Blinatumomab Bridging Therapy in High-Risk B-Acute Lymphoblastic Leukemia: A Phase 2 Study
Phase: PHASE2
Conditions: B-cell Acute Lymphoblastic Leukemia, Refractory B Acute Lymphoblastic Leukemia, Relapsed B-cell Acute Lymphoblastic Leukemia
Sponsor: Michael Burke

 
 
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Blinatumomab Bridging Therapy (BBT) 
Version No. 1.3 
 
 
 
Blinatumomab Bridging Therapy in High-Risk B-Acute Lymphoblastic 
Leukemia: A Phase 2 Study 
 
 
Blinatumomab Bridging Therapy (BBT) 
 
Version No. 1.4 
 
Version Date:  06/24/2021 
 
 
 
 
STUDY CHAIR 
 
Michael J. Burke, MD 
Associate Professor 
Medical College of Wisconsin 
Children’s Wisconsin 
Department of Pediatrics 
Division of Hematology/Oncology/BMT 
8701 Watertown Plank Road 
MFRC Suite 3018 
Milwaukee, WI 53226 
Phone:  414-955-4108 
Fax: 
 414-955-6543 
Email: mmburke@mcw.edu  
 
 
 
 
 
 
 
 
 

 
 
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STUDY COMMITTEE CONTACT INFORMATION 
 
STUDY CHAIRS 
Study Co-Chair 
Rachel Phelan, MD 
Assistant Professor 
Medical College of Wisconsin 
Children’s Wisconsin 
Department of Pediatrics 
Division of Hematology/Oncology/BMT  
8701 Watertown Plank Road 
MFRC Suite 3018 
Milwaukee, WI 53226 
Phone:  414-955-4108 
Fax: 
 414-955-6543 
Email: rphelan@mcw.edu    
 
Emergency Contact 
Michael Burke, MD 
414-907-0521 
 
Children’s Hospital Switchboard:   
414-266-2000  
Ask for Pediatric Oncologist On-Call 
 
 
 
STUDY COMMITTEE MEMBERS OR SUB INVESTIGATORS 
Richard Tower, MD 
Associate Professor 
Medical College of Wisconsin 
Children’s Wisconsin 
Department of Pediatrics 
Division of Hematology/Oncology/BMT  
8701 Watertown Plank Road 
MFRC Suite 3018 
Milwaukee, WI 53226 
Phone:  414-955-4108 
Fax: 
 414-955-6543 
Email: rtower@mcw.edu  
Christian Capitini, MD 
Assistant Professor  
University of Wisconsin 
Department of Pediatrics 
Division of Hematology, Oncology and Bone 
Marrow Transplant 
1111 Highland Ave 
WIMR 4137 
Madison, WI 53705 
Phone: 608-262-2415 
Fax:     608-265-9721 
Email: ccapitini@pediatrics.wisc.edu 
Paul Harker-Murray, MD, PhD 
Associate Professor 
Medical College of Wisconsin 
Children’s Wisconsin 
Department of Pediatrics 
Division of Hematology/Oncology/BMT  
8701 Watertown Plank Road 
MFRC Suite 3018 
Milwaukee, WI 53226 
Phone:  414-955-4108 
Fax: 
 414-955-6543 
Email: pharker@mcw.edu   
 

 
 
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STUDY COMMITTEE MEMBERS OR SUB INVESTIGATORS 
Cindy Schwartz, MD 
Professor 
Medical College of Wisconsin 
Children’s Wisconsin 
Department of Pediatrics 
Division of Hematology/Oncology/BMT  
8701 Watertown Plank Road 
MFRC Suite 3018 
Milwaukee, WI 53226 
Phone:  414-955-4108 
Fax: 
 414-955-6543 
Email: cschwartz@mcw.edu  
  
Pippa Simpson, PhD 
Director Quantitative Health Sciences and CRI 
Biostatistics Core 
Professor, Pediatrics and Surgery 
TBRC-CRI Room 3440 
8701 Watertown Plank Road 
Milwaukee, WI 53226 
Phone: 414 955 4521  
Fax: 414 955 6331 
Email: psimpson@mcw.edu  
 
Michael Burke, MD: Sponsor 
AMGEN Pharmaceuticals: Funding Sponsor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Blinatumomab Bridging Therapy (BBT) 
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TABLE OF CONTENTS 
 
Section 
Page 
STUDY COMMITTEE CONTACT INFORMATION 
2 
TABLE OF CONTENTS 
4 
PROTOCOL REVISION HISTORY 
8 
ABSTRACT 
9 
EXPERIMENTAL DESIGN SCHEMA 
10 
STUDY CALENDAR 
11 
PROTOCOL SUMMARY 
12 
LIST OF ABBREVIATIONS 
15 
1.0 
BACKGROUND  
17 
 
1.1 
Overview 
17 
 
1.2 
Rationale for Studying Blinatumomab in Relapse B-ALL 
17 
2.0 
HYPOTHESIS AND OBJECTIVES 
19 
 
2.1 
Hypothesis 
19 
 
2.2 
Primary Objectives 
19 
 
2.3 
Secondary Objectives 
19 
3.0 
STUDY DESIGN 
19 
 
3.1 
General Description 
19 
 
3.2 
Number of Subjects 
20 
 
3.3 
Primary Completion 
20 
 
3.4 
Study Completion 
20 
4.0 
PATIENT SELECTION 
20 
 
4.1 
Eligibility Criteria 
20 
 
4.2 
Inclusion Criteria 
20 
 
4.3 
Exclusion Criteria 
22 
5.0 
REGISTRATION PROCEDURES 
22 
 
5.1 
Study Entry Procedures 
22 
 
 
5.1.1 
Required Preregistration Screening Tests and Procedures 
23 
 
 
5.1.2 
Registration Process 
23 
 
 
5.1.3 
Pretreatment Period 
23 
 
5.2 
Study Procedures During Treatment 
24 
 
 
5.2.1 
Study Procedures, Cycle 1, Day 1 
24 
 
5.3 
End of Treatment 
24 
 
 
5.3.1 
End of Treatment Procedures 
24 
 
5.4 
Post-Treatment 
25 
 
 
5.4.1 
Follow-Up Visits 
25 
 
5.5 
Study Withdrawal Procedures 
25 
 
 
5.5.1 
Duration of Therapy 
25 
 
 
5.5.2 
Subject-Initiated Withdrawal 
25 
 
 
5.5.3 
Investigator-Initiated Withdrawal 
25 
 
 
5.5.4 
Sponsor-Initiated Withdrawal 
26 
 
 
5.5.5 
Withdrawal Documentation Procedure 
26 
 
 
5.5.6 
Off study Criteria 
26 
6.0 
TREATMENT PLAN 
26 
 
6.1 
Drug Administration 
26 
 
6.2 
Sample Collection and Processing for Minimal Residual Disease 
27 

 
 
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6.3 
Drug Information (Blinatumomab) 
28 
 
 
6.3.1 
Source and Pharmacology 
28 
 
 
6.3.2 
Pregnancy and Lactation 
29 
 
 
6.3.3 
Formulation and Stability  
29 
 
 
6.3.4 
IV Solution Stabilizer for Blinatumomab 
29 
 
 
6.3.5 
Guidelines for Administration 
29 
 
 
6.3.6 
IV Infusion and Infusion Set Details 
29 
 
 
6.3.7 
Infusion Pump Requirements 
29 
 
 
6.3.8 
Supplier 
30 
 
 
6.3.9 
Obtaining the Agent  
30 
 
6.4 
Supportive Care Guidelines 
31 
 
 
6.4.1 
Venous Access 
31 
 
 
6.4.2 
Antimicrobial Prophylaxis 
31 
 
6.5 
Follow-Up Period 
31 
7.0 
DOSING DELAYS/DOSE MODIFICATIONS 
31 
 
Table 1: Dose Modifications for Adverse Events (AE) Occurring During Blinatumomab 
Administration 
32 
 
7.1 
Management of Cytokine Release Syndrome (CRS), Neurologic Toxicity and 
Acute Graft Versus Host Disease During or Following Blinatumomab 
36 
 
 
7.1.1 
Cytokine Release Syndrome (CRS) 
36 
 
 
7.1.2 
Neurologic Toxicity 
36 
 
 
7.1.3 
Acute Graft Versus Host Disease (aGVHD) 
36 
8.0 
ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS 
37 
 
8.1 
Definitions 
37 
 
 
8.1.1 
Adverse Event (AE)  
37 
 
 
8.1.2 
Attribution 
37 
 
 
 
8.1.2.1 Relationship Assessment:  In-Depth Definitions 
37 
 
 
8.1.3 
Expectedness 
38 
 
 
8.1.4 
Expedited Reporting 
38 
 
 
8.1.5 
Onset and Resolution of Adverse Events 
38 
 
 
8.1.6 
Protocol Therapy 
39 
 
 
8.1.7 
Serious Adverse Event (SAE) 
39 
 
 
8.1.8 
Routine Reporting 
39 
 
8.2 
AE and SAE Reporting on Protocol 
40 
 
 
8.2.1 
Adverse Event Grading 
40 
 
8.3 
Known AEs List 
40 
 
8.4 
What and When to Report 
42 
 
8.5 
Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) 
44 
 
8.6 
Time Period and Grade of AE Capture 
44 
 
8.7 
Monitoring and Recording and Adverse Event 
44 
 
 
8.7.1 
Reporting Source 
44 
 
 
8.7.2 
Prior to the Trail 
44 
 
 
8.7.3 
Pretreatment Events Following Signed Informed Consent 
44 
 
 
8.7.4 
Treatment Events 
44 
 
 
8.7.5 
Not Serious AEs 
44 
 
8.8 
Follow-Up of Adverse Events 
44 
 
8.9 
Subject Complaints 
44 
 
8.10 
Routine Reporting Procedures for AEs 
45 

 
 
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9.0 
REPORTING AND DOCUMENTS RESULTS (MEASUREMENT OF EFFECT) 
46 
 
9.1 
Evaluation of Efficacy (or Activity) 
46 
 
 
9.1.1 
Definitions 
46 
 
9.2 
Bone Marrow Response Criteria 
46 
 
9.3 
Evaluation of Safety 
47 
10.0 STATISTICAL CONSIDERATIONS 
47 
 
10.1 
Study Endpoints/Efficacy Variables 
47 
 
 
10.1.1 
Primary Efficacy Variables 
47 
 
 
10.1.2 
Secondary Efficacy Variables 
48 
 
10.2 
Study Design 
48 
 
10.3 
Determination of Sample Size and Accrual Rate 
48 
 
 
10.3.1 
Sample Size and Power Estimate 
48 
 
 
10.3.2 
Accrual Estimates 
48 
 
10.4 
Interim Analyses and Stopping Rules 
48 
 
10.5 
Analyses Plans 
49 
 
10.6 
Analysis Population 
49 
 
10.7 
Primary Analysis (or Analysis of Primary Endpoints) 
50 
 
 
10.7.1 
Endpoints to be Collected 
50 
 
 
10.7.2 
Primary Endpoint 
50 
 
 
10.7.3 
Secondary Analysis (or Analysis of Secondary Endpoints) 
50 
 
 
 
