 
 
The planned dose escalation scheme will be as shown in Table 1. Dose 
modifications may include dose reductions, including doses lower than the starting 
dose of 0.5 mg/kg, and intermediate doses, but the maximum dose to be tested will 
not exceed 1.5 mg/kg. 
 
Chemotherapy 
Chemotherapy will consist of Ara-C 3g/m2/day for subjects ≤ 60 years 
(performance status permitting) and 1.5 g/m2/day for subjects > 60 years 
administered IV over 3 hours. 
 
Rescue medication 
Leukostasis: Initiation of chemotherapy will be expedited in subjects experiencing 
leukostasis. Additionally, leukopharesis should be considered. Subjects 


 
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developing shortness of breath with reduced saturation should be carefully 
monitored and receive oxygen.  
TLS: Subjects should be hydrated vigorously (urine output and fluid input should 
be monitored). Allopurinol and Rasburicase should be considered.   
Concomitant 
Medications 
The following concomitant medications/therapies will be allowed during the 
treatment period: 
 
Allopurinol up to 300 mg/day (with adjustment to kidney function) and/or 
Rasburicase (up to 0.2 mg/kg/day, for up to 5 days). 
 
Clinically appropriate measures in case of BL-8040-related local injection 
site reactions (e.g., corticosteroids, anti-histamines, local treatments etc.) 
and preventive treatment before subsequent doses; also relevant for subjects 
with systemic reactions. 
 
Systemic and allergic treatment for chemotherapy-related allergic reactions. 
 
Antiemetic drugs (e.g., Ondansetron) as required clinically based on local 
guidelines for patients experiencing nausea while treated with BL-8040 
only, and as a preventive approach during the combined treatment period. 
 
Gastrointestinal and kidney protective medications, routinely used in 
patients receiving chemotherapy, aiming to avoid peptic pain and TLS 
respectively (Losec, allopurinol, respectively). 
 
Prophylactic antibiotics (e.g., quinolone or cephalosporin), antifungals 
(e.g., voriconazole) and antivirals (e.g., valacyclovir). 
 
Blood products, commonly required in patients receiving chemotherapy for 
AML.  
 
Low-dose steroids (100 mg hydrocortisone or equivalent) are allowed as 
pre-medication for blood transfusion or with IV anti-fungals. 
 
B6 – provided to avoid neurotoxicity. 
 
Steroid eye drops - to prevent Ara-C induced inflammation.   
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 where 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).  
Study Endpoints 
Safety Endpoints 
 
Safety and tolerability will be the primary endpoints of this study and will 
be evaluated on the basis of the following parameters: 
 
General safety: Vital signs (oral temperature, blood pressure, pulse rate, 
respiratory rate and O2 saturation), 12-lead ECG and physical 
examination. 
 
Toxicity according to the latest version of NCI-CTCAE (currently V4.03, 
refer to Table 2) for AEs and clinical laboratory profile as follows:  
o Screening: record and report screening results, however not 
considered treatment emergent AEs.  
o Throughout the study: record and report all AEs and SAEs 
according to GCP.  
 
Efficacy Endpoints 
 
Efficacy endpoints will be secondary endpoints for this study.  
The following secondary endpoints will be assessed: 


 
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 
Response rates as assessed at final BM evaluation based on Cheson 2003 
criteria (4) (Appendix C): 
o Complete response (CR)  
o Complete response with incomplete hematological recovery of 
platelets or neutrophils (CRi) 
o Partial response (PR) 
o Overall response defined as the sum of CR, CRi and PR.  
o Complete Response composite (CRc) defined as the sum of CR 
and CRi. 
 
Change in leukemic cell apoptosis in PB and BM. 
 
Kinetics of mobilization of leukemic blasts from BM to PB. 
 
Overall survival (OS) during the long-term follow-up defined as time 
from enrollment to death from any cause. 
 
Pharmacokinetic Endpoints 
 
PK analysis of multiple injections of BL-8040. 
 
For PK analyses, blood samples will be collected on Days 1, 3 and 7 at 
pre-dose, 0.25, 0.5, 1, 2, 4, 8 and 24 hrs post BL-8040 administration. 
Additional samples will be collected on Day 5 at pre-dose and 0.5 hr post 
BL-8040 administration. 
 
Non-compartmental PK parameters for BL-8040 (see below) will be 
derived from the individual concentration obtained at each of the PK time-
points. Additional PK parameters may be derived if considered necessary: 
o Cmax - maximum BL-8040 plasma concentration 
o Tmax - time to reach the maximum BL-8040 plasma concentration 
o AUC0-t - Area under the BL-8040 plasma concentration-time 
curve from time of administration up to the last time point with a 
measurable concentration post dosing, calculated by linear up-
logarithmic down trapezoidal summation 
o AUC0-∞ - Area under the BL-8040 plasma concentration-time 
curve extrapolated to infinity, calculated as: AUC0-∞ = AUC0-t 
+ Clast/λz, where Clast is the last measurable concentration  
o λz - elimination rate constant, determined by linear regression of 
the terminal points of the ln-linear plasma concentration-time 
curve 
o t1/2 - terminal elimination half-life, defined as 0.693/λz 
 
Exploratory Endpoints 
 
CXCR4 receptor occupancy 
 
Additional pharmacodynamic endpoints relevant to CXCR4 inhibition. 
 
Anti-BL-8040 antibody titers 
Statistical Analysis  
 
Analysis Sets: 
Intention-To-Treat (ITT) analysis set: All enrolled subjects who receive at least 
one dose of study medication.  
 
Per-Protocol (PP) analysis set: All enrolled subjects who complete the study 
according to the protocol without major protocol violations.  


 
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General Statistical Methods  
All measured variables and derived parameters will be listed individually and, if 
appropriate, tabulated by descriptive statistics. Summary statistics will be 
provided for all safety, exploratory and baseline/demographic variables. For 
categorical variables, frequency tables including percentages will be presented. 
For continuous variables, descriptive statistics such as number of available 
observations, mean, median, standard deviation (SD), minimum and maximum 
will be tabulated. All available data and the tabulation of results will be displayed 
by initial dose level and with all levels pooled as a whole if applicable. 
DLT will be determined by definition and will be summarized by dose level. MTD 
will be determined by study structure and DLTs.   
The data will be analyzed as described in the Statistical Analysis Plan. 
 
Safety Analysis: 
Changes in vital signs and routine laboratory data will be presented with 
descriptive statistics to demonstrate the trend of change. 
Number of subjects with physical abnormality at each scheduled visit will be 
tabulated by body system and by dose level. ECG examination results will be 
displayed in descriptive statistics and by dose level with number of subjects with 
abnormal findings tabulated for each schedule visit. 
Adverse event incidence will be summarized descriptively by system organ class 
and preferred term using the latest version of Medical Dictionary for Regulatory 
Activities (MedDRA; currently version 14.0) and by dose level. The worst 
severity grade of AEs, as determined by the latest version of the National Cancer 
Institute Common Terminology Criteria for Adverse Events  (NCI-CTCAE; 
currently version 4.03), and their relationship to study medication will be analyzed 
by System Organ Class, preferred term and by original dose level. The action 
taken and outcome will also be analyzed accordingly. 
By subject list of toxicity severity grade will be presented in time-sequence 
manner using the latest version of NCI-CTCAE (currently 4.03) with System 
Organ Class and preferred term. The number and incidence of subjects 
experiencing toxicity will be tabulated by worst severity grade in each MedDRA 
term. Subjects experiencing toxicity ≥ grade 3 for each type of toxicity will be 
calculated and presented by original dose level. 
 
Efficacy Analysis 
95% Confidence Interval (CI) will be calculated for proportion of subjects defined 
in the secondary efficacy endpoints (4) (Appendix C) who achieve:  
Complete Response (CR)  
Complete Response with incomplete hematological recovery (CRi) 
Partial Response (PR)  
Overall Response (OR) defined as sum of CR, CRi and PR.  
Complete Response composite (CRc) defined as the sum of CR and CRi. 
Overall survival (OS) during the long-term follow-up. 


 
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GLOSSARY 
Subject and patient will be used interchangeably throughout this document. 
Abbreviation/Term 
Definition 
β-hCG 
β-human chorionic gonadotropin 
µg 
Microgram 
µL 
Microliter 
ADA 
Anti-drug antibody 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT/SGPT 
Alanine Transaminase/Serum glutamic pyruvic transaminase 
AlloSCT 
Allogeneic Stem Cell Transplantation 
AML 
Acute Myeloid Leukemia 
aPTT 
Activated Partial Thromboplastin Time 
Ara-C 
Arabinofuranosyl Cytidine / Cytarabine / Cytosine Arabinoside 
ASCT 
Autologous Stem Cell Transplantation 
AST/SGOT 
Aspartate Aminotransferase/Serum glutamic oxaloacetic transaminase 
AUC 
Area under the curve 
BM 
Bone Marrow 
BMI 
Body Mass Index 
Cmax 
Maximum plasma concentration 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CR 
Complete response 
CR1 
First Complete response 
CRc 
Complete Response composite 
CRF 
Case Report Form 
CRi 
Complete response with incomplete hematological recovery 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXCR4 
CXC Chemokine Receptor Type 4 
dL 
Deciliter 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMA 
European Medicines Agency 
FACS 
Fluorescence-activated cell sorting 
FDA 
Food and Drug Administration 
FISH 
Fluorescent In Situ Hybridization 
g 
Gram 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony-Stimulating Factor  


 
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Abbreviation/Term 
Definition 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GVHD 
graft-versus-host disease  
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCT 
Hematocrit 
HCV 
Hepatitis C Virus 
Hep C Ab 
Hepatitis C Antibody 
HGB 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HSC 
Hematopoietic Stem Cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio (for blood coagulation tests) 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IV 
Intravenous 
kg 
Kilogram 
λz 
Elimination rate constant 
m 
Meter 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
MM 
Multiple Myeloma 
MTD 
Maximum tolerated dose 
MUGA 
Multiple Gated Acquisition 
N 
Number of subjects 
NCI  
National Cancer Institute  
NOAEL  
No Observed Adverse Effect Level 
NOEL 
No Observed Effect Level 
OR 
Overall response 
OS 
Overall survival 
PB 
Peripheral blood 
PD 
Pharmacodynamic 
PI 
Principal Investigator 
PI 
Propidium Iodide 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PR 
Partial response 
PT 
Prothrombin Time  
QA 
Quality Assurance 


 
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Abbreviation/Term 
Definition 
QC 
Quality Control 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operation Procedures 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TLS 
Tumor lysis syndrome 
Tmax 
Time to reach the maximum plasma concentration 
T1/2 
Terminal elimination half-life, defined as 0.693/λz 
ULN 
Upper limit of normal 
US 
United States 
USP 
United State Pharmacopeia 
WBC 
White Blood Cell 
WFI 
Water For Injection 
WHO 
World Health Organization 
WMA 
World Medical Association 
 


 
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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 overproliferation in the stem cell 
compartment result in accumulation of non-functional cells termed myeloblasts (5). 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 (6). The five-year relative survival in US 
patients diagnosed over the period 2002-2008 was 23.4% (6). Both prognosis and treatment 
are based on the presence or absence of specific genetic abnormalities which play an 
important role as diagnostic criteria for sub-classification of AML (1; 7; 8).  
The standard treatment paradigm for AML is remission induction chemotherapy with an 
anthracycline/cytarabine based combination, followed by either consolidation chemotherapy 
or allogeneic stem cell transplantation, depending on the AML risk group. The AML risk 
group predicts the likelihood of cure with chemotherapy alone (based on cytogenetic and 
molecular parameters) and the patient's expected ability to tolerate an allogeneic stem cell 
transplantation (highly dependent on age, performance status  and co-morbidities) (9; 10; 11; 12). 
Approximately 70-80% of subjects enter complete disease remission with several 
anthracycline-based chemotherapy combinations. Consolidation with high-dose cytarabine or 
allogeneic stem-cell transplantation in high-risk patients limit overall relapse rate to 
approximately 50% (13).  
Another potential consolidative approach is the employment of autologous stem cell 
transplantation (14).   
1.2 
INVESTIGATIONAL THERAPY 
BL-8040, formerly BKT-140, is a highly selective CXC chemokine receptor 4 (CXCR4) 
antagonist co-developed by 
and BioLineRx Ltd. as a novel 
therapy for treatment of cancer. The investigational drug binds to CXCR4 with high affinity 
(IC50 0.5-10 nM) and inhibits its function (15). 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) (16). In addition, BL-8040 exhibits 
CXCR4-dependent selective cytotoxicity toward malignant cells of hematopoietic origin in 
both in vitro and in vivo models. BL-8040 significantly and preferentially stimulated 
leukemic apoptotic cell death. BL-8040 treatment induced morphological changes, 
phosphatidylserine externalization, decreased mitochondrial membrane potential, caspase-3 
activation, sub-G1 arrest and DNA double-stranded breaks (17). 
1.2.1 Nonclinical Studiesa 
The nonclinical development of BL-8040 has encompassed a large number of 
pharmacodynamic (PD), pharmacokinetic (PK), safety pharmacology, and single and 
repeated dose toxicity studies.    
Nonclinical studies in mice demonstrated the ability of BL-8040 to mobilize progenitor and 
stem cells from the BM, as well as various WBC types, such as neutrophils and monocytes (18; 
                                                 
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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19). In vitro and in vivo nonclinical studies have shown that, in addition to its activity as a 
mobilizer of WBCs, BL8040 exhibits a CXCR4-dependent preferential anti-tumor effect 
against malignant cells of hematopoietic origin (17).   
Repeat dose toxicity studies in rats included two pivotal studies of 14 days (2, 6 and 15 
mg/kg) and 28 days repeated doses (1, 3 and 6 mg/kg). Studies in dogs (5 and 7 days) were 
conducted at doses of up to 9 mg/kg, and an additional 28-day study was performed at doses 
of up to 3 mg/kg. The No Observed Adverse effect Level (NOAEL) in the 5 and 7 day repeat 
dose toxicity studies in dogs was set in the range of 2.7-3 mg/kg. The 28-day repeat dose 
toxicity study set the NOAEL at 1 mg/kg. The clinical symptoms observed in rats and dogs 
from the first day of dosing consisted of transient erythema and peripheral edema. In dogs, 
reactions similar in nature were noticed from a few minutes up to approximately 2 hours 
following SC injection. BL-8040 seemed to be better tolerated with repeated doses over time 
as the magnitude of the systemic reactions was less pronounced with time and not aggravated 
with increasing dose. There were no histopathological changes (except at the injection site) or 
significant changes in ECG, ophthalmological findings, clinical chemistry or hematology 
variables and no target organ for toxicity could be identified. 
Safety pharmacology studies were conducted in rats (respiratory and neurobehavioral studies 
at 3, 9 and 27 mg/kg dose) and dogs (cardiovascular study at 0.3, 3 and 9 mg/kg dose). The 
NOAEL in both rat studies was determined to be 3 mg/kg for BL-8040 administered by the 
SC route. At higher doses, dose-dependent effects were described, including a respiratory 
stimulant effect, piloerection, decreased urination and decrease in body temperature. In dogs, 
the No Observed Effect Level (NOEL) was determined to be 0.3 mg/kg with higher doses 
inducing a dose-dependent hypotensive effect followed by a dose-dependent hypertensive 
effect. These effects were combined with a dose-dependent tachycardia, which correlated 
with the hypertensive effect. A shortening in PR and PQ intervals as well as QRS duration 
was found especially at the peak of tachycardia, suggesting that these electrocardiographic 
changes are likely a consequence of the tachycardic properties of BL-8040. The QT interval 
was also found to be shortened in a dose-dependent manner. Analysis of QTc interval 
changes using the probabilistic method or the QT deviation method suggests that the QT 
interval shortening was related to a decrease in ventricular repolarization duration rather than 
a consequence of tachycardic properties of BL-8040. 
As indicated above, in contrast to the findings of the safety pharmacology study, the pivotal 
repeated dose toxicology studies performed on dogs reported no clear effect of BL-8040 on 
ECG parameters, including QT interval, blood pressure or pulse values examined 30 minutes 
and 24 hours after injection of BL-8040. 
Metabolic stability was evaluated in liver microsomes from male rat, male dog and pooled 
human microsomes. BL-8040 did not show degradation over the incubation period in rat liver 
microsomes. Degradation was observed in dog micrososmes (t1/2 = 5-7 hrs) and more rapidly 
in human microsomes (t1/2 = 1.3 hrs). No difference was found between incubations of 
microsomes with and without NADPH, suggesting that this degradation is not NADPH 
dependent and not related to CYP or FMO enzyme families and therefore it is considered 
highly unlikely that BL-8040 will have drug interactions based on CYP-450 metabolism.   
For additional information please refer to the Investigator’s Brochure. 


