Clinical trial NCT02763384
Conditions: T-Acute Lymphoblastic Leukemia Adult T Lymphoblastic Lymphoma
Sponsor: Washington University School of Medicine
Start date: 2016-12-02; Completion date: 2022-05-22
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The outcome of patients with relapsed or refractory adult T-acute lymphoblastic leukemia (T-ALL) and the related disease T-lymphoblastic lymphoma (T-LBL) is extremely poor with 30% of the patients responding to first salvage therapy and long-term survival of only 10%. Therefore, novel therapies for patients with relapsed/refractory T-ALL/LBL represent an unmet clinical need.

Recent data provide strong evidence that CXCR4 signaling plays a major role in T-cell leukemia cell maintenance and leukemia initiating activity, and targeting CXCR4 signaling in T-ALL cells reduces tumor growth in an animal model. In this study, the investigators propose that the addition of BL-8040 to nelarabine as a salvage therapy for patients with relapsed/refractory T-ALL/LBL will result in a higher complete remission (CR) rate than nelarabine alone without an increase in toxicity and will allow patients to proceed to a potentially curative allogeneic hematopoietic cell transplant.

Detailed description:

Arms: arm 1: * Cycle 1: BL-8040 subcutaneous daily from Day 1 to Day 6 and nelarabine intravenously over 2 hours on Days 2, 4, and 6
* Cycles 2-4: BL-8040 subcutaneous daily from Day 1 to Day 5 and nelarabine intravenously over 2 hours on Days 1, 3, and 5
* Treatment may be repeated every 21 days for up to 4 cycles
Interventions: intervention 1: BL-8040 intervention 2: Nelarabine
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
Protocol Version: 01/17/23, Amendment 2 
 
Page 1 of 33 
 
 
A Phase IIa Study of BL-8040 in Combination with Nelarabine 
for Relapsed or Refractory T-Acute Lymphoblastic Leukemia/ 
Lymphoblastic Lymphoma 
 
Washington University School of Medicine 
Section of BMT & Leukemia 
660 South Euclid Avenue, Campus Box 8007 
St. Louis, MO 63110 
 
Protocol #: 201606146 
Version Date: 01/17/2023 
 
Coordinating Center: 
Washington University School of Medicine 
 
Principal Investigator: 
Geoffrey L. Uy, M.D. 
Phone: (314) 747-8439 
E-mail: guy@wustl.edu 
 
Sub-Investigators  
Institution 
 
 
 
Daniel C. Link, M.D.  
Washington University 
Correlative Sciences 
Bader Alahmari, M.D. 
Washington University 
Co-Investigator 
Kathryn Trinkaus, Ph.D. 
Washington University 
Biostatistics 
 
 
Study Drug(s): 
 
BL-8040 
Nelarabine 
 
IND #: 
130875 
ClinicalTrials.gov #: 
NCT02763384 
 
 
 
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 
 
 


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Page 2 of 33 
 
Protocol Revision History 
 
Initial Approval Version  
 
 
 
 
 
06/29/16 
Amendment #1 Version 
 
 
 
 
 
 
10/25/17 
Amendment #2 Version 
 
 
 
 
 
 
01/17/23 
 
 


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Page 3 of 33 
 
A Phase IIa Study of BL-8040 in Combination with Nelarabine for Relapsed or 
Refractory T-Acute Lymphoblastic Leukemia/ Lymphoblastic Lymphoma 
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. 
 
 
 


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SCHEMA 
 
ELIGIBILITY (See section 3.0 for full criteria) 
1. T-acute lymphoblastic leukemia/ lymphoblastic lymphoma which has relapsed or is 
refractory to chemotherapy. 
2. Peripheral blood lymphoblasts ≤50,000 mcL.  
3. Age ≥ 18 years 
4. ECOG performance status ≤ 2. 
5. Adequate organ function defined as: 
a. Calculated creatinine clearance ≥ 50 ml/min  
b. AST, ALT, total bilirubin ≤ 2 x institutional ULN  
 
TREATMENT PLAN (See Section 7.0 for Details) 
 
 
Treatment may be repeated every 21 days until disease progression for up to 4 cycles. 
On days that both drugs are administered, BL-8040 will be administered approximately 2-4 
hours prior to nelarabine.  
 
Cycle 1 
BL-8040: 
1.5 mg/kg subcutaneous daily from Day 1 to Day 6.  
Nelarabine: 1,500 mg/m2 intravenous over 2 hours on Days 2, 4 and 6. 
 
Cycle 2-4 
BL-8040:  
1.5 mg/kg subcutaneous daily from Day 1 to Day 5.  
Nelarabine:  1,500 mg/m2 intravenously over 2 hours on Days 1, 3 and 5. 
 
 
 


