Conditions: Acute Myelogenous Leukemia Acute Lymphoblastic Leukemia Chronic Myelogenous Leukemia Non-Hodgkin's Lymphoma Non-Hodgkin Lymphoma Hodgkin Disease Hodgkins Disease Hodgkin's Disease Multiple Myeloma Myelodysplastic Syndrome Myeloproliferative Neoplasm
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 50
Healthy volunteers: yes

Brief summary:
Current protocols use G-CSF to mobilize hematopoietic progenitor cells from matched sibling and volunteer unrelated donors. Unfortunately, this process requires four to six days of G-CSF injection and can be associated with side effects, most notably bone pain and rarely splenic rupture. BL-8040 is given as a single SC injection, and collection of cells occurs on the same day as BL-8040 administration. This study will evaluate the safety and efficacy of this novel agent for hematopoietic progenitor cell mobilization and allogeneic transplantation based on the following hypotheses:

* Healthy HLA-matched donors receiving one injection of BL-8040 will mobilize sufficient CD34+ cells (at least 2.0 x 10\^6 CD34+ cells/kg recipient weight) following no more than two leukapheresis collections to support a hematopoietic cell transplant.
* The hematopoietic cells mobilized by SC BL-8040 will be functional and will result in prompt and durable hematopoietic engraftment following transplantation into HLA-identical siblings with advanced hematological malignancies using various non-myeloablative and myeloablative conditioning regimens and regimens for routine GVHD prophylaxis.
* If these hypotheses 1 and 2 are confirmed after an interim safety analysis of the data, then the study will continue and include recruitment of haploidentical donors.

Detailed description:

Arms:
arm 1: -Donors will receive subcutaneous (SC) BL-8040 in the morning (Day 1) followed by leukapheresis approximately 180 minutes (up to 270 minutes) after the injection per institutional protocol. If the donor does not reach the collection goal for mobilization (≥ 5.0 x 10\^6 CD34+ cells/kg), a second leukapheresis will be performed on Day 2 (24 hours ± 2 hours from the BL-8040 injection) in an effort to reach a total of ≥ 5 x 10\^6 CD34+ cells/kg and at least ≥ 2 x 10\^6 CD34+ cells/kg from the combined collections. arm 2: -All or part of the leukapheresis product will be infused into the recipient per institutional guidelines. The day of the infusion will be considered Day 0; if the infusion occurs over multiple days, the final day of infusion will be considered Day 0

Interventions: intervention 1: BL-8040 intervention 2: Leukapheresis intervention 3: Hematopoietic cell transplant
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol document:
Prot_SAP_000.pdf: 
Protocol Version: 10/25/17, Amendment: 4 
 
Page 1 of 64  
 
 
A Phase II Study Evaluating the Safety and Efficacy of BL-8040 for the Mobilization of Donor 
Hematopoietic Stem Cells and Allogeneic Transplantation in Patients with Advanced 
Hematological Malignancies 
 
Washington University School of Medicine 
Division of Oncology 
660 South Euclid Avenue, Campus Box 8007 
St. Louis, MO  63110 
 
Protocol#:  201602037 
Version Date: 10/25/17 
 
Coordinating  Center: 
Washington University School of Medicine 
 
Principal Investigator:  
Geoffrey Uy, M.D. 
Phone: (314) 454-8304  
E-mail: guy@wustl.edu  
 
Sub-Investigator 
 
Institution 
John DiPersio, M.D., Ph.D. 
Washington University 
Michael P. Rettig, Ph.D. 
Washington University 
Steven Devine,  M.D. 
 
Ohio State University 
Asad Bashey, MD, Ph.D. 
Northside Hospital Cancer Institute 
 
Statistician:  
 
 
Kathryn Trinkaus, Ph.D. 
 
 
Study Drug(s):  
 
BL-8040 
 
IND#: 
129176 
Clinical Trials.gov#: 
NCT02639559 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 


Protocol Version: 10/25/17, Amendment: 4 
 
Page 2 of 64  
A Phase II Study Evaluating the Safety and Efficacy of BL-8040 for the Mobilization of Donor 
Hematopoietic Stem Cells and Allogeneic Transplantation in Patients with Advanced 
Hematological Malignancies 
 
Protocol Revision History 
 
Initial Approval Version 
 
 
 
 
 
 
02/19/2016 
Amendment #1 
 
 
 
 
 
 
 
06/06/2016 
Amendment #2 
 
 
 
 
 
 
 
08/15/2016 
Amendment #3 
 
 
 
 
 
 
 
07/13/2017 
Amendment #4 
 
 
 
 
 
 
 
10/25/2017 
 
 
 


Protocol Version: 10/25/17, Amendment: 4 
 
Page 3 of 64  
A Phase II Study Evaluating the Safety and Efficacy of BL-8040 for the Mobilization of Donor 
Hematopoietic Stem Cells and Allogeneic Transplantation in Patients with Advanced 
Hematological Malignancies 
 
Principal Investigator Signature Page 
 
 
Principal Investigator (printed):       
Name of Institution:       
  
 
PI  
 
 
 
 
Signature 
Date 
 
By my signature, I agree to personally supervise the conduct of this study 
and to ensure its conduct in compliance with the protocol, informed 
consent, IRB/HRPO procedures, the Declaration of Helsinki, ICH Good 
Clinical Practices guidelines, and the applicable parts of the United 
States Code of Federal Regulations or local regulations governing the 
conduct of clinical studies. 
 
 
 
 


Protocol Version: 10/25/17, Amendment: 4 
 
Page 4 of 64  
A Phase II Study Evaluating the Safety and Efficacy of BL-8040 for the Mobilization of Donor 
Hematopoietic Stem Cells and Allogeneic Transplantation in Patients with Advanced 
Hematological Malignancies 
 
DONOR SCHEMA 
 
 
 
 
 
 
 
 
 
SCREENING OF DONOR 
(within 30 days of mobilization) 
DAY 1:  
Mobilization with BL-8040 
Leukapheresis collection 3 hours later 
Assessment of CD34 PBSC counts 
CD34+ subsets and T-cell phenotyping 
DAY 2:  
Leukapheresis collection 
CD34+ enumeration and CBC 
CD34+ subsets and T-cell phenotyping 
 
If PBSC collected are ≥ 5.0 x 106 cells/kg: 
 
NO FURTHER LEUKAPHERESIS 
REQUIRED 
 
If PBSC collected are < 5.0 x 106/kg 
 
 
If combined PBSC collected from Day 1 and Day 
2 is < 2.0 x 106/kg 
Donor withdrawn from study and treated 
according to standard mobilization procedures 
 
 
Follow up at 7 and 30 Days and annually for 5 years 


Protocol Version: 10/25/17, Amendment: 4 
 
Page 5 of 64  
RECIPIENT SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RECIPIENT SCREENING 
(within 60 days of donor mobilization) 
 
CONDITIONING REGIMEN  
 
DAY 0 
 
PBSC transplant with stem cells mobilized with subcutaneous BL-8040 
FOLLOW-UP FOR 12 MONTHS 
 
• 
Engraftment (neutrophils AND platelets) 
• 
Adverse Event   
• 
GVHD (acute and chronic) 


Protocol Version: 10/25/17, Amendment: 4 
 
Page 6 of 64  
Table of Contents 
DONOR SCHEMA ....................................................................................................................................... 4 
RECIPIENT SCHEMA ................................................................................................................................ 5 
1.0 
BACKGROUND AND RATIONALE ............................................................................................ 8 
1.1 
Background .................................................................................................................................. 8 
1.2 
Study Agent: BL-8040............................................................................................................... 10 
1.3 
Study Rationale ......................................................................................................................... 14 
1.4 
Correlative Studies Rationale and Summary ............................................................................. 15 
2.0 
OBJECTIVES ................................................................................................................................ 15 
2.1 
Primary Objective ...................................................................................................................... 15 
2.2 
Secondary Objectives ................................................................................................................ 16 
2.3 
Exploratory Objectives .............................................................................................................. 16 
2.4 
Safety Endpoints ........................................................................................................................ 16 
3.0 
PATIENT SELECTION ................................................................................................................ 16 
3.1 
Donor Eligibility Criteria........................................................................................................... 16 
3.2 
Recipient Eligibility Criteria ..................................................................................................... 17 
3.3 
Inclusion of Women and Minorities .......................................................................................... 18 
4.0 
REGISTRATION PROCEDURES ............................................................................................... 18 
4.1 
Confirmation of Patient Eligibility ............................................................................................ 19 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ...................................... 19 
4.3 
Assignment of UPN ................................................................................................................... 19 
4.4 
Evaluation of Donor and Recipient ........................................................................................... 19 
5.0 
TREATMENT PLAN .................................................................................................................... 20 
5.1 
Protocol Summary ..................................................................................................................... 20 
5.2 
Screening Period Assessments .................................................................................................. 20 
5.3 
Pre-Dose Assessments ............................................................................................................... 21 
5.4 
Mobilization of Allogeneic Stem Cell Donor ............................................................................ 21 
5.5 
Treatment of the Recipient ........................................................................................................ 24 
5.6 
Evaluation of Toxicity, Response, and Study Endpoints .......................................................... 25 
5.7 
General Concomitant Medication and Supportive Care Guidelines .......................................... 26 
5.8 
Women of Childbearing Potential ............................................................................................. 26 
5.9 
Duration of Therapy .................................................................................................................. 26 
6.0 
DOSE MODIFICATIONS............................................................................................................. 27 
7.0 
STUDY CALENDARS ................................................................................................................. 28 
7.1 
Donor ......................................................................................................................................... 28 
7.2 
Recipient ................................................................................ Error! Bookmark not defined.29 
8.0 
CORRELATIVE STUDIES ...................................................................................................... 3029 
8.1 
Pharmacokinetics and PK Monitoring ................................................................................... 3029 
8.2 
Enumeration of CD34+ Cells and Lymphocytes and CBC Analysis after BL-8040 
Administration ........................................................................................................................................ 30 
8.3 
CD34+ Subset Analysis and T-cell Phenotyping Evaluations after BL-8040 Administration
 
3130 
8.4 
Handling of Specimens .............................................................................................................. 31 
8.5 
Site Performing CD34+, Lymphocyte, CBC Analysis and T-Cell Phenotyping ....................... 31 
8.6 
Samples to Be Sent to Dr. DiPersio Laboratory at Washington University .............................. 31 
9.0 
DATA SUBMISSION SCHEDULE ......................................................................................... 3231 
9.1 
Donor Submission Schedule .................................................................................................. 3332 
9.2 
Recipient Submission Schedule ............................................................................................. 3433 
10.0 
SAFETY, PHARMACOVIGILANCE, AND REPORTING REQUIREMENTS .................... 3433 
10.1 
Definitions ............................................................................................................................. 3534 
Table 1: Severity of Adverse Events According to CTCAE (Version 4.03) .......................................... 3635 


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Table 2: Relationship of Adverse Event to Treatment ............................................................................ 3736 
10.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University .... 3938 
10.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University ....................................................................................................................... 3938 
10.4 
Reporting to the FDA ............................................................................................................ 3938 
10.5 
Notification of Serious Adverse Events to BioLineRx .......................................................... 4039 
10.6 
Reporting Requirements for Secondary Sites ........................................................................ 4140 
10.7 
Reporting to Secondary Sites ................................................................................................ 4140 
10.8 
Timeframe for Reporting Required Events ........................................................................... 4140 
11.0 
PHARMACEUTICAL INFORMATION .................................................................................. 4241 
12.0 
MEASUREMENT OF EFFECT ................................................................................................ 4241 
12.1 
Definition of Primary Efficacy Endpoint .............................................................................. 4241 
12.2 
Definition of Secondary Endpoints ....................................................................................... 4241 
12.3 
Definition of Safety Endpoints .............................................................................................. 4342 
13.0 
DATA AND SAFETY MONITORING .................................................................................... 4342 
14.0 
AUDITING ................................................................................................................................ 4443 
15.0 
STATISTICAL CONSIDERATIONS ....................................................................................... 4544 
15.1 
Primary Analysis ................................................................................................................... 4544 
15.2 
Secondary Efficacy and Safety Analyses .............................................................................. 4544 
16.0 
MULTICENTER REGULATORY REQUIREMENTS ........................................................... 4645 
17.0 
REFERENCES .......................................................................................................................... 4847 
APPENDIX 1: MINNESOTA-CIBMTR STAGING AND GRADING FOR ACUTE GVHD ............ 5150 
APPENDIX 2: Chronic GVHD Assessment .......................................................................................... 5251 
Appendix 3: MDRD Study Equation ...................................................................................................... 6463 
 
 
 


Protocol Version: 10/25/17, Amendment: 4 
 
Page 8 of 64  
1.0 
BACKGROUND AND RATIONALE 
 
1.1 
Background 
 
Patients with advanced hematologic malignancies are incurable with conventional chemotherapy 
and often require allogeneic hematopoietic cell transplantation (HCT).  The principal goals of HCT 
are to allow engraftment and development of a donor-derived immune system that can effectively 
produce an immunologic attack against the recipient’s tumor cells resulting in a graft-versus-
leukemia effect.  Early pilot studies demonstrated that granulocyte colony-stimulating factor (G-
CSF) based mobilization is a relatively safe and effective alternative to bone marrow harvesting for 
collection of hematopoietic stem cells (HSC) prior to allografting1-4.  Multiple randomized trials 
have since demonstrated an advantage of G-CSF mobilized peripheral blood stem cells (PBSC) 
compared to bone marrow (BM) for HCT.  PBSCs are associated with more rapid hematopoietic 
engraftment, similar rates of acute graft versus host disease (GVHD), and higher rates of chronic 
GVHD5-10. Based on these findings, use of PBSC in HCT is now standard practice at many 
transplant centers.    
 
CD34+ stem cell content in mobilized peripheral blood product is considered the most important 
parameter of graft quality, and is recognized as a predictor of hematopoietic engraftment after stem 
cell transplantation.  Infusion of more than 2.0 x 106 cells/kg recipient body weight (BW) CD34+ 
cells is associated with rapid and durable engraftment of recipients12-15.  Although the optimal 
CD34+ cell dose is unknown, a target of 5 x 106 CD34+ cells/kg actual recipient weight and a 
minimum a threshold of 2 x 106 CD34+cells/kg is used at many transplant centers11. The focus of 
current research in stem cell mobilization and collection is to optimize the number of stem cells 
collected by improving mobilization regimens and increasing the efficiency of apheresis collection 
by reducing the number of apheresis procedures needed to meet the stem cell dose requirement for 
HCT16.   
 
Previous studies have demonstrated a highly significant correlation between the CD34+ 
concentration in peripheral blood and the potential to collect an adequate amount of CD34+ cells 
within one or up to three leukapheresis procedures17-18. Many groups have suggested that a peak 
level of 20/μL CD34+ cells should be considered as the threshold19.  The quality of the apheresis 
product such as the number of CD34+ cells in the graft and the presence of immune competent 
cells may also impact post-transplantation outcomes.  Ultimately, the efficiency of stem cell 
mobilization is determined by the number of apheresis procedures needed and the success of 
transplantation20-21.   
 
1.1.1 
Donors Mobilized with G-CSF 
 
G-CSF is the most frequently used single agent for stem cell mobilization in the allogeneic 
setting.  G-CSF mobilizes stem cells from the bone marrow into the peripheral blood 
primarily by down-regulation of CXCL12 production by marrow stromal cells.  While it is 
relatively safe, G-CSF requires 4-5 days of administration prior to collection which may 
be inconvenient for donors and cause absence from work during the mobilization process.  
In a retrospective study performed using data from the International Bone Marrow 
Transplant Registry (IBMTR) and European Bone Marrow Transplant (EBMT) Group, 
60% of donors required more than one leukapheresis procedure to collect the target number 
of CD34+ cells, and 15% required three or more9.  Surprisingly, approximately 20% of 
donors required placement of a central venous catheter (CVC) and the overall rate of 
serious complications associated with G-CSF mobilized peripheral blood donation was 
1.1%, higher in comparison to the 0.5% rate observed following bone marrow donation.  