 
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1.2.2 Clinical Studiesa 
A single phase IIa, non-randomized, open label, single dose, dose-escalation, safety study of 
BL-8040 (formerly BKT-140) in multiple myeloma (MM) subjects has been completed 
(study BKTSC001). Eighteen subjects received a 10-day mobilization regimen consisting of 
one-day (Day 0) treatment with cyclophosphamide (3-4 g/m2) followed by daily evening 
administration of G-CSF (5 µg/kg) from Day 5 until the end of stem cell collection. On Day 
10, a single SC injection of BL-8040 was administered at the following dose levels:  0.03, 
0.1, 0.3 or 0.9 mg/kg (four subjects per dose groupb).  
Injection of BL-8040 was associated with a favorable safety profile, with no apparent trend 
toward risk with a specific dose. No clinically significant, consistent or cumulative 
abnormalities were observed for the safety parameters evaluated, including AE incidence, 
laboratory values, vital signs, ECG or physical examinations, as well as Karnofsky 
performance status. PK assessments were conducted pre-dose and 10 minc, 30 min, 1, 2, 4, 8 
and 24 hrs following study drug administration. BL-8040 was absorbed quickly and peak 
concentrations in the plasma were reached after 30 minutes, followed by a rapid decline.  
Preliminary efficacy analysis indicated a dose-dependent effect of BL-8040 on WBC and 
CD34+ stem cell mobilization, potentially synergizing with chemo-mobilization with G-CSF, 
allowing for collection of optimal CD34+ cells in a single apheresis. 
Based on the clinical experience to date, the following adverse events may be anticipated 
following administration of BL-8040: hot flushes, itching, injection site redness and swelling, 
chest pain, fever, shivering, allergic-like reaction, dyspnea and hypokalemia. 
1.3 
STUDY RATIONALE 
AML is the most common type of leukemia in adults, yet continues to have the lowest 
survival rate of all leukemias. Despite progress in the understanding of leukemia 
pathophysiology, 20-40% of patients do not achieve remission with the standard induction 
chemotherapy and 50-70% of first complete remission patients are expected to relapse within 
3 years. The prognosis following AML relapse remains uniformly poor (20; 21).  
High dose cytarabine (Ara-C) based therapy has been the cornerstone of salvage 
chemotherapy for relapsed or refractory AML for many years. The complete response rate in 
this clinical setting is approximately 30% (21). Addition of other cytotoxic agents such as 
mitoxantrone, mitoxantrone and etoposide (MEC) has produced increased toxicity without 
being confirmed to significantly improve complete response rates.  
Emerging data have highlighted the importance of the BM niche for AML growth (22; 23; 24; 25). 
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 "tumour survival factor," promoting tumour growth and protecting 
malignant cells from chemotherapy-induced apoptosis (24; 25; 26; 27; 28). A recent clinical trial 
investigating AMD3100 (plerixafor) in combination with chemotherapy in patients with 
                                                 
a In the first clinical study, the indicated doses were calculated based on total content (including active peptide, 
peptide impurities, acetic acid and water content). For example, 0.9 mg/kg was equivalent to 0.73 mg/kg active 
peptide. In the current study, the doses represent the active peptide dose only. 
b Two additional subjects received a fifth of the planned dose in the first cohort (0.006 mg/kg)  
c PK and PD assessment 10 minutes post-dose was performed only for the last three subjects in the last dose 
group  


 
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relapsed AML, observed leukemic cell mobilization, resulting in an overall response rate 
higher than expected in patients with advanced AML (29).  
In vitro studies demonstrated that BL-8040 binds and inhibits the CXCR4 chemokine 
receptor with high affinity. 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. In in-vivo animal studies, as 
well as in clinical study BKTSC001, BL-8040 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 (17).   
The current study aims to demonstrate the safety and efficacy of escalating repeated doses of 
BL-8040 administered as monotherapy and concurrently with high-dose Ara-C in the 
treatment of relapsed/refractory AML adult subjects. 
During the combined treatment period, BL-8040 will be administered 4 hrs before infusion of 
high-dose Ara-C. This is due to the fact that the peak mobilization effect observed in both 
nonclinical and clinical studies occurred at 4 hrs post-dose. It is therefore envisaged that peak 
concentrations of Ara-C will coincide with the peak mobilization of leukemic blasts into the 
peripheral blood. As BL-8040 has a short half-life (less than one hour), the potential for drug-
drug interaction with Ara-C is low. Furthermore, in vitro metabolic studies have indicated 
that it is highly unlikely that BL-8040 will have drug interactions based on CYP-450 
metabolism. 
The starting dose of BL-8040 in this study was determined based on free base concentrations 
calculated from nonclinical studies and the completed Phase IIa clinical study (BKTSC001). 
Single dose administration of BL-8040 up to 0.9 mg/kga, added to a G-CSF chemo-
mobilization regimen in MM subjects, appeared to be safe and well tolerated in the first 
clinical study with BL-8040 (BKTSC001). Animal studies did not show any organ toxicity at 
exposures exceeding those observed in the single dose human clinical trial BKTSC001 at the 
top dose of 0.9 mg/kg (13 fold in rats and 8 fold in dog based on AUC). The AUC in study 
BKTSC001 increased approximately proportionally with dose between 0.3 and 0.9 mg/kg 
(4.2 times), making it likely that the exposure (AUC) of patients in the starting dose cohort of 
0.5 mg/kgb will be proportional to the exposures observed in the previous clinical study. 
AUC0-24 measured in clinical study BKTSC001 for patients in the two highest dose cohorts 
(0.3 and 0.9 mg/kg) was 186 and 782 ng.hr/mL, respectively. Thus, it is expected that 
exposure (AUC) in the first dose cohort in study BL-8040.01 will be approximately 480 
ng.hr/mL. The AUC value is not expected to increase with successive daily administrations 
of BL-8040 in the current study, as the BL-8040 half-life (t1/2) was found to be short (less 
than one hour). Thus, the exposures reached in the toxicological studies are expected to 
exceed (21 fold in rats and 13 fold in dogs based on AUC) the predicted exposure of patients 
to the study drug at the starting dose of 0.5 mg/kg in study BL-8040.01.  
                                                 
a In the first clinical study, the indicated doses were calculated based on total content (including active peptide, 
peptide impurities, acetic acid and water content). For example, 0.9 mg/kg was equivalent to 0.73 mg/kg active 
peptide. In the current study, the doses represent the active peptide dose only. 
b Dose calculation terminology has changed between study BKTSC001 and study BL-8040.01, such that 0.5 
mg/kg in BL-8040.01 is equivalent to 0.6 mg/kg in study BKTSC001 and 0.75 mg/kg in BL-8040.01 is 
equivalent to 0.9 mg/kg in BKTSC001. 


 
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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
STUDY OBJECTIVES 
Primary  
 To assess the safety and tolerability of escalating repeated doses of BL-8040 
administered as monotherapy for two days, followed by five days of combined 
administration with high-dose Ara-C in AML adult subjects with relapsed or 
refractory disease. 
Secondary 
 To assess the clinical efficacy (response rates) of escalating repeated doses of BL-
8040 administered as monotherapy for two days, followed by five days of combined 
administration with high-dose Ara-C in AML adult subjects 
 To assess the apoptotic effect of BL-8040 on leukemic blasts when administered as 
monotherapy  
 To assess the effect of BL-8040 on mobilization of AML blasts to peripheral blood 
(PB) when administered as monotherapy  
 To assess the single and multiple dose pharmacokinetic profile of BL-8040. 
Exploratory 
 To assess additional pharmacodynamic parameters relevant to CXCR4 inhibition. 
2.2 
STUDY ENDPOINTS/OUTCOMES 
2.2.1 Safety Outcomes 
Safety and tolerability will be the primary endpoints of this study and will be evaluated on the 
basis of the following parameters: 
 General safety: vital signs (oral temperature, blood pressure, pulse rate, respiratory 
rate and O2 saturation), 12-lead ECG and physical examination. 
 Toxicity according to the latest version of NCI CTCAE (currently V4.03, refer to 
Table 2) for AEs and clinical laboratory profile as follows:  
- 
Screening: record and report screening results, however not considered treatment 
emergent AEs.  
- 
Throughout the study: record and report all AEs and SAEs according to GCP.  
2.2.2 Efficacy Endpoints 
Efficacy endpoints will be secondary endpoints for this study. The following secondary 
endpoints will be assessed: 
 Response rates as assessed at final BM evaluation based on Cheson 2003 criteria (4) 
(Appendix C):  
o Complete response (CR)  
o Complete response with incomplete hematological recovery of platelets or 
neutrophils (CRi) 
o Partial response (PR)  
o Overall response defined as the sum of CR, CRi and PR.  
o Complete Response composite (CRc) defined as the sum of CR and CRi. 


 
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 Change in leukemic cell apoptosis in PB and BM. 
 Kinetics of mobilization of leukemic blasts from BM to PB. 
 Overall survival (OS) during the long-term follow-up defined as time from enrollment 
to death from any cause. 
2.2.3 Pharmacokinetic Endpoint 
 PK analysis of multiple injections of BL-8040. 
 For PK analyses, blood samples will be collected on Days 1, 3 and 7 at pre-dose, 0.25, 
0.5, 1, 2, 4, 8 and 24 hrs post BL-8040 administration. Additional samples will be 
collected on Day 5 at pre-dose and 0.5 hr post BL-8040 administration. 
 Non-compartmental PK parameters for BL-8040 (see below) will be derived from the 
individual concentration obtained at each of the PK time-points. Additional PK 
parameters may be derived if considered necessary: 
o Cmax - maximum BL-8040 plasma concentration 
o Tmax - time to reach the maximum BL-8040 plasma concentration 
o AUC0-t - Area under the BL-8040 plasma concentration-time curve from time 
of administration up to the last time point with a measurable concentration 
post dosing, calculated by linear up-logarithmic down trapezoidal summation 
o AUC0-∞ - Area under the BL-8040 plasma concentration-time curve 
extrapolated to infinity, calculated as: AUC0-∞ = AUC0-t + Clast/λz, where Clast 
is the last measurable concentration  
o λz - elimination rate constant, determined by linear regression of the terminal 
points of the ln-linear plasma concentration-time curve 
o t1/2 - terminal elimination half-life, defined as 0.693/λz 
2.2.4 Exploratory Endpoints 
 CXCR4 receptor occupancy 
 Additional pharmacodynamic endpoints relevant to CXCR4 inhibition 
 Anti-BL-8040 antibody titers 
 
3 
STUDY DESIGN 
This will be an open-label, multicenter, phase IIa, dose escalating study in subjects with 
relapsed/refractory AML, defined according to WHO criteria (1) (Appendix B) including 
subjects who failed chemotherapy only and those who failed previous Autologous Stem Cell 
Transplantation (ASCT)/ Allogeneic Stem Cell Transplantation (AlloSCT), provided at least 
6 months have passed from transplant.  
Eligible subjects will receive SC injections of BL-8040 alone (“monotherapy period”) over 
two days (one dose per day that may be administered into one or more injection sites at the 
discretion of the Investigator) followed by concurrent administration of BL-8040 with 
standard salvage chemotherapy (“combined period”) over 5 days. During the “combined 
period,” BL-8040 will be administered 4 hours prior to chemotherapy. The chemotherapy 


 
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will consist of cytarabine (Ara-C) 1.5 or 3 g/m2/d per dose (based on age), administered IV 
over 3 hours, for 5 daysa and will not be escalated.  
The first part of the study (Part 1) will include escalating dose groups and be considered the 
‘escalation phase’. Six potential dose levels (see Table 1) will be investigated starting at 
dose level 1. Patients will be accrued in a conventional 3+3 design. Applying this study 
design, the first cohort of 3 patients will be treated at dose level 1 and evaluated for dose 
escalation.  
If at dose level 1 and beyond, 0 out of 3 patients experience DLT, then the next cohort of 3 
patients will be treated at the next dose level.  If 1 out of 3 patients develop DLT, an 
additional 3 patients will be treated at the same dose level. If no more DLT develops at that 
dose, i.e. 1 out of a total of 6 patients develops DLT, the dose escalation continues to the next 
dose level. At any given dose, if greater than 1 out of 3 patients or 1 out of 6 patients 
experience DLT, the dose level exceeds the MTD. In this situation, 3 more patients will be 
treated at the next lower dose if there are less than 6 patients already treated at that dose. 
MTD is defined as the highest dose level in which 6 patients have been treated with less than 
2 instances of DLT. 
The decision to proceed to the next higher dose level will be made by an independent DMCb 
after review of relevant safety data collected up to and including Day 30 (± 2 days; Day 28 ± 
2 of chemotherapy) of the last subject of the previous dose group. The DMC may recommend 
evaluation of intermediate doses (or doses lower than the starting dose of 0.5 mg/kg) of BL-
8040 in combination with Ara-C. The decision process for dose escalation is outlined in 
Figure 1. 
Dose escalation will be permitted until the MTD is established and protocol specific stopping 
rules for toxicity are met. If no MTD is reached, dose escalation will continue up to dose 
level 6 (2.0 mg/kg). It is anticipated that up to 36 eligible patients will be required for the 
dose escalation. 
At the discretion of the Sponsor, additional subjects may be enrolled into a selected dose 
group to confirm safety, efficacy and pharmacokinetic (PK) profile for the selected dose, 
bringing the study up to approximately 70 subjects in total. This portion of the study will be 
considered the ‘expansion phase’ (Part 2). The DMC, in consultation with the Sponsor and 
Investigators, will decide on the selected dose level for expansion based on safety data, MTD, 
other relevant toxicity considerations, and all available PK and correlative PD data. 
During Part 2 of the study, at the Investigator’s discretion and after discussion with the 
Sponsor, subjects may be treated with a second cycle of BL-8040 in combination with Ara-C 
if they are considered to have had clinical benefit during the first treatment cycle, but failed 
to achieve CR or CRi. In the event that subjects receive a second treatment cycle, the dosing 
regimen will be identical to that in the first treatment cycle. The second treatment cycle will 
start after clinical response assessment has been completed for the first treatment cycle, i.e., 
no sooner than Day 30 (± 2 days; Day 28 ± 2 of chemotherapy).  
                                                 
a  Subjects ≤ 60 years will receive Ara-C 3 g/m2/d, and those > 60 years will receive Ara-C 1.5 g/m2/d: each 
dose over 3 hours, for 5 consecutive days.  
b Data Monitoring Committee will be comprised of 3 members appointed by the Sponsor including at least one 
clinician, and persons knowledgeable of the investigational drug. 


 
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During Part 2 of the study, any DLT occurring at a frequency of > 30% will stop accrual. In 
this situation, the DMC, in consultation with the Sponsor and Investigators, may recommend 
a lower dose level for the expanded cohort. 
The study will comprise a screening period, a treatment period (monotherapy and combined 
treatment) and a follow-up period. For each dose group, visit scheduling and assessments will 
be similar (see Section ‎5 and Appendix A).  


 
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Figure 1 
BL-8040 Dose escalation decision tree 
 
 


 
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4 
STUDY POPULATION 
This study will be conducted in subjects aged 18 to 75 years diagnosed with 
relapsed/refractory AML. The exact number of subjects enrolled will depend on the toxicity 
observed in each dose group and the number of dose groups required to reach MTD. 
4.1 
INCLUSION CRITERIA 
1. Adult men and women subjects aged 18 to 75, inclusive. 
2. Confirmed diagnosis of relapsed/refractory AML (WHO criteria (1); Appendix B). 
 Refractory subjects after up to 2 cycles of induction therapya or first complete 
response (CR1) duration ≤ 90 days.  
 Relapse occurring > 90 days and ≤ 24 months since CR1b.  
3. AML relapse > 6 months since autologous or allogeneic stem cell transplantation, 
provided they are in first relapse and:  
 No active graft-versus-host disease (GVHD > grade 1). 
 No treatment with high dose steroids for GVHD (up to 20 mg Prednisolone or 
equivalent, Appendix G). 
 No treatment with immunosuppressive drugs with the exception of low dose 
cyclosporine and tacrolimus (blood levels of 0.5-0.6 µg/mL). 
4. Clinical laboratory values should be as follows: 
 WBC < 30,000/µL 
 Blasts in PB < 20,000. Treatment with Hydroxyurea is permitted up to 24 hrs 
prior to BL-8040 administration to achieve blast counts < 20,000 prior to 
enrollment. 
 Creatinine < 1.3 mg/dL; if Creatinine is > 1 mg/dL the Creatinine clearance 
should be > 40 mL/min as calculated using the Cockcroft-Gault formula.  
5. Women of childbearing potential and all men must agree to use an approved form of 
contraception (e.g. oral, transdermal patch, implanted contraceptives, intrauterine 
device, diaphragm, condom, abstinence or surgical sterility) prior to study entry and 
for the duration of study participation through 30 days after the last dose of BL-8040. 
Confirmation that female subjects are not pregnant must be established by a negative 
serum β-human chorionic gonadotropin (β-hCG) pregnancy test result obtained during 
screening. Pregnancy testing is not required for post-menopausal or surgically 
sterilized women. 
6. Subject is able and willing to comply with the requirements of the protocol. 
7. Subject is able to voluntarily provide written informed consent.  
 