10.7.3.1  Secondary Endpoints 
50 
 
 
10.7.4 
Other Analyses/Assessments 
50 
 
 
10.7.5 
Evaluation of Safety 
50 
 
 
10.7.6 
Adverse Events of Special Interest (Immediately Reportable to 
Sponsor) 
51 
11.0 DATA AND SAFETY MONITORING PLAN (DSMP) 
51 
 
11.1 
Data and Safety Management Overview 
51 
 
 
11.1.1 
Study Team 
51 
 
 
11.1.2 
Quality Assurance 
51 
 
 
11.1.3 
Clinical Trials Office 
52 
 
 
11.1.4 
DSMC 
52 
 
11.2 
Monitoring 
52 
12.0 REGULATORY COMPLIANCE, ETHICS, AND STUDY MANAGEMENT 
53 
 
12.1 
Ethical Standard 
53 
 
12.2 
Regulatory Compliance 
53 
 
12.3 
Pre-Study Documentation 
53 
 
12.4 
Institutional Review Board 
54 
 
12.5 
Informed Consent Process 
54 
 
12.6 
Subject Confidentiality and Access to Source Documents/Data 
55 
 
12.7 
Protection of Human Subjects 
55 
 
 
12.7.1 
Protection from Unnecessary Harm 
55 
 
 
12.7.2 
Protection of Privacy 
55 
 
12.8 
Changes in the Protocol 
55 
 
12.9 
Investigator Compliance 
56 
13.0 DATA HANDLING AND RECORD KEEPING 
57 
 
13.1 
Overview 
57 
 
13.2 
Data Management Responsibilities 
57 
 
 
13.2.1 
Principal Investigator 
57 

 
 
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13.2.2 
Research Coordinator 
57 
 
 
13.2.3 
Research Nurse/Medical Staff 
57 
 
 
13.2.4 
Biostatistician 
57 
 
13.3 
Source Documents 
58 
 
13.4 
Case Report Forms 
59 
 
13.5 
Study Record Retention 
59 
REFERENCES 
60 
Appendix 1 Performance Status Criteria 
62 
Appendix 2 Preparation of Blinatumomab 
63 
 
 

 
 
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PROTOCOL REVISION HISTORY 
 
 
Version 
No. 
Revision 
Date 
Summary of Changes 
Consent Revised 
Yes/No 
1.4 
06/14/2021 
PI Requested changes as follows: 
• 
Removal of Dr. Mario Otto from the protocol 
• 
Addition of TKI use for Ph+ and Ph-like B-
ALL to eligibility criteria 
• 
Addition of CMV/EBV serologies to screening 
procedures 
Yes 
• 
Added 
viral 
serologies 
to 
screening 
procedures 
1.3 
03/01/2021 
PI Requested changes as follows: 
• 
Physician visits changed to weekly in study 
calendar and Section 5.2.1 
• 
Added additional cycle of blinatumomab for 
MRD negative subjects that have issues with 
timing of donor collection on pages 
• 
Added note that MRD by HTS does not need to 
be completed within the 14 day window in 
section 5.1.3 
• 
Follow up visits to revised as “weekly in 
Section 5.4.1 
• 
Off study criteria added in Section 5.6.6 
• 
Added option of using local lab for MRD by 
flow since this can be done at CW lab  
• 
Various administrative changes 
Yes 
• 
Physician visits 
revised 
to 
weekly 
• 
Administrative 
edits 
1.2 
01/27/2021 
Added NGS testing that identifies BOTH B and T 
cell proteins. Updated under study calendar, section 
5.1.3, section 5.3.1 and section 6.2. 
No 
1.1 
10/26/2020 
FDA Requested changes as follows: 
• 
Section 6 revised to add minimal organ 
functions  
• 
Section 6.3.5 revised to add a statement 
referring to Appendix 2 which refers to the 
current USPI for volume calculations 
• 
Risk of Serious Adverse Reactions in Pediatric 
Patients due to Benzyl Alcohol Preservative 
was added to Section 6.3.7 
• 
Blinatumomab AE List in Section 8.3 was 
revised as per the risks provided by Amgen 
• 
Appendix 2 revised to add “do not shake” to #3 
discussing adding IV solution stabilizer  
• 
Appendix 2 revised to add a statement for 
Patients Weighing Under 22 kg 
• 
Appendix 2 revised to remove all volume 
calculation tables and refer to the current USPI 
for preparation 
Local Changes as follows: 
Removal of Lauren Pommert from list of Sub-
Investigators 
Yes 
• 
Added “Do not 
drive, operate 
heavy 
machinery, etc. 
under risks 
section 
• 
Added CRS, 
Neurological 
problems, and 
Infections as 
separate bullets 
to “Health 
Risks or 
Problems”  
• 
Blina AE list 
was revised 
• 
Added 
drug 
monograph for 
dexamethasone 
 

 
 
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Blinatumomab Bridging Therapy (BBT) 
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ABSTRACT 
 
 
Children, adolescents and young adults with relapse or refractory B-acute lymphoblastic leukemia (B-
ALL) often have dismal outcomes with chemotherapy alone. Despite allogeneic hematopoietic cell 
transplantation (HCT) providing a cure for some of these patients, relapse after HCT continues to be the 
most common reason of treatment failure. Identifying novel ways to improve post-HCT outcomes in these 
high-risk patients has been challenging and currently no standard approach has been found. We are testing 
the ability of a biologically active therapy in blinatumomab, an anti-CD19/CD3 bispecific T-cell engager, 
to further reduce residual leukemia immediately prior to HCT to improve post-HCT outcomes. This Phase 
2 study will deliver 1 to 2 cycles of blinatumomab (28-day continuous infusion) in up to 35 subjects with 
B-ALL that have experienced a relapse or have persistent disease. Subjects will receive blinatumomab 
immediately prior to proceeding to HCT with best available donor using an alpha/beta T-cell and B-cell 
depletion preparative transplant regimen. 

 
 
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EXPERIMENTAL DESIGN SCHEMA 
Study population: Patients, ages ≤ 25 years, with B-ALL meeting study eligibility 
 
                                                                                                               
Blinatumomab 
Cycle 1 
(28-days) 
Bone Marrow Disease 
Evaluation 
for Minimal Residual 
Disease (MRD) 
Blinatumomab 
Cycle 2 
(28-days) 
    Alpha/beta T-cell and B-cell depleted   
Allogeneic Hematopoietic Cell Transplant 
Flow Cytometry 
MRD Negative 
Y/N 
Flow Cytometry 
MRD Negative 
Y/N 
Off Study 
Yes
No 
No 
Yes

 
 
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                                                      STUDY CALENDAR 
Drug or Clinical Tests to Be Completed 
Baseline 
Days 1 to 28 
Days  
26 - 30 
Screening Assessments^ 
X 
 
 
Blinatumomab Cycle 1 and Cycle 2 (if needed) 
 
Continuous infusion 
 
Clinic Visit - History & Physical Exam 
 
weekly 
 
Performance Status 
 
weekly 
 
CBC with differential, CMP* 
 
weekly 
 
Uric acid, Phosphorus, LDH, PT, PTT, 
Urinalysis 
 
Day 1 
 
Disease Evaluation 
     Bone Marrow# (aspirate and/or Biopsy) 
     Lumbar Puncture 
 
X 
 
 
X 
X  
 Laboratory evaluations will be followed more frequently as clinically indicated 
^ See Section 5.1.3 for screening assessments 
*CMP, comprehensive metabolic panel  
#Bone marrow evaluations will be performed at the end of each cycle of blinatumomab around Day 28 
(+/- 2 days) with minimal residual disease (MRD) testing performed using flow cytometry and high-
throughput deep sequencing (HTS). Baseline blast samples will be sent for B-cell and T-cell clonality 
HTS assessment. If T-cell clonal sequences are detected on the baseline sample, T-cell clonality will 
continue to be sent along with B-cell clonality on subsequent samples.  

 
 
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Blinatumomab Bridging Therapy (BBT) 
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PROTOCOL SUMMARY 
 
Title 
Blinatumomab Bridge to Allogeneic Hematopoietic Cell 
Transplantation for B-Acute Lymphoblastic Leukemia: A Phase 2 
Study 
Protocol Short Name 
Blinatumomab Bridging Therapy (BBT) 
IND Sponsor 
N/A 
Principal Investigator/ 
Study Chair/
Coordinating 
Center/Sponsor-
Investigator 
Michael J. Burke, MD 
Pediatric Clinical Trials Office (CTO) 
8701 Watertown Plank Road 
MFRC Suite 3018 
Milwaukee, WI 53226 
Study Sites 
1) Children’s Wisconsin 
2) American Family Children’s Hospital, Madison WI 
Clinical Trial Phase 
Phase 2 Study 
Study Disease 
B-Acute Lymphoblastic Leukemia 
Main Eligibility Criteria 
Diagnosis of B-ALL in hematologic complete remission (M1 marrow; 
< 5% blasts in the bone marrow) by morphology or multi-parameter 
flow cytometry with evidence of minimal residual disease (MRD) ≥ 
0.01% AND that meets one of the following: 
 
a. Patients in first relapse or greater, OR 
b. Patients with very-high risk biology ALL that is proceeding to 
HCT in first remission (e.g. Induction failure, Severe-
hypodiploidy, Ph-like ALL), OR 
c. Patients in 1st CR with persistent disease identified as end of 
consolidation (EOC) MRD ≥ 0.01%. 
 
AND with the intent of going on to an allogeneic hematopoietic cell 
transplantation (HCT) independent of the study 
 
• Patients must have an available donor and have intention of 
proceeding directly to HCT after completion of 1 to 2 cycles of 
bridging therapy with blinatumomab. 
 
• Age ≤ 25 years at time of study enrollment 
 
• Patients must have fully recovered from the acute toxic effects 
of all prior chemotherapy, immunotherapy, or radiotherapy 
prior to entering this study. At least 7 days must have elapsed 
from prior chemotherapy. 
 
• Patients who have experienced their relapse after HCT are 
eligible, provided they have no evidence of acute or chronic 
graft-versus-host disease (GVHD) and are off all transplant 
immune suppression therapy for at least 7-days (e.g. steroids, 
cyclosporine, tacrolimus). Steroid therapy for non-GVHD 
and/or non-leukemia therapy is acceptable. 