Protocol Version: 10/25/17, Amendment: 4 
 
Page 9 of 64  
Although no long-term sequelae have been confirmed with short-term use of G-CSF, there 
can be associated morbidity including significant bone pain and rarely splenic rupture9.  
Furthermore, a small percentage of healthy donors have a poor mobilization response to 
G-CSF resulting in the need for additional apheresis collections or repeat mobilization 
cycles to collect an adequate PBSC dose23.  These challenges have prompted the evaluation 
of novel agents for stem cell mobilization with the capacity to rapidly mobilize HSCs while 
providing a better tolerated drug administration and cell collection regimen.   
 
Plerixafor (AMD3100), an inhibitor of CXCR4, has demonstrated the ability to rapidly 
mobilize stem cells out of the BM and into the peripheral circulation in healthy donors and 
cancer patients previously treated with chemotherapeutic agents24-27.  Interestingly, 
compared to G-CSF mobilized cells, a higher proportion of plerixafor-mobilized CD34+ 
cells were in G1 phase of the cell cycle and gene expression profiling indicated that these 
cells were of a more primitive type than those mobilized by G-CSF28.  Animal models 
showed that plerixafor-mobilized HSCs have a higher frequency of repopulating activity, 
suggesting an intrinsic difference in the engrafting capacity of the mobilized CD34+ cells28-
29.  Additionally, there is evidence that plerixafor-mobilized grafts have different 
characteristics compared to grafts obtained with G-CSF11.  A phase II study of 25 patients 
receiving PBSC from HLA-identical sibling donors mobilized with a single dose of 
plerixafor observed a higher content of T-CD3+ and T-CD4+ cells in plerixafor-mobilized 
grafts compared to historical controls mobilized with G-CSF30. Immune reconstitution was 
prompt despite lower numbers of CD34+ cells and engraftment kinetics and rates of GVHD 
were not significantly different to historical controls.  The differences in graft composition 
between various mobilizing agents may ultimately influence engraftment, immune 
recovery, anti-tumor activity, and patient outcomes. 
 
1.1.2 
Critical Role of CXCR4 and CXCL12 Interaction in Stem Cell Mobilization  
 
The interaction between CXC chemokine receptor (CXCR4) and its ligand, stromal derived 
factor-1 (CXCL12), plays a crucial role in hematopoietic cell chemotaxis and adhesion to 
the BM stromal cells31-34.  CXCR4 is a member of a large family of seven transmembrane 
domain receptors coupled to heterotrimeric G1 proteins that is expressed on CD34+ cells.  
Binding with its only known ligand CXCL12 (also known as SDF1), expressed on the 
surface of bone marrow stromal cells, results in activation of multiple signal transduction 
pathways ultimately triggering chemotaxis22.  Experiments with neutralizing antibodies 
directed against CXCR4 or CXCL12 showed that uncoupling the CXCL12/CXCR4 
signaling is a crucial step in G-CSF-mediated HSC mobilization33.  Targeted disruption of 
either molecule is lethal in mice, resulting in failure of HSC migration from liver to bone 
marrow, defects in B-lymphopoiesis, and cerebellar dysgenesis35-37.  Efficient mobilization 
of murine stem and progenitor cells is observed following injection of adenovirus 
expressing CXCL12 or after injection of methionine-CXCL12, both resulting in a gradient 
of CXCL12 from BM to PB38.  Treatment of mice and primates with sulfated 
polysaccharides (e.g. fucoidan) results in a rapid increase in circulating CXCL12 and 
subsequent stem cell mobilization39.  These preclinical studies confirm the importance of 
CXCR4 and CXCL12 interaction in stem cell mobilization and targeted disruption of 
CXCL12/CXCR4 interactions is an effective strategy for mobilization of HSCs40.   
 
 


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Page 10 of 64  
 
1.2 
Study Agent: BL-8040 
 
1.2.1 
Mechanism of Action  
 
BL-8040 (developed by BioLineRx Ltd., formerly developed by Biokine Therapeutics and 
known as BKT140) is a novel selective inhibitor of the CXCR4 chemokine receptor.  BL-
8040 is a 14-residue, cyclic, synthetic peptide capped with an aromatic ring.  It binds and 
inhibits the CXCR4 chemokine receptor with high affinity (IC50 4.42 nM) and has been 
shown to be a specific antagonist of CXCR4 both in vitro and in vivo studies and to have a 
slow dissociation rate from the receptor. 
 
1.2.2 
Pre-clinical Studies of Safety and Toxicology 
 
Pre-clinical pharmacology, safety pharmacology, and toxicology studies have been 
conducted by BioLineRx to provide nonclinical safety and efficacy support for subsequent 
clinical trials with BL-8040 in adult patients with hematological malignancies.  Special 
attention was paid to comparison of exposure in the safety studies with the highest systemic 
exposures reached in humans.  The mean human Cmax and AUC following administration 
of the highest dose (0.9mg/kg; equivalent to 0.73 mg/kg free base peptide on dry basis) in 
the clinical study BKTSC001, were found to be 820 ng/ml and 791 ng*h/mL, respectively. 
The mean human Cmax and AUC following  administration of the highest dose (1.0 mg/kg 
free base peptide on dry basis) in the clinical study BL-8040.02, were found to be 1090 
ng/ml and 1740 ng*h/mL, respectively. These findings were used to compare plasma drug 
exposures between animal studies and human experience. 
 
Studies have been conducted both in rats and dogs evaluating the single dose toxicity and 
repeated dose toxicity of BL-8040.  Acute toxicity was considered to be low in both rats 
and dogs following single dose administration.  Toxicokinetic evaluation of BL-8040 
single dose administration was examined following dose levels in dogs and a maximum 
tolerated dose (MTD) could not be defined despite pharmacokinetic data which showed 
that the exposures at 18 mg/kg were > 20 times and > 2 times higher than the exposures 
reached following administration of the highest dose (0.9 mg/kg; equivalent to 0.73 mg/kg 
free base peptide on dry basis) in the clinical study BKTSC001.  Repeated dose toxicity 
studies in rats and dogs showed no histopathological organ changes and no target organ 
toxicity could be identified at exposures (AUC) several times (12.5-fold in dogs and 13.5-
fold in rats) higher than the exposure in humans following a single dose of 0.9 mg/kg (0.73 
mg/kg free base peptide on dry basis) in study BKTSC001 and higher (6.3-fold in dogs and 
6.7-fold in rats) following administration of 1 mg/kg (free base peptide on dry basis) in 
clinical study BL-8040.02.  Similar clinical symptoms were observed in rats and dogs from 
the first day of dosing and consisted of transient erythema and peripheral edema.  In dogs, 
the reactions 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.  Symptoms occurred at exposure levels similar to those observed 
following administration of the highest dose (1 mg/kg) in clinical study BL-8040.02, a dose 
reported to be well tolerated. 
 
Side effects of BL-8040 in the general toxicology studies in rats and dogs included 
anaphylactoid-type reactions, such as transient erythema and peripheral edema.  Both in-
vitro and in-vivo studies indicate that BL-8040 partially activates mobilized immune cells.  


Protocol Version: 10/25/17, Amendment: 4 
 
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In response to BL-8040, known markers of immune cell activation on granulocytes were 
altered including an increase of cell surface expression of C11b, reduction of cell surface 
expression of CD62L, as well as secretion of MMP9 (a factor involved in increased motility 
of granulocytes).  BL-8040 did not have any effect on the release of pro-inflammatory 
mediators, including the cytokines TNF-α, IL-1α, IFN-γ, or ROS and NOS enzymes, in 
either in-vivo or in-vitro studies.  Likewise, BL-8040 did not have any effect on mast cell 
degranulation in an in-vitro study.  Taken together, these findings suggest that the transient 
reactions observed are related to the pharmacological action of BL-8040 and to the 
activation of immune cells rather than an effect on the release of pro-inflammatory 
mediators. 
 
1.2.3 
Pre-clinical Studies of Efficacy  
 
Cell line studies demonstrated BL-8040 has high affinity for CXCR4.  One study evaluated 
BL-8040 in a homologous displacement competitive binding assay with radio-labeled 125I-
CXCL12 to CHO cells overexpressing CXCR441.  The IC50 of BL-8040 binding to CHO-
CXCR4 cells was 2.5 nM.  An additional study further proved that BL-8040 inhibited 
CXCL12-mediated migration of human Jurkat cells and mouse splenocytes in a dose-
dependent manner in vitro (IC50 = 0.65 and 0.54 nM, respectively)42.  The antagonist 
property of BL-8040 on CXCR4 was also functionally tested in vitro, using migration 
properties of cells overexpressing CXCR4, towards the CXCL12 chemokine gradient.  The 
IC50 in these experiments was found to be of the same order of magnitude as in the 
competitive displacement method (0.54-4.42 nM). 
 
The efficacy of BL-8040 on mobilization of normal and hematopoietic stem cells was 
demonstrated by in-vivo studies in mice, where dose-dependent mobilization of WBCs to 
the peripheral blood was observed as a result of a single injection of BL-804042.  The effect 
was seen in mice at a dose range of 2.5 – 15 mg/kg, equivalent to 0.2 – 1.25 mg/kg, 
respectively, in humans.  Stem cells mobilized by BL-8040 maintained 90% of transplanted 
mice for longer than 6 months and were capable of producing long-term rescue in lethally 
irradiated secondary transplanted mice, indicating that BL-8040 treatment yielded viable 
and healthy stem cells. 
 
1.2.4 
Clinical Trial Experience with BL-8040 
 
To date, two clinical studies (BKTSC001 and BL-8040.02) have been conducted with BL-
8040 to assess stem cell mobilization, and both have been completed.  BKTSC001 
(NCT01010880) was a non-randomized, open-label, single administration, dose escalation 
study, where BL-8040 was administered to multiple myeloma (MM) patients undergoing 
treatment with chemo-mobilization and G-CSF.  Eligible subjects received a 10-day 
mobilization regimen in an ambulatory setting according to standard MM mobilization 
treatment protocol consisting of cyclophosphamide (3-4 g/m2), antiemetic drugs (e.g. 
Zofran) and 2-mercaptoethane sulfonate sodium (MESNA, prophylactic treatment for 
hemorrhagic cystitis) on Day 0.  On Day 5 until the end of stem cell collection, granulocyte 
colony-stimulating factor (G-CSF) was self-administered subcutaneously (in the evenings) 
at 5 µg/kg per day.  On Day 10, subjects received one SC injection of BL-8040 in the 
morning and G-CSF 12 hours later in the afternoon.  Stem cell collection (apheresis) was 
performed at a WBC count over 1,000 cells per 1 µL.  A total of 18 subjects were enrolled 
in this study.  BL-8040 was administered as a single SC injection to four subjects per dose 
group.  Administration of BL-8040 was associated with a favorable safety profile, with no 
apparent trend toward risk with a specific dose.  No clinically consistent or cumulative 


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Page 12 of 64  
abnormalities were observed for the safety parameters evaluated, including AE incidence, 
laboratory safety values, vital signs, ECG parameters or physical examinations, as well as 
Karnofsky status.  Single dose administration of BL-8040 caused rapid mobilization of 
WBC and CD34+ stem cells in a dose-dependent manner.  Fewer apheresis were required 
as BL-8040 dose increased.   In the highest dosage group of 0.9 mg/kg, all subjects had 
only one apheresis, with a mean of 20.9 x 106 CD34+ cells/kg collected (range: 11.5 – 26.1 
million cells/kg). 
 
BL-8040.02 (NCT02073019) was a Phase I, two-part study exploring the safety, 
tolerability, pharmacodynamic and pharmacokinetic effect of ascending doses of BL-8040 
in healthy subjects designed to support development of BL-8040 as a single agent treatment 
for hematopoietic stem cell mobilization for autologous and/or allogeneic transplantation.  
 
Part 1 (Dose Escalation) was a randomized, double-blind, placebo controlled study 
exploring the safety, tolerability, pharmacodynamic (PD) and pharmacokinetic (PK) 
profile of BL-8040. CD34+ cell mobilization was measured in healthy subjects following 
administration of up to two doses of BL-8040 (QD on 2 consecutive days). Each cohort in 
Part 1 consisted of 8 subjects; 6 subjects in each cohort were randomly allocated to receive 
BL-8040 (doses 0.5, 0.75 and 1 mg/kg) and 2 subjects randomly allocated to receive 
placebo. Part 2 involved a single cohort of 8 subjects, who have received BL-8040 at the 
selected optimal dose level of 1.0 mg/kg. A total of 26 subjects have been exposed to study 
drug and 6 to placebo. Administration of BL-8040 was associated with a favorable safety 
profile, with no apparent trend toward risk with a specific dose. Administration of BL-8040 
caused rapid mobilization of WBC and CD34+ stem cells in a dose-dependent manner.  In 
Part 1 of the study, at the highest dose tested of 1mg/kg, the mean WBC count rapidly and 
significantly rose to its peak after 4-8 hrs; from baseline levels of 5.8 (±0.97) x 109/L to 
31.4 (± 4.3) x 109/L at 4 hrs, to 33.4 (± 6.5) x 109/L at 8 hrs. WBC count remained high at 
23 hrs post the first injection, 24.8 (± 5.7). In Part 2 of the study all 8 subjects received a 
single dose of 1 mg/kg and approximately 3.5 hrs later underwent standard volume (18L 
target volume) apheresis.  At 3.5 hours after a single dose of BL-8040, the WBC count rose 
to a median of 32 x 103/µL (range; 29 – 39 x 103) and the CD34+ cell count to 43/µL 
(range; 27-84/µL).  The number of CD34+ reached its peak after 24 hrs and started to 
decline slowly after 48 hrs.  Single BL-8040 administration resulted in robust collection of 
CD34+ cells in a single apheresis session. The median CD34+ collected was 11.89 x106/kg 
(range; 5.09 - 15.23 x 106/Kg). These results suggest a potential second collection of 
CD34+ cells after 24hrs if needed without the need for second injection of BL-8040.  
 
In addition to the studies in stem cell mobilization, BioLineRx is currently investigating 
the safety and efficacy of multiple (7 consecutive administration days) escalating doses of 
BL-8040 in combination with Ara-C (Cytarabine) in adult subjects with relapsed/refractory 
acute myeloid leukemia (AML) in a Phase IIa, open-label, multicenter clinical study, BL-
8040.01 (NCT01838395).   
 
1.2.5 
BL-8040 Related Adverse Events  
 
In general the most common AEs seen in all studies conducted with BL-8040 to date are 
injection site reactions (including pain, erythema, pruritus and inflammation) and systemic 
reactions: hives, pruritus (not at the injection site), flushing, chills, rash and urticaria. Other 
isolated AEs reported among others were paresthesia, musculoskeletal pain, headache, 
constipation, tingling and elevation of liver function tests. 
 


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BKTSC001 
 
In this study BL-8040 was associated with a favorable safety profile, with no apparent trend 
toward risk with a specific dose. No clinically consistent or cumulative abnormalities were 
observed for the safety parameters evaluated, including AE incidence, laboratory safety 
values, vital signs or ECG parameters, among other. 
 
All related TEAEs (13/131) were in the higher dose groups (0.3 and 0.9 mg/kg). 
Approximately half of them were under the SOC "General Disorder and Administration 
Site Condition". Ten out of 132 events were considered mild in intensity and 23.1% 
moderate in intensity (3/133). The Investigator did not consider any of the severe events as 
related to the study drug.  
 