                                                 
a Subjects who have failed to respond to up to 2 prior induction treatment regimens will be considered eligible,. 
Prior induction therapy must include at least 1 cycle of an anthracycline (e.g., at least 45 mg/m2/dose 
daunorubicin or at least 9 mg/m2/dose idarubicin) or anthracenedione (e.g., at least 10 mg/m2/dose 
mitoxantrone) and cytarabine-based regimen. 
b Relapsed subjects must have achieved a CR or CRi lasting > 90 days, resulting from no more than 2 cycles of 
induction cytotoxic chemotherapy including at least 1 cycle of an anthracycline (e.g., at least 45 mg/m2/dose 
daunorubicin or at least 9 mg/m2/dose idarubicin) or anthracenedione (e.g., at least 10 mg/m2/dose 
mitoxantrone) and cytarabine-based regimen. An unlimited number of consolidation cycles following CR1 are 
allowed.. 


 
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4.2 
EXCLUSION CRITERIA 
1. Administration of conventional chemotherapy within 2 weeks of enrollment date. In 
the event that subjects have received chemotherapy > 2 weeks from the date of 
enrollment, they may be included provided they have recovered from the associated 
non-hematological toxicities to ≤ grade 1.  
2. Life expectancy of ≤ 2 months.  
3. Known allergy or hypersensitivity to any of the test compounds, materials or 
contraindication to test product. 
4. Use of investigational device or agents within 2 weeks of enrollment date. 
5. Low Performance Status (ECOGa > 2; Appendix E). 
6. O2 saturation < 92% (on room air), evidence of TLS > grade 2 (according to the 
Cairo-Bishop criteria (3); Appendix D) or leukostasis (2).  
7. Abnormal liver function tests: 
 Serum 
aspartate 
transaminase 
(AST/SGOT) 
or 
alanine 
transaminase 
(ALT/SGPT) 2 x upper limit of normal (ULN). 
 Serum bilirubin. Total bilirubin > 2.0 mg/dL (34 µmol/L), conjugated bilirubin > 
0.8 mg/dL. 
8. Left ventricular ejection fraction < 40 %. 
9. History of myocardial infarction or cerebrovascular accident within 6 months of 
enrollment date. 
10. Presence of active, uncontrolled infection. 
11. Known central nervous system disease (e.g., Alzheimer’s disease). 
12. Acute promyelocytic leukemia.  
13. Exposure to high dose Ara-C within 6 months of enrollment. 
14. Subject has concurrent, uncontrolled medical condition, laboratory abnormality, or 
psychiatric illness which could place him/her at unacceptable risk, including, but not 
limited to: 
 Subject has been diagnosed or treated for another malignancy within 3 years of 
enrolment, except in situ malignancy, or low-risk prostate, skin or cervix cancer 
after curative therapy 
 A co-morbid condition which, in the view of the Investigators, renders the subject 
at high risk from treatment complications. 
15. Female subjects who are pregnant or breastfeeding. 
16. Prior clinically significant grade 3-4 non-hematological toxicity to high dose Ara-C or 
grade ≥ 2 of neurological toxicity.  
17. Seropositive for HIV antibodies (HIV1 and HIV2), Hepatitis C antibody (Hep C Ab) 
or a Hepatitis B carrier (positive for Hepatitis B surface antigen [HBsAg]).  
18. Unable to comply with study requirements in the opinion of the investigator.  
19. Extramedullary AML involvement (including CNS involvement). 
 
                                                 
a ECOG = Eastern Cooperative Oncology Group 


 
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4.3 
SUBJECT IDENTIFICATION 
At screening, all subjects who signed informed consent will be identified by a subject 
number, initials and birth date; subject number will be used throughout the study.  
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.  
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 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 baseline visit or prior to first BL-8040 injection 
will be replaced by the Investigator to achieve the appropriate number of subjects per dose 
group, regardless of the reason for withdrawal.   
The subject's participation in this study may be discontinued due to the following reasons: 
 Request of regulatory agency or Sponsor or primary care physician or Investigator 
 Withdrawal of consent by subject 
 Any subject who develops intolerance to treatment. 
 Female subject who becomes pregnant. 
 Any subject who requires concomitant medication which could confound evaluation 
of the study drug. 
 Subject is unwilling or unable to continue the study or is lost to follow-up 
 Subject is non-compliant with study procedures / study protocol 
 Investigator decides that withdrawal from the study is in the best interest of the 
subject 
 Subject meets one of the stopping rules criteria during the study (see Section ‎6.2.3). 
4.6 
HANDLING OF WITHDRAWALS 
If a subject is withdrawn from the study, either at his or 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 (see 
Section ‎5.4). 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. 
Premature withdrawal may occur for any of the following reasons: 


 
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1. Death 
2. Disease progression/relapse 
3. Pregnancy 
4. AE  
5. Subject request 
6. Investigator request 
7. Sponsor request 
8. Other party’s request 
If withdrawal is caused by an AE that the Investigator considers may be related to the study 
drug, it will be reported to the Internal Safety Committee, institutional review 
board/independent ethics committee (IRB/IEC) and Sponsor. 
Any serious AE (SAE) must be reported to the Sponsor or Sponsor's designee by telephone or 
fax 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.  
Regulatory Authorities also have the right to terminate the study for any reason. 
5 
STUDY PROCEDURES AND ASSESSMENTS 
Schedule of events for this study are 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 -7 TO DAY 0) 
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 signing of informed consent, adult 
male and female subjects aged ≥18 years will be screened for study eligibility by assessment 
of inclusion and exclusion criteria.  
The following assessments should be done at screening visit 1: 
 Confirmation of relapsed/refractory AML within 2 weeks prior to screening based on 
BM biopsy or aspiration or PB results. 
 Collection of demographic data and medical history. 
 Physical examination (including height and weight measurements and assessment of 
cerebellar function). 


 
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 Vital signs (blood pressure, pulse rate, oral temperature, O2 saturation levels and 
respiration rate). 
 ECOG performance status (Appendix E). 
 12-lead electrocardiogram (ECG).  
 Echocardiogram (ECHO)/Multiple Gated Acquisition (MUGA).  
 Chest X-ray.  
 Safety laboratory assessments including hematology, biochemistry, coagulation (PT 
and aPTT) and serum pregnancy test (for women of child bearing potential).  
 HIV, HCV and HBV serology. 
 Clinical evaluation of leukostasis (2) related symptoms (visual symptoms, shortness of 
breath and decreased oxygen saturation in blood measured by pulse oximetry) and 
TLS (according to Cairo–Bishop criteria (3); Appendix D).  
 BM biopsy and aspirate will be conducted within 7 days prior to commencement of 
the treatment for baseline assessment of leukemic cell numbers and apoptosis by 
caspase-3 staining. CXCR4 levels and other relevant parameters will be measured in 
BM by IHC and/or other techniques and will be analyzed for correlation to efficacy. 
In subjects who receive cytoreductive therapy, BM samples will be collected post 
therapy and prior to BL8040 administration.  
If any of the assessments listed above were performed within 3 weeks prior to the screening 
visit, a repeat assessment will not be required at screening and the data will be acceptable 
for study purposes.  
5.2 
TREATMENT PERIOD (VISITS 2-8 AND 10-16, DAY 1 TO DAY 7)a 
Treatment period is comprised of BL-8040 monotherapy (2 days) followed by combined 
therapy period (5 days) as follows: 
Monotherapy period – On Day 1 (Baseline, enrollment day) and Day 2, eligible subjects will 
receive BL-8040 monotherapy administered by SC injection(s), once daily in the morning. 
Subjects considered suitable for a second treatment cycle during the expansion phase will 
receive BL-8040 monotherapy on Days 1 and 2 of the additional cycle as described above. 
Combined therapy period – On Days 3-7, subjects will be treated once daily in the morning 
with BL-8040 SC injection(s) followed by chemotherapy 4 (± 0.5) hours later. The 
chemotherapy will consist of Ara-C 1.5 or 3 g/m2 administered IV over 3 hours (3 g/m2/d for 
subjects ≤ 60 years, 1.5 g/m2/d for subjects > 60 years).  
Subjects considered suitable for a second treatment cycle during the expansion phase will 
receive BL-8040 in combination with Ara-C on Days 3-7 of the additional cycle as described 
above. 
The following assessments will be conducted at the treatment visits: 
 Laboratory safety evaluationsb: 
                                                 
a Treatment Period refers to Visits 2-8 and also Visits 10-16 for expansion phase subjects who receive a second 
treatment cycle... 
b Subjects considered suitable for a second treatment cycle during the expansion phase will undergo the same 
laboratory safety evaluations during the second cycle with the exception of coagulation and partial 
biochemistry. 


 
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o Hematology (CBC) and biochemistry samples will be collected daily on Days 
1-7 prior to administration of BL-8040. 
o Coagulation (PT and aPTT) will be evaluated on Day 1 pre-dose and 24 hrs 
post-dose, and on Day 7 at 24 hrs post-dose.  
o WBC counts, including differential and leukemic cell count, will be measured 
on Days 1, 2, 3 and 7 at 4 and 8 hrs post BL-8040 injection.  
o Partial biochemistry samples (electrolytes and kidney function) will be 
collected on Days 1, 2, 3 and 7 at 4 and 8 hrs post BL-8040 injection. 
o Additional hematology, biochemistry and coagulation samples may be 
collected at the discretion of the Investigator or upon Sponsor's request. 
 Anti-drug antibody (ADA) and complement activation: 
o Blood samples for assessment of ADA and complement activation will be 
collected pre-dose and at 4 hrs post BL-8040 administration on Days 1 and 7. 
On Day 3 an ADA sample will be collected pre-dose only.  
 PK samplinga: 
o Blood samples for BL-8040 PK analysis will be collected on Days 1, 3 and 7 
at pre-dose, 0.25, 0.5, 1, 2, 4, 8 and 24 hrs post BL-8040 administration.  
o Samples will also be collected on Day 5 at pre-dose and 0.5 hr post BL-8040 
administration.  
o PK sampling may be discontinued during the expansion phase at the discretion 
of the Sponsor. The Sponsor will notify sites when PK sample collection can 
be halted. 
 12-lead ECGs: 
o 12-lead ECGs will be recorded on Days 1, 3 and 7 at pre-dose, 0.5, 1, 2, 4, 8 
and 24 hrs post BL-8040 administration. 
o For subjects receiving a second treatment cycle during the expansion phase, 
ECGs will only be recorded on Days 1 and 7 of the second cycle at pre-dose 
and 4 hrs post BL-8040 administration. 
o Additional ECGs may be recorded at the discretion of the Investigator or upon 
Sponsor's request. 
 BM biopsy and/or aspirateb: 
o Bone marrow biopsy and/or aspiration will be performed on Day 3 (prior to 
BL-8040 injection) for quantitative assessment of leukemic blast number and 
apoptosis of leukemic cells in the BMc using caspase-3 staining. 
 FACS analysisd: 
o Leukemic blasts in peripheral blood (PB) will be assessed by analysis of 
surface markers on Days 1 and 3 at pre-dose, 4e and 24 hrs post BL-8040 
                                                 
a PK sampling will only be performed during the first treatment cycle for subjects in the expansion phase. 
b Day 3 BM sampling will only be performed during the first treatment cycle for subjects in the expansion 
phase.  
c Subjects who do not undergo BM evaluation on Day 3 will still be included in the safety and efficacy 
evaluation.  
d FACS analysis will only be performed during the first treatment cycle for subjects in the expansion phase. 
e 4 hr post-dose samples on Day 3 to be taken prior to administration of Ara-C. 


 
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injection. Additional signaling pathway proteins may be assessed at the 
discretion of the Sponsor. 
o Leukemic cell apoptosis in PB will be assessed by Annexin V and Propidium 
iodide (PI) analysis on Days 1 and 3 at pre-dose, 4a and 24 hrs post BL-8040 
injection.  
o CXCR4 occupancy will be measured in the PB of dose escalation phase 
subjects, using the CXCR4 antibodies 12G5 and 1D9, on Days 1 and 3 at pre-
dose, 4a and 24 hrs post BL-8040 injection. 
 FISH analysisb: 
o In the expansion phase of the study, subjects with identifiable chromosomal 
abnormalities at baseline will be assessed by FISH in PB and/or BM aspirate 
collected on Days 1 and 3 at pre-dose, 4a and 24 hrs post BL-8040 injection.  
 Clinical evaluations: 
o Vital signs, physical examination, including assessment of cerebellar function 
and recording of adverse events (AEs) and concomitant medications will be 
performed daily on Days 1-7 prior to administration of BL-8040. For 
expansion phase subjects receiving a second treatment cycle, the same 
assessments will be performed daily on Days 1-7 prior to administration of 
BL-8040.  
o Clinical evaluation of leukostasis (2) related symptoms (visual symptoms, 
shortness of breath and decreased oxygen saturation in blood measured by 
pulse oximetry) and TLS (according to Cairo–Bishop criteria (3); Appendix D) 
will be assessed on Day 1 and upon commencement of such symptoms or 
when WBC ≥ 30,000/µL. 
5.3 
FOLLOW-UP PERIOD (VISITS 9 AND 17)c 
The follow-up period will start after completion of Ara-C chemotherapy and continue for up 
to 6 weeks after initiation of salvage chemotherapy with Ara-C, i.e., up to Day 44. Expansion 
phase subjects who receive a second treatment cycle will also be followed for up to 6 weeks 
after initiation of Ara-C during the second cycle, i.e., up to Day 44 of the second cycle. 
Bone marrow biopsy and aspiration will be performed on Day 30 (± 2 days; 28 ± 2 days from 
initiation of salvage chemotherapy) unless, in the opinion of the Investigator, earlier 
biopsy/aspiration is indicated based on early appearance of blast cells in PB. The follow-up 
period will end when a BM biopsy and/or aspirate, performed between Day 20 – 44, provides 
definite assessment of response to therapy. Bone marrow aspirate collected during this time 
frame will be examined by FACS analysis for final assessment of leukemic cell numbers. 
In subjects who do not show sufficient BM recovery by Day 30 (in the absence of leukemic 
cells), BM biopsy and aspiration will be repeated 2 weeks later (Day 44) to exclude aplasia. 
Additional bone marrow aspirations may be performed at the Investigator’s discretion to 
assess response.   
The following assessments will also be performed during the follow-up period:  
                                                 
a 4 hr post-dose samples on Day 3 to be taken prior to administration of Ara-C. 
b FISH analysis will only be performed during the first treatment cycle for patients in the expansion phase. 
c Follow-up period refers to Visit 9 and Visit 17 for expansion phase subjects who receive a second treatment 
cycle. 


 
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 Haematology and biochemistry tests will be performed at least twice a week for the 
duration of the follow-up period 
 Time to recovery of WBC and platelets  
 Recording AEs and concomitant medications. 
 Collection of an ADA sample at the end of the follow-up period. 
For expansion phase subjects receiving a second treatment cycle, bone marrow 
biopsy/aspiration and follow-up assessments following the second treatment cycle will be 
performed as described above. However, ADA sample collection will only take place at the 
end of the follow-up period following the first treatment cycle. 
5.4 
LONG-TERM FOLLOW-UP 
Subjects participating in the expansion phase will be followed for up to 5 years after 
completion of the Follow-up period. Sites will contact subjects by telephone at approximately 
3 month intervals (± 1 month) after the end of the Follow-up period to determine AML status 
and survival. 
5.5 
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. 
At this visit the activities relating to the study period at which time the subject discontinued 
will be performed. For example, if the subject discontinues during the Treatment period, the 
visit activities will be similar to those described in Section ‎5.2. Activities may include (but 
not be limited to): AE assessment, concomitant medications, laboratory safety tests, vital 
signs and physical examination by the Investigator. 
This visit may be performed on the same day as an originally scheduled visit or could be 
conducted separately. Data collection at these visits should primarily be guided according to 
principles to protect subject safety and wellbeing.   
5.6 
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. 
5.7 
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, laboratory safety assessments and clinical evaluation of 
leukostasis and TLS. 