 
 
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Blinatumomab Bridging Therapy (BBT) 
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Study Rationale 
Relapse of childhood B-Acute Lymphoblastic Leukemia (B-ALL) is a 
vexing clinical problem with high rates of subsequent relapse and death 
with current treatment approaches. This trial will determine if 
blinatumomab used as a bridge to allogeneic hematopoietic cell 
transplantation (HCT) can reduce rates of subsequent relapse and 
improve survival. If successful, this strategy could become standard of 
care for patients going to HCT for B-ALL with residual disease.  
Primary Objectives 
To determine the efficacy of blinatumomab given immediately prior to 
HCT as “bridging therapy” to eliminate minimal residual disease as 
measured by Flow Cytometry in children, adolescents, and young adults 
with relapse or refractory B-ALL. 
Secondary Objectives 
To compare the results of Flow Cytometry-based versus molecular 
High-Throughput Deep Sequencing (HTS)-based minimal residual 
disease (MRD) testing following blinatumomab prior to HCT in 
children, adolescents, and young adults with relapse or refractory B-
ALL and how they correlate with post-HCT outcomes. 
Study Design 
This Phase 2 study will determine the effectiveness of delivering 1 to 2 
cycles of blinatumomab (Days 1-28) as bridging therapy in children, 
adolescent and young adults with relapse or persistent MRD B-ALL. 
Eligible subjects will receive 1 or 2, 28-day cycles of blinatumomab 
prior to proceeding to HCT. Centralized MRD assessment will be 
performed after completion of the 28-days of blinatumomab using both 
flow cytometry (University of Washington, Brent Wood, MD or local 
lab if applicable) and High-Throughput Deep Sequencing (HTS) MRD 
technologies (Adaptive Technologies, Seattle, WA). Subjects who 
achieve flow cytometry negative MRD (<0.01%) after a single cycle of 
blinatumomab can proceed directly to HCT whereas subjects who 
remain MRD positive by flow cytometry may receive a 2nd cycle of 
blinatumomab. Additionally, subjects who achieved MRD negativity 
after Cycle 1 but are unable to proceed to HCT based on the 
timing/scheduling of the donor collection, a 2nd cycle of blinatumomab 
may be given. Subjects who remain MRD positive by flow cytometry 
after a 2nd cycle of blinatumomab will come off study.  
 
This is part one of two-part study. The current study is measuring the 
timing of blinatumomab in relation to HCT. In the second part of the 
study, the subjects move on to receive a transplant if eligible. 
Study Agent/Intervention 
Description 
Blinatumomab 
Number of Subjects 
Up to 35 subjects (25 evaluable subjects are needed who are able to 
proceed to HCT) 
Subject Participation 
Duration 
Patients may continue treatment for 1 to 2 cycles of blinatumomab 
prior to either coming off protocol or proceeding to HCT. 
Duration of Follow up 
All subjects, including those who discontinue protocol therapy early, 
will be followed for 30 days from the end of blinatumomab or until the 
start of the transplant preparative regimen (or other therapy), whichever 
occurs earlier.  

 
 
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Blinatumomab Bridging Therapy (BBT) 
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Estimated Time to 
Complete Enrollment 
30 - 36 months 
Statistical Methodology 
 
We will summarize by and compare the subgroups, within the context 
of a Phase 2 study, of those who are MRD negative by Flow Cytometry 
(< 0.01%) AND High-Throughput Deep Sequencing (HTS) (MRD 
undetectable) will be compared to those subjects who are MRD 
negative by only Flow Cytometry (HTS MRD positive) by 
demographics and by # of cycles (incomplete, 1 or 2). For comparison 
of continuous data, we will use a t-test or non-parametric Mann 
Whitney test, if needed due to distribution. For categorical data we will 
use a Fisher exact test.  
 
Sample Size and Power Estimate 
 
It is expected that the study will complete in 30 to 36 months. If there 
is an 80% rate of MRD negative subjects, a total of 25 evaluable 
subjects will be recruited. The 95% confidence interval will be 
(0.59,0.93) with 25 patients. If we must recruit 35 total subjects, we 
would expect that the proportion will be no less than 0.67 with a 95% 
CI of (0.47,0.83). 
 
We expect ~40% (10 patients) will be MRD negative by HTS 
(undetectable MRD). With 25 evaluable subjects recruited the 95% CI 
would be (0.21,0.61). 

 
 
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Blinatumomab Bridging Therapy (BBT) 
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 LIST OF ABBREVIATIONS 
 
AE 
 
 
adverse event 
ALL 
 
 
acute lymphoblastic leukemia 
ALT 
 
 
Alanine Aminotransferase 
ANC  
 
absolute neutrophil count 
AST 
 
 
aspartate aminotransferase 
AUC  
 
area under the concentration time curve 
BMT  
 
bone marrow transplant 
BP 
 
 
blood pressure 
BUN  
 
blood urea nitrogen 
CW 
 
 
Children’s Wisconsin 
CI 
 
 
confidence interval 
CNS 
 
 
central nervous system 
 
CR 
 
 
complete remission 
CRF 
 
 
case report forms 
CTCAE 
 
Common Terminology Criteria for Adverse Events 
CTEP  
 
Cancer Therapy Evaluation Program 
CTMS  
 
Clinical Trials Management System  
CTO  
 
Clinical Trials Office 
DCTD  
 
Division of Cancer Treatment and Diagnosis 
DLT 
 
 
dose limiting toxicity 
DSMC  
 
data safety monitoring committee 
DSMP  
 
data safety monitoring plan 
ECHO  
 
echocardiogram 
FISH  
 
fluorescence in situ hybridization 
GVHD  
 
graft versus host disease 
HCT  
 
hematopoietic cell transplantation 
HSCT  
 
hematopoietic stem cell transplantation 
HSV  
 
herpes simplex virus 
HTS 
 
 
high-throughput deep sequencing 
IRB 
 
 
Institutional Review Board 
ISO 
 
 
International Organization for Standardization 
LDH  
 
lactate dehydrogenase 
MACC Fund Center Midwest Athletes Against Childhood Cancer Fund Center 
MCW  
 
Medical College of Wisconsin 
MCWCC DSMC 
Medical College of Wisconsin Cancer Center Data Safety Monitoring Committee 
MRD  
 
minimal residual disease 
MUGA 
 
multi gated acquisition scan 
NCI 
 
 
National Cancer Institute 
NGS  
 
Next generation sequencing 
NOS  
 
not otherwise specified 
OnCore™ 
 
Online Enterprise Research Management Environment 
ORR  
 
overall response rate  
OS 
 
 
overall survival 
PCP 
 
 
pneumocystis carinii pneumonia 
PCR 
 
 
polymerase chain reaction 
Pediatric CTO  
Pediatric Cancer/Blood Disorder Clinical Trials Office 
PI 
 
 
principal investigator 

 
 
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PR 
 
 
partial response 
RFS 
 
 
relapse free survival 
SAE 
 
 
serious adverse event 
SRC 
 
 
Scientific Review Committee 
SUSAR 
 
suspected unexpected serious adverse reaction 
TRM  
 
transplant related morbidity 
ULN  
 
upper limit of normal 
UPIRSO 
 
unanticipated problems involving risks to subjects or others 
USP 
 
 
United States Pharmacopeia 
WBC  
 
white blood count 
 
 
 

 
 
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1.0  
BACKGROUND  
 
1.1  
Overview 
 
Acute lymphoblastic leukemia (ALL) remains one of the most common hematologic diseases for 
which allogeneic hematopoietic cell transplantation (HCT) is currently used.1 Despite improved 
outcomes of HCT over time for ALL, relapse remains a considerable problem and the leading 
cause of treatment failure.2 There is mounting evidence to support that for patients in 
hematological complete remission (< 5% leukemia in the bone marrow), the presence of minute 
amounts of leukemia (known as minimal residual disease (MRD)), identified immediately prior to 
HCT is associated with higher rates of ALL relapse following HCT.3-12 This trial will determine 
if blinatumomab used as a bridge to HCT can reduce rates of subsequent relapse and improve post-
HCT survival. If successful, this strategy could become standard of care for patients going to HCT 
for B-ALL with residual disease.  
 
1.2  
Rationale for Studying Blinatumomab in Relapse B-ALL  
 
Survival for relapse of B-ALL is suboptimal with outcomes ranging 30-50%.13 Additionally, there 
is mounting evidence to support that for patients in hematological remission, the presence of 
minimal residual disease (MRD), identified immediately prior to allogeneic hematopoietic cell 
transplantation (HCT), is associated with higher rates of relapse following HCT. Patients who 
have MRD identified prior to HCT, have relapse rates of 50-60% compared to 10-20% for patients 
who are MRD negative.6 In the Children’s Oncology Group (COG) study ASCT0431 reporting 
HCT outcomes in 144 pediatric patients with relapse ALL, those who achieved MRD negativity 
pre-HCT identified by flow cytometry (FC) reported significantly less relapse at 1-year (20% 
versus 60%, p=0.4).12 Even more impressive was the predictability of relapse using high 
throughput sequencing (HTS) for MRD detection which was superior to FC. Patients on the 
ASCT0431 study who achieved HTS-MRD negativity pre-HCT had no relapses compared to those 
who were HTS-MRD positive (0% versus 16%, p=0.02) and significantly greater overall survival 
(96% versus 77%, p=0.003).14 Additionally, post-HCT HTS-MRD detection was better at 
predicting relapse than FC-MRD (p<0.0001), especially early after HCT (day 30 FC-MRD 
positive relapse rate, 35%; HTS-MRD positive relapse rate, 67%; p=0.004). Thus, introducing 
therapies for patients who are MRD positive prior to HCT to eliminate MRD and potentially 
improve post-HCT survival, is a promising approach and the primary focus of this study.  
 
Blinatumomab is a promising novel agent for the treatment of B-lineage lymphoid malignancies.15-
19 Blinatumomab is a bispecific single-chain antibody that targets the CD19 antigen and redirects 
CD3+ T-cells for selective lysis of tumor cells. In a Phase 2 trial of adult B-ALL, patients with 
MRD persistence or relapse after Induction and Consolidation therapy received Blinatumomab as 
a 4-week continuous intravenous infusion at a dose of 15 μg/m2/24 hours.19 Of 21 treated patients, 
16 became MRD negative as assessed by quantitative polymerase chain reaction (QT-PCR) for 
either rearrangements of immunoglobulin or T-cell receptor genes, or specific genetic aberrations. 
Among the 16 responders, 12 had been molecularly refractory to previous chemotherapy. 
Probability for relapse-free survival was 78% at a median follow-up of 405 days. Blinatumomab 
was similarly effective and well tolerated in an anecdotal report of a small series of pediatric 
cases.16 
 
Blinatumomab has been evaluated in children with relapsed/refractory ALL in Phase 1/2 study 
conducted by the Children’s Oncology Group (COG) (MT103-205/AALL1121) and the I-BFM 

 
 
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European childhood leukemia cooperative group with extremely promising results. Forty-nine 
patients were treated in the Phase 1 portion and 44 patients in the Phase 2.20  Four patients had 
dose-limiting toxicities in Cycle 1 (Phase 1). Three experienced Grade 4 cytokine-release 
syndrome (one attributed to Grade 5 cardiac failure); one had fatal respiratory failure. The 
maximum-tolerated dosage was 15 µg/m2/d. Blinatumomab pharmacokinetics was linear across 
dosage levels and consistent among age groups. On the basis of the Phase 1 data, the recommended 
Blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m2/d for the first 7 days, 
followed by 15 µg/m2/d thereafter. Among the 70 patients who received the recommended dosage, 
27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) 
of whom achieved complete MRD response. The most frequent Grade ≥ 3 adverse events were 
anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and 1 
patient (1%) had cytokine-release syndrome of Grade 3 and 4, respectively. Two patients (3%) 
interrupted treatment after Grade 2 seizures. This trial was the first such trial in pediatrics and 
demonstrated anti-leukemic activity of single-agent Blinatumomab with complete MRD response 
in children with relapsed/refractory B-ALL.  
 