There were six SAEs reported throughout the study, affecting 4/18 subjects (22.2%); one 
subject in the 0.006 mg/kg dose group, two subjects in the 0.1 mg/kg dose group and one 
subject in the 0.3 mg/kg group. Two concurrent SAEs in a single 0.3 mg/kg subject (chest 
pain and dyspnea) were considered by the Investigator as possibly treatment related. These 
events were assessed as unrelated by the sponsor's Medical Safety Officer since:  (i) they 
recurred upon later treatment with G-CSF only, (ii) the events were similar to those 
anticipated with administration of G-CSF, and (iii) AEs were reported 30 hrs post injection, 
long after the drug was eliminated according to the PK profile (BL-8040 t1/2 is 0.5 hr, see 
Table 5-1). An additional SAE of hypokalemia occurred following BL-8040 administration 
and was determined to be unrelated by the Investigator. Upon review of the CRF, the 
Sponsor’s Medical Safety Officer assessed the hypokalemia as severe in intensity and 
possibly related to the BL-8040. Three other SAEs (two cases of neutropenic fever and one 
case of sepsis) occurred prior to study drug administration and were anticipated side effects 
of chemotherapeutic agents applied in conditioning for cell therapy and therefore 
determined unrelated to BL-8040. 
 
There were very few laboratory abnormalities determined to have been clinically 
significant, and fewer still post-dosing or associated with an AE. Only one laboratory result 
(hypokalemia) was considered to be possibly related to BL-8040 by the Sponsor's Medical 
Safety officer. Blood glucose and LDH tended to slightly increase post-administration, but 
were not associated with notable negative effects. Physical examination and vital sign 
parameters were normal or stable in nearly all subjects following BL-8040 administration. 
 
BL-8040.01 
 
To date five dosing cohorts have been completed, in which BL-8040 doses of 0.5 - 1.5 
mg/kg were investigated.  A total of 22 subjects were exposed to doses escalating according 
to the protocol’s escalation scheme. Only one grade 3 related serious adverse event (SAEs) 
of Sweet syndrome was reported and assessed as possibly related to BL-8040. The event 
was reported at the dose level 1.5 mg/kg. It is known that Sweet syndrome occurs in 
patients with AML, and this particular patient subsequently showed progressive disease. 
According to the protocol three more patients were recruited for a total of 6 patients.  An 
independent Data Monitoring Committee reviewed the safety data of all cohorts and 
considered BL-8040 safe and well tolerated at doses up to 1.5 mg/kg. The DMC approved 
the initiation of the dose expansion part of the study using this dose level.  
 
The 22 subjects dosed to date, reported 348 adverse events (AEs), among which 70% (242 
events) of the AEs were assessed as unlikely or unrelated to the study drug. Within the 


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events assessed as possible, probably or definitely related to BL-8040 (30%), 36% (38) 
were grade 1, 53% (56) were grade 2, 9% (10) were grade 3 (1 thrombocytopenia, 1 
headache, and SAE of Sweet Syndrome, 5 injection site reactions and 2 systemic reactions) 
and 1% (1) were grade 4 (a case of neutropenia). Injection site reactions and systemic 
reactions were found to be the most common adverse events reported. During this study in 
order to mitigate the systemic reactions, pre-treatment with intravenous steroids and anti-
histamines was implemented in some patients according to the investigator’s judgment. In 
addition, a new method of reconstitution was developed to enable dilution of BL-8040; and 
rotation of the site of injection at each dosing was recommended with intent to minimize 
injection site reactions. 
 
Thirteen out of 22 subjects reported 22 serious adverse events (SAEs), only one was 
assessed as possible related and was already described above.  To date, the maximum 
tolerated dose (MTD) was not reached when treating AML patients with seven consecutive 
days of 1.5 mg/kg BL-8040.  
 
BL-8040.02 
 
No Serious Adverse Events were reported in all dose levels. All the AEs but three were 
mild or moderate, severe AEs included: transient syncope (resolved in one min), two events 
of asthenia (resolved within 15 - 30 min). Most common BL-8040 related AEs included 
injections site (IS) reactions characterized by pain, edema and erythema; transient and mild 
systemic 
reactions 
(rash, 
chills, 
pruritus, 
urticaria, 
hot 
flashes/flushing,    
hives, hypotension, chest pain, nausea). All resolved spontaneously within 30 - 120 
minutes. Additional less frequent AE’s included asthenia, peripheral swelling, paresthesia, 
hyperhidrosis, tachycardia, edema peripheral, dizziness, headache and pallor. Pre-
medication with steroids and anti-histamines was effective in reducing the frequency and 
magnitude of the systemic reactions. 
 
1.2.6 
Rationale for Dosing and Regimen 
 
The dose of 1 mg/kg SC injection was chosen based on the safety and efficacy data from 
the BKTSC001, BL-8040.02, and the ongoing BL-8040.01 studies.  In general, BL-8040 
was observed to be associated with a favorable safety profile with the most common AEs 
being injection site irritation, flushing, and itching, and systemic reactions that were 
successfully managed with premedication. 
 
In the 1 mg/kg dosage group of the BL-8040.02 healthy volunteers study, all 8 subjects 
receiving BL-8040 single agent treatment required only one apheresis to collect a mean of 
11.89 x 106 CD34+ cells/kg.  In the 0.9 mg/kg dosage group of the BKTSC001 study, all 
4 subjects required only one apheresis to collect a mean of 20.9 x 106 CD34+ cells/kg after 
treatment with G-CSF in combination with a single BL-8040 administration.  
 
Overall, the 1mg/kg dose selected to be used in this study was found to be safe in all studies 
to date and highly efficacious for SC mobilization and collection in the healthy volunteer 
study. 
 
1.3 
Study Rationale  
 
Current protocols use G-CSF to mobilize hematopoietic progenitor cells from matched sibling and 
volunteer unrelated donors.  Unfortunately, this process requires four to six days of G-CSF injection 


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Page 15 of 64  
and can be associated with side effects, most notably bone pain and rarely splenic rupture9.  BL-
8040 is associated with few side effects, is given as a single SC injection, and collection of cells 
occurs on the same day as BL-8040 administration.  This study will evaluate the safety and efficacy 
of this novel agent for hematopoietic progenitor cell mobilization and allogeneic transplantation 
based on the following hypotheses: 
 
1. Healthy HLA-matched donors receiving one injection of BL-8040 will mobilize sufficient 
CD34+ cells (at least 2.0 x 106 CD34+ cells/kg recipient weight) following no more than two 
leukapheresis collections to support a hematopoietic cell transplant. 
 
2. The hematopoietic cells mobilized by SC BL-8040 will be functional and will result in prompt 
and durable hematopoietic engraftment following transplantation into HLA-identical siblings 
with advanced hematological malignancies using various non-myeloablative and 
myeloablative conditioning regimens and regimens for routine GVHD prophylaxis. 
 
3. If these hypotheses 1 and 2 are confirmed after an interim safety analysis of the data, then the 
study will continue and include recruitment of haploidentical donors.   
 
1.4 
Correlative Studies Rationale and Summary 
 
The ability of BL-8040 to mobilize normal hematopoietic progenitor cells will be examined via 
peripheral blood samples collected prior to the administration of BL-8040 (pre-treatment baseline 
assessment), at 0.5 and 1 hour post BL-8040 administration, at 3 hours (immediately before 
apheresis) post BL-8040 administration, immediately post-completion of apheresis, and 24 hours 
post BL-8040 administration (Section 8.2).  Peripheral blood samples will be analyzed by CBC and 
flow cytometry to enumerate the CD34+ cells and lymphocytes that are mobilized over time on 
Day 1.  
 
Because the composition of CD34+ cell subsets, mesenchymal stem cells, NK cells, and T cell 
subsets may influence recipient outcomes in terms of engraftment, anti-tumor activity, graft versus 
host disease, morbidity, and mortality, these subsets will be analyzed from samples taken prior to 
administration of BL-8040 (pre-treatment baseline assessment), at 3 hours (before the beginning of 
the apheresis), immediately post-completion of apheresis, from the mobilized product, and 24 hours 
post BL-8040 administration (Section 8.3.1).  
 
If a second leukapheresis is required, peripheral blood samples for CBC and enumeration of CD34+ 
cells will also be collected immediately prior to the second leukapheresis (approximately 24 hours 
after BL-8040 injection) and immediately post-completion of apheresis (Section 8.2).   
 
The results of these studies will be used to design further therapeutic trials. 
 
 
2.0 
OBJECTIVES 
 
2.1 
Primary Objective 
 
To assess the efficacy of a single injection of BL-8040 to mobilize ≥ 2 x 106 CD34+ cells/kg of 
recipient weight after no more than two leukapheresis collections from healthy donors. 
 
 


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2.2 
Secondary Objectives 
 
1. To assess the safety (see Section 2.4 for definition) and tolerability of BL-8040 in healthy 
donors.  
2. To assess the kinetics of neutrophil and platelet recovery post-transplant in patients undergoing 
allogeneic stem cell transplant. 
3. To determine the incidence of primary and secondary graft failure up to one year after 
transplantation of hematopoietic cells mobilized with BL-8040. 
4. To determine the incidence of grade 2-4 acute graft versus host disease (GvHD) in patients 
who have undergone transplantation of hematopoietic cells mobilized with BL-8040. 
5. To determine the incidence of chronic GvHD at 1 year in patients who have undergone 
transplantation of hematopoietic cells mobilized with BL-8040. 
6. To determine the proportion of subjects who collect 5 x 106 CD34+ cells/kg of recipient weight 
in a single leukapheresis and in 2 leukapheresis sessions  
7. To determine the incidence of CMV reactivation after transplantation of hematopoietic cells 
mobilized with BL-8040 in CMV seropositive recipients 
8. To determine the incidence of treatment-related mortality and disease relapse/progression after 
transplantation of hematopoietic cells mobilized with BL-8040 
9. To determine the probability of event free and overall survival after transplantation of 
hematopoietic cells mobilized with BL-8040 
10. To determine the change in peripheral blood CD34+ cells concentration from baseline 
throughout  Day 1 and Day 2 (if a second leukapheresis is required) 
11. To assess the pharmacokinetic profile of BL-8040. 
 
2.3 
Exploratory Objectives 
 
1. To measure alterations in CXCR4 expression and receptor occupancy in the peripheral blood 
of healthy donors following treatment with BL-8040. 
2. To determine the kinetics of mobilization of CD34+ cells and characterize CD34+ subsets 
mobilized by BL-8040. 
3. To characterize the cellular composition of the HSPC graft including T-cell subpopulations in 
peripheral blood and in the stem cell product. 
 
2.4 
Safety Endpoints 
 
1. To assess the number of recipients with primary graft failure 
2. To assess the incidence of acute and chronic graft versus host disease in recipients  
3. To assess the time to neutrophil engraftment and time to platelet engraftment in recipients 
4. Long term safety of the donors after treatment with BL-8040 
 
 
3.0 
PATIENT SELECTION 
 
3.1 
Donor Eligibility Criteria  
 
3.1.1 
Donor Inclusion Criteria  
 
1. Age 18 to 70 years of age.  
2. ECOG performance status of 0 or 1. 
3. PART 1: Donor must be a 5/6 or 6/6 HLA-matched sibling willing to donate PBSC for 


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transplant. 
PART 2: Donor must be a 5/6 or 6/6 HLA-matched sibling or ≥3/6 HLA haploidentical 
donor willing to donate PBSC for transplant.  Haploidentical donors will be allowed to 
participate upon investigator decision and based on the data reached from 5/6 or 6/6 
HLA matched transplant done during Part 1 of the study. 
4. Adequate organ function defined by: 
a. serum creatinine within normal limits or a minimum creatinine clearance (CrCl) 
value of ≥ 60 ml/min calculated using the Modification of Diet in Renal Disease 
(MDRD) Study equation (Appendix 3) 
b. AST, ALT and total bilirubin ≤ 2x institutional upper limit of normal.  
5. Women of childbearing potential and men must agree to use adequate contraception 
with two different forms, including one barrier method, during participation in the 
study and for 2 weeks following dosing with BL-8040. Abstinence is acceptable if this 
is the established and preferred contraception for the subject. 
6. Female subjects must have a negative urine or serum pregnancy test within 10 days 
prior to taking study medication if of childbearing potential or must be of non-
childbearing potential.  If the urine test is positive or cannot be confirmed as negative, 
a serum pregnancy test will be required.  The serum pregnancy test must be negative 
for the subject to be eligible.  Non-childbearing potential is defined as: 
a. ≥ 45 years of age and has not had menses for > 2 years 
b. Amenorrheic for > 2 years without a hysterectomy and oophorectomy and a FSH 
value in the postmenopausal range upon pretrial (screening) evaluation 
c. Post-hysterectomy, oophorectomy, or tubal ligation.   
7. Able and willing to comply with the requirements of the protocol. 
8. Able to understand and willing to sign an IRB-approved written informed consent 
document. 
 
3.1.2 
Donor Exclusion Criteria 
 
1. Received any investigational agent within 30 days and/or 5 half-lives (of the other 
investigational agent), whichever is longer, of receiving BL-8040.  
2. Active HIV or hepatitis B or C infection 
3. Pregnant or breastfeeding.   
4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
5. Known allergy or hypersensitivity to any of the test compounds, materials, or 
contraindication to test products. 
6. Any malignancies in the 2 years prior to baseline, excluding: basal cell carcinoma, in 
situ malignancy, low-risk prostate cancer, cervix cancer after curative therapy. 
7. A comorbid condition which, in the view of the investigators, renders the subject at 
high risk from treatment complications.  
 
3.2 
Recipient Eligibility Criteria 
 
3.2.1 
Recipient Inclusion Criteria  
 
1. Age 18 to 75 years   
2. ECOG performance status of 0-2 (inclusive) 
3. One of the following diagnoses:  


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a. Acute myelogenous leukemia (AML) in 1st or subsequent remission 
b. Acute lymphoblastic leukemia (ALL) in 1st or subsequent remission 
c. Chronic myelogenous leukemia (CML) in chronic or accelerated phase  
d. Non-Hodgkin lymphoma (NHL) or Hodgkin’s disease (HD) in 2nd or greater 
complete remission, partial remission 
e. Chronic lymphocytic leukemia (CLL) 
f. Multiple myeloma (MM) 
g. Myelodysplastic syndrome (MDS)  
h. Myeloproliferative 
neoplasm 
(MPN) 
excluding 
primary 
or 
secondary 
myelofibrosis 
4. Adequate organ function defined by: 
a. a creatinine clearance (CrCl) value of ≥ 60 ml/min by MDRD study equation 
b. AST, ALT and a total bilirubin ≤ 2x institutional upper limit of normal.  
5. Adequate cardiac function with a left ventricular ejection fraction ≥ 40%.  
6. Adequate pulmonary function defined as NO severe or symptomatic restrictive or 
obstructive lung disease, and formal pulmonary function testing showing an FEV1 
≥50% of predicted and a DLCO ≥ 40% of predicted, corrected for hemoglobin.  
8. Female subjects must have a negative urine or serum pregnancy test if of childbearing 
potential or be of non-childbearing potential.  If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.  The serum pregnancy 
test must be negative for the subject to be eligible.  Non-childbearing potential is 
defined as: 
a. ≥ 45 years of age and has not had menses for > 2 years 
b. Amenorrheic for > 2 years without a hysterectomy and oophorectomy and a FSH 
value in the postmenopausal range upon pretrial (screening) evaluation 
c. Post-hysterectomy, oophorectomy, or tubal ligation. 
9. Able to understand and willing to sign an IRB-approved written informed consent 
document.  
 
3.2.2 
Recipient Exclusion Criteria 
 
1. Recipient must not have received any investigational drug within 30 days of starting 
conditioning treatment.   
2. Pregnant or breastfeeding. 
3. Active HIV or hepatitis B or C infection. 
4. Any medical condition which, in the opinion of the clinical investigator, would 
interfere with the evaluation of the patient.  Subjects with a clinically significant or 
unstable medical or surgical condition or any other condition that cannot be well-
controlled by the allowed medications permitted in the study protocol that would 
preclude safe and complete study participation, as determined by medical history, 
physical examinations, ECG, laboratory tests, or chest-X-ray and according to the 
investigator’s judgment. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial.  
 