 
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5.7.1 Adverse Events (AEs) 
Adverse Events will be assessed at all study visits throughout the study. 
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 14.0) (see Section ‎7.1 for more details). 
5.7.2 Concomitant Medications 
Concomitant medication use will be recorded from Baseline (Visit 2) through all study visits.  
5.7.3 Vital Signs 
Vital signs will be measured at Screening (Visit 1) and daily during the Treatment Period 
(Visits 2-8 and 10-16 for expansion phase subjects who receive a second treatment cycle).  
Vital signs will include blood pressure, pulse rate, oral temperature, oxygen saturation and 
respiration rate after at least 5 minutes 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.  
5.7.4 Electrocardiogram 
ECG will be performed at Screening (Visit 1) and during the Treatment Period on Days 1, 3 
and 7 (Visits 2, 4 and 8). ECG printed recording will be collected at pre-dose, 0.5, 1, 2, 4, 8 
and 24 hrs post BL-8040 administration. For subjects receiving a second treatment cycle 
during the expansion phase, ECGs will be recorded on Days 1 and 7  (Visits 10 and 16) of the 
second cycle at pre-dose and 4 hrs post BL-8040 administration; additional ECGs post BL-
8040 will be performed at the discretion of the Investigator or upon Sponsor’s request. The 
subject should rest for at least 10 minutes before measurement is 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 
the source documentation file. 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. 
5.7.5 Physical Examination 
Physical examination will be conducted at Screening (Visit 1), and during the Treatment 
Period (Visits 2-8 and 10-16 for expansion phase subjects who receive a second treatment 
cycle). Height will be recorded only at Visit 1 (screening).  
Physical examination will include weight measurements, 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. 
Neurological assessment must include examination of cerebellar function. 
Information about the physical examination must be present in the source documentation at 
the study site. Significant findings that are present prior to the start of study drug must be 


 
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included in the Relevant Medical History/ Current Medical Conditions CRF. Significant 
findings made after the start of study drug which meet the definition of an AE must be 
recorded on the AE CRF module.  
5.7.6 Laboratory Safety Assessments  
All clinical laboratory safety assessments, listed below, will be performed by local 
laboratories at the participating sites at Screening (Visit 1), daily during the Treatment Period 
(Visits 2-8 and 10-16 for expansion phase subjects who receive a second treatment cycle) and 
at least twice weekly during the follow-up period (Visit 9 and Visit 17 for expansion phase 
subjects who receive a second treatment cycle).  
Laboratory safety sampling will include the parameters listed below. The exact time-points 
for each one of the tests are specified in Appendix A. 
 
Evaluations 
Parameters 
Hematology 
Red blood cell 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, potassium, magnesium, calcium and phosphorus  
Liver function tests: AST, ALT, ALP, total bilirubin, 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 a  
Pregnancy test - a serum -HCG pregnancy test for women of childbearing potential 
 
A serum pregnancy test, if applicable, will be collected at screening. The serum pregnancy 
test will be performed at the local laboratory. 
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: 
- 
Intervention is required 
- 
Changes in dose are required (decrease, discontinued, interrupted) 
- 
Other treatment/therapy is required 
- 
Associated with other diagnoses 
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 
                                                 
a To be collected at screening only. 


 
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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. 
5.7.7 Anti-drug antibody (ADA) assessment 
Blood sampling for assessment of ADA formation and complement activation will be 
performed pre-dose and at 4 hrs post BL-8040 administration on Days 1 and 7 and at the end 
of the follow-up period. On Day 3 an ADA sample will be collected pre-dose only (Visits 2, 
4, 8 and 9)a.
 
5.7.8 Leukostasis and Tumor Lysis Syndrome (TLS) 
Clinical evaluation of leukostasis and TLS will be performed at Screening (Visit 1), baseline 
(Day 1, Visit 2 and Visit 10 for expansion phase subjects who receive a second treatment 
cycle) and during the Treatment Period upon commencement of symptoms or when WBC ≥ 
30,000/µL. 
Leukostasis (2) related symptoms include visual symptoms, shortness of breath and decreased 
oxygen saturation in blood measured by pulse oximetry. 
TLS will be evaluated using the Cairo-Bishop criteria (3) (Appendix D). 
5.8 
EFFICACY ASSESSMENTS 
5.8.1 Response rate 
Response rate will be evaluated at the final BM evaluationb based on Cheson 2003 criteria (4) 
(Appendix C): 
o Complete response (CR)  
o Complete response with incomplete hematological recovery of platelets or 
neutrophils (CRi) 
o Partial response (PR) 
o Overall response defined as the sum of CR, CRi and PR.  
o Complete response composite (CRc) defined as the sum of CR and CRi. 
5.8.2 Leukemic cells apoptosis in PB 
Assessment of leukemic cell apoptosis in PB will be performed on Days 1 and 3 (Visits 2 and 
4) at pre-dose, 4c and 24 hrs post BL-8040 injection. Apoptosis will be assessed by 
immunocytochemistry and flow cytometry, using Annexin V and propidium iodide (PI) 
apoptosis detection kits according to the manufacturer’s instructions. 
5.8.3 Leukemic cells apoptosis in BM 
Assessment of leukemic cell apoptosis in BM will be conducted within 7 days prior to 
commencing study treatment (Visit 1) and on Day 3 (pre-dose; Visit 4). Quantitative 
                                                 
a Expansion phase subjects who receive a second treatment cycle will have ADA and complement activation 
samples collected during the first treatment cycle only. 
b Expansion phase subjects who receive a second treatment cycle will have BM evaluation performed at the 
end of both treatment cycles. The second BM evaluation will be used to define the subject’s clinical response. 
c 4 hr post-dose samples on Day 3 to be taken prior to administration of Ara-C. 


 
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assessment of apoptotic cells in BM biopsies and aspirates will be conducted using caspase-3 
staining.  
5.8.4 Leukemic blast counts in PB 
Leukemic blast count in PB will be assessed by FACS analysis of surface markers on Days 1 
and 3 (Visits 2 and 4) at pre-dose, 4a and 24 hrs post BL-8040 injection. Additional signalling 
pathway proteins may be assessed at the discretion of the Sponsor.  
5.8.5 Assessment of Chromosomal Abnormalities by FISH  
In the expansion phase of the study, subjects with identifiable chromosomal abnormalities at 
baseline will be further assessed by FISH in PB and/or BM aspirate collected on Days 1 and 
3 (at pre-dose, 4a and 24 hrs post BL-8040 injection.  
5.8.6 CXCR4 receptor occupancy in PB 
CXCR4 occupancy will be measured in the PB of dose escalation phase subjects, using the 
CXCR4 antibodies 12G5 and 1D9, on Days 1 and 3 (Visits 2 and 4) at pre-dose, 4a and 24 hrs 
post BL-8040 injection. 
5.9 
PK ASSESSMENTS 
BL-8040 PK parameters will be determined on the basis of blood samples collected on Days 
1, 3, 5 and 7 (Visits 2, 4, 6 and 8).  
Blood samples for BL-8040 PK analysis will be collected on Days 1, 3 and 7 at pre-dose, 
0.25, 0.5, 1, 2, 4, 8 and 24 hrs post BL-8040 administration. Additional samples will be 
collected on Day 5 (Visit 6) at pre-dose and 0.5 hr post BL-8040 administration. PK 
parameters are listed in Section ‎2.2.3. 
No PK blood samples will be collected from expansion phase subjects who receive a second 
treatment cycle. 
PK sampling may be discontinued during the expansion phase at the discretion of the 
Sponsor. The Sponsor will notify sites when PK sample collection can be halted. 
PK analysis will be conducted by a central laboratory using a validated High Performance 
Liquid Chromatography (HPLC) method. 
5.10 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. 
5.11 TIME WINDOWS FOR SAFETY, PK AND EFFICACY ASSESSMENTS 
The time windows shown below will apply to post-dose safety (ECG and laboratory safety 
evaluations), efficacy (FACS analysis of leukemic cell mobilisation and apoptosis and 
CXCR4 receptor occupancy) and PK assessments. 
 
 
                                                 
a 4 hr post-dose samples on Day 3 to be taken prior to administration of Ara-C. 


 
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Time-point 
Safety 
Efficacy 
PK 
0.25 hr 
 
 
± 2 min 
0.5 hr 
± 5 min 
 
± 5 min 
1 hr 
± 10 min 
 
± 10 min 
2 hrs 
± 15 min 
 
± 15 min 
4 hrs 
± 30 min 
± 30 min 
± 30 min 
8 hrs 
± 30 min 
 
± 30 min 
24 hrs 
± 1 hr 
± 1 hr 
± 1 hr 
 
6 
INVESTIGATIONAL PRODUCT 
6.1 
IDENTITY OF INVESTIGATIONAL PRODUCT 
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, a white to off-white powder synthetic polypeptide, is freely soluble in water and in 
0.45% Sodium Chloride (half normal saline). It is manufactured in accordance with cGMP by 
 
6.2 
STUDY DRUG ADMINISTRATION AND DOSAGE 
6.2.1 BL-8040 
On Days 1 and 2, subjects will receive once daily SC injections of BL-8040 in the morning 
according to the dose group to which they are assigned.  
Between Days 3 and 7, BL-8040 will be administered once daily by SC injection(s) 4 (+/- 
0.5) hrs prior to administration of standard chemotherapy (chemotherapy will be initiated on 
Day 3). The same instructions are applicable for expansion phase subjects who receive a 
second treatment cycle. 
The BL-8040 injection site will be rotated on Days 1-7, to minimize the severity of any local 
injection site reactions. At the discretion of the Investigator, a single dose administration may 
be split and injected into more than one site. The same instructions are applicable for 
expansion phase subjects who receive a second treatment cycle. 
During the expansion phase of the study, subjects with blast values of ≥ 30,000 and < 
50,000/µL and/or WBC counts of ≥ 50,000 and < 60,000/µL, 24 hrs following the first BL-
8040 injection, will not receive the second injection. Provided there are no signs of 
leukostasis on detailed physical examination, they will proceed directly to the combination 
therapy stage (protocol Day 3). In this situation, subjects will not receive BL-8040 prior to 
the first dose of Ara-Ca, but will receive BL-8040 prior to Ara-C on subsequent days 
provided blast count is < 30,000/µL and WBC counts is < 50,000/µL. 
                                                 
a Subjects who skip Day 2 due to blast counts ≥ 30,000 and < 50,000 and or WBC counts ≥ 50,000 and < 
60,000/mL 24 hrs following the 1st dose of BL-8040, will proceed directly to protocol Day 3. All Day 3 
assessments and procedures will be performed with the exception of BL-8040 administration and the following 
post-dose assessments: PK profiling, ECG measurements, WBC count (differential and leukemic cells), partial 
 


 
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Similarly, subjects with blast values of ≥ 30,000 and < 50,000/µL and/or WBC counts of ≥ 
50,000 and < 60,000/µL 24 hrs following the second BL-8040 injection will be given the first 
dose of Ara-C without receiving BL-8040a, provided there are no signs of leukostasis on 
detailed physical examination, but will receive BL-8040 prior to Ara-C on subsequent days 
provided blast count is < 30,000/µL and WBC counts is < 50,000/µL. 
The planned dose escalation scheme will be as shown in Table 1. Dose modifications may 
include dose reductions, including doses lower than the starting dose of 0.5 mg/kg, and 
intermediate doses, but the maximum dose to be tested will not exceed 2.0 mg/kg. 
6.2.2 Chemotherapy 
Chemotherapy will consist of Ara-C 3 g/m2/day for subjects ≤ 60 years (performance status 
permitting) and 1.5 g/m2/day for subjects > 60 years administered IV over 3 hours. 
6.2.3 Stopping Rules and Dose Limiting Toxicities 
Dose-limiting toxicity (DLT)b is defined as a clinically significant adverse event or abnormal 
laboratory value assessed as unrelated to disease progression, intercurrent illness or 
concomitant medications and occurring during the safety period (30 daysc) that meets any of 
the following criteria (refer to Table 2 for CTCAE severity grading): 
 CTCAE grade 3 AST (SGOT) or ALT (SGPT) or bilirubin for ≥ 7 days 
 CTCAE grade 4 AST (SGOT) or ALT (SGPT) of any duration 
 All other clinically significant, non-hematological NCI common terminology criteria 
that are CTCAE grade 3 or 4  
To be considered a DLT such toxicity must be possibly, probably or definitely related to BL-
8040. 
An adverse event must be clinically significant to define DLT e.g. nausea and vomiting, 
alopecia, study drug-related fever, electrolyte abnormalities (including  K, Na, Cl, HCO3, 
Mg, Ca, bilirubin) that are ≤ grade 3 will not constitute DLT.  Myelosuppression and 
cytopenias are expected outcomes of leukemia treatment and per se will not constitute DLT. 
Only prolonged myelosuppression, as defined by the NCI criteria specific for leukemia, i.e. 
marrow cellularity < 5% on Day 42 or later (6 weeks) from start of therapy without evidence 
of leukemia, will be considered in defining MTD and DLT.   
Subjects experiencing ≥ grade 3 BL-8040 related toxicity, either in the monotherapy or 
combined treatment period (excluding hematological toxicity), will be withdrawn from the 
                                                                                                                                                        
biochemistry and assessment of CXCR4 receptor occupancy, leukemic blast apoptosis and mobilization 
(FACS and FISH). BM biopsy and/or aspiration must be performed prior to Ara-C administration. 
a Subjects with blast counts ≥ 30,000 and < 50,000 and/or WBC counts ≥ 50,000 and < 60,000/µL 24 hrs 
following the 2nd dose of BL-8040, will undergo all Day 3 assessments and procedures with the exception of 
BL-8040 administration and the following post-dose assessments: PK profiling, ECG measurements, WBC 
count (differential and leukemic cells), partial biochemistry and assessment of CXCR4 receptor occupancy, 
leukemic blast apoptosis and mobilization (FACS and FISH). BM biopsy and/or aspiration must be performed 
prior to Ara-C administration. 
b Only BL-8040 related or possibly related, grade 3-4 toxicities define DLT. For example, bone pain at grade 
3/4 will not necessarily be defined as DLT, based on physician's decision and accounting for other 
administered drugs. 
c In case of prolonged BM recovery it will be evaluated again at 6 weeks and considered part of the DLT 
assessment. 


 
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study, but followed for toxicity. Subjects who experience toxicity, which is not related to BL-
8040, either during monotherapy or within the combination therapy period, will be allowed to 
continue BL-8040 treatment at the Investigator's discretion.  
BL-8040 injections will be stopped in case of a significant increase in WBC and/or blasts 
(WBC ≥ 60,000/µL and/or blasts ≥ 50,000/µL, respectively) measured prior to administration 
of the next BL-8040 injection and/or evidence of leukostasis, TLS or grade 3-4 allergic 
reaction. These subjects will be withdrawn from the study and will be followed-up for safety 
for up to 6 weeks. In addition, during the escalation phase, subjects with blast values of ≥ 
30,000 and < 50,000/µL and/or WBC counts of ≥ 50,000 and < 60,000/µL 24 hrs following 
BL-8040 injection on Days 1-6, will be withdrawn from the study and replaced. 
During the expansion phase of the study, subjects with blast values of ≥ 30,000 and < 
50,000/µL and/or WBC counts of ≥ 50,000 and < 60,000/µL, 24 hrs following the first BL-
8040 injection, will not receive the second injection. Provided there are no signs of 
leukostasis on detailed physical examination, they will proceed directly to the combination 
therapy stage (protocol Day 3). In this situation, subjects will not receive BL-8040 prior to 
the first dose of Ara-Ca, but will receive BL-8040 prior to Ara-C on subsequent days 
provided blast count is < 30,000/µL and WBC counts is < 50,000/µL. 
Similarly, subjects with blast values of ≥ 30,000 and < 50,000/µL and/or WBC counts of ≥ 
50,000 and < 60,000/µL 24 hrs following the second BL-8040 injection will be given the first 
dose of Ara-C without receiving BL-8040b, provided there are no signs of leukostasis on 
detailed physical examination, but will receive BL-8040 prior to Ara-C on subsequent days 
provided blast count is < 30,000/µL and WBC counts is < 50,000/µL. 
Subjects who do not receive BL-8040 on Days 2 and/or 3, will not provide the full data set 
required for assessment of secondary endpoints relating to leukemic blast apoptosis and 
mobilization. However, they will be considered eligible for assessment of the secondary 
efficacy endpoint relating to response rate. 
During the combination therapy, if blast values are ≥ 30,000/µL, BL-8040 administration will 
be discontinued.  
6.2.4 Rescue medication 
Leukostasis 
Initiation of chemotherapy will be expedited in subjects experiencing leukostasis. 
Additionally, leukopharesis should be considered. Subjects developing shortness of breath 
with reduced saturation should be carefully monitored and receive oxygen.  
 