In December 2014, the COG opened a Phase 3 study group-wide (>100 institutions) investigating 
blinatumomab in combination with chemotherapy for children, adolescents and young adults with 
1st relapse B-ALL (AALL1331; NCT02101853). The dose used in this study for patients who are 
in remission is 15 µg/m2/d (maximum dose of 28 mcg/d). This study continues to accrue. 
 
The level of single agent activity seen with blinatumomab has not been seen in recent Phase 1 ALL 
studies outside the use of tyrosine kinase inhibitors (TKI) in patients with Philadelphia 
chromosome positive (Ph+) ALL.  
 
Neurological adverse events have been described with blinatumomab and will be closely 
monitored on this study. One potential concern regards the safety of combining blinatumomab 
with IT chemotherapy which is given prior to starting blinatumomab on this study. However, in 
the previous Phase 1/2 pediatric study cited above, IT methotrexate or IT triples were included 
prior to Cycle 1, at Day 15 of Cycle 1 and at Day 29 of each cycle with no unusual or increased 
CNS side effects reported.20 
 
Cytokine release syndrome (CRS) has also been described with blinatumomab. This has been more 
prevalent in patients with a higher leukemia burden, however, can occur in any patient treated with 
blinatumomab. Pre-medication with dexamethasone will be mandated in the protocol, and at the 
suggestion of the development of CRS, even after the premedication doses, additional 
dexamethasone administration is suggested. There is a published case report suggesting that for 
cases of life-threatening cytokine release syndrome for which dexamethasone and supportive care 
measures are not adequate, consideration may be given to the administration of tocilizumab, the 
anti-IL-6 monoclonal antibody.21 
 
On July 11, 2017, the US FDA approved blinatumomab for treatment of relapsed or refractory B-
cell ALL in adults and children and in March 2018, the US FDA granted accelerated approval to 
blinatumomab to treat adults and children with B-cell ALL who are in remission but still have 
MRD. The FDA approved dose of blinatumomab in children and adults who have < 5% leukemia 
blasts in the bone marrow is 15 µg/m2/d (patients < 45kg; not to exceed 28 µg/d) and 28 µg/d 
(patients ≥ 45 kg) as a continuous infusion for 28 days.  
 
 

 
 
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2.0 
HYPOTHESIS AND OBJECTIVES 
 
2.1 
Hypothesis 
 
Blinatumomab will successfully reduce the leukemia disease burden (as measured by HTS) for 
children, adolescents and young adults with relapse or persistent MRD B-ALL when given prior 
to HCT, resulting in improved post-HCT outcomes. 
 
2.2    Primary Objectives 
 
To determine the efficacy of blinatumomab given immediately prior to HCT as “bridging therapy” 
to eliminate MRD using flow cytometry in children, adolescents and young adults with relapse or 
persistent MRD B-ALL. 
 
2.3    Secondary Objectives 
 
To compare the results of Flow Cytometry-based versus molecular High-Throughput Deep 
Sequencing-based minimal residual disease (MRD) testing following blinatumomab prior to HCT 
in children, adolescents and young adults with relapse or persistent MRD B-ALL and how these 
MRD correlate with post-HCT outcomes. 
 
3.0  
STUDY DESIGN 
 
3.1 
General Description 
 
This Phase 2 study will determine the effectiveness of delivering 1 to 2 cycles of blinatumomab 
(Days 1-28) as bridging therapy in children, adolescent and young adults with B-ALL and MRD. 
Eligible subjects, ages ≤ 25 years with the diagnosis of B-ALL in hematologic complete remission 
(< 5% leukemia in the bone marrow) and evidence of MRD (≥ 0.01%), will receive 1 or 2, 28-day 
cycles of blinatumomab prior to proceeding to HCT. Centralized MRD assessment will be 
performed after completion of the 28-days of blinatumomab using both Flow Cytometry 
(University of Washington, Brent Wood, MD or local lab if applicable) and High-Throughput 
Deep Sequencing (HTS) MRD technologies (Adaptive Technologies, Seattle, WA). Subjects who 
achieve Flow Cytometry negative MRD (< 0.01%) after a single cycle of blinatumomab can 
proceed directly to HCT whereas subjects who remain MRD positive by Flow Cytometry may 
remain on study to receive a 2nd cycle of blinatumomab. Additionally, subjects who achieved MRD 
negativity after Cycle 1 but are unable to proceed to HCT based on the timing/scheduling of the 
donor collection, a 2nd cycle of blinatumomab may be given. This additional cycle of 
blinatumomab for subjects awaiting donor collection, may be 28 days but can be less if the HCT 
is ready to proceed (e.g. 14-day blinatumomab infusion). Subjects who remain MRD positive by 
Flow Cytometry after a 2nd cycle of blinatumomab will be considered a treatment failure and come 
off study. For patients who achieve MRD negativity via Flow Cytometry and proceed to HCT, 
centralized HTS MRD assessment (Adaptive Technologies, Seattle, WA) will be used to determine 
which conditioning regimen will be given as patients who are MRD negative by Flow Cytometry 
but have MRD identified by HTS will receive standard myeloablative conditioning whereas 
patients achieving MRD negativity with both Flow Cytometry and HTS (MRD undetectable), will 
receive non-myeloablative conditioning. This is part one of a two-part study. The current study is 
measuring the timing of blinatumomab in relation to HCT. In the second part of the study, the 
subjects move on to receive a transplant if they achieve an MRD negative status. 

 
 
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3.2   
Number of Subjects  
 
This Phase 2 study will enroll up to 35 subjects with the goal of achieving 25 evaluable subjects 
who become MRD negative based on Flow Cytometry after completing 1 to 2 cycles of 
blinatumomab and successfully proceed to HCT.  
3.3  
Primary Completion 
 
The study will reach primary completion for enrollment 30 to 36 months from the time the study 
opens to accrual.                                                  
 
3.4  
Study Completion 
 
The study will reach final study completion 42-48 months from the time the study opens to accrual. 
 
4.0 
PATIENT SELECTION 
 
Study entry is open to patients regardless of gender or ethnic background.  While there will be 
every effort to seek out and include females and minority patients, the patient population is 
expected to be no different than that of other acute leukemia studies at the Medical College of 
Wisconsin. 
 
4.1  
Eligibility Criteria  
 
Patients must have baseline evaluations performed prior to the start of blinatumomab and must 
meet all inclusion and exclusion criteria. In addition, the patient must be thoroughly informed 
about all study aspects, including the study visit schedule and required evaluations and all 
regulatory requirements for informed consent. The written informed consent must be obtained 
from the patient prior to enrollment. The following criteria apply to all patients enrolled onto the 
study unless otherwise specified.  
 
4.2  
Inclusion Criteria 
 
4.2.1  Diagnosis of B-ALL in hematologic complete remission (defined as an M1 marrow, < 5% 
blasts) with MRD in the bone marrow (≥ 0.01%) by multi-parameter flow cytometry and 
that meets one of the following: 
 
• Patients in first relapse or greater; 
 
OR 
 
• Patients with very-high risk biology ALL that is proceeding to HCT in first remission 
(e.g. Induction failure, Severe-hypodiploidy, Ph-like ALL); 
 
OR 
 
• Patients who have persistent MRD after Consolidation therapy (End of Consolidation 
(EOC) MRD positive ≥ 0.01%); 
 

 
 
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      AND with the intent of going on to an allogeneic hematopoietic cell 
transplantation (HCT) independent of this study 
 
4.2.2 Patients must have an available donor and have intention of proceeding directly to HCT 
after completion of 1 to 2 cycles of Bridging therapy with blinatumomab. 
 
4.2.3  Age ≤ 25 years at time of study enrollment 
 
4.2.4 Karnofsky Performance Status ≥ 50% for patients 16 years and older and Lansky Play 
Score ≥ 50 for patients under 16 years of age (see Appendix 1) 
 
4.2.5 Have acceptable organ function as defined within 7 days of study registration: 
 
Renal: creatinine clearance ≥ 60 mL/min/1.73m2 or serum creatinine based on age/gender 
as follows: 
 
Age 
Maximum Serum 
Creatinine (mg/dl) 
Male 
Female 
1 month to < 6 months 
0.4 
0.4 
6 months to < 1 year 
0.5 
0.5 
1 year to < 2 years 
0.6 
0.6 
2 years to < 6 years 
0.8 
0.8 
6 years to < 10 years 
1.0 
1.0 
10 years to < 13 years 
1.2 
1.2 
13 years to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
 
Hepatic: ALT < 5 x upper limit of normal (ULN) and total bilirubin ≤ 1.5 x upper limit of 
normal (ULN) for age 
 
Cardiac: left ventricular ejection fraction ≥ 40% by ECHO/MUGA 
 
4.2.6 At least 7 days must have elapsed from prior chemotherapy. 
 
4.2.7 Patients who have experienced their relapse after HCT are eligible, provided they have no 
evidence of acute or chronic Graft-versus-Host Disease (GVHD) and are off all transplant 
immune suppression therapy for at least 7-days (e.g. steroids, cyclosporine, tacrolimus). 
Steroid therapy for non-GVHD and/or non-leukemia therapy is acceptable. 
 
4.2.8 Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For 
agents that have known adverse events occurring beyond 7 days after administration, this 
period must be extended beyond the time during which adverse events are known to occur. 
The duration of this interval must be discussed with the study chair. Patients with 
Philadelphia-chromosome positive or Philadelphia-chromosome like (PH-Like) BALL are 
an exception to this eligibility criteria as concomitant TKI therapy is allowed on study 
(e.g. imatinib, dasatinib, nilotinib).  
 

 
 
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4.2.9 Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the 
last dose of monoclonal antibody (i.e. Inotuzumab = 12 days).  
 