 
4.0 
REGISTRATION PROCEDURES 
 
Donors and recipients must not start any protocol intervention prior to the signature of informed consent 


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Page 19 of 64  
and registration through the Siteman Cancer Center. 
 
The following steps must be taken before registering patients to this study: 
 
1. Signature of Informed Consent 
2. Confirmation of patient eligibility by Washington University 
3. Registration of patient in the Siteman Cancer Center OnCore database 
4. Assignment of unique patient number (UPN) 
 
Once the patient has been entered in the Siteman Cancer Center OnCore database, the WUSM coordinator 
will forward verification of enrollment and the UPN via email. 
 
4.1 
Confirmation of Patient Eligibility 
 
Confirm patient eligibility by collecting the information listed below and scanning and emailing it 
to the research coordinator listed in the Siteman Cancer Center Clinical Trials Core Protocol 
Procedures for Secondary Sites packet at least one business day prior to registering patient:  
 
1. Your name and contact information (telephone number, fax number, and email address) 
2. Your site PI’s name, the registering MD’s name, and your institution name 
3. Patient’s race, sex, and DOB 
4. Three letters (or two letters and a dash) for the patient’s initials 
5. Current approved protocol version date 
6. Copy of signed consent form (patient name may be blacked out) 
7. Planned date of enrollment 
8. Completed eligibility checklist, signed and dated by a member of the study team 
9. Copy of appropriate source documentation confirming patient eligibility 
 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database 
 
Registrations may be submitted Monday through Friday between 8am and 5pm CT. Urgent late 
afternoon or early morning enrollments should be planned in advance and coordinated with the 
Washington University research coordinator.  Registration will be confirmed by the research 
coordinator or his/her delegate by email within one business day. Verification of eligibility and 
registration should be kept in the patient chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center OnCore database at 
Washington University. 
 
4.3 
Assignment of UPN 
 
Each patient will be identified with a unique patient number (UPN) for this study.  Patients will 
also be identified by first, middle, and last initials.  If the patient has no middle initial, a dash will 
be used on the case report forms (CRFs).  All data will be recorded with this identification number 
on the appropriate CRFs. 
 
4.4 
Evaluation of Donor and Recipient 
 
Recipients will be evaluated for eligibility prior to donor study enrollment, including reviewing 
and signing the informed consent document and confirming all eligibility criteria (except donor 
stem cell collection).  Following preliminary confirmation of recipient eligibility, donors will be 


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Page 20 of 64  
consented and checked for eligibility.  At the time a donor has been cleared for study entry (i.e., 
upon completion of the donor’s eligibility process), a study identification number will be assigned 
to both the donor and the recipient.  This process constitutes formal study entry.   
 
Should the donor be treated per protocol (mobilization and leukapheresis) only to have the recipient 
fail eligibility prior to transplantation (due to declining performance status, unacceptable lab 
results, or other reasons), the donor will be followed per protocol but the donor/recipient pair will 
be replaced for study evaluation. 
 
 
5.0 
TREATMENT PLAN 
 
5.1 
Protocol Summary  
 
This is a phase II open label study to assess the efficacy and safety of the CXCR4 inhibitor BL-
8040 in allogeneic transplants.  An initial cohort of 10 donor/recipient pairs will be enrolled in Part 
1 of the study consisting only of recipients with advanced hematological malignancies and their 
HLA-identical (5/6 or 6/6 HLA antigen matched) sibling donors.  If there are no safety concerns 
regarding graft failure/rejection after the interim safety review of these 10 Part 1 pairs, then Part 2 
of the study will open which will permit enrollment of recipients with either matched sibling or 
haploidentical donors.  During the study, we are aiming to collect ≥ 5.0 x 106 CD34+ cells/kg actual 
recipient weight with a minimum of 2.0 x 106 CD34+ cells/kg actual recipient weight in up to two 
apheresis sessions.  The primary study endpoint is efficacy, defined as the ability to mobilize ≥ 2.0 
x 106 CD34+ cells/kg actual recipient weight.  
 
All aspects of the hematopoietic cell transplant for this study including donor selection, graft 
processing and characterization, and infusion of hematopoietic cells are to be performed in 
accordance with the standards established by FACT, The Foundation for the Accreditation of 
Cellular Therapy, cGMP and GTP guidelines relating to human tissue intended for transplantation 
(21 CFR parts 1270 & 1271) and general biologic products standards (21 CFR part 610). 
 
5.2 
Screening Period Assessments 
 
The following assessments should be done at screening; unless otherwise specified, all of these 
assessments can be done or completed until baseline. The screening period will be up to 30 days 
for the donor.  Recipient screening will be done according to institutional standards. 
 
Donors: 
 
• 
Signature of informed consent 
• 
Collection of medical history, demographics 
• 
Collection of concomitant medications 
• 
Physical examination 
• 
Vital signs: temperature, blood pressure, pulse, and respiratory rate 
• 
ECOG assessment 
• 
HLA typing  
• 
Blood for CBC 
• 
Blood for CMP 
• 
Urine pregnancy test for women of childbearing potential to be done within 72 hours of 
dosing (if urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required) 


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Page 21 of 64  
• 
Serology for hepatitis B and C and HIV 
• 
ECG 
• 
Review of inclusion/exclusion criteria 
 
Recipients: 
• 
Signature of informed consent 
• 
Collection of medical history, demographics 
• 
Collection of concomitant medications 
• 
Physical examination 
• 
ECOG assessment 
• 
HLA typing  
• 
Blood for CBC 
• 
Blood for CMP and LDH 
• 
Urine pregnancy test for women of childbearing potential, to be done within 72 hours of the 
start of conditioning (if urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required) 
• 
Serology for hepatitis B and C and HIV 
• 
Confirmation of adequate cardiac function, i.e. LVEF ≥40% by Echo, MUGA, or similar 
• 
Pulmonary function test 
• 
Review of inclusion/exclusion criteria 
 
5.3 
Pre-Dose Assessments 
 
Pre-dose assessments are to be done on the day of BL-8040 injection, before the injection. 
  
Donors: 
• 
Vital signs: temperature, blood pressure, pulse, and respiratory rate 
• 
Blood for PK 
• 
Blood for CBC  
• 
FACS for CD34+ cells and lymphocytes, and CD34+ subset analysis and T-cell 
phenotyping 
 
Recipients: 
• 
Pre-transplant assessment according to institutional guidelines  
 
5.4 
Mobilization of Allogeneic Stem Cell Donor  
 
Donors will be mobilized as outpatients with subcutaneous (SC) BL-8040 in the morning (Day 1) 
followed by leukapheresis approximately 180 minutes (up to 270 minutes) after the injection per 
institutional protocol.  If the donor does not reach the collection goal for mobilization (≥ 5.0 x 106 
CD34+ cells/kg), a second leukapheresis will be performed on Day 2 (24 hours ± 2 hours from the 
BL-8040 injection) in an effort to reach a total of ≥ 5 x 106 cells/kg and at least   2 x 106 cells/kg 
from the combined collections. Donors who cannot mobilize ≥ 2 x 106 cells/kg after two apheresis 
section will be considered mobilization failures (See Section 5.4.4 for information regarding 
mobilization failure). 
 
5.4.1 
BL-8040 Administration 
 
In part 1, BL-8040 will be administered at a dose of 1 mg/kg SC injection on Day 1.   


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In part 2, BL-8040 will be administered at a dose of 1.25 mg/kg SC injection on Day 1. 
 
The following procedures will be performed after injection of BL-8040 on Day 1:   
• 
Temperature, blood pressure, pulse, and respiratory rate will measured at 1, 2, 3-4, 
6, and 8 hours ± 15 min following the end of the BL-8040 injection.   
• 
Approximately 3 hours following injection of BL-8040 (between 180 minutes and 
270 minutes is acceptable), begin leukapheresis procedure to process a minimum 
of three blood volumes according to institutional guidelines  
• 
At various times pre- and post-injection (see Sections 8.1-8.3), obtain venous 
samples for PK, CBC, and cytometric flow analysis (enumeration of CD34+ cells 
and lymphocytes, Section 8.2) and CD34+ subset analysis and T-cell phenotyping 
(Section 8.3).  At the completion of leukapheresis, a sample from the leukapheresis 
product (no more than 10% of product) will be obtained for CBC and flow 
cytometric analysis (CD34+ subset and T cell phenotype analysis, Section 8.3.2).  
Cryopreservation of leukapheresis product will be performed according to 
institutional guidelines. 
 
If a Day 2 leukapheresis is needed, the following procedures will be performed: 
• 
Temperature, blood pressure, pulse, and respiratory rate will be measured 
immediately before and following the leukapheresis procedure.   
• 
Cryopreservation of leukapheresis product will be performed according to 
institutional guidelines.  
• 
Venous samples for CBC and enumeration of CD34+ cells will be collected at 
specific time points (Section 8.2).   
 
5.4.2 
Premedication before BL-8040 Injection  
 
Premedication or treatment for local and systemic reaction will be allowed as per 
Investigator discretion. 
• 
Pre-treatment of subjects prior to BL-8040 injection is allowed with the following 
concomitant 
medications: 
promethazine, 
hydroxyzine, 
diphenhydramine, 
acetaminophen, and steroids. 
• 
Other drugs may also be given as premedication at the Investigator’s discretion. 
• 
Clinically appropriate measures in case of BL-8040 related local injection site 
reactions (e.g., corticosteroids, anti-histamines, local treatments, etc.) may be taken. 
• 
Additional medications/therapies to manage treatment-emergent conditions will be 
allowed at the discretion of the Investigator in consultation with the Manufacturer, 
in advance when possible. 
 
5.4.3 
Leukapheresis 
 
Donors will undergo no less than three blood volumes leukapheresis (LP) starting 
approximately 180 minutes (up to 270 minutes) after injection of BL-8040 per institutional 
protocol.  When possible, pheresis will be performed using the same model of pheresis 
machine in order to maintain consistency.  At the end of the leukapheresis, the collected 
graft will be analyzed by standard flow cytometry for CD34+ cell content. The goal for 
hematopoietic stem and progenitor cell collection will be ≥5.0 x 106 CD34+ cells/kg actual 
recipient weight with a minimum of 2.0 x 106 CD34+ cells/kg actual recipient weight.   
 
If the first leukapheresis product contains ≥ 5.0 x 106 CD34+ cells/kg actual recipient 


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weight, the mobilization with BL-8040 will be considered completed and successful. If the 
first leukapheresis product contains < 5.0 x 106 CD34+ cells/kg actual recipient weight, a 
second leukapheresis will be performed approximately 24 hours after the injection of BL-
8040 (i.e. Day 2). If the sum of the grafts collected after two days is ≥ 2.0 x 106 CD34+ 
cells/kg actual recipient weight, the mobilization with BL-8040 will be considered 
completed and successful.   
 
If a donor fails to mobilize a graft containing at least 2.0 x 106 CD34+ cells/kg actual 
recipient weight after two leukapheresis procedures, mobilization will be considered 
unsuccessful.  These donors will proceed with G-CSF mobilization per standard institution 
guidelines and will be followed for safety purposes for a period of five years after receiving 
BL-8040 (Refer to Section 5.4.5).   
 
For the transplant purposes, up to 5.0 x 106 CD34+ cells/kg actual recipient weight will be 
cryopreserved in DMSO per Institutional guidelines and infused in the recipient. Any 
additional cells will be aliquotted and cryopreserved for future donor cellular infusions to 
the recipient per Institutional guidelines.  
 
5.4.4 
Mobilization Failure with BL-8040 
 
Donors are required to undergo a minimum of three blood volumes apheresis/day for up to 
two days (i.e. two leukapheresis procedures) to be considered evaluable for the primary 
endpoint.  If the donor fails to collect ≥ 2.0 x 106 CD34+ cells/kg actual recipient weight 
due to the inability to undergo a minimum of three blood volumes apheresis/day, the donor 
will be removed from the protocol and the donor/recipient couple will be replaced.  The 
donor will still be followed for safety purposes according to the protocol (Section 5.2.4).   
 
If the donor is able to undergo a minimum of three blood volumes apheresis/day, but the 
sum of the two leukapheresis products is < 2.0 x 106 CD34+ cells/kg actual recipient 
weight, treatment will be considered unsuccessful (mobilization failure).  In this case, the 
donor will be removed from protocol and will be mobilized with G-CSF according to the 
standard institutional procedures.  The donor/recipient couple will not be replaced, but 
followed for safety purposes according to the protocol (Sections 5.4.5 and 5.5.5).  If the 
patient is unable to obtain sufficient cells for transplant from the G-CSF mobilization, the 
BL-8040 product may be pooled with the G-CSF mobilized product for transplant.  
Recipient outcomes will be collected and described but will not considered part of the 
primary analysis. 
 
5.4.5 
Donor Follow-Up 
 
Donors will be closely monitored during treatment and mobilization with BL-8040 for 
adverse events for 5 years post-administration of BL-8040.  AEs and concomitant 
medications will be obtained at the 30 day follow-up visit/phone call. New AEs reported 
during this period and those that are still open will be followed until resolution or 
stabilization. Adverse events will be graded according to the NCI CTCAE version 4.03.  
Hypocalcemia documented during the leukapheresis procedure is a known transient side 
effect and will not require additional follow-up unless determined to be clinically indicated 
by the treating physician.  The donor will have a CBC with differential count drawn at 7 
days and 30 days post-completion of BL-8040 administration.  If the donor’s CBC has 
clinically significant changes from baseline in the opinion of the treating physician at 30 
days post-administration of BL-8040, the donor will continue to have CBCs drawn monthly 


Protocol Version: 10/25/17, Amendment: 4 
 
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until resolution. Telephone contact will be made by the research study coordinator annually 
for 5 years.  Long term donor follow up will be performed in accordance to the consensus 
statement from the Worldwide Network for Blood and Marrow Transplantation and limited 
to three items: survival, onset of malignancies and onset of autoimmune diseases. In the 
case of a positive reply, the level of evidence should be indicated, that is if the diagnosis 
was confirmed by medical data.43 See Section 7.1 for donor follow-up schedule of events. 
 
5.5 
Treatment of the Recipient 
 
Once it is determined that an allograft of ≥ 2.0 x 106/kg has been obtained following BL-8040 
injection, the recipients may start their transplant conditioning regimen.  On the day of 
transplantation (Day 0), the previously cryopreserved allograft will be thawed and infused into the 
recipient (refer to Section 5.5.3).   
 
5.5.1 
Administration of Conditioning Regimen  
 
Once it is determined that a sufficient allograft has been obtained following BL-8040 
injection, the recipients will undergo myeloablative or reduced intensity conditioning 
chemotherapy as per institutional guidelines.  Conditioning chemotherapy and/or radiation 
regimens permitted in this study are: 
• 
Fludarabine and busulfan 
• 
Fludarabine and cyclophosphamide +/- TBI 
• 
Fludarabine and melphalan 
• 
Busulfan and cyclophosphamide  
• 
Cyclophosphamide and TBI 
 
Additional regimens may be allowed with approval of the Primary Investigator. 
 
5.5.2 
GVHD Prophylaxis  
 
GVHD prophylaxis will be administered to all patients per institutional guidelines. 
 
5.5.3 
Stem Cell Transplantation  
 
All or part of the leukapheresis product will be infused into the recipient per institutional 
guidelines. The day of the infusion will be considered Day 0; if the infusion occurs over 
multiple days, the final day of infusion will be considered Day 0.  
 
On the day of transplantation (Day 0), the cryopreserved allograft will be thawed and up 
to 5.0 x 106 CD34+ cells/kg (but not less than 2.0 x 106 CD34+ cells/kg) actual recipient 
weight will be infused into the recipient.   
 
5.5.4 
General Concomitant Medication and Supportive Care Guidelines  
 
Concomitant medications and supportive care measures, such as growth factors, will be 
administered at the discretion of the treating physician. 
 
If the recipient requires a donor lymphocyte infusion (DLI) as determined by the treating 
physician, data will be collected on the number of cells infused and all grade 3-5 AEs (see 
Section 11.1.7 for exceptions) will be recorded from Day 0 to Day 30 post DLI.  