                                                 
a Subjects who skip Day 2 due to blast counts ≥ 30,000 and < 50,000 and or WBC counts ≥ 50,000 and < 
60,000/µL 24 hrs following the 1st dose of BL-8040, will proceed directly to protocol Day 3. All Day 3 
assessments and procedures will be performed with the exception of BL-8040 administration and the following 
post-dose assessments: PK profiling, ECG measurements, WBC count (differential and leukemic cells), partial 
biochemistry and assessment of CXCR4 receptor occupancy, leukemic blast apoptosis and mobilization 
(FACS and FISH). BM biopsy and/or aspiration must be performed prior to Ara-C administration. 
b Subjects with blast counts ≥ 30,000 and < 50,000 and/or WBC counts ≥ 50,000 and < 60,000/µL 24 hrs 
following the 2nd dose of BL-8040, will undergo all Day 3 assessments and procedures with the exception of 
BL-8040 administration and the following post-dose assessments: PK profiling, ECG measurements, WBC 
count (differential and leukemic cells), partial biochemistry and assessment of CXCR4 receptor occupancy, 
leukemic blast apoptosis and mobilization (FACS and FISH). BM biopsy and/or aspiration must be performed 
prior to Ara-C administration. 


 
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Tumour Lysis Syndrome 
Subjects should be hydrated vigorously (urine output and fluid input should be monitored). 
Allopurinol and Rasburicase should be considered.  
6.3 
MANUFACTURING OF STUDY MEDICATION 
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 a separate study manual. 
6.4 
PACKAGING AND LABELING OF STUDY MEDICATION 
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: 
 
 
 
 
 
 
  
6.5 
DISTRIBUTION AND SHIPMENT OF STUDY MEDICATION 
The investigational medicinal product will be packed and shipped in appropriate boxes. If, 
upon arrival at the clinical investigation site, study drug supplies appear to be damaged, the 
study monitor should be contacted immediately.  
Each shipment of study drug supplies for the study will be accompanied by a shipment form 
describing the contents of the shipment, product certificate of analysis, acknowledgement of 
receipt and other appropriate documentation. The shipment form will assist in maintaining 
current and accurate inventory records. The study staff will confirm the receipt of clinical 
supply to the study monitor. 
All study supplies should arrive at the Pharmacy/Investigational site in sufficient quantity and 
in time to enable dosing as scheduled. The Sponsor or its representative must notify the 
Principal Investigator’s designee prior to dispatch of drug supplies, with the anticipated date 
of their arrival.   
6.6 
STORAGE, DISPENSING AND RETURN OF THE INVESTIGATIONAL MEDICINAL 
PRODUCT 
Vials of BL-8040 for injection should be stored in the refrigerator (2-8°C) in its original 
packaging, protected from light. 
Records should also be kept by the Investigator or designee as to how much study drug was 
dispensed to each subject. The study monitors must periodically check the study drug 
supplied to ensure expiry date and sufficient amount of study drug, and be sure that drug 
accountability is being performed at each visit, and the drug accountability logs are 
maintained.  
All investigational products must be kept in a secure area with access to the study drug 
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Only trained personnel under the supervision of either the Investigator or the local pharmacist 
are authorized to dispense and administer study drug to participating subjects.  
Further details and instructions will be provided in the Pharmacy Manual. 
6.7 
ACCOUNTABILITY AND COMPLIANCE OF INVESTIGATIONAL MEDICINAL PRODUCT 
Each delivery must be acknowledged by the hospital pharmacist (or authorized study team 
member responsible for the investigational medicinal product) by filling in the receipt record 
form and returning it by fax/email to the Sponsor or designee. Accurate, complete and timely 
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.   
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.  
Concomitant medication use will be recorded from Baseline (Visit 2) through end of the 
Treatment Period (Visit 8 / Day 7). The following information should be recorded: 
treatment's name (generic, if possible), indication, dose and start and stop dates. 
6.8.1 Allowed Medications 
The following concomitant medications/therapies will be allowed during the treatment 
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 Allopurinol up to 300 mg/day (with adjustment to kidney function) and/or 
Rasburicase (up to 0.2 mg/kg/day, for up to 5 days).  
 Clinically appropriate measures in case of BL-8040-related local injection site 
reactions (e.g., corticosteroids, anti-histamines, local treatments etc.) and preventive 
treatment before subsequent doses; also relevant for subjects with systemic reactions. 
 Systemic and allergic treatment for chemotherapy-related allergic reactions. 
 Antiemetic drugs (e.g., Ondansetron) as required clinically based on local guidelines 
for patients experiencing nausea while treated with BL-8040 only, and as a preventive 
approach during the combined treatment period. 
 Gastrointestinal and kidney protective medications, routinely used in patients 
receiving chemotherapy, aiming to avoid peptic pain and TLS respectively (Losec, 
allopurinol, respectively). 
 Prophylactic antibiotics (e.g., quinolone or cephalosporin), antifungals (e.g., 
voriconazole) and antivirals (e.g., valacyclovir). 
 Blood products, commonly required in patients receiving chemotherapy for AML.  
 Low-dose steroids (100 mg hydrocortisone or equivalent) are allowed as pre-
medication for blood transfusion or with IV anti-fungals. 
 B6 – provided to avoid neurotoxicity. 
 Steroid eye drops - to prevent Ara-C induced inflammation.   
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 
where 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). 
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:  
 Results in subject's withdrawal by the Investigator 
 Is associated with an SAE 
 Is associated with clinical signs or symptoms 
 Is considered by the physician to be of clinical significance 
A new condition or the worsening of a pre-existing condition will be considered an AE.  
AEs do not include the following: 
 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 
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 Overdose of concomitant medication without any signs or symptoms unless the 
subject is hospitalized for observation.  
 Hospitalization for elective surgery planned prior to study (situation where an 
untoward medical occurrence has not occurred). 
 Disease progression 
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 14.0).  
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: 
 Mild (Grade 1): The AE is noticeable to the subject but does not interfere with routine 
activity, no medical intervention is required;   
 Moderate (Grade 2): The AE interferes with routine activity but responds to 
symptomatic therapy or rest; 
 Severe (Grade 3): The AE significantly limits the subject’s ability to perform routine 
activities despite symptomatic therapy; 
 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: 


 
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 Recovered: The subject has fully recovered from the AE with no residual effects 
observable 
 Recovered with sequelae: The subject has recovered from the AE with residual effects 
observable 
 Improved: the subject status improved but has not been fully recovered 
 Ongoing: AE is not recovered 
 Fatal 
 Unknown 
AEs will be coded by Data Management using the latest version of MedDRA (currently 
version 14.0) 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 
 
 
Relationship 
Criteria 
Unrelated  
The patient did not receive the study medication. 
OR 
The temporal sequence of the AE onset relative to administration of the study 
medication is not reasonable. 
OR 
There is another obvious cause of the AE. 
Unlikely  
There is evidence of exposure to the study medication. However, it does not follow a 
reasonable temporal sequence from administration of drug. 
It does not follow a known response pattern to the suspected drug. 
It does not re-appear or worsen upon re-challenge. 
There is another more likely cause of the AE. 
Possible  
There is evidence of exposure to the study medication. 
The temporal sequence of the AE onset relative to the administration of the study 
medication is reasonable. 
The AE could have been due to another equally likely cause. 
Probable 
There is evidence of exposure to the study medication. 
The temporal sequence of the AE onset relative to administration of the study 
medication is reasonable. 
The AE is more likely explained by the study medication than by another cause. 
A direct cause and effect relationship between the suspected drug and the adverse event 
is likely. 
It disappears or decreases upon cessation of drug administration or reduction in dose. 
Related 
There is evidence of exposure to the study medication. 
The temporal sequence of the AE onset relative to administration of the study 
medication is reasonable. 
The AE is more likely explained by the study medication than by another cause. 
The AE shows a pattern consistent with previous knowledge of the study medication. 
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has been demonstrated.  
It disappears or decreases upon cessation of drug administration or reduction in dose. 
 
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: 
 death (regardless of the cause) 
 a life-threatening experience 
 inpatient hospitalization or prolongation of existing hospitalization (any inpatient 
hospital admission that includes a minimum of an overnight stay in a health care 
facility) 
 a persistent or significant disability/incapacity 
 a congenital anomaly or birth defect 
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. 


 
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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, 5.1.9 and FDA guidance “Safety Reporting Requirements for INDs and BA/BE 
Studies” (Dec 2012). 
High dose chemotherapy is a recognized condition with a relatively high morbidity and/or 
high mortality.  
Under these circumstances, it seems appropriate that the SAEs, clearly related to the high 
dose chemotherapy could be an exception for an immediate systematic reporting. 
These AEs will be thoroughly handled and followed up through the CRF (AE form) and will 
be reviewed monthly by the medical safety officer and could be re-qualified for reporting if 
necessary. 
Each event must be carefully analyzed by the Investigator’s designee to decide whether the 
SAE could be considered as an exception or must be immediately reported.  
7.5 
NOTIFICATION OF SERIOUS ADVERSE EVENT (SAE) 
Initial notification of SAEs 
An Initial SAE report form must be completed and sent by fax/email to the Medical 
Monitor within 24 hours of the Investigator’s knowledge of the event. Any fatal or life-
threatening event should be reported immediately, by phone, fax or email. Reporting 
SAEs to regulatory authorities and/or IRBs will comply with local regulations. 
 
Medical Monitor 
 
 
 
 
 
The Initial SAE report will be followed within 24 hours by a completed SAE report including 
a sufficiently detailed narrative to allow for a medical assessment of the case, as well as 
copies of hospital case reports, results of applicable diagnostic tests, laboratory results, 
biopsy results, autopsy reports and other documents when requested and applicable. 
Minimum criteria for a valid initial SAE case: 
For regulatory purposes, initial SAE reports should be submitted to Medical Monitor and/or 
the Sponsor immediately and should include: 
- 
A suspected investigational medicinal product, 
- 
An identifiable subject (e.g. study subject code number), 
- 
An AE with the Investigator’s assessment of seriousness and relationship to study 
drug, 
- 
An identifiable reporting source (Investigator contact details). 


 
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Once sent, the SAE form and accompanying documentation should be placed in the SAE 
section of the Investigator’s site file. 
In addition, all SUSARs and relevant SAEs will be reported to the IRB/IEC and regulatory 
authorities as required by local regulations and ICH-GCP guidelines.  
Follow-up of SAEs:  
Follow-up of all SAEs that occur during the study will continue until their satisfactory 
resolution or stabilization. In outstanding cases, it may be defined as “ongoing without 
further follow-up” if mutually agreed by the Investigator and Sponsor. 
A Follow-up SAE Report Form must be completed by the site (marked as “Follow-up 
report”) and sent to the Medical Monitor within a reasonable timeframe (an SAE Follow-up 
report is required whether or not there is any additional information to the initial report).   
The contact information for Follow-up SAE reporting is the same as for initial SAE reports 
(see above section).  
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.  
8 
STATISTICAL ANALYSIS  
8.1 
SAMPLE SIZE CONSIDERATION 
As this is a Phase IIa study, the exact number of subjects enrolled will depend on the toxicity 
observed in each dose group and the number of dose groups required to reach MTD. If all six 
dose groups are required and if each dose group is expanded to 6 subjects (see stopping rules 
Section ‎6.2.3 and Figure 1), then a total of 36 subjects will be enrolled into the dose 
escalation part of the study. 
Once a dose has been selected for the expansion phase, additional subjects may be enrolled 
in that dose group up to a total of approximately 70 subjects in the study. 
8.2 
ANALYSIS SETS 
Intention-To-Treat (ITT) Analysis Set: All enrolled subjects who receive at least one dose of 
study medication.  
Per-Protocol (PP) Analysis Set: All enrolled subjects who complete the study according to 
the protocol without major protocol violations.  
8.3 
STATISTICAL METHODS 
All measured variables and derived parameters will be listed individually and, if appropriate, 
tabulated by descriptive statistics. Summary statistics will be provided for all safety, 
exploratory and baseline/demographic variables. For categorical variables, frequency tables 
including percentages will be presented. For continuous variables, descriptive statistics such 
as number of available observations, mean, median, standard deviation (SD), minimum and 
maximum will be tabulated. All available data and the tabulation of results will be displayed 
by initial dose level and with all levels pooled as a whole if applicable. 
Dose limiting toxicity will be determined by definition and will be summarized by dose level. 
The MTD will be determined by study structure and DLTs.   
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8.3.1 Safety Analysis 
Changes in vital signs and routine laboratory data will be presented with descriptive statistics 
to demonstrate the trend of change. 
Number of subjects with physical abnormality at each scheduled visit will be tabulated by 
body system and by dose level. ECG examination results will be displayed in descriptive 
statistics and by dose level with number of subjects with abnormal findings tabulated for each 
schedule visit. 
Adverse event incidence will be summarized descriptively by system organ class and 
preferred term using the latest version of MedDRA (currently version 14.0) and by dose 
level. The worst severity grade of AEs, as determined by the latest version of NCI-CTCAE 
(currently version 4.03), and their relationship to study medication will be analyzed by 
System Organ Class, preferred term and by original dose level. The action taken and outcome 
will also be analyzed accordingly. 
By subject list of toxicity severity grade will be presented in time-sequence manner using the 
latest version of NCI-CTCAE (currently version 4.03) with System Organ Class and 
preferred term. The number and incidence of subjects experiencing toxicity will be tabulated 
by worst severity grade in each MedDRA term. Subjects experiencing toxicity ≥ grade 3 for 
each type of toxicity will be calculated and presented by original dose level. 
8.3.2 Efficacy Analysis 
95% Confidence Interval (CI) will be calculated for proportion of subjects defined (4) 
(Appendix C) in the secondary efficacy endpoints who achieve:  
Complete Response (CR)  
Complete Response with incomplete hematological recovery (CRi) 
Partial Response (PR)  
Overall Response (OR) defined as sum of CR, CRi and PR.  
Complete Response composite (CRc) defined as the sum of CR and CRi. 
Overall survival (OS) during the long-term follow-up. 
8.3.3 PK Analysis 
Individual PK parameters and the mean, SD and 95% CI values will be tabulated for each 
dose group. 
Dose proportionality/linearity in relation to Cmax and AUC will also be assessed if there is 
sufficient data available in each dose group. 
All tests will be two-tailed and a p value of 
or less will be considered statistically 
significant. 
9 
ETHICS 
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 
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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 (Appendix F).  
- 
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. 
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. 
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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  
An Internal Safety Committee 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. The decision to 
proceed to the next dose group will be made by this committee. 
This Internal Safety Committee will assess the progress of the clinical trial, the safety data 
and will recommend to the Sponsor and to the Investigator whether to continue, modify or 
stop the trial. 
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.   
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 
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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 
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.   


 
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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. 
10.4 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 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.   
10.4.1 Source Document 
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. 
10.4.2 Recording of Data on Case Report Form (CRF) 
The development of the CRF will be the responsibility of the Sponsor or its designee. 
All the pertinent data will be recorded on an electronic Case Report Form (eCRF). All eCRFs 
will be completed in English and will be reviewed by study monitors for accuracy and 
completeness. The eCRFs should be completed at the time of the subject's visit, with the 
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responsible for verifying that all data entries in the eCRFs are accurate and correct. The 
Principal Investigator 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.  
(EDC) system on the electronic CRFs (eCRFs):   
After the enrollment of the first patient, a study monitor will periodically monitor the 
progress of the study by conducting onsite visits. This 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 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. 
10.4.3 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. 
10.5 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. 
Clinical trial supplies include, but are not limited to: CRFs, lab supplies, rescue medications 
and study drugs. 
10.6 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: 
- 
Missing value checks 


 
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- 
Range checks 
- 
Consistency checks 
- 
Sequence checks 
- 
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 14.0). 
Prior and concomitant medications will be coded according to the World Health Organization 
(WHO) Drug Dictionary.  
11 STUDY ADMINISTRATION 
11.1 PARTICIPATING CENTERS 
Approximately 5 sites in the USA and 5 sites in Israel are planned.  
Additional sites may be added in the event of slow recruitment. 
11.2 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 
- 
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) 
- 
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 
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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. 
11.3 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: 
- 
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 
11.4 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. 
11.5 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. 


 
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11.6 CONFIDENTIALITY AND PUBLICATION OF STUDY RESULTS 
11.6.1 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 11.6.2, throughout the duration of the study and 
after its completion, Recipients shall (i) 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. 
11.6.2 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).  
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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 
could otherwise be detrimental to Sponsor's intellectual property interest or have other 
adverse 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 which Sponsor in good faith determines falls within (a) to (d) above. 
 