4.2.10 Immunotherapy: At least 42 days after the completion of any type of immunotherapy (e.g. 
tumor vaccines or CAR T-cell therapy) except monoclonal antibodies. 
 
4.2.11 XRT: Cranio or craniospinal XRT is prohibited during protocol therapy. ≥ 90 days must 
have elapsed if prior TBI, cranio or craniospinal XRT 
 
4.2.12  Sexually active females of child-bearing potential must agree to use adequate 
contraception (diaphragm, birth control pills, injections, intrauterine device [IUD], 
surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of 
treatment and for 2 months after the last dose of chemotherapy.   Sexually active men 
must agree to use barrier contraceptive for the duration of treatment and for 2 months 
after the last dose of chemotherapy. 
 
4.2.13 Voluntary written consent before performance of any study-related procedure not part of 
normal medical care, with the understanding that consent may be withdrawn by the 
subject at any time without prejudice to future medical care. 
 
4.3   
Exclusion Criteria 
 
4.3.1 History of CNS3 disease and/or active central nervous system (CNS) disease (≥ CNS2)  
 
4.3.2 Receiving concomitant chemotherapy (with the exception of a tyrosine kinase inhibitor 
(e.g. imatinib, dasatinib, nilotinib) for Philadelphia-chromosome positive or Philadelphia-
chromosome Like (Ph-Like) BALL), radiation therapy; immunotherapy or other anti-
cancer therapy other than is specified in the protocol.  
 
4.3.3 Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting 
ongoing signs/symptoms related to the infection and without improvement, despite 
appropriate antibiotics or other treatment) 
 
4.3.4 Pregnant or lactating. The agents used in this study are known to be teratogenic to a fetus 
and there is no information on the excretion of agents into breast milk. All females of 
childbearing potential must have a blood test or urine study within 7-days prior to the start 
of blinatumomab to rule out pregnancy. 
 
4.3.5 Known allergy to blinatumomab 
 
4.3.6 Participating in a concomitant Phase 1 or 2 study 
 
5.0 
REGISTRATION PROCEDURES (STUDY ENTRY, STUDY PROCEDURES, END OF 
TREATMENT AND WITHDRAWL PROCEDURES) 
 
Registration will occur after eligibility is confirmed and the patient/parent has signed the subject 
consent, but before any treatment has been administered. Questions regarding eligibility should 
be directed to the Principal Investigator: Michael Burke, MD (phone 414-955-4198; email 

 
 
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mmburke@mcw.edu ) 
 
The eligibility checklist will be completed at the time of study enrollment. 
 
5.1 
 Study Entry Procedures 
 
5.1.1  Required Preregistration Screening Tests and Procedures 
 
Screening assessments must be performed within 14-days prior to enrollment. Any results falling 
outside of the reference ranges may be repeated at the investigator’s discretion. All on-study visit 
procedures are allowed a window of ± 2 days unless otherwise noted. Treatment or visit delays for 
public holidays or weather conditions do not constitute a protocol violation. 
A written, signed informed consent form (ICF) and a Health Insurance Portability and 
Accountability Act (HIPAA) authorization must be obtained before any study-specific 
assessments are initiated. A copy of the signed ICF and HIPAA form will be given to the subject 
and a copy will be filed in the medical record. The original will be kept on file with the study 
records.  
 
 
All patients who are consented will be registered in the Online Enterprise Research Management 
 
Environment (OnCore™), the MCW Cancer Center and Pediatric Clinical Trials Office (CTO) 
 
Clinical Trial  Management System. The system is password protected and meets HIPAA 
 
requirements. 
 
5.1.2  Registration Process 
 
Upon completion of the screening evaluation, eligibility confirmation and obtaining written 
consent, the patient will be registered in the study file by the Department of Pediatrics 
Division of Hematology/Oncology/BMT MACC Fund Center CTO). 
 
5.1.3  Pretreatment Period 
 
Screening Assessments:  The screening procedures and assessments must be completed within 
14-days of the Day 1 visit (or the first day of blinatumomab infusion). 
 
• Physical examination 
• Vital signs 
• Complete medical history 
• Baseline conditions assessment 
• Documentation of disease assessment (disease-specific staging criteria) 
• Performance status (ECOG, KPS, etc.) 
• Measurable disease  
o Bone marrow aspirate and/or biopsy (morphology, cytogenetics, FISH and minimal 
residual disease (MRD) via HTS and flow cytometry). Baseline blast samples will 
be sent for B-cell and T-cell clonality HTS assessment, since B-lymphoblasts may 
have detectable T cell receptor (TCR) clones. If T-cell clonal sequences are 
detected on the baseline sample, T-cell clonality will continue to be sent along with 
B-cell clonality on subsequent samples (Note that prior MRD by HTS is required, 
but does not need to be completed within the 14 day window). 

 
 
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o Lumbar Puncture (CSF cytology and cell count) 
• History of prior treatments and any residual toxicity relating to prior treatment 
• Baseline medications taken within 14-days of Day 1 
• Complete blood count (CBC) with differential and platelet count 
• Blood chemistry assessment, including:  
Alkaline phosphatase, aspartate aminotransferase/alanine aminotransferase 
(ALT/AST), total bilirubin, calcium, phosphorus, blood urea nitrogen (BUN), 
creatinine, total protein, albumin, glucose, potassium, sodium, chloride, 
bicarbonate, uric acid, lactate dehydrogenase (LDH).  
• Coagulation assessment, including prothrombin time, partial thromboplastin time, 
international normalized ratio (PT/PTT/INR) 
• Urinalysis 
• Serum or urine pregnancy test (if applicable) within 7-days prior to the start of 
blinatumomab 
• Electrocardiogram (EKG) 
• Cardiac assessment (ECHO, MUGA, etc.) 
• CMV serology and EBV serology prior to the start of the first cycle of blinatumomab 
 
5.2   
Study Procedures During Treatment 
 
Patients must meet eligibility criteria on Day 1 to be treated as per this protocol.  
 
5.2.1  Study Procedures, Cycle 1 (and cycle 2, if applicable), Weekly 
 
• Physical examination 
• Vital signs 
• Performance status 
• Evaluation of adverse events 
• Concomitant medications 
• CBC with differential and platelet count 
• Blood chemistry assessment, including:  
o Alkaline phosphatase, ALT/AST, total bilirubin, calcium, BUN, creatinine, 
total protein, albumin, glucose, potassium, sodium, chloride, bicarbonate,  
• Coagulation assessment, including PT/PTT/INR (Day 1) 
• Urinalysis, uric acid, LDH, phosphorus (Day 1) 
 
5.3  
End of Treatment  
 
5.3.1  End of Treatment Procedures 
 
To be completed on treatment Day 28 ± 2 days. 
• Bone marrow aspirate and/or biopsy (morphology, cytogenetics, FISH and minimal 
residual disease via HTS and flow cytometry). Baseline blast samples will be sent for B-
cell and T-cell clonality assessment. If T-cell clonal sequences are detected on the 
baseline sample, T-cell clonality will continue to be sent along with B-cell clonality on 
subsequent samples. If no trackable T-cell sequences are detected, only B-cell HTS will 
be followed.  

 
 
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• Lumbar puncture (CSF cytology and cell count) 
 
5.4  
Post-Treatment 
 
5.4.1  Follow-Up Visits 
 
All subjects, including those who discontinue protocol therapy early, will be followed for 30 days 
from the completion of blinatumomab or until the start of the transplant preparative regimen (or 
other therapy), whichever occurs earlier. 
 
The following procedures will be performed at the follow-up visit(s): Weekly 
• Physical examination 
• Vital signs 
• Performance status 
• Evaluation of adverse events 
• Concomitant medications 
• CBC with differential and platelet count 
• Blood chemistry assessment, including:  
o Alkaline phosphatase, ALT/AST, total bilirubin, calcium, BUN, creatinine, total 
protein, albumin, glucose, potassium, sodium, chloride, bicarbonate,  
 
5.5   
Study Withdrawal Procedures 
 
5.5.1  Duration of Therapy 
 
Treatment will be limited to 1 to 2 cycles of blinatumomab. An additional cycle of Blinatumomab 
bridging therapy can be given if needed based on timing of donor collection. This additional cycle 
for subjects awaiting donor collection, may be 28 days but can be less if the HCT is ready to 
proceed (e.g. 14-day blinatumomab infusion). Subjects will receive protocol therapy unless: 
• Subject withdraws consent or is non-compliant 
• Disease progression 
• Inter-current illness that prevents further administration of treatment 
• Unacceptable toxicity 
 
5.5.2  Subject-Initiated Withdrawal  
 
A subject may decide to withdraw from the study at any time. 
 
5.5.3 Investigator-Initiated Withdrawal 
 
The Investigator will withdraw a patient whenever continued participation is no longer in the 
patient’s best interests. Reasons for withdrawing a patient include, but are not limited to, disease 
progression, the occurrence of an adverse event or a concurrent illness, a subject’s request to end 
participation, a subject’s noncompliance or simply significant uncertainty on the part of the 
Investigator that continued participation is prudent. There may also be administrative reasons to 
terminate participation, such as concern about a subject’s compliance with the prescribed treatment 
regimen.  
 

 
 
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5.5.4  Sponsor-Initiated Withdrawal 
 
Sponsor’s decision to discontinue the study. 
 
5.5.5  Withdrawal Documentation Procedure 
 
The reason for study withdrawal and the date the subject was removed from the study must be 
documented in the case report form (CRF). As this study will enroll up to 35 patients in order to 
capture 25 evaluable subjects, it will account for subjects that may withdraw from study. Any 
subject who receives any amount of blinatumomab will be evaluable for toxicity and followed 
until they either come off study or begin a new treatment for their leukemia, which would include 
HCT. 
 
 
5.5.6 Off Study Criteria 
 Death 
 Lost to follow-up 
 Patient enrollment onto another anti-cancer therapeutic study with exception to 
Part 2 of this study 
 Withdrawal of consent for any further data submission 
 Protocol defined follow up criteria met 
 
6.0 
TREATMENT PLAN 
 
6.1 
Drug Administration 
 
Up to 2 cycles of continuous infusion blinatumomab will be given based on the end of Cycle 1 
disease response. Cycle 2 of blinatumomab can be given to subjects who have achieved remission 
(< 5% marrow blasts) after Cycle 1 but have persistent disease identified by multi-parameter flow 
cytometry (minimal residual disease (MRD) positive ≥ 0.01%) after Cycle 1. Additionally, 
subjects who achieved MRD negativity after Cycle 1 but are unable to proceed to HCT based on 
the timing/scheduling of the donor collection, a 2nd cycle of blinatumomab may be given. This 
additional cycle of blinatumomab for subjects awaiting donor collection, may be 28 days but can 
be less if the HCT is ready to proceed (e.g. 14-day blinatumomab infusion). 
 