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TABLE OF CONTENTS 
 
SCHEMA ................................................................................................................................ 4 
1.0 
BACKGROUND AND RATIONALE .................................................................................. 7 
1.1 
T-Acute Lymphoblastic Leukemia / Lymphoblastic Lymphoma ..................................... 7 
1.2 
Nelarabine for Relapsed / Refractory T-ALL/LBL ............................................................ 7 
1.3 
Critical Role of CXCR4 and CXCL12 Interaction in T-ALL ................................................. 7 
1.4 
Study Agent: BL-8040 ...................................................................................................... 8 
1.5 
Study Rationale ............................................................................................................... 8 
2.0 
OBJECTIVES ................................................................................................................. 9 
2.1 
Primary Objective  ....................................................................................................... 9 
2.2 
Secondary Objectives ...................................................................................................... 9 
2.3 
Exploratory Objectives .................................................................................................... 9 
3.0 
ELIGIBILITY CRITERIA ................................................................................................... 9 
3.1 
Inclusion Criteria ............................................................................................................. 9 
3.2 
Exclusion Criteria........................................................................................................... 10 
4.0 
REGISTRATION PROCEDURES ..................................................................................... 10 
4.1 
Confirmation of Patient Eligibility ................................................................................. 11 
4.2 
Patient Registration in the Siteman Cancer Center OnCore Database ........................ 11 
4.3 
Assignment of UPN ....................................................................................................... 11 
5.0 
STUDY CALENDAR ..................................................................................................... 12 
6.0 
DATA SUBMISSION SCHEDULE ................................................................................... 13 
7.0 
TREATMENT PLAN ..................................................................................................... 13 
7.1 
Agent Administration .................................................................................................... 13 
7.2 
Dose Modifications ....................................................................................................... 14 
7.3 
Response Evaluation ..................................................................................................... 14 
7.4 
Supportive Care ............................................................................................................ 14 
7.5 
Women of Childbearing Potential ................................................................................ 15 
7.6 
Duration of Treatment .................................................................................................. 15 
7.7 
Follow-up ...................................................................................................................... 15 
7.8 
Removal from Study ..................................................................................................... 15 
8.0 
RESPONSE EVALUATION ............................................................................................ 16 
9.0 
PHARMACEUTICAL INFORMATION ............................................................................ 17 


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9.1 
BL-8040 ......................................................................................................................... 17 
9.2 
Nelarabine ..................................................................................................................... 19 
10.0 CORRELATIVE STUDIES .............................................................................................. 20 
11.0 STATISTICAL CONSIDERATIONS .................................................................................. 21 
11.1 
Study Design.................................................................................................................. 21 
11.2 
Monitoring Rule for Excess Mortality ........................................................................... 22 
12.0 REGULATORY AND REPORTING REQUIREMENTS ........................................................ 22 
12.1 
Definitions ..................................................................................................................... 23 
12.2 
Reporting to the Human Research Protection Office (HRPO) at Washington University
 
25 
12.3 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University .............................................................................................................. 25 
12.4 
Reporting Requirements for Secondary Sites ............................................................... 25 
12.5 
Reporting to Secondary Sites ........................................................................................ 26 
12.6 
Reporting to the FDA .................................................................................................... 26 
12.7 
Notification of Serious Adverse Events to BioLineRx ................................................... 27 
12.8 
Timeframe for Reporting Required Events ................................................................... 27 
12.9 
Exceptions in the Reporting of AE and SAE .................................................................. 28 
13.0 DATA AND SAFETY MONITORING .............................................................................. 28 
14.0 AUDITING ................................................................................................................. 29 
15.0 MULTICENTER REGULATORY REQUIREMENTS ............................................................ 30 
16.0 REFERENCES .............................................................................................................. 32 
 
 
 


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1.0 
BACKGROUND AND RATIONALE 
 
1.1 
T-Acute Lymphoblastic Leukemia / Lymphoblastic Lymphoma 
 
T-acute lymphoblastic leukemia (T-ALL), and the related disease T-lymphoblastic 
lymphoma (T-LBL), is an aggressive malignant neoplasm of the bone marrow. It 
accounts for 20% of all cases of ALL and is more common in adults than children [1]. 
With the use of modern therapy, 90% of people diagnosed with T-ALL and T-LBL will 
achieve first remission with 5-year overall survival (OS) of 48% [1]. Despite 
improvements to first-line therapy, the outcome of adult ALL (B-cell and T-cell 
subtype) after relapse, and in patients with failure to standard induction therapy, is 
extremely poor with 30% of the patients responding to first salvage therapy and long-
term survival of only 10%[2-4]. These relapsed patients will have a chance of cure if 
they receive an allogeneic hematopoietic cell transplant (alloHCT) after first salvage 
therapy; however, only a small fraction of them will be candidates for such therapy 
due to refractory disease at time of relapse, and for those patients who fail the first 
salvage therapy, the outcome is dismal [5]. Novel therapies for ALL (including 
blinatumomab, inotuzumab, and CD19 chimeric antigen receptor T cells) have 
demonstrated significant promise in ALL but target only antigens specific to patients 
with B-ALL.[6] Therefore, novel therapies for patients with relapsed/refractory T-
ALL/LBL represent an unmet clinical need.  
 
1.2 
Nelarabine for Relapsed / Refractory T-ALL/LBL 
 
Nelarabine is a pro-drug of the nucleoside analog ara-G. In trials of patients with 
relapsed or refractory T-ALL/LBL, nelarabine results in a complete remission (CR) 
rate of 15-30% [7, 8]. One group reported on 126 patients treated with the regimen 
of 1.5 g/m2 per day on Days 1, 3, and 5 in multiple 21-day cycles [8]. Forty-five 
patients achieved CR (36%) and 12 a partial remission (PR). Of the CR patients, 80% 
were able to proceed to alloHCT. The OS was 24% at 1 year and 11% at 6 years, with 
allo-HCT patients achieving an OS of 31% at 3 years. Nelarabine was granted 
accelerated approval by the FDA for treatment of patients who have been refractory 
to or relapsed after two chemotherapy regimens based on CR rates from two single 
arm phase 2 studies [9].  CR rates with single agent nelarabine lag behind what is 
already achieved with the use of immunotherapy alone in patients with relapse B-
ALL. Thus, optimal combination regimens with nelarabine need to be evaluated.  
 