 


 
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1. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le 
Beau MM, Hellstrom-Lindberg E, Tefferi A, Bloomfield CD. The 2008 revision of the World 
Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: 
rationale and important changes. Blood 2009; 114(5): 937-951. 
2. Majhail, NS and Lichtin AE. Acute leukemia with a very high leukocyte count: confronting 
a medical emergency. Cleveland Clinic Journal of Medicine 2004; 71(8): 633-637. 
3. Cairo, MS and Bishop, M. Tumour lysis syndrome: new therapeutic strategies and 
classification. British Journal of Hematology 2004; 127(1): 3-11. 
4. Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, 
Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, 
Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD. Revised 
recommendations of the International Working Group for Diagnosis, Standardization of 
Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in 
Acute Myeloid Leukemia. Journal of Clinical Oncology 2003; 21(24): 4642-4649. 
5. Stone RM, O'Donnell MR, Sekeres MA. Acute myeloid leukemia. American Society of 
Hematology Education Program 2004: 98-117. 
6. SEER Cancer Statistics Review 2005-2009.   HYPERLINK "http://seer.cancer.gov"   
http://seer.cancer.gov . (Accessed November 2012). 
7. Estey EH. Acute myeloid leukemia: 2012 update on diagnosis, risk stratification and 
management. American Journal of Hematology 2012; 87(1): 89-99. 
8. Riva L, Luzi L, Pelicci PG. Genomics of acute myeloid leukemia: the next generation. 
Frontiers in Oncology 2012; 2: 40. 
9. Roboz GJ. Current treatment of acute myeloid leukemia. Current opinions in Oncology 
2012; 24(6): 711-719. 
10. Sorror ML, Maris MB, Storb R, Baron F, Sandmaier BM, Maloney DG, Storer B. 
Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk 
assessment before allogeneic HCT. Blood 2005; 106: 2912-2919. 
11. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, Wheatley 
K, Harrison CJ, Burnett AK, National Cancer Research Institute Adult Leukaemia Working 
Group. Refinement of cytogenetic classification in acute myeloid leukemia: determination of 
prognostic significance of rare recurring chromosomal abnormalities among 5876 younger 
adult patients treated in the United Kingdom Medical Research Council trials. Blood 2010; 
116(3): 354-365. 
12. Schlenk RF, Döhner K, Krauter J, Fröhling S, Corbacioglu A, Bullinger L, Habdank M, 
Späth D, Morgan M, Benner A, Schlegelberger B, Heil G, Ganser A, Döhner H, German-
Austrian Acute Myeloid Leukemia Study Group. Mutations and treatment outcome in 
cytogenetically normal acute myeloid leukemia. New England Journal of Medicine 2008; 
358(18): 1909-1918. 
13. Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. 
Journal of Clinical Oncology 2011; 29(5): 487-494. 
14. Vellenga E, van Putten W, Ossenkoppele GJ, Verdonck LF, Theobald M, Cornelissen JJ, 
Huijgens PC, Maertens J, Gratwohl A, Schaafsma R, Schanz U, Graux C, Schouten HC, 
Ferrant A, Bargetzi M, Fey MF, Löwenberg B, Dutch-Belgian Hemato-Oncology Cooperative 


 
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Group. Autologous peripheral blood stem cell transplantation for acute myeloid leukemia. 
Blood 2011; 118(23): 6037-6042. 
15. Tamamura H, Hiramatsu K, Kusano S, Terakubo S, Yamamoto N, Trent JO, Wang Z, 
Peiper SC, Nakashima H, Otaka A, Fujii N. Synthesis of potent CXCR4 inhibitors possessing 
low cytotoxicity and improved biostability based on T140 derivatives. Organic Biomolecular 
Chemistry 2003; 1(21): 3656-3662. 
16. Peled A, Petit I, Kollet O, Magid M, Ponomaryov T, Byk T, Nagler A, Ben-Hur H, Many 
A, Shultz L, Lider O, Alon R, Zipori D, Lapidot T. Dependence of human stem cell 
engraftment and repopulation of NOD/SCID mice on CXCR4. Science 1999; 283(5403): 845-
848. 
17. 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. 
18. Abraham M, Biyder K, Begin M, Wald H, Weiss ID, Galun E, Nagler A, Peled A. 
Enhanced unique pattern of hematopoietic cell mobilization induced by the CXCR4 
antagonist 4F-benzoyl-TN14003. Stem Cells 2007; 25(9): 2158-2166. 
19. Abraham M, Beider K, Wald H, Weiss ID, Zipori D, Galun E, Nagler A, Eizenberg O, 
Peled A. The CXCR4 antagonist 4F-benzoyl-TN14003 stimulates the recovery of the bone 
marrow after transplantation. Leukemia 2009; 23(8): 1378-1388. 
20. Robak T, Wierzbowska A. Current and emerging therapies for acute myeloid leukemia. 
Clinical Therapeutics 2009; 31(2): 2349-2370. 
21. Ofran Y, Rowe JM. Treatment for relapsed acute myeloid leukemia: what is new? Current 
Opinion in Hematology 2012; 19(2): 89-94. 
22. Giles FJ, Keating A, Goldstone AH, Avivi I, Willman CL, Kantarjian HM. Acute myeloid 
leukemia. American Society of Hematology Education Program 2002: 73-110. 
23. Mayani H. Composition and function of the hemopoietic microenvironment in human 
myeloid leukemia. Leukemia 1996; 10(6): 1041-1047. 
24. 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. 
25. 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. 
26. 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. 
27. Becker PS. Dependence of acute myeloid leukemia on adhesion within the bone marrow 
microenvironment. Scientific World Journal 2012; 2012. 
28. 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. 


 
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29. 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 of chemosensitization with the CXCR4 antagonist plerixafor in relapsed or 
refractory acute myeloid leukemia. Blood 2012; 119(17): 3917-3924. 
30. 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 2010; 115(3): 453-
474. 
31. de Greef GE, van Putten WL, Boogaerts M, Huijgens PC, Verdonck LF, Vellenga E, 
Theobald M, Jacky E, Löwenberg B, Dutch-Belgian Hemato-Oncology Co-operative Group 
HOVON, Swiss Group for Clinical Cancer Research SAKK. Criteria for defining a complete 
remission in acute myeloid leukaemia revisited. An analysis of patients treated in HOVON-
SAKK co-operative group studies. British Journal of Hematology 2005; 128(2):. 184-91. 
 
 


 
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13 APPENDICES 
APPENDIX A SCHEDULE OF ASSESSMENTS 
Study Procedures 
Screening Period 
Treatment Period23 
Follow-up 
Period1, 24, 26  
Monotherapy Period 
Combined Therapy Period 
Study Day  
Day - -
7  to Day 0 
Day 1/BL 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Up to Day 44  
Study Visit 
1 
2 / 10 
3 / 11 
4 / 12 
5 / 13 
6 / 14 
7 / 15 
8 / 16 
9 / 17 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
Demographic & medical history  
X 
 
 
 
 
 
 
 
 
Physical examination2, 3 
X4 
X 
X 
X 
X 
X 
X 
X 
 
Vital signs3, 5  
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
 
 
 
 
 
 
 
 
ECG6 
X 
X 
 
X16, 17  
(Visit 4 only) 
 
 
 
X 
 
ECHO/MUGA & Chest X-ray 
X 
 
 
 
 
 
 
 
 
Hematology3  
X 
X 
X 
X 
X 
X 
X 
X 
X7 
White blood cell (WBC) count8 
 
X 
X 
X16, 17 
 
 
 
X 
 
Biochemistry3 
X 
X 
X 
X 
X 
X 
X 
X 
X7 
Partial biochemistry9 
 
X 
X 
X16, 17  
 
 
 
X 
 
Coagulation10 
X 
X 
 
 
 
 
 
X 
 
Anti-drug antibody assessment25 
 
X  
(Visit 2 only) 
 
X 
(Visit 4 only) 
 
 
 
X  
(Visit 8 only) 
X  
(Visit 9 only) 
Serum β-hCG 
X 
 
 
 
 
 
 
 
 
HIV, HBV, HCV serology 
X 
 
 
 
 
 
 
 
 
Clinical evaluation of leukostasis and TLS 
X 
X  
upon commencement of symptoms or when WBC > 30,000/µL 
 
Bone Marrow (BM) biopsy/aspirate 
X11,22 (within 7 days 
prior to BL-8040) 
 
 
X20,22 (pre 
BL-8040 
Visit 4 only) 
 
 
 
 
X12, 13, 22 
CXCR4 expression and occupancy in PB14 and BM (dose 
escalation phase subjects only) 
X15 
X  
 
X16, 17  
 
 
 
 
 
 
BL-8040 SC injections 
 
X 
X16 
X16, 17 
X 
X 
X 
X 
 
Ara-C Chemotherapy18 
 
 
 
X 
X 
X 
X 
X 
 
Pharmacokinetic (PK) sampling19 
 
X 
 
X16, 17  
 
X 
 
X 
 
Leukemic cell apoptosis in BM (Caspase-3 
staining/Annexin V analysis) 
X 
 
 
X16, 17 
(Visit 4 only) 
 
 
 
 
 
Leukemic blasts (FACS and FISH)20 
 
X 
 
X16, 17  
 
 
 
 
 


 
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Study Procedures 
Screening Period 
Treatment Period23 
Follow-up 
Period1, 24, 26  
Monotherapy Period 
Combined Therapy Period 
Study Day  
Day - -
7  to Day 0 
Day 1/BL 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Up to Day 44  
Study Visit 
1 
2 / 10 
3 / 11 
4 / 12 
5 / 13 
6 / 14 
7 / 15 
8 / 16 
9 / 17 
Leukemic cell apoptosis in PB (Annexin V and PI 
analysis)21 
 
X 
 
X16, 17 
 
 
 
 
 
 
Adverse events 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
BL= Baseline, ECG = electrocardiogram,  ECHO/MUGA = echocardiogram/Multiple Gated Acquisition, ECOG – Eastern Cooperative Oncology Group, TLS = tumor lysis syndrome 
 
1. The follow-up period will start after completion of Ara-C chemotherapy and continue for up to 6 weeks after initiation of salvage chemotherapy with Ara-C, i.e., up to Day 44. 
The follow-up period will end when a BM biopsy and/or aspirate, performed between Day 20 – 44, provides definite assessment of response to therapy. 
2. Physical examination, including weight measurement.  
3. To be performed before BL-8040 administration on Days 1-7. 
4. Height will be measured at screening only. 
5. Vital signs will include blood pressure, pulse rate, oral temperature, O2 saturation levels and respiration rate. To be performed daily before BL-8040 administration on Days 1-7. 
6. Single 12-lead ECG recording at screening. On Days 1, 3 and 7 printed recordings will be collected at pre-dose, 0.5, 1, 2, 4, 8 and 24 hrs post BL-8040 administration. Expansion 
phase subjects who receive a second treatment cycle will only have ECG recordings on Days 1 and 7, i.e., visits 10 and 16 of the second cycle at pre-dose and 4 hrs post BL-8040 
administration.. 
7. Haematology and biochemistry tests will be performed at least twice per week for the duration of the follow-up period. 
 
8. WBC count (differential and leukemic cell count) will be measured at 4 and 8 hrs post BL-8040 injection.  
9. Partial biochemistry (electrolytes and kidney function) will be measured at 4 and 8 hrs post BL-8040 injection. Sampling for partial biochemistry is not required for 
expansion phase subjects who receive a second treatment cycle, i.e., on visits 10, 11, 12 and 16. 
10. Coagulation will be evaluated at screening, on Day 1 pre-dose and 24 hrs post-dose, and on Day 7 at 24 hrs post-dose. Sampling for coagulation is not required for expansion 
phase subjects who receive a second treatment cycle, i.e., on visits 10 and 16. 
11. In subjects who receive cytoreductive therapy, BM samples will be collected post therapy and prior to BL8040 administration. 
12. Bone marrow biopsy and aspiration will be performed on Day 30 (28 days from initiation of salvage chemotherapy) unless, in the opinion of the Investigator, earlier 
biopsy/aspiration is indicated based on early appearance of blast cells in PB. 
13. In subjects who do not show sufficient BM recovery by Day 30 (in absence of leukemia), BM biopsy and aspiration will be repeated 2 weeks later (Day 44) to exclude aplasia. 
14. CXCR4 receptor occupancy will be measured in the PB on Days 1 and 3 at pre-dose, 4 and 24 hrs post BL-8040. 
15. CXCR4 levels will be measured by IHC in pre- BL-8040 BM biopsy samples and will be analyzed for correlation to efficacy. 
16. Subjects participating in the expansion phase only will skip Day 2 if their blast counts are ≥ 30,000 and < 50,000/µL and/or their WBC counts are ≥ 50,000 and < 60,000/µL 24 
hrs following the 1st dose of BL-8040 and will proceed directly to protocol Day 3. All Day 3 assessments and procedures will be performed with the exception of BL-8040 
administration and the following post-dose assessments: PK profiling, ECG measurements, WBC count (differential and leukemic cells), partial biochemistry and assessment of 
CXCR4 receptor occupancy, leukemic blast apoptosis and mobilization. BM biopsy and/or aspiration must be performed prior to Ara-C administration. 


 
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17. Subjects participating in the expansion phase only with blast counts ≥ 30,000 and < 50,000/µL and/or their WBC counts are ≥ 50,000 and < 60,000/µL 24 hrs following the 2nd 
dose of BL-8040, will undergo all Day 3 assessments and procedures with the exception of BL-8040 administration and the following post-dose assessments: PK profiling, ECG 
measurements, WBC count (differential and leukemic cells), partial biochemistry and assessment of CXCR4 receptor occupancy, leukemic blast apoptosis and mobilization. BM 
biopsy and/or aspiration must be performed prior to Ara-C administration. 
18. Chemotherapy will consist of Ara-C 3 g/m2/day for subjects ≤ 60 years and 1.5 g/m2/day for subjects > 60 years administered intravenously over 3 hrs, 4 hrs (+/- 1 hr) after BL-
8040 administration. 
19. Blood samples for BL-8040 PK analysis will be collected on Days 1, 3 and 7 at pre-dose, 0.25, 0.5, 1, 2, 4, 8 and 24 hrs post BL-8040 administration. Samples will also be 
collected on Day 5 at pre-dose and 0.5 hrs post BL-8040 administration. PK sampling is not required for expansion phase subjects who receive a second treatment cycle, i.e., 
on visits 10, 12, 14 and 16. 
20. Leukemic blasts in PB and/or BM aspirate will be assessed by FACS and FISH (subjects with identifiable chromosomal abnormalities in the expansion phase only) analysis on 
samples collected on Days 1 and 3 (Visits 2 and 4) at pre-dose, 4 and 24 hrs post BL-8040. Sampling for FACS and FISH analysis is not required for expansion phase 
subjects who receive a second treatment cycle, i.e., on visits 10 and 12. 
21. Leukemic cell apoptosis will be assessed from PB samples collected on Days 1 and 3 at pre-dose, 4 and 24 hrs post BL-8040. Sampling for leukemic cell apoptosis is not 
required for expansion phase subjects who receive a second treatment cycle, i.e., on visits 10 and 12. 
22. Bone marrow biopsies/aspirates will be examined by H&E and FACS analysis for assessment of leukemic cell numbers.  
23. At the Investigator’s discretion, subjects participating in the expansion phase may be treated with a second treatment cycle if they are considered to have had clinical benefit, but 
not achieved CR or CRi (Study Visits 10-17). The second treatment cycle will start after clinical response assessment has been completed for the first treatment cycle, i.e., no 
sooner than Day 30 (± 2 days; Day 28 ± 2 of chemotherapy). 
24. Subjects participating in the expansion phase will be followed for up to 5 years after completion of the follow-up period. Sites will contact subjects by telephone at approximately 
3 month intervals (± 1 month) after the end of the follow-up period to determine AML status and survival. 
25. Blood samples for ADA and complement activation will be collected pre-dose and at 4 hrs post BL-8040 administration on Days 1 and 7. On Day 3 an ADA sample will be 
collected pre-dose only. In addition, an ADA sample will be collected at the end of the follow-up period (Visit 9). Expansion phase subjects who receive a second treatment cycle 
will have ADA samples collected during the first treatment cycle only. 
26. For expansion phase subjects receiving a second treatment cycle, bone marrow biopsy/aspiration and follow-up assessments following the second treatment cycle will be the same 
as those following the first treatment cycle (with the exception of sampling for ADA – see footnote 25). Both follow-up periods (Visits 9 and 17) will end when a BM biopsy 
and/or aspirate, performed between Day 20 – 44 of the relevant cycle, provides definite assessment of response to therapy. 
 


 
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APPENDIX B AML DIAGNOSIS CRITERIA  
AML diagnosis is based on WHO classification of myeloid neoplasm and acute (1).  
 