Minimal Organ Functions to be Met Before the Start of the Blinatumomab Infusion 
 
Patients must meet the following criteria (prior to blinatumomab infusion) 
• No oxygen requirement with oxygen saturations > 90%. 
• AST, ALT < 5x upper limit of normal for age; bilirubin < 2 mg/dL. 
• Hemoglobin > 8 mg/dL prior to infusion. (May be transfusion dependent). 
• Renal function: serum creatinine < 2 x normal for age. 
• Exhibit overt hematologic manifestations of relapse or persistent disease. Evidence of 
recurrent/persistent disease based primarily on flow cytometry, cytogenetics, chimerism 
analysis, or other molecular studies does not by itself represent grounds for exclusion. 
 
Blinatumomab will be given as a 28-day continuous infusion with 14-days in between Cycle 1 and 
Cycle 2 as per the package insert and FDA approved labeling.  

 
 
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Cycle 
Patient Weight 
Greater Than or Equal to 45kg 
(Fixed-dose) 
Patient Weight 
Less Than 45kg 
(BSA-based dose) 
 
1: Days 1-28 
 
 
Days 29-42 
 
 
28 mcg/day 
 
 
14-day treatment-free interval 
 
15 mcg/m2/day 
(not to exceed 28 mcg/day) 
 
14-day treatment-free interval 
 
2: Days 1-28 
 
 
Days 29-42 
 
 
28 mcg/day 
 
 
14-day treatment-free interval 
 
15 mcg/m2/day 
(not to exceed 28 mcg/day) 
 
14-day treatment-free interval 
 
 
Hospitalization is recommended for the first 3 days of Cycle 1 and the first 2 days of Cycle 2 (if 
needed).  
 
Pre-medicate with prednisone or equivalent for MRD-positive B-cell Precursor ALL.  
 
For patients ≥ 18 years of age, pre-medicate with prednisone 100 mg intravenously or equivalent 
(e.g., dexamethasone 16 mg) 1 hour prior to the first dose of blinatumomab in each cycle.  
 
For pediatric patients (<18 years of age), pre-medicate with 5 mg/m2 of dexamethasone, to a 
maximum dose of 20 mg prior to the first dose of blinatumomab in Cycle 1 and when restarting 
an infusion after an interruption of 4 or more hours in the first cycle.  
 
6.2 Sample Collection and Processing for Minimal Residual Disease  
 
Type of Sample 
Instructions and Timing of Sample Collection 
Bone Marrow Samples 
for Flow Cytometry 
MRD 
• At the end of each blinatumomab cycle (Day 28 ± 2 days). 
 
Bone Marrow Samples 
for Flow Cytometry 
MRD Bone Marrow 
Collection and Shipping 
Procedure 
• 
Bone marrow required for Flow Cytometry clinical evaluation MRD 
testing should be collected and shipped according to the standard 
procedures for the local institution.  These samples will be evaluated 
by an approved Flow Cytometry Laboratory.  
• 
Results of the clinical evaluation Flow Cytometry MRD testing at each 
timepoint will be communicated to each local institution by the 
approved Flow Cytometry Laboratory, and results should be entered 
into the EDC system by local Clinical Research Coordinators. 
Bone Marrow Samples 
for High Throughput 
Sequencing MRD 
Samples  
• At time of enrollment prior to start of blinatumomab 
• At the end of each blinatumomab cycle (Day 28 ± 2 days). 
• Baseline blast samples will be sent for B-cell and T-cell clonality 
assessment. If T-cell clonal sequences are detected on the baseline 
sample, T-cell clonality will continue to be sent along with B-cell 
clonality on subsequent samples. If no trackable T-cell sequences are 
detected, only B-cell HTS will be followed. 
 

 
 
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Type of Sample 
Instructions and Timing of Sample Collection 
Bone Marrow Sample for 
High Throughput 
Sequencing MRD 
Collection Procedure 
• Collect minimum of 2 mL of marrow into a syringe and place marrow 
into a large purple EDTA tube that are commonly used in all hospitals. 
Mix well 
• Reposition marrow aspirates needle at least once during procedure to 
ensure the maximum quality of marrow 
 
Specimen Labeling for 
High Throughput 
Sequencing MRD 
Sample 
Each tube must be labeled with the study ID number, along with the date 
the sample was obtained.  No personal identifying patient information 
should be included in the specimen or transmittal form. 
Specimen Packaging and 
Shipping for High 
Throughput 
Sequencing MRD 
Sample 
 
 
 
Adaptive has fresh collection kits with EDTA tubes, ambient packs and 
pre-paid FedEx labels for domestic sites to use in this trial.  Domestic 
samples should be shipped same day as collection at ambient temperature 
for overnight delivery to Adaptive.  Adaptive is open to accept ambient 
samples Monday-Saturday.  Include the completed and signed Test 
Requisition Form (obtained from Adaptive’s diagnostic Portal) with 
shipment and send a sample shipment notification email to 
clinicalservices@adaptivebiotech.com. 
Ship specimens to: 
Adaptive Biotechnologies 
Attn: CLIA Clinical Laboratory 
1551 Eastlake Ave E, Ste 200 
Seattle, WA 98102 
 
6.3  
Drug Information (Blinatumomab) 
 
(Blincynto®, AMG103, MT103, recombinant bispecific antibody derivative) 
 
6.3.1 Source and Pharmacology  
 
Blinatumomab is a fusion protein composed of two single-chain antibodies (scFv), murine anti-
CD19 scFv and murine anti-CD3 scFv. Through CD3 binding, blinatumomab recruits and engages 
T cells for redirected lysis of CD19-positive B cells, including those expressed with B-cell 
malignancies. T cells are bound by its anti-CD3 moiety, whereas B cells are bound by the anti-
CD19 moiety. The subsequent serial lysis of multiple malignant cells by a single blinatumomab-
activated T cell closely resembles a natural cytotoxic T cell reaction. Treatment with 
blinatumomab is associated with a rapid depletion of peripheral B cells, accompanied by T cell 
activation and a transient increase in cytokines.  
 
Blinatumomab consists of a single chain of 504 amino acids with a molecular weight of 
approximately 54 kDa. The pharmacokinetics of Blinatumomab was assessed over a dose range 
from 5 to 90 mcg/m2/day (approximately equivalent to 9-162 mcg/day). Following continuous 
intravenous infusion, the steady state serum concentration (Css) was achieved within a day and 
remained stable over time. The estimated mean (SD) volume of distribution based on terminal 
phase (Vz) was 4.52 (2.89) L. The estimated mean (SD) systemic clearance was 2.92 (2.83) L/hour 
and the estimated mean (SD) half-life was 2.11(1.42) hours. Negligible amounts of blinatumomab 
were excreted in the urine at the tested clinical doses. Like other protein therapeutics, 
blinatumomab is expected to be degraded into small peptides and amino acids via catabolic 

 
 
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pathways. At the clinical doses of 9 mcg/day and 28 mcg/day for the treatment of adult 
relapsed/refractory ALL, the mean (SD) Css was 211 (258) pg/mL and 621 (502) pg/mL, 
respectively.  
 
Currently there are no known drug incompatibilities or interactions with blinatumomab.   
 
6.3.2 Pregnancy and Lactation  
 
Pregnancy Category Unknown: The effect of blinatumomab on fertility has not been evaluated. 
Blinatumomab is not recommended in pregnant women and in women of childbearing potential 
not using contraception. It is not known whether blinatumomab or its metabolites are excreted in 
human milk. Women are not allowed to breastfeed while receiving blinatumomab.  
 
6.3.3 Formulation and Stability  
 
Blinatumomab is available as a 38.5 mcg preservative-free, white to off-white lyophilized powder 
for injection in 4 mL single-use vial. The agent is formulated with 3.68 mg citric acid monohydrate, 
105 mg trehalose dihydrate, and 25.55 mg lysine hydrochloride, and 0.7 mg polysorbate 80, pH 7. 
The stopper of the vial is latex free.  
 
6.3.4 IV Solution Stabilizer for Blinatumomab is not for reconstitution of blinatumomab; 
it is a component of the final intravenous product. The stabilizer is available as a 10 mL single-use 
vial of a preservative-free, clear, colorless-to-slightly yellow liquid solution. Each solution consists 
of 25 mM citric acid monohydrate, 1.25 M L-lysine hydrochloride, and 0.1% (w/v) polysorbate 
80, pH 7. The stopper of the vial is latex free.  
 
Store intact vials of blinatumomab and the IV solution stabilizer of blinatumomab refrigerated at 
2° to 8°C (36° to 46°F). Protect from light. Shelf life stability studies of the intact vials of 
blinatumomab and stabilizer solution are on-going. The stability of the final prepared IV solution 
is 8 days when stored refrigerated at 2° to 8°C. For storage prior to administration, the prepared 
infusion solution must be kept at 2° C to 8° C (36°F to 46°F). The total storage and administration 
time must not exceed 8 days. Once at room temperature, discard the IV bag after 96 hours.  
 
6.3.5 Guidelines for Administration 
 
See Treatment and Dose Modifications sections of the protocol. Premedication with 
dexamethasone is required prior to the first dose of blinatumomab in the first cycle, prior to a step 
dose and when restarting an infusion after an interruption of 4 or more hours in the first cycle. 
Refer to the current USPI for volume calculations. 
 
6.3.6 IV Infusion and Infusion Set Details  
 
Blinatumomab must be administered through a central line at rate of 5 mL/hr IV over 24 hours 
through an acceptable IV line. Only PVC non-DEHP lines with a 0.2 μm inline filter are 
acceptable. Do not flush the IV line as it will create an IV bolus to be administered into the patient. 
For outpatient administration, use FDA approved pumps. Only the exact volume should be 
administered; any remaining overfill should be discarded appropriately.  
 
6.3.7 Infusion Pump Requirements 

 
 
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Use a programmable pump that is approved by the appropriate regulatory authority for the country 
in which the subject is undergoing treatment. The pump alarm must be visual and auditory. The 
pump must be lockable. Elastomeric pumps are NOT allowed. CADD pumps are allowed; 
however, the cassettes used in CADD pumps are not compatible with blinatumomab and thus, not 
allowed. 
 
Record all infusion interruptions. Technical or logistical interruption must be as minimal as 
possible and re-start the infusion as soon as possible. If an interruption is longer than four hours, 
the re-start of the infusion must take place in the hospital under supervision of the investigator. 
Monitor patients for potential adverse events as described in the protocol and the Investigator 
Brochure.  
 
Monitor patients for cytokine release syndrome, tumor lysis syndrome, and infusion reaction. 
Refer to protocol for specific recommendation. Monitor patients for psychiatric events such as 
confusion, disorientation, and cognitive attention disturbances. Patients should not drive or operate 
dangerous machinery while receiving blinatumomab.  
 