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Page 25 of 64  
 
5.5.5 
Recipient Follow-Up 
 
Recipients will be closely monitored for serious adverse events (see Section 11.1.7 for 
exceptions), neutrophil and platelet recovery, and GVHD.  These will be recorded in 
medical records and transcribed into case report forms.  Serious adverse events will be 
graded according to the NCI CTCAE version 4.03 and all grade 3-5 nonhematologic AEs 
will be collected from start of conditioning through Day 100 or until relapse or start of 
subsequent treatment for their hematologic malignancy, whichever comes first.  
 
See Section 7.2 for recipient follow-up schedule of events. All recipients will be followed 
post-transplant regardless of relapse, subsequent treatment, etc.  
 
5.5.6 
Failure to Engraft 
  
If any recipient receiving the BL-8040 mobilized allograft does not have evidence of 
absolute neutrophil count (ANC) of at least 500/µL by Day +28 following transplantation, 
the donor will be contacted to begin G-CSF mobilization immediately and the recipient 
will be treated according to standard institutional policies for engraftment failure.  The 
recipient will still be monitored for safety per protocol. 
 
5.6 
Evaluation of Toxicity, Response, and Study Endpoints 
 
5.6.1 
Donor and Recipient Toxicity Evaluations  
  
All donors who receive BL-8040 are evaluable for toxicity (including CBC recovery). 
 
All recipients who receive any hematopoietic cells mobilized with BL-8040 are evaluable 
for toxicity, hematopoietic recovery, GVHD and disease relapse.  
 
5.6.2 
Donor and Recipient Response Evaluations  
 
Donors are required to undergo a minimum of 3 blood volumes of apheresis / day and up 
to two apheresis (depends on the number of cells collected) to be evaluable for efficacy.  
 
Recipients who receive hematopoietic cells mobilized with BL-8040 only will be evaluable 
for engraftment.  
 
5.6.3 
Evaluation of Donor/Recipient Pairs for Study Endpoints 
 
If a donor fails to collect ≥ 2.0 x 106 CD34+ cells/kg actual recipient weight despite 
undergoing at least 3 blood volumes of apheresis/day for 2 days, the donor will be 
considered evaluable, but will be considered a mobilization failure that will count towards 
the primary analysis (see Section 13.1.1).   
 
If a donor collects ≥ 2.0 x 106 CD34+ cells/kg actual recipient weight and the recipient fails 
eligibility prior to transplantation (due to declining performance status, unacceptable lab 
results, or other reasons), the donor will be followed for safety per protocol, but the 
donor/recipient pair will not be considered evaluable and will be replaced. 
 
 


Protocol Version: 10/25/17, Amendment: 4 
 
Page 26 of 64  
 
5.7 
General Concomitant Medication and Supportive Care Guidelines  
 
Concomitant medications and supportive care measures will be given at the discretion of the 
treating physician whenever medically necessary.   
 
5.8 
Women of Childbearing Potential  
 
Women of childbearing potential (women with regular menses, amenorrhea, irregular cycles, using 
a contraceptive method that precludes withdrawal bleeding, or who have had a tubal ligation) are 
required to have a negative pregnancy test within 10 days prior to the first dose of BL-8040 (donor) 
or prior to start of conditioning (recipient). 
 
Non-childbearing potential is defined as (by other than medical reasons): 
• 
≥ 45 years of age and has not had menses for greater than 2 years. 
• 
Amenorrheic for > 2 years without a hysterectomy and oophorectomy and an FSH value in the 
postmenopausal range upon pretrial (screening) evaluation. 
• 
Post-hysterectomy, oophorectomy, or tubal ligation. 
 
Donors or recipients (female or male along with their female partners) are required to use two forms 
of acceptable contraception, including one barrier method, during participation in the study and for 
2 weeks following the dose of BL-8040 (donor) or 2 weeks following the stem cell transplant 
(recipient). 
 
If a donor or recipient is suspected to be pregnant, BL-8040 administration to the donor and/or stem 
cell transplant to the recipient should be immediately discontinued.  In addition, a positive urine 
test must be confirmed by a serum pregnancy test.  If it is confirmed that the recipient or donor is 
not pregnant, the donor may resume dosing and the recipient may receive the transplant. 
 
If a female donor or recipient or female partner of a male donor or recipient becomes pregnant 
during treatment or within 1 month after the dose of BL-8040 (donor) or the stem cell transplant 
(recipient), the investigator must be notified in order to facilitate outcome follow-up. 
 
5.9 
Duration of Therapy 
 
If at any time the constraints of this protocol are considered to be detrimental to the donor and/or 
recipient’s health and/or the donor and/or recipient no longer wishes to continue protocol therapy, 
the protocol therapy should be discontinued and the reason(s) for discontinuation documented in 
the case report forms. 
 
Donor and /or recipient may be removed from the protocol treatment or study for any of the 
following reasons: 
• 
Death 
• 
Adverse event(s) that, in the judgment of the investigator, may cause severe or 
permanent harm or which rule out continuation of study drug 
• 
General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the primary investigator 
• 
Suspected pregnancy 
• 
Serious noncompliance with the study protocol 
• 
Lost to follow-up 


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Page 27 of 64  
• 
Patient request, i.e. withdrawal of consent 
• 
Study termination by the Sponsor, Investigator or regulatory agency 
 
 
6.0 
DOSE MODIFICATIONS  
 
Dose modifications for BL-8040 are not permitted.   


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Page 28 of 64  
7.0 
STUDY CALENDARS 
 
7.1 
Donor 
 
 
Screening1 
Day 1 
Day 2 
Day 7  
(± 3d) 
Day 30  
(± 7d) 
1 Yr  
(± 30d) 
2 Yr  
(± 30d) 
3 Yr  
(± 30d) 
4 Yr  
(± 30d) 
5 Yr 
(± 30d) 
Pre-
dose 
0.5h 
post 
1h 
post 
2h 
post 
3-4h post  
(prior to 
LP) 
6h 
post 
8h post  
(end of 
LP) 
24h post  
(prior to 
LP) 
30h post  
(end of 
LP) 
Labs/Procedures 
Physical exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC 
X 
X 
 
 
 
X 
 
X 
X 
X3 
X 
X4 
 
 
 
 
 
CMP 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV IgG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA typing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
X3 
 
 
 
 
 
 
 
Correlative Studies 
PK monitoring 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
 
 
 
 
 
 
CD34 enumeration 
 
X 
X 
X 
 
X 
 
X 
X 
X3 
 
 
 
 
 
 
 
Lymphocyte subsets 
 
X 
X 
 
 
X 
 
X 
X 
X3 
 
 
 
 
 
 
 
T-cell phenotyping 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
CD34+ subset analysis 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
1: Screening assessments should occur within 30 days prior to registration 
2: On leukapheresis product 
3: Only if leukapheresis is required on Day 2 
4: If CBC has not returned to baseline, continue checking monthly CBCs until hematologic recovery is observed.5: No more than 10 days prior to dose. 
 


Protocol Version: 10/25/17, Amendment: 4 
 
Page 29 of 64  
7.2 
Recipient 
 
The timing of screening assessments will match institutional standards. 
 
Screening 
Day 1-21 
Day 30 
(± 5d) 
Day 60 
(± 5d) 
Day 100 
(± 14d) 
Day 180 
(± 14d) 
Day 270 
(± 14d)  
Day 365 
(± 14d) 
Year 2 
(± 28d) 
Year 3 
(± 28d) 
Physical Exam 
X 
X1 
X 
X 
X 
X 
X 
X 
 
 
CBC  
X 
X1 
X 
X 
X 
X 
X 
X 
 
 
BMP / CMP & LDH 
X 
X3 
X 
X 
X 
X 
X 
X 
 
 
CMV IgG4 
X 
X4 
X 
X 
X 
X 
X 
X 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
HLA Typing 
X 
 
 
 
 
 
 
 
 
 
Lymphocyte Subset-13+CD25+ 
 
 
X 
 
X 
X 
 
X 
 
 
Disease Restaging 
 
 
X 
 
X 
X 
 
X 
 
 
Chimerism Analysis 
 
 
X 
 
X 
X 
 
X 
 
 
Acute GVHD Assessment 
 
X2 
X 
X 
X 
X 
X 
X 
 
 
Chronic GVHD Assessment 
 
 
 
 
X 
X 
X 
X 
 
 
Survival and relapse/progression 
 
 
 
 
 
 
 
X 
X5 
X5 
1: To occur daily until engraftment 
2: To occur weekly starting at the time of neutrophil engraftment. 
3: BMP daily, with CMP and LDH to be performed at least twice weekly until engraftment 
4: CMV IgG performed at screening and CMV PCR post transplant per institutional standard  
5: May be a telephone call in lieu of a clinic visit 
 
 


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Page 30 of 64  
 
 
8.0 
CORRELATIVE STUDIES 
 
8.1 
Pharmacokinetics and PK Monitoring  
 
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: 
• 
Cmax - maximum BL-8040 plasma concentration 
• 
Tmax - time to reach the maximum BL-8040 plasma concentration 
• 
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 
• 
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  
• 
λz - elimination rate constant, determined by linear regression of the terminal points of the 
ln-linear plasma concentration-time curve 
• 
t1/2 - terminal elimination half-life, defined as 0.693/λz 
 
At the following time points on Day 1, approximately 4 mL of peripheral blood will be collected 
in EDTA tube(s) for pharmacokinetic analysis:  
• 
Prior to SC injection of BL-8040 
• 
0.5 hours after administration of BL-8040  
• 
1 hour after the administration of BL-8040 
• 
3 hours after the administration of BL-8040 (just prior to leukapheresis) 
• 
8 hours post-completion of drug injection (immediately after leukapheresis) 
• 
24 hours after administration of BL-8040 
 
Ship PKs to: 
Shedeka Marriott 
Washington University School of Medicine 
660 South Euclid Avenue, CB 8615 
St. Louis, MO 63110 
 
8.2 
Enumeration of CD34+ Cells and Lymphocytes and CBC Analysis after BL-8040 
Administration  
 
At the following time points on Day 1, approximately 3 mL of peripheral blood will be collected 
in EDTA tube(s) for enumeration of CD34+ cells and lymphocytes.  The latter is ordered as an 
“allogeneic transplant flow cytometry panel +CD25” measuring CD2, CD3, CD4, CD8, CD19, 
CD20, CD25, and CD56 and is performed at the local study center hematology laboratory or a 
Sponsor designated central laboratory.   
 
Day 1 Enumeration of CD34+ cells and lymphocytes (3 mL blood, EDTA) and CBC (EDTA) 
• 
Prior to SC injection of BL-8040 
• 
0.5 hours (+/- 15 min) after administration of BL-8040 (CD34+ only) 
• 
1 hour (+/- 30 min) after administration of BL-8040 (CD34+ only) 
• 
3hours (+/- 1 hour) after the administration of BL-8040 and just prior to leukapheresis  


Protocol Version: 10/25/17, Amendment: 4 
 
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• 
8 hours (+/- 2 hours) post-completion of drug injection (immediately after 
leukapheresis) 
• 
24 hours (+/- 2 hours) after administration of BL-8040  
 
If a second leukapheresis is required (Day 2), approximately 3 mL of peripheral blood will be 
collected in EDTA tube(s) for enumeration of CD34+ cells and lymphocytes and CBC at 24h (prior 
to leukapheresis) and 30h (end of leukapheresis) post BL-8040 injection.   
 
The actual time of the sample must be documented. 
 
The used tubes and color codes and required procedures may change during the study.  In this case, 
the Manufacturer will provide separate description on the required collection methods. 
 
8.3 
CD34+ Subset Analysis and T-cell Phenotyping Evaluations after BL-8040 
Administration  
 
8.3.1 
Peripheral Blood Samples  
 
At the following time points on Day 1, approximately 16 mL of peripheral blood will be 
collected in EDTA tubes for CD34+ subset analysis and T-cell phenotyping. 
 
Day 1 CD34+ subset analysis (8 mL blood, EDTA) and T-cell phenotyping (8 mL blood, 
Na Hep) 
• 
Prior to SC injection of BL-8040 
• 
3-4 hours after the administration of BL-8040 (prior to leukapheresis) 
• 
24 hours (+/- 2 hours) after administration of BL-8040 
 
If a second leukapheresis is required (Day 2), approximately 16 mL of peripheral blood 
will be collected in EDTA tube(s) for CD34+ subset analysis and T-cell phenotyping at 24 
h (prior to leukapheresis) post BL-8040 injection.   
 
The actual time of the sample must be documented. 
 
8.3.2 
Sampling of Leukapheresis Product  
 
In addition to the peripheral blood samples collected, on Day 1, 10 to 15 mL of the final 
leukapheresis product (no greater than 10% of volume of the entire leukapheresis product) 
will be collected and sent to the laboratory of Dr. DiPersio on cold pack (See Section 8.6). 
 
8.4 
Handling of Specimens 
 
All samples will be labeled with patient initials, study number, date and time of collection. 
 
8.5 
Site Performing CD34+, Lymphocyte, CBC Analysis and T-Cell Phenotyping 
 
Samples will be analyzed at the Washington University study center hematology laboratory as 
appropriate.   
 
8.6 
Samples to Be Sent to Dr. DiPersio’s Laboratory at Washington University  
 


Protocol Version: 10/25/17, Amendment: 4 
 
Page 32 of 64  
The samples for CD34+ subset analysis and T-cell phenotyping will be sent on the same day on 
cold pack to the laboratory of Dr. DiPersio on the 6th floor of the Southwest Tower for analysis.  
Shipping address is: 
DiPersio Lab c/o Leah Gehrs / Mike Rettig 
Washington University Medical School 
4940 Parkview Place 
626P Southwest Tower 
St. Louis, MO 63110-1025 
 
 
9.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to the schedule listed 
in this section.  Any queries generated by Washington University must be responded to within 28 days of 
receipt by the participating site.  The Washington University research team will conduct a regular review 
of data status at all secondary sites, with appropriate corrective action to be requested as needed. 
 
 


Protocol Version: 10/25/17, Amendment: 4 
 
Page 33 of 64  
 
9.1 
Donor Submission Schedule 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Donor On-Study Form 
Donor Medical and Surgical History Form 
Donor CBC Form 
At baseline 
Donor Study Drug Dosing 
After dose of BL-8040 
Donor Leukapheresis Log 
Donor CBC Form (multiple time points) 
Day 1 
Day 2 (if required) 
Donor Correlative Log 
(multiple time points) 
Day 1 
Day 2 
Donor Follow-Up Form 
Donor CBC Form 
Day 7 
Day 30 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
Adverse Events 
Continuous from baseline through safety follow-up 
visit  
MedWatch Form 
See Section 10.0 for reporting requirements 
Concomitant Medications 
Continuous from baseline through leukapheresis 
 
 
 


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Page 34 of 64  
 
9.2 
Recipient Submission Schedule 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to registration 
Recipient On-Study Form 
Recipient Medical and Surgical History Form At baseline 
Recipient Conditioning Form 
Completion of conditioning 
Recipient Transplant Form 
After engraftment (or Day 30) 
Recipient Disease Response Form 
Day 30 
Day 100 
Day 180 
Day 365 
Recipient Acute GVHD Assessment Form 
Week 3 
Day 30 
Day 60 
Day 100 
Day 180 
Day 270 
Day 365 
Recipient Chronic GVHD Assessment Form 
Day 100 
Day 180 
Day 270 
Day 365 
Recipient CBC Form 
Baseline 
Day 0 
Day 30 
Day 60 
Day 100 
Day 180 
Day 270 
Day 365 
Recipient CMV Reactivation 
Any time CMV testing occurs (will be performed 
as per institutional standard) 
Recipient Relapse / Progression Form 
Time of relapse / progression 
Recipient Survival Form 
Day 365 
Year 2 
Year 3 
Adverse Events 
Continuous from start of conditioning through 
day 100  
MedWatch Form 
See Section 10.0 for reporting requirements 
 
 
10.0 
SAFETY, PHARMACOVIGILANCE, AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require reporting as outline 
below. 
 