 
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APPENDIX C AML RESPONSE DEFINITION FOR CLINICAL TRIALS  
Responses to AML treatment have been defined using the following criteria developed by an 
International Working Group (4; 30; 31): 
 
Category 
Definitiona 
Complete remission (CR)b 
Bone marrow blasts < 5%;  
absence of blasts with Auer rods;  
absence of extramedullary disease;  
absolute neutrophil count > 1.0 x 109/L (1000/µL);  
platelet count > 100 x 109/L (100,000/µL);  
independence of red cell transfusions. 
CR with incomplete recovery 
(CRi)c 
All CR criteria except for: 
residual neutropenia (< 1.0 x 109/L [1000/µL]) or 
thrombocytopenia (< 100 x 109/L [100,000/µL]) 
Partial remission (PR) 
Relevant in the setting of phase 1 and 2 clinical trials only;  
all hematologic criteria of CR;  
decrease of bone marrow blast percentage to 5% to 25%; and 
decrease of pretreatment bone marrow blast percentage by at 
least 50% 
 
 
 
 
 
 
                                                 
a Definitions of response criteria are based primarily on Cheson 2003 criteria (4). 
b All criteria need to be fulfilled; marrow evaluation should be based on a count of 200 nucleated cells in an 
aspirate with spicules; if ambiguous, consider repeat exam after 5 to 7 days; flow cytometric evaluation may 
help to distinguish between persistent leukemia and regenerating normal marrow; a marrow biopsy should be 
performed in cases of dry tap, or if no spicules are obtained; no minimum duration of response required. 
c The criterion of CRi is of value in protocols using intensified induction or double induction strategies, in 
which hematologic recovery is not awaited, but intensive therapy will be continued. In such protocols, CR may 
even not be achieved in the course of the entire treatment plan. In these instances, the overall remission rate 
should include CR and CRi patients. Some patients may not achieve complete hematologic recovery upon 
longer observation times. 


 
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APPENDIX D CAIRO-BISHOP CRITERIA FOR DIAGNOSIS OF TUMOR LYSIS SYNDROME 
(TLS) 
 


 
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APPENDIX E 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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APPENDIX F DECLARATION OF HELSINKI (2008) 
WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by 
the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53th WMA General Assembly, Washington 2002 (Note of Clarification on paragraph 29 
added) 
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30 added) 
59th WMA General Assembly, Seoul, October 2008 
A. INTRODUCTION  
1. The World Medical Association (WMA) has developed the Declaration of 
Helsinki as a statement of ethical principles for medical research involving 
human subjects, including research on identifiable human material and data.  
The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should not be applied without consideration of all other relevant 
paragraphs. 
2. Although the Declaration is addressed primarily to physicians, the WMA 
encourages other participants in medical research involving human subjects to 
adopt these principles. 
3. It is the duty of the physician to promote and safeguard the health of patients, 
including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfillment of this duty. 
4. The Declaration of Geneva of the WMA binds the physician with the words, 
"The health of my patient will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act in the patient's 
best interest when providing medical care." 
5. Medical progress is based on research that ultimately must include studies 
involving human subjects. Populations that are underrepresented in medical 
research should be provided appropriate access to participation in research. 
6. In medical research involving human subjects, the well-being of the individual 
research subject must take precedence over all other interests. 
7. The primary purpose of medical research involving human subjects is to 
understand the causes, development and effects of diseases and improve 
preventive, diagnostic and therapeutic interventions (methods, procedures and 
treatments). Even the best current interventions must be evaluated continually 
through research for their safety, effectiveness, efficiency, accessibility and 
quality. 
8. In medical practice and in medical research, most interventions involve risks 
and burdens. 


 
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9. Medical research is subject to ethical standards that promote respect for all 
human subjects and protect their health and rights. Some research populations 
are particularly vulnerable and need special protection. These include those 
who cannot give or refuse consent for themselves and those who may be 
vulnerable to coercion or undue influence. 
10. Physicians should consider the ethical, legal and regulatory norms and 
standards for research involving human subjects in their own countries as well 
as applicable international norms and standards. No national or international 
ethical, legal or regulatory requirement should reduce or eliminate any of the 
protections for research subjects set forth in this Declaration. 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
11. It is the duty of physicians who participate in medical research to protect the 
life, health, dignity, integrity, right to self-determination, privacy, and 
confidentiality of personal information of research subjects. 
12. Medical research involving human subjects must conform to generally 
accepted scientific principles, be based on a thorough knowledge of the 
scientific literature, other relevant sources of information, and adequate 
laboratory and, as appropriate, animal experimentation. The welfare of animals 
used for research must be respected.  
13. Appropriate caution must be exercised in the conduct of medical research that 
may harm the environment. 
14. The design and performance of each research study involving human subjects 
must be clearly described in a research protocol. The protocol should contain a 
statement of the ethical considerations involved and should indicate how the 
principles in this Declaration have been addressed. The protocol should include 
information regarding funding, sponsors, institutional affiliations, other 
potential conflicts of interest, incentives for subjects and provisions for treating 
and/or compensating subjects who are harmed as a consequence of 
participation in the research study. The protocol should describe arrangements 
for post-study access by study subjects to interventions identified as beneficial 
in the study or access to other appropriate care or benefits. 
15. The research protocol must be submitted for consideration, comment, guidance 
and approval to a research ethics committee before the study begins. This 
committee must be independent of the researcher, the sponsor and any other 
undue influence. It must take into consideration the laws and regulations of the 
country or countries in which the research is to be performed as well as 
applicable international norms and standards but these must not be allowed to 
reduce or eliminate any of the protections for research subjects set forth in this 
Declaration. The committee must have the right to monitor ongoing studies. 
The researcher must provide monitoring information to the committee, 
especially information about any serious adverse events. No change to the 
protocol may be made without consideration and approval by the committee. 
16. Medical research involving human subjects must be conducted only by 
individuals with the appropriate scientific training and qualifications. Research 
on patients or healthy volunteers requires the supervision of a competent and 
appropriately qualified physician or other health care professional. The 
responsibility for the protection of research subjects must always rest with the 


 
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physician or other health care professional and never the research subjects, 
even though they have given consent. 
17. Medical research involving a disadvantaged or vulnerable population or 
community is only justified if the research is responsive to the health needs and 
priorities of this population or community and if there is a reasonable 
likelihood that this population or community stands to benefit from the results 
of the research. 
18. Every medical research study involving human subjects must be preceded by 
careful assessment of predictable risks and burdens to the individuals and 
communities involved in the research in comparison with foreseeable benefits 
to them and to other individuals or communities affected by the condition 
under investigation. 
19. Every clinical trial must be registered in a publicly accessible database before 
recruitment of the first subject. 
20. Physicians may not participate in a research study involving human subjects 
unless they are confident that the risks involved have been adequately assessed 
and can be satisfactorily managed. Physicians must immediately stop a study 
when the risks are found to outweigh the potential benefits or when there is 
conclusive proof of positive and beneficial results. 
21. Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the inherent risks and burdens to the 
research subjects. 
22. Participation by competent individuals as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or 
community leaders, no competent individual may be enrolled in a research 
study unless he or she freely agrees. 
23. Every precaution must be taken to protect the privacy of research subjects and 
the confidentiality of their personal information and to minimize the impact of 
the study on their physical, mental and social integrity. 
24. In medical research involving competent human subjects, each potential 
subject must be adequately informed of the aims, methods, sources of funding, 
any possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may 
entail, and any other relevant aspects of the study. The potential subject must 
be informed of the right to refuse to participate in the study or to withdraw 
consent to participate at any time without reprisal. Special attention should be 
given to the specific information needs of individual potential subjects as well 
as to the methods used to deliver the information. After ensuring that the 
potential subject has understood the information, the physician or another 
appropriately qualified individual must then seek the potential subject's freely-
given informed consent, preferably in writing. If the consent cannot be 
expressed in writing, the non-written consent must be formally documented 
and witnessed. 
25. For medical research using identifiable human material or data, physicians 
must normally seek consent for the collection, analysis, storage and/or reuse. 
There may be situations where consent would be impossible or impractical to 
obtain for such research or would pose a threat to the validity of the research. 


 
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In such situations the research may be done only after consideration and 
approval of a research ethics committee. 
26. When seeking informed consent for participation in a research study the 
physician should be particularly cautious if the potential subject is in a 
dependent relationship with the physician or may consent under duress. In such 
situations the informed consent should be sought by an appropriately qualified 
individual who is completely independent of this relationship. 
27. For a potential research subject who is incompetent, the physician must seek 
informed consent from the legally authorized representative. These individuals 
must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the population represented 
by the potential subject, the research cannot instead be performed with 
competent persons, and the research entails only minimal risk and minimal 
burden. 
28. When a potential research subject who is deemed incompetent is able to give 
assent to decisions about participation in research, the physician must seek that 
assent in addition to the consent of the legally authorized representative. The 
potential subject's dissent should be respected. 
29. Research involving subjects who are physically or mentally incapable of 
giving consent, for example, unconscious patients, may be done only if the 
physical or mental condition that prevents giving informed consent is a 
necessary characteristic of the research population. In such circumstances the 
physician should seek informed consent from the legally authorized 
representative. If no such representative is available and if the research cannot 
be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them 
unable to give informed consent have been stated in the research protocol and 
the study has been approved by a research ethics committee. Consent to remain 
in the research should be obtained as soon as possible from the subject or a 
legally authorized representative. 
30. Authors, editors and publishers all have ethical obligations with regard to the 
publication of the results of research. Authors have a duty to make publicly 
available the results of their research on human subjects and are accountable 
for the completeness and accuracy of their reports. They should adhere to 
accepted guidelines for ethical reporting. Negative and inconclusive as well as 
positive results should be published or otherwise made publicly available. 
Sources of funding, institutional affiliations and conflicts of interest should be 
declared in the publication. Reports of research not in accordance with the 
principles of this Declaration should not be accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
31. The physician may combine medical research with medical care only to the 
extent that the research is justified by its potential preventive, diagnostic or 
therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the 
patients who serve as research subjects. 


 
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32. The benefits, risks, burdens and effectiveness of a new intervention must be 
tested against those of the best current proven intervention, except in the 
following circumstances: 
 
The use of placebo, or no treatment, is acceptable in studies where no 
current proven intervention exists; or  
 
Where for compelling and scientifically sound methodological reasons 
the use of placebo is necessary to determine the efficacy or safety of an 
intervention and the patients who receive placebo or no treatment will not 
be subject to any risk of serious or irreversible harm. Extreme care must 
be taken to avoid abuse of this option. 
33. At the conclusion of the study, patients entered into the study are entitled to be 
informed about the outcome of the study and to share any benefits that result 
from it, for example, access to interventions identified as beneficial in the 
study or to other appropriate care or benefits. 
34. The physician must fully inform the patient which aspects of the care are 
related to the research. The refusal of a patient to participate in a study or the 
patient's decision to withdraw from the study must never interfere with the 
patient-physician relationship. 
35. In the treatment of a patient, where proven interventions do not exist or have 
been ineffective, the physician, after seeking expert advice, with informed 
consent from the patient or a legally authorized representative, may use an 
unproven intervention if in the physician's judgment it offers hope of saving 
life, re-establishing health or alleviating suffering. Where possible, this 
intervention should be made the object of research, designed to evaluate its 
safety and efficacy. In all cases, new information should be recorded and, 
where appropriate, made publicly available. 
22.10.2008 


 
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APPENDIX G CORTICOSTEROID COMPARISON CHART 
 
 

SAP_001.pdf: 
 
BioLineRx.com 
Israel Headquarters 
Modi’in Technology Park 
2 HaMa’ayan Street 
Modi’in 7177871, Israel 
Phone: +972.8.642.9100  
 
NCT Number: 
NCT01838395 
Sponsor Study Number: 
BL-8040.01 
Official Study Title: 
A Phase IIa, Multicenter, Open-Label Study Designed to 
Evaluate the Safety and Efficacy of Escalating Doses of BL-
8040 in Adult Subjects with Relapsed/Refractory Acute 
Myeloid Leukemia 
Document Version and Date: 
Statistical Analysis Plan, version 1.6, 14 January 2016  
 
 


 
 
1357 GARDEN ROAD, WYNNEWOOD, PA 19096 • (610) 645 5708 FAX: (484) 534 8570 • BSC@biomedstat.com •  
                                                                               www.biomedstat.com 
 
Biomedical Statistical Consulting 
QUALITY IN DESIGN, IMPLEMENTATION, & PRESENTATION SINCE 1986 
 
 
 
A Phase IIa, Multicenter, Open-label Study Designed to Evaluate the Safety and 
Efficacy of Escalating Doses of BL-8040 in Adult Subjects with Relapsed/Refractory 
Acute Myeloid Leukemia 
 
BL-8040 
 
 
 
 








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Table of Contents 
1.0 
Introduction ....................................................................................................................... 8 
2.0 
Study Objectives and Design ............................................................................................ 9 
2.1 
Primary Study Objective ................................................................................................. 9 
2.2 
Secondary Study Objectives............................................................................................ 9 
2.3 
Exploratory Objectives .................................................................................................... 9 
2.4 
Study Design Synopsis .................................................................................................... 9 
2.4.1 
Dose escalation protocol ......................................................................................... 9 
2.4.2 
Dose limiting toxicity ............................................................................................ 11 
2.4.3 
Study population ................................................................................................... 11 
2.4.4 
Inclusion and exclusion criteria............................................................................. 11 
2.5 
Criteria for evaluation ................................................................................................... 11 
2.5.1 
Safety ..................................................................................................................... 11 
2.5.2 
Efficacy ................................................................................................................. 12 
2.5.3 
Pharmacokinetics and ............................................................................................ 13 
2.5.4 
Other ...................................................................................................................... 13 
3.0 
Statistical Methods .......................................................................................................... 15 
3.1 
Overview ....................................................................................................................... 15 
3.2 
Analysis Sets ................................................................................................................. 15 
3.2.1 
Full analysis set (ITT) ........................................................................................... 15 
3.2.2 
Per-protocol set (PP) ............................................................................................. 15 
3.3 
Baseline Comparability ................................................................................................. 15 
3.4 
Efficacy Analysis .......................................................................................................... 15 
3.5 
Safety Analysis .............................................................................................................. 16 
3.6 
Sample Size ................................................................................................................... 16 
3.7 
Treatment assignment and blinding .............................................................................. 16 
3.8 
Handling of missing values ........................................................................................... 16 
3.9 
Protocol Deviations analysis populations ..................................................................... 16 
3.10 
Multiple comparisons .................................................................................................... 17 
3.11 
Site poolability .............................................................................................................. 17 
4.0 
Presentation of Results.................................................................................................... 18 
4.1 
Handling of Dose Groups .............................................................................................. 18 
4.2 
Enrollment & Demographic and Baseline comparisons- ITT analysis set ................... 18 
4.3 
Exposure-ITT analysis set ............................................................................................. 19 
4.4 
Safety- safety analysis set ............................................................................................. 19 
4.4.1 
Adverse Events ...................................................................................................... 19 
4.4.2 
Vital Signs and ECOG .......................................................................................... 20 
4.4.3 
Physical Examination ............................................................................................ 21 
4.4.4 
Analysis of Laboratory Data ................................................................................. 21 
4.4.5 
ECG ....................................................................................................................... 21 
4.4.6 
Efficacy ................................................................................................................. 22 
4.4.7 
End-of-Study Status .............................................................................................. 22 
5.0 
Appendix: Tables and Listings TOC ............................................................................. 23 


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LIST OF ABBREVIATIONS 
 
 
Abbreviation/Term 
Definition 
β-hCG 
β-human chorionic gonadotropin 
µg 
Microgram 
µL 
Microliter 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT/SGPT 
Alanine Transaminase/Serum glutamic pyruvic transaminase 
AlloSCT 
Allogeneic Stem Cell Transplantation 
AML 
Acute Myeloid Leukemia 
aPTT 
Activated Partial Thromboplastin Time 
Ara-C 
Arabinofuranosyl Cytidine / Cytarabine / Cytosine Arabinoside 
ASCT 
Autologous Stem Cell Transplantation 
AST/SGOT 
Aspartate Aminotransferase/Serum glutamic oxaloacetic transaminase 
AUC 
Area under the curve 
BM 
Bone Marrow 
BMI 
Body Mass Index 
Cmax 
Maximum plasma concentration 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CR 
Complete response 
CRF 
eCRF 
Case Report Form  
Electronic Case Report Form 
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXCR4 
CXC Chemokine Receptor Type 4 
dL 
Deciliter 
DLT 
Dose limiting toxicity 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EMA 
European Medicines Agency 
FACS 
Fluorescence-activated cell sorting 
FDA 
Food and Drug Administration 
FISH 
Fluorescent In Situ Hybridization 
g 
Gram 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony-Stimulating Factor 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GVHD 
graft-versus-host disease 
HBsAg 
Hepatitis B Surface Antigen 