Risk of Serious Adverse Reactions in Pediatric Patients Due to Benzyl Alcohol Preservative:  
Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and 
infants treated with benzyl alcohol-preserved drugs, including BLINCYTO (with preservative). 
The “gasping syndrome” is characterized by central nervous system depression, metabolic 
acidosis, and gasping respirations.  
 
When prescribing BLINCYTO (with preservative) for pediatric patients, consider the combined 
daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative) 
(contains 7.4 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The 
minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.  
 
Due to the addition of bacteriostatic saline, 7-day infusion bags of Blinatumomab solution contain 
benzyl alcohol and are not recommended for use in any patients weighing less than 22 kg. Prepare 
Blinatumomab solution for infusion with preservative-free saline in 24-hour or 48-hour infusion 
bags for patients weighing less than 22 kg.  Please refer to Appendix 2 for infusion instructions 
for patients weighing less than 22 kg. 
 
6.3.8 Supplier  
 
Blinatumomab and the solution stabilizer for blinatumomab is supplied by Amgen, Inc. and will 
be distributed by Amgen to Children’s Hospital of Wisconsin and American Family Children’s 
Hospital/University of Wisconsin. Do not use commercial supply. 
 
6.3.9 Obtaining the Agent  
 
6.3.9.1    Agent Ordering 
 
Amgen supplied agent may be requested by the eligible participating investigator (or their 
authorized designee) at each participating institution (Children’s Hospital of Wisconsin and 
American Family Children’s Hospital/University of Wisconsin).  
 

 
 
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To request shipment for this order: gccs@amgen.com or Fax orders to (805) 376-9807 
ATTN: Amgen GCSCM CDCs 
 
 
Order: 
____ Initial        ____ Resupply 
____ Rush (shipment within 72 hours of receipt) 
Provide Justification: 
Study Title: 
 
Study Sponsor: 
 
Sponsor Study #: 
Amgen Reference #: 
Product Description 
Blinatumomab (AMG 103) 
Quantity Requested 
Blinatumomab (AMG 103) 
38.5 μg/vial; 15 vials 
per box 
vials/ boxes 
 
 
 
IV Solution Stabilizer for  
Blinatumomab (AMG 103) 
10 mL vial; 6 vials per 
box 
vials/ boxes 
 
 
 
Site Comments 
 
 
Investigator: 
Date of Request: 
Amgen Site#: 
Preferred Arrival Date: 
 
Shipments are processed on Monday through Thursday 12:00 p.m. PST. Drug Shipment    
            
Requests received on Thursday after 12:00 p.m. PST will be shipped on the following Monday. 
 
6.4  
Supportive Care Guidelines  
 
All supportive measures consistent with optimal patient care will be given throughout the study. 
 
6.4.1     Venous Access 
 
A central venous access device, preferably a double lumen, is strongly recommended for this 
study. 
 
Anti-emetics will be used according to standard medical practice. Growth factor use is allowed on 
this study. 
 
6.4.2     Antimicrobial Prophylaxis 
 
Patients should be placed on standard of care prophylaxis during this time period at the discretion 
of the treating physician according to institutional guidelines for PCP, HSV, bacterial and fungus. 
 
6.5  
Follow-Up Period 
 

 
 
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All subjects, including those who discontinue protocol therapy early, will be followed for 30 days 
after the last dose of blinatumomab or until the start of the transplant preparative regimen (or 
other therapy), whichever occurs earlier. 
 
Subjects removed from the study treatment for unacceptable SAEs will be followed until resolution 
or stabilization of the adverse event. SAEs will be followed until completion.  
 
7.0  
DOSING DELAYS/DOSE MODIFICATIONS  
 
The most frequent serious adverse events noted in patients treated with blinatumomab to 
date are disorders of the nervous system, both peripheral and central, and systemic cytokine 
release syndrome (CRS). Both categories of events are more likely to occur within the first 
week of treatment with blinatumomab, and both categories of events are usually reversible 
and able to be managed with attentive supportive care.  
 
AEs related to blinatumomab that require treatment interruption (according to table below) and do 
not resolve to CTCAE (Version 5.0) ≤ Grade 1 within 14 days will require permanent 
discontinuation of blinatumomab treatment. If the patient is eligible to continue protocol therapy 
(e.g. HCT), then the patient may, at the discretion of the investigator and family, continue to 
receive protocol therapy. Otherwise, the patient will be off protocol therapy.  
 
In the case that the AE(s) DO resolve within 14 days, blinatumomab treatment may resume at a 
reduced dose of 5 mcg/m2/day to complete the 28-day course (not counting the duration of 
treatment interruption).  
 
NOTE: For Grade 4 Nervous System/Psychiatric, Grade 3 or 4 Central Nervous System: Seizure 
and Grade 4 thromboembolic AEs, blinatumomab must be permanently discontinued.  
 
For patients who had experienced a ≥ Grade 2 Neurologic Systems and Psychiatric AE related to 
blinatumomab, no dose escalation beyond 5 mcg/m2/day will be permitted for subsequent 
cycles. For patients who experienced other AEs related to blinatumomab, subsequent cycles will 
begin at the reduced dose of 5 mcg/m2/day but may escalate to 15 mcg/m2/day after 7 days if 
there are no significant blinatumomab-related AEs. 
 
A second AE that requires interruption will require permanent discontinuation of treatment and 
the patient will be off protocol therapy.  
 
The resumption of the infusion at the reduced dose should be accompanied by dexamethasone 
premedication as indicated in the relevant subsection of Section 4.0, should be performed in the 
hospital under supervision of the investigator and patients should be observed for at least 72 hours 
after the start of the next infusion before considering discharge to the outpatient setting. 
 
Table 1: Dose Modifications for Adverse Events (AE) Occurring During Blinatumomab 
Administration 
 

 
 
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Category: AE 
(CTCAE v5.0) 
AE 
Grade 
Patients Greater Than 
or Equal to 45 kg 
Patients Less Than 45 kg 
Cytokine Release 
Syndrome (CRS) 
3 
 
Withhold blinatumomab 
until resolved, then 
restart blinatumomab at 
9 mcg/day. Escalate to 
28 mcg/day after 7 days 
if the toxicity does not 
recur. 
Withhold blinatumomab 
until resolved, then restart 
blinatumomab at 5 
ncg/m2/day. Escalate to 15 
mcg/m2/day after 7 days if 
the toxicity does not recur. 
4 
Discontinue blinatumomab permanently 
Neurologic Toxicity 
Seizure 
Discontinue blinatumomab permanently if more than 
one seizure occurs. 
3 
Withhold blinatumomab 
until no more than Grade 
1 (mild) and for at least 3 
days, then restart 
blinatumomab at 9 
mcg/day. Escalate to 28 
mcg/day after 7 days if 
the toxicity does not 
recur. If the toxicity 
occurred at 9 mcg/day, 
or if the toxicity takes 
more than 7 days to 
resolve, discontinue 
blinatumomab 
permanently.  
Withhold blinatumomab 
until no more than Grade 1 
(mild) and for at least 3 
days, then restart 
blinatumomab at 5 
mcg/m2/day. Escalate to 15 
mcg/m2/day after 7 days if 
the toxicity does not recur. 
If the toxicity occurred at 5 
mcg/m2/day, or if the 
toxicity takes more than 7 
days to resolve, discontinue 
blinatumomab permanently.  
4 
Discontinue blinatumomab permanently 
Other Clinically 
Relevant Adverse 
Reactions 
3 
Withhold blinatumomab 
until no more than Grade 
1 (mild), then restart 
blinatumomab at 9 
mcg/day. Escalate to 28 
mcg/day after 7 days if 
the toxicity does not 
recur. If the toxicity 
takes more than 14 days 
to resolve, discontinue 
blinatumomab 
permanently.  
Withhold blinatumomab 
until no more than Grade 1 
(mild), then restart 
blinatumomab at 5 
mcg/m2/day. Escalate to 15 
mcg/m2/day after 7 days if 
the toxicity does not recur. 
If the toxicity takes more 
than 14 days to resolve, 
discontinue blinatumomab 
permanently.  
 
4 
Considering discontinuing blinatumomab permanently 
 
Table Footnotes 
  
1. Grading of cytokine release syndrome (CRS) severity should be performed according to that of 

 
 
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Lee et al (see below table). As many of the symptoms of CRS overlap with those of other medical 
complications such as infection, attribution should be carefully considered. Accurate application 
of this grading system requires clinical judgment to confirm that the symptoms are most likely due 
to CRS rather than to another medical condition. In all grades of CRS, aggressive supportive care 
is required. In Grade 2 or 3 CRS, careful monitoring of cardiac function is strongly suggested. 
 
 
 
 
 
Grade 1 Symptoms are not life threatening and require symptomatic treatment only, e.g. 
fever, nausea, fatigue, headache  
Grade 2 Symptoms require and respond to moderate intervention  
Oxygen requirement < 40%, or  
Hypotension responsive to fluids or low dose of one vasopressor, or  
Grade 2 organ toxicity  
Grade 3 Symptoms require and respond to aggressive intervention  
Oxygen requirement >=40%, or  
Hypotension requiring high dose of one vasopressor or multiple vasopressors, or  
Grade 3 organ toxicity or grade 4 transaminitis  
Grade 4 Life-threatening symptoms  
Requirement for ventilator support, or  
Grade 4 organ toxicity (excluding transaminitis)  
 
2. In patients with ALL receiving BLINCYTO in clinical studies, neurological toxicities have 
occurred in approximately 65% of patients. Among patients that experienced a neurologic event, 
the median time to the first event was within the first 2 weeks of BLINCYTO treatment and the 
majority of events resolved. The most common (≥ 10%) manifestations of neurological toxicity 
were headache, and tremor; the neurological toxicity profile varied by age group. Grade 3 or higher 
(severe, life-threatening, or fatal) neurological toxicities following initiation of BLINCYTO 
administration occurred in approximately 13% of patients and included encephalopathy, 
convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and 
coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve 
disorders. The majority of neurologic events resolved following interruption of BLINCYTO, but 
some resulted in treatment discontinuation. There is limited experience with BLINCYTO in 
patients with active ALL in the central nervous system (CNS) or a history of neurologic events. 
Patients with a history or presence of clinically relevant CNS pathology were excluded from 
clinical studies. 
 
Monitor patients receiving BLINCYTO for signs and symptoms of neurological toxicities. Advise 
outpatients on BLINCYTO to contact their healthcare professional if they develop signs or 
symptoms of neurological toxicities. Interrupt or discontinue BLINCYTO as recommended in 
Table 1 above. 
 
Of note, most AEs in the psychiatric disorder category are unlikely to be caused by blinatumomab 
and generally require supportive care rather than dose modification or discontinuation of 
blinatumomab (e.g., Insomnia, Depression, Anxiety). Psychiatric AEs that may reflect underlying 
central nervous system toxicity (e.g., Confusion, Delirium, Hallucinations, Psychosis) are of 

 
 
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greater interest, particularly if accompanied by other AEs in the nervous system disorders 
category” follow the recommendations from the USPI.  
 