1.3 
Critical Role of CXCR4 and CXCL12 Interaction in T-ALL 
 
CXCL12 (also known as stromal-derived factor-1, SDF-1) is a chemokine 
constitutively produced at high levels by bone marrow stromal cells. CXCL12, through 
interaction with its major receptor CXCR4, regulates many aspects of T cell biology, 
including proliferation, survival, and migration [10-13]. CXCR4 is expressed on most 
malignant hematopoietic cells, including T-ALL. Two recent studies provide strong 
preclinical evidence that CXCR4 signaling provides key signals that are required for T 


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ALL cell survival and expansion [14, 15]. Of particular interest, data suggest that 
CXCR4 signaling is required for T-ALL leukemia-initiating activity. Relevant to this 
proposal, treatment with a CXCR4 antagonist reduced the growth of primary human 
T-ALL in a xenotransplant mouse model. Of note, prior studies also have implicated 
CXCR4 signaling in resistance to chemotherapy [16]. A clinical trial investigating 
CXCR4 inhibition in combination with chemotherapy in patients with relapsed acute 
myeloid leukemia showed a higher response rate than expected in patients with 
advanced disease [17]. Based on these observations, we hypothesize that the addition 
of an inhibitor of CXCR4 to chemotherapy will improve the response rate of patients 
with T-ALL.  
 
1.4 
Study Agent: BL-8040 
 
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 0.5-
5.2 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 [18, 19]. Compared 
to other inhibitors of CXCR4 such as plerixafor, BL-8040 is a more potent 
hematopoietic stem cell mobilizing agent and also induces apoptosis as a single agent 
against malignant hematopoietic cells [20]. Therefore, we propose to conduct a pilot 
study of BL-8040 in combination with nelarabine in adults with relapsed or 
refractory T-ALL/LBL. Two clinical trials with BL-8040 have been reported so far 
with promising safety and efficacy [21, 22]. In both studies the most common adverse 
events (AEs) seen are injection site reactions and systemic reactions: hives, pruritus, 
flushing, chills, rash and urticaria. 
 
1.5 
Study Rationale 
 
The outcomes of patients with relapsed/refractory T-ALL/LBL are dismal and the 
only chance of cure is to undergo alloHCT soon after achieving second CR. However, 
with current strategies, only a small percentage of patients will respond to first 
salvage therapy. Recent data provide strong evidence that CXCR4 signaling plays a 
major role in T-cell leukemia cell maintenance and leukemia initiating activity, and 
targeting CXCR4 signaling in T-ALL cells reduces tumor growth in an animal model. 
Thus, we propose the addition of BL-8040 to nelarabine as a salvage therapy for 
patients with relapsed/refractory T-ALL/LBL. Our hypothesis is that such strategy 
will result in a higher CR rate than nelarabine alone without an increase in toxicity so 
that a higher percentage of patients with relapsed/refractory T-ALL/LBL will 
respond and proceed to alloHCT without delay.  
 
 
 


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2.0 
OBJECTIVES 
 
2.1 
Primary Objective   
 
To assess the safety and tolerability of BL-8040 when administered with nelarabine 
in patients with T- ALL/LBL.  
 
2.2 
Secondary Objectives  
 
1. To estimate the composite complete remission (CRc=CR+CRi) and the overall 
response rate (CR, CRi + PR) for patients with T-ALL/LBL treated with the 
combination of BL-8040 plus nelarabine.  
2. To determine the time to response, duration of response, disease-free, event-free 
and overall survival of patients treated with BL-8040 plus nelarabine. 
3. To estimate the rate of patients who proceed to alloHCT after treatment.  
 
2.3 
Exploratory Objectives 
  
1. To describe the pharmacodynamic effects of BL-8040 on T-lymphoblasts in 
including inhibition of CXCR4 signaling on lymphoblasts, mobilization of 
lymphoblasts into the peripheral circulation, induction of apoptosis in 
lymphoblasts, and alterations in lymphoblast cell cycle status.   
2. To describe the interaction of pretreatment disease and patient characteristics 
including morphology, CXCR4 expression on lymphoblasts, cytogenetics, 
immunophenotype, WBC, and performance status on clinical outcomes. 
 
 
 
3.0 
ELIGIBILITY CRITERIA 
 
3.1 
Inclusion Criteria 
 
1. Diagnosis of T-acute lymphoblastic leukemia/ lymphoblastic lymphoma 
according to WHO criteria which has relapsed or is refractory to chemotherapy. 
2. Peripheral blood lymphoblasts ≤ 50,000 mcL. Hydroxyurea and/or leukapheresis 
is permitted to reduce the peripheral blast count prior to enrollment and 
treatment. 
3. Age ≥ 18 years 
4. ECOG performance status ≤ 2. 
5. Adequate organ function defined as: 
a. Calculated creatinine clearance ≥ 50 ml/min using the Cockroft-Gault formula 
b. AST, ALT, total bilirubin ≤ 2 x institutional ULN except for Gilbert’s disease or 
when in the opinion of treating physician elevated levels are due to direct 


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Page 10 of 33 
involvement of leukemia (e.g., hepatic infiltration or biliary obstruction due to 
leukemia), in which case ALT and AST may be elevated up to ≤ 5 x IULN. 
6. Women of childbearing potential and men must agree to use adequate 
contraception with a highly effective method (hormonal or barrier method of 
birth control, abstinence) prior to study entry and for the duration of study 
participation. Abstinence is acceptable if this is the established and preferred 
contraception for the subject. 
7. Female subjects must have a negative urine or serum pregnancy test within 72 
hours prior to start of study treatment 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. 
Documented 
hysterectomy or oophorectomy must be confirmed with medical records of 
the actual procedure or confirmed by an ultrasound.  Tubal ligation must be 
confirmed with medical records of the actual procedure. 
8. Able to understand and willing to sign an IRB-approved written informed consent 
document.  
 
3.2 
Exclusion Criteria 
 
1. Previous treatment with nelarabine for relapsed or refractory disease. 
2. Pregnant or nursing. 
3. Received any other investigational agent or systemic cytotoxic chemotherapy 
within the preceding 2 weeks. 
4. Active CNS involvement with leukemia  
5. Active HIV or hepatitis B or C infection. 
6. 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, laboratory tests, and according to the 
investigator’s judgment. 
 