The Washington University Human Research Protection Office (HRPO) requires that all events meeting 
the definition of unanticipated problem or serious noncompliance be reported as outlined in Section 10.2. 


Protocol Version: 10/25/17, Amendment: 4 
 
Page 35 of 64  
 
The FDA requires that all serious and unexpected adverse events be reported as outlined in Section 10.4.  
In addition, any fatal or life-threatening adverse experiences where there is a reasonable possibility of 
relationship to study intervention must be reported. 
 
BioLineRX requires that all SAEs be reported as outlined in Section 10.5. 
 
10.1 
Definitions 
 
10.1.1 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 not planned at the Screening visit. 
• 
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, the dates of occurrence, duration, severity, 
relationship to study medication, action taken to study drug, outcome, and whether 
considered non-serious or serious. 
 
Once the subject has signed the informed consent form (ICF), AEs will be recorded up to 
and including 30 days after the last dose of the treatment drug for donors. AEs from time 
of consent to immediately prior to receiving BL-8040 will be captured as baseline events.  
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 10.1.2. 
 
In addition, any AEs at least possibly related to study drug that occurs up to 5 years after 
the BL-8040 dose (donor) should be recorded. 


Protocol Version: 10/25/17, Amendment: 4 
 
Page 36 of 64  
 
For recipients, Grade 3-5 nonhematologic AEs will be recorded from the start of the 
conditioning regimen until Day +100 post transplant.   
 
AE severity (Table 1) will be recorded and graded according to NCI-CTCAE (v 4.03). 
 
Table 111: 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 non-invasive 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. 
 
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/her opinion of the relationship of the AE to 
treatment with the study drug, using the criteria outlined in Table 2.  
 
The possible outcomes of the AEs are classified as follows: 
• 
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 
• 
Ongoing: AE is not recovered 
• 
Fatal 
• 
Unknown 
 
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. The 
Investigator will assess severity and relationship to study drug (See Table 1 and Table 2 
respectively). 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. 
 
 


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Table 222: 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. 
A direct cause and effect relationship between the suspected drug and 
the adverse event has been demonstrated. 
It disappears or decreases upon cessation of drug administration or 
reduction in dose. 
 
10.1.2 Serious Adverse Events (SAEs) 
 
An SAE is any AE occurring at any dose that suggests a significant hazard or side effect, 
regardless of the Investigator’s opinion on the relationship to the investigational medicinal 
product and which 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 


Protocol Version: 10/25/17, Amendment: 4 
 
Page 38 of 64  
facility) 
• 
A persistent or significant disability/incapacity 
• 
A congenital anomaly or birth defect 
• 
Significant Medical event 
 
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. 
 
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 that 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. 
 
10.1.3 Suspected Unexpected Serious Adverse Events (SUSARs) 
 
A serious adverse event which is assessed as related and is unexpected will be considered 
as SUSAR and should be reported in an expedited manner (see Sections 10.8 and 10.9). 
 
Definitions:  
• 
Unexpected: a case in which in terms of nature, severity, or frequency given (a) 
the research procedures that are described in the protocol-related documents, such 
as the IRB-approved research protocol and informed consent document; and (b) 
the characteristics of the subject population being studied; is not expected to be 
present 
• 
Relationship: related or possibly related to participation in the research (“possibly 
related” means there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the research); and 
• 
suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
10.1.4 Noncompliance 
 
Definition: failure to follow any applicable regulation or institutional policies that govern 
human 
subjects 
research 
or 
failure 
to 
follow 
the 
determinations 
of 
the 
IRB.  Noncompliance may occur due to lack of knowledge or due to deliberate choice to 
ignore regulations, institutional policies, study protocol, or determinations of the IRB. 
 
 


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10.1.5 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks that result in substantial harm to 
subjects or others, or that materially compromises the rights or welfare of participants. 
 
10.1.6 Protocol Exceptions 
 
Definition: A planned deviation from the approved protocol that are under the research 
team’s control. Exceptions apply only to a single participant or a singular situation.  No 
exceptions to the eligibility criteria (Section 3.0) will be considered. 
 
Local IRB pre-approval of all protocol exceptions must be obtained prior to the event.  For 
secondary sites, the Washington University PI will issue approval of the exception, but it 
must also be submitted to the local IRB with documentation of approval forwarded to 
Washington University.  Washington University IRB approval is not required for protocol 
exceptions occurring at secondary sites. 
 
10.2 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
 
The PI is required to promptly notify the IRB of the following events: 
 
• 
Any unanticipated problems involving risks to participants or others which occur at WU, 
any Barnes Jewish Hospital (BJH) or Saint Louis Children’s Hospital (SLCH) institution, 
or that impacts participants or the conduct of the study. 
• 
Noncompliance with federal regulations or the requirements or determinations of the IRB. 
• 
Receipt of new information that may impact the willingness of participants to participate 
or continue participation in the research study. 
 
These events must be reported to the IRB within 10 working days of the occurrence of the event 
or notification to the PI of the event.  The death of a research participant that qualifies as a 
reportable event should be reported within 1 working day of the occurrence of the event or 
notification to the PI of the event. 
 
10.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University 
 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or any BJH 
or SLCH institution that has been reported to and acknowledged by HRPO as reportable.  
(Unanticipated problems reported to HRPO and withdrawn during the review process need not be 
reported to QASMC.) 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgment via email to a QASMC 
auditor. 
 
10.4 
Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting requirements.  PLEASE 
NOTE THAT REPORTING REQUIREMENTS FOR THE FDA DIFFER FROM 
REPORTING REQUIREMENTS FOR HRPO/QASMC.  It is the responsibility of the 
Washington University principal investigator to report any unanticipated problem to the FDA as 


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follows: 
 
• 
Report any unexpected fatal or life-threatening adverse experiences (Section 10.1.2) 
associated with use of the drug (i.e., there is a reasonable possibility that the experience 
may have been caused by the drug) by telephone or fax no later than 7 calendar days after 
initial receipt of the information.   
• 
Report any serious, unexpected adverse experiences (Section 10.1.2), as well as results 
from animal studies that suggest significant clinical risk within 15 calendar days after 
initial receipt of this information.   
 
All MedWatch forms will be sent by the investigator or investigator’s team to the FDA at the 
following address or by fax: 
 
Food and Drug Administration 
Center for Drug Evaluation and Research 
Division of Oncology Drug Products 
5901-B Ammendale Rd. 
Beltsville, MD 20705-1266 
FAX: 1-800-FDA-0178 
 
Secondary sites must submit a completed MedWatch form to the Washington University PI and 
research coordinator within 4 calendar days (for fatal or life-threatening adverse experiences) or 
11 calendar days (for serious, unexpected adverse experiences).  The Washington University PI 
will be responsible for submitting all MedWatch forms from secondary sites to the FDA within the 
timeframes specified above. 
 
10.5 
Notification of Serious Adverse Events to BioLineRx 
 
Initial notification of SAEs 
An initial SAE report form must be completed and sent by fax/email to the BioLineRx 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.  
 
Medical Monitor 
Dr. Abi Vainstein-Haras 
Mobile +972 54 4709208 
Email: safety8040@biolinerx.com 
Fax: + 972-8-642-9137 
 
The initial SAE report will be followed within 24 hours by a completed SAE report including a 
sufficiently detailed narrative, 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 BioLineRx immediately and 
should include: 
• 
Protocol identification 
• 
A suspected investigational medicinal product, 
• 
An identifiable subject (e.g. study subject code number), 


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• 
An AE with the Investigator’s assessment of seriousness and relationship to any the study 
drugs, 
• 
An identifiable reporting source i.e. Investigator contact details. 
 
Follow-up of SAEs 
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). 
 
10.6 
Reporting Requirements for Secondary Sites 
 
The research team at each secondary site is required to promptly notify the Washington University 
PI and research coordinator of all reportable events (as described in Section 7.6) within 1 working 
day of the occurrence of the event or notification of the secondary site’s PI of the event.  This 
notification may take place via email if there is not yet enough information for a formal written 
report (using either an FDA MedWatch form if required or an institutional SAE reporting form if 
not).  A formal written report must be sent to the Washington University PI and research 
coordinator within 10 working days of the occurrence of the event or notification of the secondary 
site’s PI of the event.  The death of a research participant that qualifies as a reportable event should 
be reported within 1 working day of the occurrence of the event or notification of the secondary 
site’s PI of the event. 
 
The research team at a secondary site is responsible for following its site’s guidelines for reporting 
applicable events to its site’s IRB according to its own institutional guidelines.  The research team 
at Washington University is responsible for reporting all applicable events to the FDA. 
 
10.7 
Reporting to Secondary Sites 
 
The Washington University PI (or designee) will notify the research team at each secondary site of 
all reportable events that have occurred at other sites within 10 working days of the occurrence of 
the event or notification of the PI of the event.  This includes events that take place both at 
Washington University and at other secondary sites, if applicable. 
 
10.8 
Timeframe for Reporting Required Events 
 
Adverse events will be collected on donors from first dose of study treatment (Day 1) through the 
Day +30 visit. Adverse events will be collected on recipients from the start of conditioning through 
the Day +100 visit. 
 
Unexpected CTCAE grade 4 or 5 nonhematologic AEs experienced by transplant recipients must 
be reported within 24 hours of knowledge of the event.  Unexpected CTCAE grade 3 
nonhematologic AEs must be reported within 3 business days of knowledge of the events. 
 
Expected AEs will be reported using NCI’s CTCAE Version 4.03 at regular intervals as defined in 
Section 9.0.   
 
 
 


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11.0 
PHARMACEUTICAL INFORMATION  
 
Refer to Section 1.2 
 
 
12.0 
MEASUREMENT OF EFFECT 
 
12.1 
Definition of Primary Efficacy Endpoint 
 
12.1.1 Adequate Allograft  
 
For the purposes of this study, an adequate allograft is defined as a graft that contains ≥ 
2.0x106 CD34+ cells/kg actual recipient weight collected in no more than two 
leukapheresis sessions using BL-8040 as the sole mobilizing agent 
 
12.2 
Definition of Secondary Endpoints 
 
12.2.1 Neutrophil Engraftment 
 
Time to neutrophil engraftment is measured by determining the first of 3 consecutive 
measurements of neutrophil count ≥ 500/μL following conditioning regimen induced nadir. 
 
12.2.2 Platelet Engraftment 
 
Time to platelet engraftment is measured by determining the first of 3 consecutive 
measurements of platelet count ≥ 20,000/μL without platelet transfusion support for 7 days. 
 
12.2.3 Graft Failure / Graft Rejection 
 
Graft failure/rejection will be defined as an ANC < 500 /μL after Day 28 post-HCT and 
bone marrow biopsy with < 5% cellularity in the absence of evidence of disease. 
 
12.2.4 CMV Reactivation  
 
CMV reactivation will be defined as a positive test for CMV viremia as determined by an 
antigenemia assay or quantitative PCR that results in the administration of antiviral 
treatment directed against CMV. 
 
12.2.5 Relapse or Disease Progression  
 
Disease relapse occurs in recipients who entered transplant in CR.  Progression occurs in 
recipients with existent disease at transplant who meet criteria for progressive disease post-
transplant.  A recipient will be considered relapsed when there is a recurrence of the 
original malignant disease after transplantation.  Date of relapse/progression is defined as 
the date at which the first observation of hematologic, radiographic, or cytogenetic changes 
which signify progression/relapse is made.  
 
12.2.6 Event Free Survival  
 
An event is defined as either graft failure (Section 12.2.3), disease relapse as evidenced by 


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hematologic, radiographic, or cytogenetic changes, or death. The event free survival is the 
time from Day 0 to occurrence of the first event.   
 
12.2.7 Overall Survival  
 
The time from Day 0 to death.  
 
12.3 
Definition of Safety Endpoints 
 
12.3.1 Acute GVHD 
 
Acute GVHD rate and severity for the first year after PBSC infusion will be assessed based 
on the Minnesota-Center for International Blood and Marrow Transplant Research 
(CIBMTR) GVHD grading system (Appendix 1)44, 45, 46.  All grades of severity of acute 
GVHD will be collected. 
 
12.3.2 Chronic GVHD 
 
Chronic GVHD rate and severity for the first 365 days after PBSC infusion will be assessed 
based on the NIH criteria (Appendix 2). 
   
12.3.3 Treatment Related Mortality  
 
Death that results from a transplant procedure related complication (e.g. infection, organ 
failure, hemorrhage, GVHD) rather than from relapse of the underlying disease or an 
unrelated cause. 
                
 
13.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, an 
independent Data and Safety Monitoring Committee (DSMC) report will be prepared by the study 
statistician with assistance from the study team, will be reviewed by the DSMC, and will be submitted to 
the Washington University Quality Assurance and Safety Monitoring Committee (QASMC).  This report 
will include: 
• 
HRPO protocol number, protocol title, Principal Investigator name, data coordinator name, 
regulatory coordinator name, and statistician 
• 
Date of initial HRPO approval, date of most recent consent HRPO approval/revision, date of HRPO 
expiration, date of most recent QA audit, study status, and phase of study 
• 
History of study including summary of substantive amendments; summary of accrual suspensions 
including start/stop dates and reason; and summary of protocol exceptions, error, or breach of 
confidentiality including start/stop dates and reason 
• 
Study-wide target accrual and study-wide actual accrual including numbers from participating sites 
• 
Protocol activation date at each participating site 
• 
Average rate of accrual observed in year 1, year 2, and subsequent years at each participating site 
• 
Expected accrual end date and accrual by site 
• 
Objectives of protocol with supporting data and list the number of participants who have met each 
objective 
• 
Measures of efficacy 
• 
Early stopping rules with supporting data and list the number of participants who have met the early 


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stopping rules 
• 
Summary of toxicities at all participating sites 
• 
Abstract submissions/publications 
• 
Summary of any recent literature that may affect the safety or ethics of the study  
 
Further DSMC responsibilities are described in the DSMC charter. 
 
Until such a time as the first secondary site activates this protocol, a semi-annual DSM report to be prepared 
by the study team will be submitted to the QASM Committee beginning 6 months after study activation at 
Washington University. 
 
The study Principal Investigator and coordinator will monitor for serious toxicities on an ongoing basis. 
Once the principal investigator or coordinator becomes aware of an adverse event, the AE will be reported 
to the HRPO and QASMC according to institutional guidelines (please refer to Section 10.0). 
 
Refer to the Washington University Quality Assurance and Data Safety Monitoring Committee Policies 
and Procedures for full details on the responsibilities of the DSMC at https://siteman.wustl.edu/wp-
content/uploads/2015/10/QASMC-Policies-and-Procedures-03.31.2015.pdf 
 
In addition, the study may be monitored by BioLineRx or a designee.  On-site monitoring of all study 
records including source documentation may be performed to ensure accuracy and completeness of case 
report forms.  
 
 
14.0 
AUDITING 
 
As coordinating center of this trial, Washington University (via the Quality Assurance and Safety 
Monitoring Committee (QASMC) will monitor each participating site to ensure that all protocol 
requirements are being met; that applicable federal regulations are being followed; and that best practices 
for patient safety and data collection are being followed per protocol.  Participating sites will be asked to 
send copies of all audit materials, including source documentation.  The audit notification will be sent to 
the Washington University Research Patient Coordinator, who will obtain the audit materials from the 
participating institution. 
 
Notification of an upcoming audit will be sent to the research team one month ahead of the audit. Once 
accrual numbers are confirmed, and approximately 30 days prior to the audit, a list of the cases selected for 
review (up to 10 for each site) will be sent to the research team. However, if during the audit the need arises 
to review cases not initially selected, the research team will be asked to provide the additional charts within 
two working days. 
 