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Abbreviation/Term 
Definition 
HBV 
Hepatitis B Virus 
HCT 
Hematocrit 
HCV 
Hepatitis C Virus 
Hep C Ab 
Hepatitis C Antibody 
HGB 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HSC 
Hematopoietic Stem Cells 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio (for blood coagulation tests) 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
IV 
Intravenous 
kg 
Kilogram 
λz 
Elimination rate constant 
m 
Meter 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
min 
Minute 
mL 
Milliliter 
MM 
Multiple Myeloma 
MTD 
Maximum tolerated dose 
MUGA 
Multiple Gated Acquisition 
N 
Number of subjects 
NCI 
National Cancer Institute 
NOAEL 
No Observed Adverse Effect Level 
NOEL 
No Observed Effect Level 
OR 
Overall response 
PB 
Peripheral blood 
PD 
Pharmacodynamic 
PI 
Principal Investigator 
PI 
Propidium Iodide 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PR 
Partial response 
PT 
Prothrombin Time 
QA 
Quality Assurance 
QC 
Quality Control 
RBC 
Red Blood Cell 
SAE 
Serious Adverse Event 


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SC 
Subcutaneous 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operation Procedures 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
TLS 
Tumor lysis syndrome 
Tmax 
Time to reach the maximum plasma concentration 
T1/2 
Terminal elimination half-life, defined as 0.693/λz 
ULN 
Upper limit of normal 
US 
United States 
USP 
United State Pharmacopeia 
WBC 
White Blood Cell 
WFI 
Water For Injection 
WHO 
World Health Organization 
WMA 
World Medical Association 
 
 


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1.0 Introduction 
This Statistical Analysis Plan (SAP) is intended to document the primary, secondary, 
and supporting objectives of planned statistical analyses as well as the methods to be 
used to meet these objectives. 
The remaining text in this section and the text in Section 2 are taken with reference 
from the current version of the Clinical Study Protocol (V.7) and is provided here as 
background.  
Acute myeloid leukemia (AML) represents a group of clonal hematopoietic stem 
cell disorders in which both failure to differentiate and overproliferation in the stem 
cell compartment result in accumulation of non-functional cells termed myeloblasts. 
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%. 
Both prognosis and treatment are based on the presence or absence of specific genetic 
abnormalities, which play an important role as diagnostic criteria for sub-classification 
of AML. 
The standard treatment paradigm for AML is remission induction chemotherapy 
with 
an anthracycline/cytarabine 
based combination, followed by either 
consolidation chemotherapy or allogeneic stem cell transplantation, depending on 
the AML risk group. The AML risk group predicts the likelihood of cure with 
chemotherapy alone (based on cytogenetic and molecular parameters) and the 
patient's expected ability to tolerate an allogeneic stem cell transplant (highly 
dependent on age, performance status and co-morbidities). Approximately 70-80% 
of subjects enter complete disease remission with several anthracycline-based 
chemotherapy combinations. Consolidation with high-dose cytarabine or allogeneic 
stem-cell transplantation in high-risk patients limit overall relapse rate to 
approximately 50%. 
 
Another potential consolidative approach is the employment of autologous stem 
cell transplantation. 
BL-8040, formerly BKT-140, is a highly selective CXC chemokine receptor 4 
(CXCR4) antagonist co-developed by 
and BioLineRx Ltd. 
as a novel therapy for treatment of cancer. The investigational drug binds to CXCR4 
with high affinity (IC50 0.5-10 nM) and inhibits its function. 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 
addition, BL-8040 exhibits CXCR4-dependent selective cytotoxicity toward 
malignant cells of hematopoietic origin in both in vitro and in vivo models. BL-
8040 significantly and preferentially stimulated leukemic apoptotic cell death. BL-
8040 treatment induced morphological changes, phosphatidylserine externalization, 
decreased mitochondrial membrane potential, caspase-3 activation, sub-G1 arrest 
and DNA double-stranded breaks. 




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administered 4 hours prior to chemotherapy. The chemotherapy will consist of 
cytarabine (Ara-C) 1.5 or 3 g/m2/d per dose (based on age), administered IV over 
3 hours, for 5 daysa and will not be escalated. 
 
The first part of the study (Part 1) will include escalating dose groups and be 
considered the ‘escalation phase’. Six potential levels will be investigated starting 
at dose level 0.5 mg/kg. Patients will be accrued in a conventional 3+3 design. 
Applying this study design, the first cohort of 3 patients will be treated at dose 
level 1 and evaluated for dose escalation. 
If at dose level 1 and beyond, 0 out of 3 patients experience dose-limiting 
toxicity (DLT), then the next cohort of 3 patients will be treated at the next 
dose level. If 1 out of 3 patients develop DLT, an additional 3 patients will be 
treated at the same dose level. If no more DLT develops at that dose, i.e. 1 out of 
a total of 6 patients develops DLT, the dose escalation continues to the next dose 
level. At any given dose, if greater than 1 out of 3 patients or 1 out of 6 
patients experience DLT, the dose level exceeds the maximum tolerated dose 
(MTD). In this situation, 3 more patients will be treated at the next lower dose if 
there are less than 6 patients already treated at that dose. MTD is defined as the 
highest dose level in which 6 patients have been treated with less than 2 instances 
of DLT. 
The decision to proceed to the next higher dose level will be made by an 
independent Data Monitoring Committee (DMC) after review of relevant safety data 
collected up to and including Day 30 (± 2 days; Day 28 ± 2 of chemotherapy) of the 
last subject of the previous dose group. The DMC may recommend evaluation of 
intermediate doses (or doses lower than the starting dose of 0.5 mg/kg) of BL- 
8040 in combination with Ara-C.  
Dose escalation will be permitted until the MTD is established and protocol specific 
stopping rules for toxicity are met. If no MTD is reached, dose escalation will 
continue up to dose level 6 (2.0 mg/kg). It is anticipated that up to 36 eligible 
patients will be required for the dose escalation. 
At the discretion of the Sponsor, additional subjects may be enrolled into a 
selected dose group to confirm safety, efficacy and pharmacokinetic (PK) profile 
for the selected dose, bringing the study up to approximately 70 subjects in total. 
This portion of the study will be considered the ‘expansion phase’ (Part 2). The 
DMC, in consultation with the Sponsor and Investigators, will decide on the 
selected dose level for expansion based on safety data, MTD, other relevant toxicity 
considerations, and all available PK and correlative PD data. 
During Part 2 of the study, at the Investigator’s discretion and after discussion with 
the Sponsor, subjects may be treated with a second cycle of BL-8040 in combination 
with Ara-C if they are considered to have had clinical benefit during the first 
treatment cycle, but failed to achieve complete remission (CR or CRi). In the event 
that subjects receive a second treatment cycle, the dosing regimen will be identical 
to that in the first treatment cycle. The second treatment cycle will start after clinical 
response assessment has been completed for the first treatment cycle, i.e., no sooner 
than Day 30 (± 2 days; Day 28 ± 2 of chemotherapy). 


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The study will comprise a screening period, a treatment period (monotherapy and 
combined treatment) and a follow-up period. For each dose group, visit scheduling 
and assessments will be similar. 
2.4.2 Dose limiting toxicity 
Dose-limiting toxicity (DLT) is defined as a clinically significant adverse event or 
abnormal laboratory value assessed as unrelated to disease progression, intercurrent 
illness or concomitant medications and occurring during the safety period (30 days)1 
that meets any of the following criteria (refer to Table 2 in Clinical Study Protocol 
for CTCAE severity grading):  
 CTCAE grade 3 AST (SGOT) or ALT (SGPT) or bilirubin for ≥ 7 days 
 CTCAE grade 4 AST (SGOT) or ALT (SGPT) of any duration 
 All other clinically significant, non-hematological NCI common terminology 
criteria that are CTCAE grade 3 or 4 
To be considered a DLT such toxicity must be possibly, probably or definitely 
related to BL-8040. 
During Part 2 of the study, any DLT occurring at a frequency of > 30% in the 
expanded cohort will stop accrual at the selected dose level. In this situation, the 
DMC, in consultation with the Sponsor and Investigators, may recommend a lower 
dose level for the expanded cohort.  
2.4.3 Study population 
This study will be conducted in subjects aged 18 to 75 years diagnosed with 
relapsed/refractory AML. The exact number of subjects enrolled will depend on 
the toxicity observed in each dose group and the number of dose groups required to 
reach MTD. 
2.4.4 Inclusion and exclusion criteria 
Inclusion and exclusion criteria are outlined in Section 4.1 and 4.2, respectively, of 
the Clinical Study Protocol. 
2.5 
Criteria for evaluation  
2.5.1 Safety 
The DLT and MTD for repeated doses of BL-8040 will be assessed by evaluating 
the frequency, severity and duration of treatment-related AEs, and clinically-
significant changes in 12-lead ECGs, vital signs and physical examination findings. 
All patients will be monitored for safety continually throughout the dosing period 
and up to 6 weeks after initiation of salvage chemotherapy with Ara-C (up to Day 
44). Expansion phase subjects who receive a second treatment cycle will also be 
followed for up to 6 weeks after initiation of Ara-C during the second cycle, i.e., up 
to Day 44 of the second cycle. 
                                                 
1 In case of prolonged BM recovery it will be evaluated again at 6 weeks and considered part of the DLT 
assessment. The safety period for subjects who receive a second treatment cycle in the expansion phase will 
be 30 days after the start of the second treatment cycle or up to 6 weeks in the event of delay in BM recovery.   


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AEs will be monitored continually after administration of study therapy.  AEs will 
be coded by using the MedDRA (currently version 16.1) and graded according to 
NCI CTCAE, Version 4.03.  Toxicities will be classified by type, grade, onset, 
duration and relationship to study therapy.  
The decision to proceed to the next higher dose level will be made by an 
independent DMC after review of relevant safety data collected up to and including 
Day 30 (± 2 days; Day 28 ± 2 of chemotherapy) of the last subject of the previous 
dose group.  Until the MTD is established, dose escalation will continue unless 
protocol specific stopping rules for toxicity are met. If no MTD is reached, dose 
escalation will continue up to dose level 6 (2.0 mg/kg). 
Vital signs (including temperature, blood pressure, pulse rate, respiratory rate, and 
O2 saturation) will be monitored at the screening visit and prior to BL-8040 
administration on each of the 7 days in the treatment period (monotherapy for 2 days 
and combined therapy for 5 days). For expansion phase subjects receiving a second 
treatment cycle, vital signs will also be measured daily prior to BL-8040 
administration during the second cycle.  
Electrocardiograms will be recorded on Days 1, 3 and 7 at pre-dose, 0.5, 1, 2, 4, 
8 and 24 hrs post BL-8040 administration. For subjects receiving a second treatment 
cycle during the expansion phase, ECGs will only be recorded on Days 1 and 7 of 
the second cycle at pre-dose and 4 hrs post BL-8040 administration. 
Hematology (CBC) and biochemistry samples will be collected daily on Days 1-7 
prior to BL-8040 administration.  Coagulation (PT and PTT) will be evaluated on 
Day 1 at pre-dose and 24 hrs post-dose, and on Day 7 at 24 hrs post-dose. White 
blood cell (WBC) counts, including differential and leukemic cell count, will be 
measured on Days 1, 2, 3 and 7 at 4 and 8 hrs post BL-8040 injection. Partial 
biochemistry samples (electrolytes and kidney function) will be collected on Days 
1, 2, 3 and 7 at 4 and 8 hrs post BL-8040 injection. Subjects considered suitable for 
a second treatment cycle during the expansion phase will undergo the same 
laboratory safety evaluations during the second cycle with the exception of 
coagulation and partial biochemistry evaluation. Additional samples may be 
collected at the discretion of the Investigator or upon Sponsor’s request. 
Physical examination, including assessment of cerebellar function will be performed 
daily on Days 1-7 prior to administration of BL-8040. For expansion phase subjects 
receiving a second treatment cycle, the same assessments will be performed daily on 
Days 1-7 prior to administration of BL-8040.  
Clinical evaluation of leukostasis related symptoms (visual symptoms, shortness of 
breath and decreased oxygen saturation in blood measured by pulse oximetry) 
and TLS (according to Cairo–Bishop criteria) will be assessed on Day 1 and upon 
commencement of such symptoms or when WBC ≥ 30,000/µL. 
2.5.2 Efficacy 
Efficacy will be assessed by tumor response. The following secondary endpoints will 
be assessed: 
• Response rates as assessed at final BM evaluation based on Cheson 2003 
criteria (Clinical Study Protocol, Appendix C): 






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3.0 Statistical Methods 
3.1 
Overview 
The data collected in this study will be summarized in descriptive statistics tables 
that provide mean values and mean changes from baseline, median and standard 
deviations, and number of patients for continuous data, or counts and percentages 
for categorical data, where appropriate.  Summaries will be provided overall by dose 
group. The data from Part 1 and Part 2 will be summarized in separate tables. Patient 
listings will be provided for all data summarized in tables.  Processing of clinical 
data and generation of tables and listings will be implemented using SAS™ (SAS 
Institute, Cary NC), version 9.3 or higher. 
3.2 
Analysis Sets 
3.2.1 Full analysis set (ITT)   
All patients enrolled who receive at least one dose of BL-8040 will comprise the 
intent-to-treat (ITT) full-analysis set.  Efficacy and safety analyses will be performed 
using the ITT analysis set. 
3.2.2 Per-protocol set (PP)   
All patients enrolled who complete the study according to the protocol without major 
protocol violations will comprise this analysis set.  Efficacy evaluations will be 
repeated in the Per Protocol analysis set as a sensitivity analysis.   
3.3 
Baseline Comparability 
Patients in each dose group will be summarized using tables and descriptive 
statistics for demographic and baseline clinical variables. This analysis will be 
conducted in the ITT population  
3.4 
Efficacy Analysis 
Efficacy analysis will be conducted on all patients who receive at least one dose of 
study drug (intent-to-treat population). Efficacy evaluations will be repeated in the 
Per Protocol analysis set as a sensitivity analysis. The clinical efficacy parameters 
for patients will be response rates at final BM evaluation: 
• Complete Response (CR),  
• Complete response with incomplete hematological recovery of platelets or 
neutrophils (CRi)  
• Partial response (PR) 
• Overall response defined as the sum of CR, CRi, and PR 
• Composite Complete Response (CRc) defined as the sum of CR and CRi. 
• Overall survival (OS) during study follow-up. 
The proportion of patients in the ITT analysis data set having each type of response 
will be tabulated.  This will be repeated for the Per Protocol analysis set. 
When determining response for patients receiving two cycles in the expansion phase, 
the endpoints will be determined after completing the second cycle.  


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It is noted that the primary endpoint of this study is not efficacy and that results from 
patients receiving different dose levels of study drug will not be compared directly 
by statistical means. 
3.5 
Safety Analysis 
The safety analysis will include all patients enrolled in the study who received at 
least one dose of study drug (i.e., the ITT population).  AE data will be listed 
individually and summarized by System organ class (SOC), high level term (HLT) 
and preferred terms (PT) for each treatment group.  Changes in vital signs and 
routine laboratory data will be presented with descriptive statistics to demonstrate 
the trend of change. 
 
Numbers of subjects with physical abnormality at each scheduled visit will be 
tabulated by body system and by dose level. ECG examination results will be 
displayed in descriptive statistics and by dose level with number of subjects with 
abnormal findings tabulated for each schedule visit. 
Each AE (based on preferred NCI-CTCAE, Version 4.03, terminology) will be 
counted only once for a given patient and summarized descriptively by SOC, HLT, 
and PT using the latest version of MedDRA (version 16.1) and by dose level 
and part of the study (Part 1 and Part 2).  If the same AE occurs on multiple 
occasions, the highest severity and worst-case relationship will be assumed when 
constructing summary tables.  The number and percentages of patients reporting 
AEs within SOC, HLT, and PT will be presented. 
3.6 
Sample Size 
The exact number of subjects enrolled will depend on the toxicity observed in each 
dose group and the number of dose groups required to reach MTD. If all six dose 
groups are required and if each dose group is expanded to 6 subjects (see stopping 
rules in the Clinical Protocol Section 6.2.3 and Figure 1), then a total of 36 subjects 
will be enrolled into the dose escalation part of the study. 
 
Once a dose has been selected for the expansion phase, additional subjects may 
be enrolled in that dose group up to a total of approximately 70 subjects in the study. 
3.7 
Treatment assignment and blinding 
Since this is an open-label study, there is no specific method of assigning patients 
to the treatment group.  All patients who meet the inclusion criteria and do not have 
any of the exclusion criteria will be entered into this study. There will be no blinding 
in this study. 
3.8 
Handling of missing values 
Since this is an open-label study with no inferential analysis, there will be no 
imputation of missing values.  All analysis will be based on observed variable 
values.  
3.9 
Protocol Deviations analysis populations 
All analyses will be conducted on an intention-to-treat (ITT) basis, i.e., all patients 
will be analyzed.  In cases of clinically significant protocol deviations, sensitivity 


















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1.2.4.4.7 
 
 
  
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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Vitals and Physical Exam 
1.3.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Labs 
1.5.1.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ECG 
1.6.1.1 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
End of Study 
1.8.1.1 
 
 
 
 
 
 
 
 
 
 
Figures 
1