 
4.0 
REGISTRATION PROCEDURES 
 
Patients must not start any protocol intervention prior to registration through the Siteman 
Cancer Center. 
 
The following steps must be taken before registering patients to this study: 


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1. Confirmation of patient eligibility by Washington University 
2. Registration of patient in the Siteman Cancer Center database 
3. 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. Research coordinator name and contact information (telephone number, fax 
number, and email address) 
2. 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. Currently 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. 
 


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5.0 
STUDY CALENDAR 
 
Tests & Observations 
Baseline1  
Cycle 1 
Cycle 2-4 
Follow-up 
 
 
D1 
D82 
D152 
D1 
D82 
D152 
 
History 
X 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
 
 
 
Performance status 
X 
 
 
 
 
 
 
 
Adverse event 
assessment 
X 
X 
X 
X 
X 
X 
X 
 
Follow-up 
 
 
 
 
 
 
 
H 
Laboratory Studies 
 
 
 
 
CBC with differential 
X 
A 
X 
X 
A 
X 
X 
 
Basic metabolic panel 
(Na, K, Cl, CO2, Ca, BUN, 
Creatinine, Glucose,) 
X 
B 
X 
X 
X 
X 
X 
 
AST, ALT, Alk Phos, 
total bilirubin 
X 
X 
X 
X 
X 
X 
X 
 
LDH, uric acid, 
phosphorus 
X 
B 
X 
X 
X 
X 
X 
 
Pregnancy test for 
WOCBP 
X 
 
 
 
BM biopsy /aspirate 
X 
C 
C 
 
CT or PET/CT 
X 
D 
D 
 
Lumbar puncture 
E 
 
 
 
Research Studies 
 
 
 
 
BM biopsy /aspirate 
F 
 
 
 
Peripheral blood  
 
G 
 
 
Notes: 
1 
All baseline examinations are to be performed within 14 days of the start of therapy. 
2 
± 2 days 
A 
Performed prior to and 3 (± 1) hours post-dose of BL-8040 on C1, D1 to D5.  From C2-4 prior to BL-8040 
dosing. 
B 
Performed daily on C1, D1-6 
C 
For patients with marrow disease at baseline, a bone marrow biopsy and aspiration should be performed 
after every cycle until clearance of marrow leukemic blasts (<5%) is documented.    
D 
For patients with measurable extramedullary disease at baseline, a CT scan should be performed at the end 
of Cycle 1, 2 and 4 for response assessment.  A PET/CT scan should be used to confirm any response.   
E 
For patients who have signs or symptoms of CNS involvement 
F 
Bone marrow biopsy and aspirate 5-10 ml in EDTA containing tube at baseline 
G 
Peripheral blood 30 ml in heparin containing tube on C1 D1 immediately prior to administration of BL-
8040, 3 ± 1 hour after the first dose of BL-8040, and approximately 24 hours after the first dose of BL-8040 
(prior to the second dose of BL-8040). 
H 
Assessment at 30 +/-2 days post-treatment and for relapse and/or survival every 3 months for a maximum 
of 2 years. 
 
 


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6.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to 
the schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent  
Prior to registration 
On-Study 
Medical and Surgical History 
Treatment History 
Prior to starting treatment 
Treatment Record 
Every cycle 
CBC 
C1D1 
C1D2 
C1D8 
C1D15 
C1D21 
Days 1, 8, 15, and 21 of each cycle thereafter 
Adverse Event  
Continuous 
Off Treatment  
Completion of treatment 
Follow Up  
Every 3 months for 2 years 
Response Assessment  
Every cycle and at the end of treatment 
MedWatch  
See Section 12 for reporting requirements 
Correlative Blood 
Baseline 
Cycle 1 Day 1 
Cycle 1 Day 2 
Correlative Bone Marrow 
Baseline 
30-Day Mortality 
Day 30 
Death 
Death 
 
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.  
 
 
7.0 
TREATMENT PLAN 
 
7.1 
Agent Administration 
 
Cycle 1 
BL-8040: 1.5 mg/kg subcutaneous daily from Day 1 to Day 6.  
Nelarabine: 1,500 mg/m2 intravenously over 2 hours on Days 2, 4 and 6. 
 
 


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Cycle 2-4 
BL-8040: 1.5 mg/kg subcutaneous daily from Day 1 to Day 5.  
Nelarabine: 1,500 mg/m2 intravenously over 2 hours on Days 1, 3 and 5. 
 
On days that both drugs are administered, BL-8040 should be administered 
approximately 2-4 hours prior to nelarabine.  Treatment may be repeated every 21 
days for up to 4 cycles or until disease progression, whichever occurs first.  
 
7.2 
Dose Modifications 
 
The doses of nelarabine and BL-8040 will be calculated based on actual body weight. 
Nelarabine should be discontinued for grade ≥ 2 neurological events. BL-8040 should 
be held for a peripheral blood blast count which exceeds 50,000/mcL and upon 
clinical signs of leukostasis. Skipped doses of BL-804 will not be made up.  No other 
dose modifications are permitted for either BL-8040 or nelarabine. Subsequent cycles 
of therapy should be delayed for clinically significant grade ≥ 3 nonhematologic 
toxicity until resolution to grade ≤ 2.  For subjects achieving a morphologic leukemia 
free state (<5% BM blasts, no circulating lymphoblasts), nelarabine should be delayed 
until neutrophil recovery (ANC > 1,000/mcL). If dose delay is required beyond 28 
days, the subject will be permanently discontinued from study treatment.  
 
7.3 
Response Evaluation 
 
For patients with marrow disease at baseline, a bone marrow biopsy and aspiration 
should be performed after every cycle until clearance of marrow leukemic blasts 
(<5%) is documented.    
 
For patients with measurable extramedullary disease at baseline, a CT scan should be 
performed at the end of Cycle 1, 2 and 4 for response assessment.  A PET/CT scan 
should be performed to confirm any response.   
 