Items to be evaluated include: 
• 
Subject screening and enrollment 
• 
Reporting of adverse events 
• 
Maintenance of HIPAA compliance 
• 
Completeness of regulatory documentation 
• 
Completeness of participant documentation 
• 
Acquisition of informed consent 
• 
IRB documentation 
• 
Issues of protocol adherence 
 


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Page 45 of 64  
Additional 
details 
regarding 
the 
auditing 
policies 
and 
procedures 
can 
be 
found 
at 
https://siteman.wustl.edu/wp-content/uploads/2015/10/QASMC-Policies-and-Procedures-03.31.2015.pdf  
 
 
15.0 
STATISTICAL CONSIDERATIONS 
 
15.1 
Primary Analysis  
 
15.1.1 Primary Analysis Set  
 
The full analysis set (FAS) will consist of all donors having received a dose of BL-8040.  
The FAS will be the primary analysis set for all efficacy and safety analyses. 
 
15.1.2 Primary Efficacy Analysis and Sample Size Calculation  
 
We predict that approximately 90% of donors will collect ≥ 2.0 x 106 CD34+ cells/kg 
within two apheresis sessions.  The power analysis was performed assuming type 1 error 
(alpha) = 0.025, one sided non-inferiority test (0.7 reference (inferiority), true response rate 
of 0.9, inferiority margin = 0.001)47.  To achieve 0.9 power, a total of 24 evaluable subjects 
will be enrolled. 
 
15.1.3 Accrual 
 
Approximately 1 – 3 donor/recipient pairs per month. 
 
15.1.4 Stopping Rules 
 
14.1.4.1 Stopping Rule for Continuation of Study Enrollment 
 
 
As a stopping rule to ensure that the rate of graft failure does not exceed 5%, there 
are three planned interim looks and no more than 1 graft failure can be observed 
in the first 5 patients, no more than 2 in the first 10 patients, and no more than 2 in 
the first 15 patients.  If the number of graft failures exceeds the specified numbers, 
no further patients will be enrolled on study.  The stopping rule was determined 
using Pocock boundary48.   
 
14.1.4.2 Stopping Rule for Enrollment of Haploidentical Donor/Recipient 
Pairs 
 
We will first enroll 10 patients with matched sibling donors.  If no instances of 
graft failure are observed among the initial 10 sibling/recipient pairs enrolled, we 
will then enroll patients with either matched sibling or haploidentical donors.  If 
one graft failure is observed among the initial 10 subjects, then the study will not 
enroll haploidentical donor/recipient pairs. 
 
15.2 
Secondary Efficacy and Safety Analyses 
 
15.2.1 Safety Analysis 
 
AEs (all, grade (for recipients), severity (for donors), relatedness to study drug, serious 
AEs, and AEs leading to deaths) recorded during the study will be summarized and listed.  


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Page 46 of 64  
 
Laboratory values will be summarized and categorized based on their normality status.  
Individual data listing will also be provided.   
 
Data from vital signs and physical examinations will be listed and summarized. 
 
15.2.2 Kinetics of Neutrophil and Platelet Engraftment 
 
Summary of number of recipients with neutrophil engraftment by Day +28 along with 95% 
confidence intervals and listings will be provided.  Kaplan-Meier models will be used to 
estimate median time to neutrophil engraftment including 95% confidence intervals.  Time 
to neutrophil engraftment is measured by determining the first 3 consecutive measurements 
of neutrophil count ≥ 500/μL following conditioning regimen induced nadir. 
 
Summary of number of recipients with platelet engraftment along with 95% confidence 
intervals and listings will be provided.  Kaplan-Meier models will be used to estimate 
median time to platelet engraftment including 95% confidence intervals.  Time to platelet 
engraftment is measured by determining the first of 3 consecutive measurements of platelet 
count ≥ 20,000/uL without platelet transfusion support for 7 days. 
 
15.2.3 Acute and Chronic GVHD 
 
Summary of number of recipients with acute GVHD and chronic GVHD along with 95% 
confidence intervals and listings will be provided.  If there is sufficient number of recipients 
with events additional Kaplan-Meier models will be used to estimate median times to acute 
GVHD, chronic GVHD, relapse, disease progression, and death of any cause with 95% 
confidence intervals. 
 
 
16.0 
MULTICENTER REGULATORY REQUIREMENTS 
 
Washington University requires that each participating site sends its informed consent document to be 
reviewed and approved by the Washington University Regulatory Coordinator (or designee) prior to 
IRB/IEC submission.    
 
Site activation is defined as when the secondary site has received official written documentation from the 
coordinating center that the site has been approved to begin enrollment.  At a minimum, each participating 
institution must have the following documents on file at Washington University prior to study activation: 
• 
Documentation of IRB approval of the study in the form of a letter or other official document from 
the participating institution’s IRB.  This documentation must show which version of the protocol 
was approved by the IRB. 
• 
Documentation of IRB approval of an informed consent form. The consent must include a statement 
that data will be shared with Washington University, including the Quality Assurance and Safety 
Monitoring Committee (QASMC), the DSMC (if applicable), and the Washington University study 
team. 
• 
Documentation of FWA, signed FDA Form 1572 (if applicable), and the CVs of all participating 
investigators. 
• 
Protocol signature page signed and dated by the investigator at each participating site. 
 
The coordinating center Principal Investigator (or designee) is responsible for disseminating to the 


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Page 47 of 64  
participating sites all study updates, amendments, reportable adverse events, etc.  Protocol/consent 
modifications and IB updates will be forwarded electronically to the secondary sites within 4 weeks of 
obtaining Washington University IRB approval.  Activated secondary sites are expected to submit 
protocol/consent/IB modifications to their local IRBs within 4 weeks of receipt unless otherwise noted.  
Upon the secondary sites obtaining local IRB approval, documentation of such shall be sent to the 
Washington University study team within 2 weeks of receipt of approval. 
 
Documentation of participating sites’ IRB approval of annual continuing reviews, protocol amendments or 
revisions, all SAE reports, and all protocol violations/deviations/exceptions must be kept on file at 
Washington University. 
 
The investigator or a designee from each institution must participate in a regular conference call to update 
and inform regarding the progress of the trial. 
 
 
 


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17.0 
REFERENCES 
 
1. Schmitz N, Dreger P, Linch DC, et al. Randomised trial of filgrastim-mobilised peripheral blood 
progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. 
Lancet 1996;347:353-357. 
2. Korbling M, Huh YO, Durett A, et al. Allogeneic blood stem cell transplantation: peripheralization and 
yield of donor–derived primitive hematopoietic progenitor cells (CD34+ Thy-1dim) and lymphoid 
subsets, and possible predictors of engraftment and graft-versus-host disease. Blood. 1995;86:2842-
2848. 
3. Vigorito AC, Azevedo WM, Marques JF, et al. A randomized, prospective comparison of allogeneic 
bone marrow and peripheral blood progenitor cell transplantation in the treatment of haematological 
malignancies. Bone Marrow Transplant. 1998;22:1145-1151. 
4. Champlin RE, Schmitz H, Horowitz MM, et al. Blood stem cells compared with bone marrow as a 
source of hematopoietic cells for allogeneic transplantation.  IBMTR Histocompatibility and Stem Cell 
Sources Working Committee and the European Group for Blood and Marrow Transplantation (EBMT). 
Blood. 2000;95:3702-3709. 
5. Bensinger WI, Martin PJ, Storer B, et al. Transplantation of bone marrow as compared with peripheral 
–blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med. 
2001;344:175-181. 
6. Couban S, Simpson DR, Barnett MJ, et al. A randomized multicenter comparison of bone marrow and 
peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. 
Blood 2002; 100:1525-1531. 
7. Powels R, Mehta J, Kulkarni S, et al. Allogeneic blood and bone-marrow stem cell transplantation in 
haematological malignant diseases: a randomized trial. Lancet 2000; 355:1231-1237. 
8. Anderlini P, Rizzo JD, Nugent ML, et al. Peripheral blood stem cell donation: an analysis from the 
International Bone Marrow Transplant Registry (IBMTR) and European Group for Blood and Marrow 
Transplant (EBMT) databases. Bone Marrow Transplant 2001;27:689-692. 
9. Cutler C, Giri S, Jeyapalan S, et al. Acute and chronic graft-versus-host disease after allogeneic 
peripheral-blood stem cell and bone-marrow transplantation: a meta-analysis. J Clin Oncol 
2011;19:3685-3691. 
10. Anasetti C, Logan BR, Lee SJ, et al. Peripheral-blood stem cell versus bone marrow from unrelated 
donors. NEJM. 2012;367(16):1487-1496. 
11. Saraceni F, Shem-Tov N, Olivieri A, and Nagler A. Mobilized peripheral blood grafts include more 
than hematopoietic stem cells: the immunological perspective. Bone Marrow Transplantation. 2015:1-
6. 
12. Pusic I, Jiang SY, Landua S, et al. Impact of mobilization and remobilization strategies on achieving 
sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant. 2008; 
14:1045-1056. 
13. Hosing C, Saliba RM, Ahlawat S, et al. Poor hematopoietic stem cell mobilizers: a single institution 
study of incidence and risk factors in patients with recurrent or relapsed lymphoma.  Am J Hematol 
2009;84:335-337. 
14. Pavone V, Gaudio F, Console G, et al. Poor mobilization is an independent prognostic factor in patients 
with malignant lymphomas treated by peripheral blood stem cell transplantation. Bone Marrow 
Transplant. 2006;37:719-724. 
15. Akhtar S, Weshi AE, Rahal M, et al. Factors affecting autologus peripheral blood stem cell collection 
in patients with relapsed or refractory diffuse large cell lymphoma and Hodgkin lymphoma: a single 
institution result of 168 patients. Leuk Lymphoma. 2008;49:769-778. 
16. Kindwall-Keller, T. Peripheral stem cell collection: from leukocyte growth factor to removal of 
catheter. J Clin Apheresis. 2014;29:199-205. 


Protocol Version: 10/25/17, Amendment: 4 
 
Page 49 of 64  
17. Fruehauf S, Haas R, Conradt C, et al. Peripheral blood progenitor cell (PBPC) counts during steady-
state hematopoiesis allow to estimate the yield of mobilized PBPC after filgrastim (R-metHuG-CSF)-
supported cytotoxic chemotherapy.  Blood. 1995;85:2619-2626. 
18. Fruehauf S, Schmitt K, Veldwijk MR, et al. Peripheral blood progenitor cell (PBPC) counts during 
steady-state haemopoiesis enable the estimation of the yield of mobilized PBPC after granulocyte 
colony-stimulating factor supported cytotoxic chemotherapy: an update on 100 patients. Br J Haematol. 
1999;105:786-794. 
19. Mohty M, Ho AD. In and out of the niche: perspectives in mobilization of hematopoietic stem cells. 
Experimental Hematology. 2011;39:723-729. 
20. Weaver CH, Hazelton B, Birch R, et al. An analysis of engraftment kinetics as a function of the CD34 
content of peripheral blood progenitor cell collections in 692 patients after the administration of 
myeloablative chemotherapy. Blood. 1995;86:3961-3969. 
21. Bensinger W, Appelbaum F, Rowley S, et al. Factors that influence collection and engraftement of 
autologous peripheral-blood stem cells. J Clin Oncol. 1995;13:2547-2555. 
22. Petit I, Szyper-Kravitz M, Nagler A, et al. G-CSF induces stem cell mobilization by decreasing bone 
marrow SDF-1 and up-regulating CXCR4. Nat Immunol. 2002;3:687-694. 
23. Moncada V, Bolan C, Yau YY, Leitman SF. Analysis of PBPC cell yields during large-volume 
leukapheresis of subjects with a poor mobilization response to filgrastim. Transfusion 2003;43:495-
501. 
24. Devine SM, Flomenberg N, Vesole DH, et al. Rapid mobilization of CD34+ cells following 
administration of the CXCR4 antagonist AMD3100 to patients with multiple myeloma and non-
Hodgkin’s lymphoma. J Clin Oncol. 2004;22:1095-1102. 
25. Flomenberg N, Devine SM, DiPersio JF, et al.  The use of AMD3100 plus G-CSF for autologoust 
hematopoietic progenitor cell mobilization is superior to G-CSF alone. Blood. 2005;106:1867-1874. 
26. Liles WC, Broxmeyer HE, Rodger E, et al. Mobilization of hematopoietic progenitor cells in healthy 
volunteers by AMD3100, a CXCR4 antagonist. Blood. 2003;102:2728-2730. 
27. Liles WC, Rodger E, Broxmeyer HE, et al. Augmented mobilization and collection of CD34+ 
hematopoietic cells from normal human volunteers simulated with granulocyte-colony stimulating 
factor by single-dose administration of AMD3100, a CXCR4 antagonist. Transfusion. 2006;45:295-
300. 
28. Larochelle A, Krous A, Metzger M, et al. AMD3100 mobilizes hematopoietic stem cells with long-
term repopulating capacity in nonhuman primates. Blood. 2006;107:3772-3778. 
29. Hess DA, Bonde J, Craft TC, et al. Human progenitor cells rapidly mobilized by AMD3100 repopulate 
NOD/SCID mice with increased frequency in comparison to cells from the same donor mobilized by 
granulocyte colony stimulating factor. Biol Blood Marrow Transplant. 2007;13(4):398-411. 
30. Devine SM, Vij R, Rettig M, et al. Rapid mobilization of functional donor hematopoietic cells without 
G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction.  Blood 2008;122:990-998. 
31. Peled A, Petit I, Kollet O, et al. Dependence of human stem cell engraftment and repopulation of 
NOD/SCID mice on CXCR4. Science. 1999;283:845-848. 
32. Levesque JP, Hendy J, Takamatsu Y, et al. Disruption of the CXCR4/CXCL12 chemotactic interaction 
during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest. 
2003;111:187-196. 
33. Lapidot T.  Mechanisms of human stem cell migration and repopulation of NOD/SCID and B2mnull 
NOD/SCID mice.  The role of SDF-1/CXCR4 interactions. Ann N Y Acad Sci. 2001;938:83-95. 
34. Lapidot T, Petit I. Current understanding of stem cell mobilization: the roles of chemokines, proteolytic 
enzymes, adhesion molecules, cytokines, and stromal cells. Exp Hematol. 2002;30:973-981. 
35. Tachibana K, Hirota S, Iizasa H, et al. The chemokine receptor CXCR4 is essential for vascularization 
of the gastrointestinal tract. Nature. 1998;393:591-594. 
36. Zou YR, Kottmann AH, Kuroda M, et al. Function of the chemokine receptor CXCR4 in 
haematopoiesis and in cerebellar development. Nature. 1998;393:595-599. 


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37. Moore MA, Hattori K, Heissig B, et al. Mobilization of endothelial and hematopoietic stem and 
progenitor cells by adenovector-mediated elevation of serum levels of SDF-1, VEGF, and angiopoietin-
1. Ann N Y Acad Sci. 2001;938:36-45; discussion 45-37. 
38. Sweeney EA, Lortat-Jacob H, Priestley GV, et al. Sulfated polysaccharides increase plasma levels of 
SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells. Blood. 2002;99:44-
51. 
39. Calandra G, Bridger G, Fricker S.  CXCR4 in clinical hematology. Curr Top Microbiol Immunol 2010; 
341:173-91. 
40. Jacobson O, et al. PET of tumor CXCR4 expression with 4-18F-T140. J Nucl Med 2010. 51(11):1796-
1804. 
41. Tamamura H, et al. Identification of a CXCR4 antagonist, a T140 analog, as an anti-rheumatoid arthritis 
agent. FEBS Lett 2004. 569(1-3):99-104. 
42. Abraham M, et al. Enhanced unique pattern of hematopoietic cell mobilization induced by the CXCR4 
antagonist 4F-benzoyl-TN14003. Stem Cells 2007. 25(9):2158-2166. 
43. Halter JP, van Walraven SM, Worel N, et al. Allogeneic hematopoietic stem cell donation-standardized 
assessment of donor outcome data: a consensus statement from the Worldwide Network for Blood and 
Marrow Transplantation (WBMT). Bone Marrow Transplant 2013;48:220-5. 
 