7.4 
Supportive Care 
 
Hydroxyurea 
and/or 
leukapheresis 
is 
permitted 
to 
prevent 
or 
treat 
hyperleukocytosis. Concurrent intrathecal chemotherapy is permitted during 
treatment either as prophylaxis or treatment for CNS involvement of leukemia.  
 
In case of TLS, subjects should be hydrated vigorously (urine output and fluid input 
should be monitored).  Allopurinol, rasburicase, or any other treatment according to 
institutional practice should be considered. 
 
Premedication and/or treatment with steroids and/or antihistamines is 
recommended in order to reduce the systemic reactions with BL-8040.  Analgesics or 
local anesthetics (e.g. EMLA®) may be used for injection site pain management. 
 


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Supportive care including the use of antiemetics, antibiotic prophylaxis, and colony 
stimulating factors will be at the discretion of the treating physician and guided by 
institutional practices.  
 
7.5 
Women of Childbearing Potential 
 
Women of childbearing potential should remain on birth control for 30 days after the 
last day of treatment, and men with partners who are of childbearing potential should 
use birth control for 90 days.  Birth control method must be considered highly 
effective (hormonal or barrier method of birth control, abstinence). 
 
Non-childbearing potential is defined as: 
• ≥ 45 years of age and has not had menses for > 2 years 
• Amenorrheic for > 2 years without a hysterectomy and oophorectomy and a 
FSH value in the postmenopausal range upon pretrial (screening) evaluation 
• Post-hysterectomy, 
oophorectomy, 
or 
tubal 
ligation. 
Documented 
hysterectomy or oophorectomy must be confirmed with medical records of 
the actual procedure or confirmed by an ultrasound.  Tubal ligation must be 
confirmed with medical records of the actual procedure. 
 
7.6 
Duration of Treatment 
 
If the constraints of this protocol are considered to be detrimental to the patient’s 
health and/or the patient no longer wishes to continue protocol therapy, the protocol 
therapy must be discontinued and the reason(s) for discontinuation documented. All 
decisions regarding future therapy for both responding and refractory patients will 
be at the discretion of the treating physician.  
 
Patients will be considered to have completed treatment upon completion of 4 cycles, 
disease progression, or administration of additional antileukemic therapy including 
alloHCT.  All decisions regarding future therapy for both responding and refractory 
patients will be at the discretion of the treating physician.   
 
7.7 
Follow-up 
 
Patients removed from treatment for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event. Patients will be followed for a 
minimum of 30 days post-treatment for adverse events. Patients achieving a CR or 
CRi will be followed for disease relapse and/or death every 3 months following 
completion of treatment for a maximum of 2 years.  
 
7.8 
Removal from Study 
 
Patients may be removed from the study at the discretion of the treating physician 
and / or Principal Investigator for any of the following reasons: 


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Page 16 of 33 
• Death 
• Adverse event(s) that in the opinion of the investigator may cause severe or 
permanent harm or which rule out continuation of study drug 
• Changes in the patient’s condition that render him/her unacceptable for further 
treatment in the opinion of the investigator 
• Suspected pregnancy 
• Patient or investigator choice  
• Major violation of the study protocol 
• Lost to follow-up 
• Study termination 
 
 
8.0 
RESPONSE EVALUATION 
 
The following criteria will be used to assess the response to treatment. 
 
Complete Remission (CR): A CR requires the following: an absolute neutrophil count (segs 
and bands) > 1,000/mcL, no circulating lymphoblasts, platelets ≥ 100,000/mcL; and < 5% 
marrow leukemia blast cells with complete disappearance of all measurable disease as 
confirmed by physical examination, CT scan and/or FDG-PET (Deauville criteria score of 1, 
2, or 3). 
 
Morphologic complete remission with incomplete blood count recovery (CRi): Defined 
as CR with the exception of neutropenia < 1,000/mcL or thrombocytopenia <100,000/mcL.  
 
Partial Remission (PR): A PR requires all of the CR criteria except that marrow may still 
contain 5-25% leukemia blast cells. An absolute neutrophil count (segs and bands) ≥ 
1000/mcL, no circulating blasts, and platelets > 100,000/mcL are requires as for a CR. For 
patients with measurable disease, a reduction of 50% or more in the sum of the products of 
the perpendicular diameters of all measurable lesions compared with pretreatment 
measurements and with no new or enlarging lesions.  
 
Refractory Disease: Failure to achieve a CR/CRi with persistence of leukemia cells after 
treatment. 
 
Relapsed Disease: The reappearance of unequivocal leukemia blasts cells in the blood or 
the bone marrow (>5%) or in any other extramedullary site after a CR/CRi. 
 
Time to neutrophil recovery: Defined as the date of the first dose of study drug to the date 
that the absolute neutrophil count is >1,000/mcL. 
 
Time to platelet recovery:  Defined as the date of the first dose of study drug to the date 
that the platelet count is >100,000/mcL in the absence of platelet transfusions. 
 
Overall survival: Defined as the date of first dose of study drug to the date of death from 


Protocol Version: 01/17/23, Amendment 2 
 
Page 17 of 33 
any cause. 
 
Event-free survival: Defined as the interval from the date of first dose of study drug to date 
of treatment failure, recurrence, or death due to any cause. 
 
Duration of remission: Defined as the interval from the date CR/CRi is documented to the 
date of recurrence. 
 
Relapse-free survival: For patients achieving a complete remission, defined as the interval 
from the date of first documentation of CR/CRi to the date of recurrence or death due to any 
cause.  
 
 
9.0 
PHARMACEUTICAL INFORMATION 
 
9.1 
BL-8040 
 
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 0.54-
5.2 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.  
 
Availability 
BL-8040 drug product is formulated as a sterile and non-pyrogenic lyophilized 
powder containing 73mg/vial BL-8040 (free base, on dry basis). Reconstitution 
instructions will be provided separately in a pharmacy manual. Lyophilized BL-8040 
is filled and packed in clear Type I glass vials (DIN 6R) with 20 mm rubber stoppers 
and sealed with 20 mm aluminum caps. BL-8040 can be injected within 24 hours after 
reconstitution if stored in the refrigerator, 5°C ± 3°C (36 to 46°F). 
 
Storage & Stability 
Vials of BL-8040 for injection should be stored in the refrigerator (5°C ±3°C) in their 
original package, protected from light. BL-8040 is to be injected within six hours after 
reconstitution. 
 
Administration 
BL-8040 will be administered by slow SC injection. Injection sites should be rotated 
daily. 
 
Toxicity 
Preclinical Studies 
The nonclinical development of BL-8040 has encompassed a large number of 


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pharmacodynamic, pharmacokinetic (PK), safety pharmacology, and single and 
repeated dose toxicity studies.  
 
BL-8040 exhibits CXCR4-dependent selective cytotoxicity toward malignant cells 
both in vivo and in vitro and induces apoptotic cell death in cancer cells [20, 23-25][3–
6]. BL-8040 leads to phospharidylserine externalization, decreased mitochondrial 
membrane potential, caspase activation, subsequent sub-G1 arrest and DNA double-
stranded breaks in leukemic and Multiple Myeloma cells [20]. These effects were 
shown to be specific; BL-8040 did not affect the viability of human keratinocytes and 
normal human hematopoietic cells [20]. This property of direct apoptotic effects on 
top of the mobilization capacity, distinguishes BL-8040 from other CXCR4 antagonists 
such as Mozobil/Plerixafor[20]. In addition, administration of BL-8040 induces the 
mobilization of NK cells, T cells and B-cells from the BM and lymph nodes into the 
periphery. Using a syngeneic cancer model in mice it was demonstrated that BL-8040 
may eliminate the immunological barrier and allow the accumulation of immune cells 
within the tumor microenvironment (unpublished data). 
 
BL-8040 exhibited very high binding to human plasma proteins (99.2%) and high 
binding to the proteins in rat and dog plasma (94.9-96.9%) in the range of tested 
concentrations.  
 
The subcutaneous injection (SC) of BL-8040 was tested in GLP toxicology studies in 
dogs, and Rats with the main identified AE’s being a transient and local erythema at 
the injection site and peripheral edema. These reactions were noticed from a few 
minutes up to approximately 2 hours following the injection. There were no 
significant changes in terms of histopathology, Electrocardiogram (ECG), 
ophthalmological findings, blood chemistry or hematological variables. No target 
organ for toxicity could be identified.  
 
Clinical Studies 
 
BL-8040 has demonstrated safety and initial clinical efficacy in several Phase I and II 
studies: 
• A Phase IIa, non-randomized, open-label, single dose, dose escalation, safety 
study of BL-8040 in multiple myeloma subjects on top of G-CSF has been 
completed (NCT01010880, study BKTSC001).  
• A clinical trial for the treatment of adult relapsed/refractory Acute Myeloid 
Leukemia (AML) with a combination of BL-8040 and cytarabine (Ara-C) is 
currently ongoing (NCT01838395; BL-8040.01). 
• A 
Phase 
I, 
Two 
Part 
Study 
Exploring 
the 
Safety, 
Tolerability, 
Pharmacodynamic and Pharmacokinetic Effect of Ascending Doses of BL-8040 
in Healthy Subjects (NCT02073019, study BL-8040.02). 
• An Investigator Initiated Phase II study termed the “BLAST study” (Study No. 
UKH062014) is ongoing in Germany. This is a double-blind placebo controlled 
study that will assess the efficacy of BL-8040 as an add-on therapy to Ara-C for 


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consolidation therapy in AML patients in first complete remission.  
 
In general, the most common AEs seen in all studies conducted with BL-8040 are 
injection site reactions, including: pain, erythema, pruritus and inflammation, and 
systemic reactions including among others: hives, pruritus (not at the injection site), 
flushing, chills, rash and urticaria. Other isolated AEs reported among others were 
paresthesia, musculoskeletal pain, headache, constipation, tingling, and elevation of 
liver function tests. 
 
For details concerning these studies please refer to the BL-8040 IB. 
 
9.2 
Nelarabine 
 
Mechanism of action: 
Nelarabine 
is 
a 
pro-drug 
of 
the 
deoxyguanosine 
analogue 
9-β-D-
arabinofuranosylguanine (ara-G), a nucleoside metabolic inhibitor. Nelarabine is 
demethylated by adenosine deaminase (ADA) to ara-G, mono-phosphorylated by 
deoxyguanosine kinase and deoxycytidine kinase, and subsequently converted to the 
active 5'-triphosphate, ara-GTP. Accumulation of ara-GTP in leukemic blasts allows 
for incorporation into deoxyribonucleic acid (DNA), leading to inhibition of DNA 
synthesis and cell death. Other mechanisms may contribute to the cytotoxic and 
systemic toxicity of nelarabine. 
 
Availability 
The commercially available supply of nelarabine will be used for this study.  
Nelararbine is supplied as a clear, colorless, sterile solution in glass vials. Each vial 
contains 250 mg of nelarabine (5 mg nelarabine per mL) and the inactive ingredient 
sodium chloride (4.5 mg per mL) in 50 mL Water for Injection, USP.  
 
Preparation, Storage, Stability and Administration 
Please refer to the FDA-approved package insert for product information, extensive 
preparation instructions, and a comprehensive list of adverse events. 
 