44. MacMillan ML, DeFor TE, Weisdorf DJ. What predicts high risk acute graft-versus-host disease 
(GVHD) at onset? identification of those at highest risk by a novel acute GVHD risk score. Br J 
Haematol 2012;157:732-741. 
45. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. 
Bone Marrow Transplant 1995;15:825-828. 
46. Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR Severity Index for grading acute graft-versus-host 
disease: retrospective comparison with Glucksberg grade. Br J Haematol 1997;97:855-864. 
47. Chow S, Shao J, Wang H. 2008.  Sample Size Calculations in Clinical Research. 
48. Dessert Pocock S. When (not) to stop a clinical trial for benefit. JAMA 2005; 294(17) 
 
 
 
 
 
 
 
 
 


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APPENDIX 1: MINNESOTA-CIBMTR STAGING AND GRADING FOR ACUTE GVHD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APPENDIX 2: Chronic GVHD Assessment 
 
Date of Assessment: _________________________              
 
SKIN (Patient History and Exam) 
Score 0 
 
Score 1 
 
Score 2 
 
Score 3 
 
 
Skin 
Score 
0 
1 
2 
3 
No Symptoms 
< 18% BSA with 
disease signs but 
NO sclerotic 
features 
19-50% BSA OR 
involvement with 
superficial sclerotic 
features “not 
hidebound” (able to 
pinch 
>50% BSA OR deep 
sclerotic features 
“hidebound” (unable 
to pinch) OR 
impaired mobility, 
ulceration or severe 
pruritus 
NIH item that scores maximum severity based on: 
→ Percent body surface area involved by erythema OR 
→ Degree of sclerotic features OR 
→ Impaired mobility OR 
→ Ulceration OR 
→ Severe pruritus  
 
Maculopapular rash 
 
 
 
  
 
Erythroderma  
 
 
Lichen planus-like features 
 
 
  
 
Poikiloderma 
 
 
 
Papulosquamous lesions or ichthyosis 
  
 
Sclerotic features 
 
 
Hyperpigmentation 
 
 
 
  
 
Pruritus  
 
 
Hypopigmentation 
 
 
 
  
 
Hair Involvement 
 
 
Keratosis pilaris 
 
 
  
 
Nail Involvement 
 
 
Erythema 
 
 
 
 
 
 
% BSA involved: ________ 
 
 
 
 
 
 
 
 
 
 
 


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*% BSA Reference 
 
 


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cGVHD signs and symptoms seen with NAILS, SCALP, BODY HAIR 
Score 0 
 
Score 1 
 
Score 2 
 
Score 3 
 
 
Check all that apply: 
 
Distinctive (seen in Chronic GVHD, but insufficient alone to establish diagnosis of Chronic GVHD) 
Dystrophy 
 
 
 
 
 
 
Longitudinal ridging, splitting, or brittle features 
 
Onycholysis 
 
 
Pterygium unguis 
 
 
 
 
 
Nail loss (usually symmetic; affects most nails) 
 
New onset of scarring or nonscarring scalp  
 
 
alopecia (after recovery from chemoradiotherapy) 
 
Scaling, papulosquamous lesions 
 
 
 
 
Other features/common (seen with both Acute and Chronic GVHD) 
Thinning scalp hair, typically patchy, course or dull  
 
(not explained by endocrine or other causes) 
 
 
Premature gray hair 
 
 
 
 
 
 
Please describe: 
Patient timeline, extent of finding, duration/rapidity of onset, relationship to immunosuppression and 
likely attributability to GVHD 
_____________________________________________________________________________________
_____________________________________________________________________________________
__________________________ 
 
 
 
 
 
 
 


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cGVHD signs and symptoms seen with MOUTH 
Score 0 
 
Score 1 
 
Score 2 
 
Score 3 
 
 
Oral 
Score 
0 
1 
2 
3 
No Symptoms 
Mild symptoms with 
disease signs but not 
limiting oral intake 
significantly 
Moderate symptoms 
with disease signs 
with partial 
limitation of oral 
intake 
Severe symptoms 
with disease signs on 
examination with 
major limitation of 
oral intake 
 
Oral Exam 
Check all that apply: 
 
Diagnostic (sufficient to establish Chronic GVHD) 
Lichen-type features 
 
 
 
 
 
Hyperkeratotic plaques  
 
 
 
Restriction of mouth opening from sclerosis 
 
 
 
Distinctive (seen in Chronic GVHD, but insufficient alone to establish diagnosis of Chronic GVHD) 
Xerostomia 
 
 
 
 
 
 
Mucocele 
 
 
 
 
 
 
Muscosal atrophy 
 
 
 
 
 
Pseudomembranes 
 
 
 
 
 
Ulcers  
 
 
 
 
 
 
 
Other features/common (seen with both Acute and Chronic GVHD) 
Gingivitis 
 
 
 
 
 
 
Mucositis 
 
 
 
 
 
 
Erythema 
 
 
 
 
 
 
Pain 
 
 
 
 
 
 
 
 
Please describe: 
Patient timeline, extent of finding, duration/rapidity of onset, relationship to immunosuppression and 
likely attributability to GVHD 
_____________________________________________________________________________________
_____________________________________________________________________________________
__________________________ 
 
 
 


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cGVHD signs and symptoms seen with EYES 
Score 0 
 
Score 1 
 
Score 2 
 
Score 3 
 
 
Eye 
Score 
0 
1 
2 
3 
No Symptoms 
Mild dry eye symptoms 
not affecting ADL 
(requiring eye drops 
<3x per day) OR 
asymptomatic signs of 
keratoconjunctivitis 
sicca 
Moderate dry eye 
symptoms partially 
affecting ADL 
(requiring eye drops 
>3x per day or 
punctal plugs) 
without vision 
impairment 
Severe dry eye 
symptoms 
significantly affecting 
ADL (special eyewear 
to relieve pain) OR 
unable to work 
because of ocular 
symptoms OR loss of 
vision cause by 
keratoconjunctivitis 
sicca 
 
Nuances for a patient using drops < 3 x per day: 
▪ 
 But wearing a Boston Scleral lens → Score 3 
▪ 
 But had punctal plugs placed  7 days → Score 2 
▪ 
 But had plugs placed a month ago →Score 1 
 
Check all that apply: 
 
Distinctive (seen in Chronic GVHD, but insufficient alone to establish diagnosis of Chronic GVHD) 
New onset dry, gritty, or painful eyes 
 
 
 
Cicatricial 
 
 
 conjunctivitis 
 
Keratoconjunctivitis sicca 
 
 
 
 
Confluent areas of punctate keratopathy  
 
 
 
Other features/common (seen with both Acute and Chronic GVHD) 
Photophobia 
 
 
 
 
 
 
Periorbital hyperpigmentation 
 
 
 
Blepharitis (erythema of the eyelids with edema) 
 
 
Please describe: 
Patient timeline, extent of finding, duration/rapidity of onset, relationship to immunosuppression and 
likely attributability to GVHD 
_____________________________________________________________________________________
_____________________________________________________________________________________
__________________________ 
 
 
 


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cGVHD signs and symptoms seen with GI TRACT 
Score 0 
 
Score 1 
 
Score 2 
 
Score 3 
 
 
GI Tract 
Score 
0 
1 
2 
3 
No Symptoms 
Symptoms such as 
dysphagia, anorexia, 
nausea, abdominal 
pain or diarrhea 
without significant 
weight loss (<5%) 
Symptoms with mild 
to moderate weight 
loss (5-15%) 
Symptoms associated 
with significant 
weight loss >15%, 
requires nutritional 
supplement for most 
calorie needs OR 
esophageal dilation  
 
Check all that apply: 
 
Diagnostic (sufficient to establish Chronic GVHD) 
Esophageal web 
 
 
 
 
Strictures or stenosis in the upper to mid third 
 
of the esophagus 
 
 
 
 
 
 
Other features/common (seen with both Acute and Chronic GVHD) 
Exocrine – pancreatic insufficiency 
 
 
 
Anorexia 
 
 
 
 
 
 
Nausea  
 
 
 
 
 
 
Vomiting 
 
 
 
 
 
 
Diarrhea 
 
 
 
 
 
 
Weight loss 
 
 
 
 
 
 
Failure to thrive (infants and children) 
 
 
 
Please describe: 
Patient timeline, extent of finding, duration/rapidity of onset, relationship to immunosuppression and 
likely attributability to GVHD 
_____________________________________________________________________________________
_____________________________________________________________________________________
__________________________ 
 
 
 


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cGVHD signs and symptoms seen with LIVER 
Score 0 
 
Score 1 
 
Score 2 
 
Score 3 
 
 
Liver 
Score 
0 
1 
2 
3 
Normal LFT 
Elevated Bilirubin, 
AP, AST or ALT 
<2x ULN 
Bilirubin >3 mg/dl 
or Bilirubin, 
enzymes 2-5 x ULN 
Bilirubin or enzymes 
>5 x ULN 
 
Check all that apply: 
 
Other features/common (seen with both Acute and Chronic GVHD) 
Total Bilirubin, alkaline phosphatase  
 >2x upper limit of normal 
 
 
 
 
ALT or AST > 2 x upper limit of normal  
 
 
Please describe: 
Patient timeline, extent of finding, duration/rapidity of onset, relationship to immunosuppression and 
likely attributability to GVHD 
_____________________________________________________________________________________
_____________________________________________________________________________________
__________________________ 
 
 


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cGVHD signs and symptoms seen with LUNGS 
Score 0 
 
Score 1 
 
Score 2 
 
Score 3 
 
 
Lung 
Score 
0 
1 
2 
3 
No Symptoms 
 
FEV1 > 80%   OR 
LFS = 2 
Mild symptoms 
(shortness of breath 
after climbing 1 
flight of steps) 
FEV1 60-79%   OR 
LFS 3-5 
Moderate symptoms 
(shortness of breath 
after walking on flat 
ground) 
FEV1 40-59%   OR 
LFS 6-9 
Severe symptoms 
(shortness at rest 
requiring O2) 
FEV1 >39%   OR 
LFS 10-12 
 
FEV1:______  
 
Not done
 
 
NA
 
DLCO: ______  
Not done
 
 
NA
 
LFS: ________  
Not done
 
 
NA
 
 
Check all that apply: 
 
Diagnostic (sufficient to establish Chronic GVHD) 
Bronchiolitis obliterans diagnosed with lung biopsy 
 
 
Distinctive (seen in Chronic GVHD, but insufficient alone to establish diagnosis of Chronic GVHD) 
Bronchiolitis obliterans diagnosed with PFTs 
and radiology  
 
 
 
 
 
 
Other features/common (seen with both Acute and Chronic GVHD) 
Bronchiolitis obliterans with organizing pneumonia (BOOP) 
 
 
Please describe: 
Patient timeline, extent of finding, duration/rapidity of onset, relationship to immunosuppression and 
likely attributability to GVHD 
_____________________________________________________________________________________
_____________________________________________________________________________________
__________________________ 
 
 


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cGVHD signs and symptoms seen with MUSCLE, FASCIA, JOINTS 
Score 0 
 
Score 1 
 
Score 2 
 
Score 3 
 
 
Muscles, 
Fascia & 
Joints 
Score 
0 
1 
2 
3 
No Symptoms 
 
 
Mild tightness of 
arms or legs, 
normal or mild 
decreased range of 
motion (ROM) 
AND not affecting 
ADL  
Tightness of arms or 
legs OR joint 
contractures, 
erythema thought 
due to fasciitis, 
moderate decrease 
ROM AND mild to 
moderate limitation 
to ADL 
Contractures WITH 
significant decrease 
of ROM AND 
significant limitation 
of ADL (unable to tie 
shoes, button shirt, 
dress self etc.) 
 
Check all that apply: 
 
Diagnostic (sufficient to establish Chronic GVHD) 
 
Fasciitis 
 
 
 
 
 
 
Joint stiffness or contracture secondary to sclerosis 
 
 
Distinctive (seen in Chronic GVHD, but insufficient alone to establish diagnosis of Chronic GVHD) 
Myositis or polymyositis 
 
 
 
 
 
Other features/common (seen with both Acute and Chronic GVHD) 
Edema  
 
 
 
 
 
 
Muscle cramps  
 
 
 
 
Arthralgia or arthritis 
 
 
 
 
 
 
Please describe: 
Patient timeline, extent of finding, duration/rapidity of onset, relationship to immunosuppression and 
likely attributability to GVHD 
_____________________________________________________________________________________
_____________________________________________________________________________________
__________________________ 
 
 
 


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cGVHD signs and symptoms seen with GENITALIA 
Score 0 
 
Score 1 
 
Score 2 
 
Score 3 
 
 
Genitalia 
Score 
0 
1 
2 
3 
No Symptoms 
 
 
Symptomatic with 
mild signs on exam 
AND no effect on 
coitus and minimal 
discomfort with 
gynecologic exam 
Symptomatic with 
moderate signs on 
exam AND with 
mild dyspareunia 
OR with discomfort 
with gynecologic 
exam 
Symptomatic WITH 
advanced sign 
(stricture, labial, 
agglutination, or 
severe ulceration) 
AND severe pain 
with coitus or 
inability to insert 
vaginal speculum  
 
Check all that apply: 
 
Diagnostic (sufficient to establish Chronic GVHD) 
Lichen planus-like features 
 
 
 
 
Vaginal scarring or stenosis 
 
 
 
 
 
Distinctive (seen in Chronic GVHD, but insufficient alone to establish diagnosis of Chronic GVHD) 
Erosion  
 
 
 
 
 
Fissures 
 
 
 
 
 
 
Ulcers  
 
 
 
 
 
 
 
 


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Other Indicators 
None 
Mild 
Moderate 
Severe 
Not Assessed 
Ascites (serositis) 
 
 
 
 
 
Myasthenia Gravis 
 
 
 
 
 
Polymyositis 
 
 
 
 
 
Platelets less than 
100,000/ul 
 
 
 
 
 
Pericardial effusion 
 
 
 
 
 
Nephrotic syndrome 
 
 
 
 
 
Cardiomyopathy 
 
 
 
 
 
Cardiac conduction defects 
 
 
 
 
 
Progressive onset 
 
 
 
 
 
Pleural Effusion(s) 
 
 
 
 
 
Peripheral Neuropathy 
 
 
 
 
 
Eosinophilia >500ul 
 
 
 
 
 
Coronary artery 
i
l
t
 
 
 
 
 
 
Other, specify:_________________________________________________ 
 
 


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Does the patient have chronic GVHD?  
Yes 
    No 
    
If yes, specify Severity: Mild 
 
Moderate 
 
 
Severe 
    
 
 
 NIH CGVHD Global Severity Category reflects overall disability 
SEVERITY 
ORGAN SCORE 
NO. OF ORGANS 
Mild 
All 1 (0 for Lung) 
1-2 
Moderate 
All 1 (0 for Lung) 
3 or more 
At least one 2 (1 for Lung) 
1-2 
Severe 
At least one 3 (2 for Lung) 
1 or more 
 
Were there additional exams performed?   Yes 
 No 
    
If yes, check all that apply: 
Procedure 
Date 
Result 
Biopsy               
 
 
CT Scan             
 
 
 
 
 
MRI                   
 
 
 
 
 
Photo                
 
 
Schirmer Eye Test    
 
 
 PFT 
 
 
 LFT 
 
 
Ultrasound/Echocardiogram     
 
 
X-Ray                 
 
 
Other:__________________        
 
 
Signature: ________________________________   Date: __________________ 
 
 


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Appendix 3: MDRD Study Equation 
 
eGFR = 175 x (SCr)-1.154 x (age)-0.203 x 0.742 [if female] x 1.210 [if Black] 
 
where eGFR is estimated glomerular filtration rate (in mL/min/1.73 m2) 
SCr is standardized serum creatinine (in mg/dL) 
and age is in years 
 
 
Cite: Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new equation 
to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-12.