Toxicity 
Likely >10%: Peripheral edema, Fatigue, fever, somnolence, dizziness, headache, 
hypoesthesia, Petechiae, Hypokalemia, Nausea, diarrhea, vomiting, constipation. 
Anemia, 
neutropenia, 
thrombocytopenia, 
leukopenia, 
neutropenic 
fever. 
Transaminases increased. Peripheral neuropathy, weakness, paresthesia, myalgia, 
Cough, dyspnea. 
 
Less likely 1% to 10%: Hypotension, sinus tachycardia, chest pain, Ataxia, confusion, 
insomnia, depressed level of consciousness, depression, seizure, motor dysfunction, 
amnesia, balance disorder, sensory loss, aphasia, attention disturbance, cerebral 
hemorrhage, coma, encephalopathy, hemiparesis, intracranial hemorrhage, lethargy, 
leukoencephalopathy, loss of consciousness, mental impairment, nerve paralysis, 


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neuropathic pain, nerve palsy, paralysis, sciatica, sensory disturbance, speech 
disorder. Hypocalcemia, hyper-/hypoglycemia, hypomagnesemia, stomatitis, taste 
perversion. Albumin decreased, bilirubin increased, AST increased. Arthralgia, back 
pain, muscle weakness, rigors, limb pain. Blurred vision, nystagmus, Creatinine 
increased. Pleural effusion, pneumonia, sinusitis, Infection. 
 
<1% (Limited to important or life-threatening): Craniospinal demyelination, 
neuropathy (peripheral) (similar to Guillain-Barré syndrome), opportunistic 
infection, pneumothorax, progressive multifocal leukoencephalopathy (PML), 
respiratory arrest, rhabdomyolysis, tumor lysis syndrome. 
 
 
10.0 
CORRELATIVE STUDIES 
 
A bone marrow biopsy and aspirate will be obtained at baseline for correlative studies. 
Approximately 1 cm of the core biopsy should be placed in saline.  Approximately 5 mL of 
aspirate should be collected in a heparin containing tube.   
 
In addition, 30 ml of peripheral blood will be collected in a heparin containing tube on cycle 
1, day 1 immediately before and approximately 3 hours ± 1 hour after dosing of BL-8040.   
On day 2 of cycle 1, and additional 30 ml of peripheral blood will be collected in a heparin 
containing tube prior to the administration of BL-8040 or nelarabine. A separate 1 mL 
sample collected in an EDTA containing tube at the same time points will be used for a 
complete blood count. 
 
Samples should be maintained at room temperature and delivered or sent by overnight mail 
to the laboratory of Daniel C. Link located at Room 613 Southwest Tower of the Washington 
University Medical Center. 
 
Shipping address: 
Washington University 
Division of Oncology 
Attn: Link Lab, SWT 7th fl 
4940 Parkview Place 
St. Louis, Mo 63110 
(314) 362-8771 
 
Preclinical studies predict that treatment with a CXCR4 antagonist will induce T-ALL 
apoptosis through mobilization from perivascular niches in the bone marrow and through 
decreased c-Myc expression. To test these predictions, bone marrow and peripheral blood 
will be obtained from patients at baseline.  Peripheral blood will also be obtained 3 ± 1 hour 
after the first dose of BL-8040 and approximately 24 hours after the first dose of BL-8040 
(prior to the second dose of BL-8040). The following assays will be performed on these 
samples.  
 


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1. Quantification of T-ALL cell number in blood and bone marrow at each time to 
assess T-ALL mobilization.    
2. Assessment of T-ALL CXCR4 cell surface expression by flow cytometry using 
monoclonal antibodies that are (clone 12G5) and are not (1D9) sensitive to BL-
8040 binding. 
3. Assessment of T-ALL migration in response to CXCL12 using a transwell assay. 
4. Assessment of T-ALL apoptosis in the blood before and after BL-8040 
administration using   flow cytometry to measure cell activated caspase 3 
expression.  
5. Assessment of T-ALL cell cycle status in the blood using flow cytometry to assess 
Ki67 and DAPI staining.   
6. Assessment of T-ALL c-Myc mRNA and c-Myc target gene mRNA expression using 
real time RT-PCR of RNA obtained from sorted T- ALL cells.    
7. Assessment of CXCL12 and other niche factor expression in the bone marrow at 
baseline. 
 
Specimens will also be retained for future research, including possible future genetic 
research.  Blood, bone marrow, and data will be retained indefinitely in a coded fashion in 
Dr. Link’s lab.  In order for these specimens and this data to be accessed in the future for 
additional research, the study PI must provide formal permission after reviewing a written 
request, and other appropriate approvals must be obtained by the investigator. 
 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Study Design 
 
This is an open label pilot study consisting of up to 20 patients. Demographic and 
clinical characteristics will be summarized using mean ± SD or median, IQR and 
extreme values for continuous values. Frequencies, percentages and confidence 
intervals will be reported for counts and proportions. Adverse events will be graded 
using NCI CTCAE v4.03 and summarized by patient, grade, frequency and time of 
occurrence. Kaplan-Meier product limit estimators will be used to estimate median 
and time-specific disease-free and overall survival. Cox proportional hazards 
regression will be used to describe time to neutrophil and platelet engraftment with 
early death treated as a competing risk. Additional Cox models may be used for time 
to event modeling to explore the effect of covariate adjustment. Pharmacodynamic 
data will be analyzed using descriptive statistics as described above, and plots. 
Differences between baseline and BL-8040 treated marrow will analyzed for 
significance using paired T-tests or Wilcoxon signed rank tests, as appropriate. 
 
Futility: No inferential procedures are planned, so futility cannot be defined as loss of 
power or inability of reject null hypotheses. With respect to safety, futility will be 


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addressed by the monitoring rule described below.  With respect to tolerability, 
futility will be defined as the loss of no more than 4 patients, or 20% (6%, 44%) of 
the planned sample size, due to delayed hematologic recovery as defined in section 7 
or death occurring within the first 30 days of treatment or.   
 
11.2 
Monitoring Rule for Excess Mortality 
 
The estimated 30-day mortality in a population of patients with relapsed or 
refractory ALL is approximately 10%.  Toxicity will be reviewed on a continuous 
basis.   
 
Thirty day mortality will be monitored using a continuous toxicity monitoring rule: 
 
Suspend the study for 
review of the # deaths on or 
before 30 days due to 
toxicity is greater than: 
In the following number 
of enrolled patients: 
1 
6 
2 
14 
3 
20 
 
The probability is low (.055) of inappropriate early suspension if the true rate is 5% 
and remains low (.27) if the true rate is 11%. The probability is high (.68) of correct 
early suspension if the true rate is 20%. 
 
 
12.0 
REGULATORY 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 12.2. 
 
The FDA requires that all serious and unexpected adverse events be reported as outlined in 
Section 12.6.  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 events described in Section 12.7 be reported as outlined in that 
section. 
 
 


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Page 23 of 33 
 
12.1 
Definitions 
 
12.1.1 Adverse Events (AEs) 
 
Definition: any unfavorable medical occurrence in a human subject including 
any abnormal sign, symptom, or disease. 
 
Grading: the descriptions and grading scales found in the revised NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for all toxicity reporting.  
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions 
for the terms listed that should be used are those provided by the Department 
of Health and Human Services’ Office for Human Research Protections (OHRP) 
available at http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
12.1.2 Serious Adverse Event (SAE) 
 
Definition:  any adverse drug experience occurring at any dose that results in 
any of the following outcomes: 
o Death 
o A life-threatening adverse drug experience 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions) 
o A congenital anomaly/birth defect 
o Any other experience which, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
All unexpected SAEs must be reported to the FDA. 
 
12.1.3 Unexpected Adverse Experience 
 
Definition: any adverse drug experience, the specificity or severity of which 
is not consistent with the current investigator brochure (or risk information, 
if an IB is not required or available). 
 
Events that are both serious AND unexpected must be reported to the FDA.  
 
12.1.4 Life-Threatening Adverse Experience  
 
Definition: any adverse drug experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e., it 


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does not include a reaction that, had it occurred in a more severe form, might 
have caused death. 
 
Life-threatening adverse experiences must be reported to the FDA. 
 
12.1.5 Unanticipated Problems 
 
Definition: 
• Unexpected (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; 
• 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. 
 
12.1.6 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, 
or 
determinations of the IRB. 
 
12.1.7 Serious Noncompliance 
 
Definition: noncompliance that materially increases risks, that results in 
substantial harm to subjects or others, or that materially compromises the 
rights or welfare of participants. 
 
12.1.8 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. 
 
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 


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Page 25 of 33 
University IRB approval is not required for protocol exceptions occurring at 
secondary sites. 
 
12.2 
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 BJH or 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. 
 
12.3 
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. 
 
12.4 
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. 
 


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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. 
 
12.5 
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. 
 
12.6 
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 follows: 
 
• Report any unexpected fatal or life-threatening adverse experiences (Section 
12.1.4) 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 12.1.2), 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. 


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Page 27 of 33 
 
12.7 
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. Anna Emde 
Mobile +972 54 2802352 
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), 
• 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). 
 
12.8 
Timeframe for Reporting Required Events 
 
Adverse events will be collected from first dose of study treatment through 30 days 
after the last study treatment.  
 
 


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12.9 
Exceptions in the Reporting of AE and SAE 
 
According to EU and FDA detailed guidance on the collection, verification and 
presentation of adverse reaction reports arising from clinical trials on medicinal 
products for human use, regarding clinical trials in high morbidity or mortality 
diseases, it is acceptable to define some exceptions in the immediate reporting of 
specific SAEs. Refer to EU guidance ENTR/CT3, 5.1.9 and FDA guidance “Safety 
Reporting Requirements for INDs and BA/BE Studies” (Dec 2012). 
 
These AEs will be thoroughly handled and followed up through the CRF (AE form) 
and will be reviewed by the medical safety officer and could be re-qualified for 
reporting if necessary. 
 
Each event must be carefully analyzed by the Investigator’s or designee to decide 
whether the SAE could be considered as an exception or if it must be immediately 
reported. 
 
Exceptions for AE/SAE reporting are: 
All myelosuppression related adverse events: anemia, neutropenia, lymphopenia, 
leukopenia, leukocytosis. 
 
Grade 1-2 fatigue, weakness, nausea, alopecia, bone, joint or muscle pain, electrolyte 
abnormalities 
(sodium, 
potassium, 
carbon 
dioxide, 
calcium, 
magnesium, 
phosphorus) and glucose. 
 
 
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) will be specifically convened 
for this trial to review toxicity data at least once every 6 months following activation of the 
first secondary site.  A DSMC will consist of no fewer than 3 members including 2 clinical 
investigators and a biostatistician.  Like investigators, DSMC members are subject to the 
Washington University School of Medicine policies regarding standards of conduct. 
Individuals invited to serve on the DSMC will disclose any potential conflicts of interest to 
the trial principal investigator and/or appropriate university officials, in accordance with 
institution policies. Potential conflicts that develop during a trial or a member’s tenure on a 
DSMC must also be disclosed.  
 
The DSM 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 Quality Assurance and 
Safety Monitoring Committee (QASMC).  This report will include: 
 
• HRPO protocol number, protocol title, Principal Investigator name, data coordinator 


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Page 29 of 33 
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 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 12.0). 
 
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 
 
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 


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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 
 
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 
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. 
 
1. 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. 
2. 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. 
3. Documentation of FWA, signed FDA Form 1572 (if applicable), and the CVs of all 
participating investigators. 


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4. 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 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. 
 


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16.0 
REFERENCES 
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4. 
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18. 
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