3. In the first days of treatment, transient DIC-like pictures may develop. Because patients are at risk 
for capillary leak syndrome and cytokine release syndrome, appropriate supportive care with 
dexamethasone (described above), blood products and factors (packed red cells, platelets, 
cryoprecipitate, fresh frozen plasma), vitamin K, and/or albumin should be considered according 
to institutional standards of care. Particularly in the first week of infusion, when the risk of 
capillary leak and cytokine release is more prominent, appropriate use of blood products and 
factors is preferred if laboratory indications suggest the need for replacement, as large volumes of 
crystalloid fluids tend to exacerbate the capillary leak.  
 
4. In the first days of treatment, a rapid transient drop in platelets, neutrophils and/or hemoglobin 
may be observed. These effects are not necessarily cytokine-mediated. Counts typically recover to 
baseline during treatment, and usually within two weeks of starting blinatumomab. Transfusion of 
blood and platelets should be performed according to appropriate institutional standards.  
 
5. In the first days of treatment, transient increases in transaminases up to over 1000 U/L may 
develop. These have generally returned to baseline in the 1st week of treatment.  
 
6. Decrease in serum immunoglobulins have been observed in patients treated with blinatumomab. 
Intravenous immunoglobulin should be administered according to institutional standards but is 
recommended for any patient with a total IgG level below 400. Immunoglobulin must not be 
administered through the line through which blinatumomab is actively being infused.  
 
* Definitions of supportive care abbreviations:  
 
DEX: Dexamethasone should be administered at a total daily dose of at least 0.2 - 0.4 mg/kg/day 
(maximum 24 mg per day) administered preferably intravenous divided 3 - 4 times daily for at 
least 1 day but no more than 4 days. The dose should then be stopped or tapered as clinically 
indicated. 
 
SZ: Appropriate imaging should be performed to evaluate for possible hemorrhage or thrombosis, 
and other diagnostic procedures should be performed as clinically appropriate. Prophylactic 
anticonvulsant treatment with a therapeutic dose of institutional standard agents (e.g., lorazepam, 
phenytoin, levetiracetam) should be administered if seizures develop, and continued throughout 
the blinatumomab infusion. Anti-convulsant therapy should be considered starting at least 24 - 48 
hours prior to any subsequent blinatumomab infusions and continuing for the remainder of those 
treatment cycles. Diagnostic measures to exclude potential infectious causes should be conducted 
once the patient has stabilized (i.e., a lumbar puncture to evaluate for bacterial, viral or fungal 
sources should be performed). Any identified pathology should be treated as clinically appropriate.  
 
CNS: A daily finger-nose-finger or writing sample test is recommended according to age-
appropriate activities for patients. In adults treated with blinatumomab, it has been found that a 
daily handwriting sample can often predict future nervous system toxicity before the clinical 
toxicity develops. In case of a change in finger-nose-finger or handwriting test it is recommended 
to start dexamethasone on the schedule above to prevent possible deterioration of nervous system 
toxicity. Patients who experience nervous system toxicity in the first cycle typically do not experience 
it again in subsequent cycles, although it is possible. 

 
 
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7.1 
Management of Cytokine Release Syndrome (CRS), Neurologic Toxicity and Acute 
Graft Versus Host Disease During or Following Blinatumomab 
 
7.1.1 Cytokine Release Syndrome (CRS) 
 
Treatment of CRS will be based on CTCAE (version 5.0) grading.  
 
Close monitoring of fluid status by intake and output should be undertaken for the first week of 
blinatumomab infusion. Efforts to keep patients balanced between intake and output should be 
maintained, even if diuretic therapy (furosemide or similar) is needed to do this. Careful attention 
to fluid status may prevent deterioration from capillary leak, however even with meticulous 
attention some patients will experience pulmonary edema and require more aggressive respiratory 
support. Treating physicians should use their clinical judgment and institutional standards for 
whatever supportive care measures are needed during this period of time.  
 
See Table 1 for indications to stop infusion of blinatumomab based on toxicity and CTCAE 
Grade. 
 
Grade 1: Infectious work-up, initiation/escalation of antibiotics per institutional standards. IV 
fluids, anti-pyretic therapy as indicated with cooling blankets and acetaminophen (avoid NSAIDs). 
Supportive care measures. 
 
Grade 2: Admission to hospital (if not admitted). IV fluids, infectious work-up, supportive care 
measures. 
 
Grade ≥ 3: Admission to Intensive Care Unit. Tocilizumab (8 mg/kg IV x 1; max dose 800 mg). 
Give a 2nd dose of tocilizumab if no response within 12-24 hours. Can give up to 2 doses of 
tocilizumab in 24 hours. For persistent symptoms, give solumedrol (1-2 mg/kg/day). 
 
7.1.2 Neurologic Toxicity 
 
Treatment of neurologic toxicity will be based on CTCAE (version 5.0) grading.  
 
See Table 1 for indications to stop infusion of blinatumomab based on toxicity and CTCAE 
Grade. 
 
 
Grade 1: Clinical vigilance, monitoring, supportive care 
 
 
 
Grade 2: Admission to hospital (if not admitted), neuro-checks Q4 hours, supportive care. 
Dexamethasone (10 mg IV/PO every 6-12 hours; max dose 10 mg Q6 hours) can be started at 
discretion of provider. 
 
 
Grade ≥ 3: Admission to Intensive Care Unit. Dexamethasone 10 mg IV/PO every 6-12 hours 
(max dose 10 mg Q6 hours). If not improving, consider tocilizumab (8 mg/kg IV x 1; max dose 
800 mg). Can give up to 2 doses of tocilizumab in 24 hours. 
 
7.1.3 Acute Graft Versus Host Disease (aGVHD) 
 

 
 
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Treatment of aGVHD that may flare/recur in patients includes both general supportive care of the 
patient and specific therapy directed at suppressing the immune process resulting in aGVHD. 
Specific therapy of aGVHD is based on the overall clinical grade of involvement. The grading of 
aGVHD is part of routine clinical care for patients receiving allogeneic blood or marrow 
transplants. 
 
1) Patients with Grade 1 aGVHD in the setting of matched unrelated, mismatched unrelated or 
mismatched related donors may receive treatment of Grade 1 aGVHD at the discretion of the 
attending physician.  
2) First line therapy for Grade ≥ 2 aGVHD: 
(a) Oral prednisone 1-2.5 mg/kg/day (or equivalent methylprednisolone at the discretion 
of the physician).  
(b) Topical steroids to affected areas of skin. Continue creams until one week after 
resolution of skin rash. 
(c) Use other immunosuppressive medications as clinically warranted. The introduction of 
other second line therapies will depend on clinical severity of steroid refractory 
aGVHD and donor type. 
 
8.0   
ADVERSE EVENTS: DEFINITIONS AND REPORTING REQUIREMENTS 
 
8.1   
Definitions 
 
8.1.1 Adverse Event (AE): Any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or condition temporally associated with the use of any study 
procedure or treatment, regardless of whether it is considered related to the study procedure 
or treatment. Any worsening of a pre-existing condition or illness will be considered an 
adverse event.  The investigator will evaluate all adverse experiences as to their severity 
and relationship to the vaccine as well as the regimen as a whole. 
 
8.1.2 Attribution: An assessment of the relationship between the AE and the medical 
intervention. CTCAE (Version 5.0) does not define an AE as necessarily “caused by a 
therapeutic intervention”. After naming and grading the event, the clinical investigator 
must assign an attribution to the AE using the following attribution categories:  
 
Relationship 
Attribution Description 
Unrelated to investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related to the intervention 
Unlikely 
The AE is doubtfully related to the intervention 
Related to investigational 
agent/intervention 
Possible 
The AE may be related to the intervention 
Probable 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention 
 
8.1.2.1 Relationship Assessment:  In-Depth Definitions 
 
For all collected AEs, the clinician who examines and evaluates the subject will determine the 
adverse event’s causality based on temporal relationship and his/her clinical judgment. The degree 
of certainty about causality will be graded using the categories below: 

 
 
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• Definitely Related: There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to drug administration and 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (de-challenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory re-
challenge procedure if necessary.  
 
• Probably Related: There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time sequence to administration of the drug, is unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (de-challenge). Re-challenge information is not 
required to fulfill this definition.  
 
• Possibly Related: There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, 
the influence of other factors may have contributed to the event (e.g., the subject’s clinical 
condition, other concomitant events). Although an adverse drug event may rate only as 
“possibly related” soon after discovery, it can be flagged as requiring more information 
and later be upgraded to “probably related” or “definitely related”, as appropriate. 
 
• Unlikely: A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the event 
did not occur within a reasonable time after administration of the trial medication) and in 
which other drugs or chemicals or underlying disease provides plausible explanations (e.g., 
the subject’s clinical condition, other concomitant treatments).  
 
• Unrelated: The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician.  
 
8.1.3  Expectedness: An AE is considered unexpected if the specificity or severity of the AE is 
not consistent with the protocol drug toxicity tables found in Section 8.0, or with available 
product information, or with the general investigational plan, or is unexpected in the 
professional opinion of the treating investigator. 
 
8.1.4  Expedited Reporting: SAE reporting to the coordinating site within five (5) calendar 
days of learning of the event 
 
 8.1.5 Onset and Resolution of Adverse Events:  If an adverse event occurs more than once in 
a course (cycle) of therapy only the most severe grade of the event should be reported. 
• If an adverse event progresses through several grades during one course of therapy, 
only the most severe grade should be reported. 
• The duration of the AE is defined as the duration of the highest (most severe) grade 
of the Adverse Effects. 
• The resolution date of the AE is defined as the date at which the AE returns to baseline 

 
 
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or less than Grade 1, whichever level is higher (note that the resolution date may 
therefore be different from the date at which the grade of the AE decreased from its 
highest grade).  If the AE does not return to baseline the    resolution date should be 
recorded as "ongoing." 
• An adverse event that persists from one course to another should only be reported 
once unless the grade becomes more severe in a subsequent course.  An adverse event 
which resolves and then recurs during a different course, must be reported each 
course it recurs. 
 
8.1.6   Protocol Therapy: Any of the study interventions (drugs) administered as part of this study. 
 
8.1.7  Serious Adverse Event (SAE): An adverse event that results in any of the following 
outcomes: 
 
Death of Patient:  An event that results in the death of a patient. 
 
Life-Threatening:  An event that, in the opinion of the investigator, would have resulted in 
immediate fatality if medical intervention had not been taken.  This does not include an event that 
would have been fatal if it had occurred in a more severe form. 
 
Hospitalization:  An event that results in an admission to the hospital for any length of time.  This 
does not include an emergency room visit or admission to an outpatient facility. Additionally, any 
hospitalization for the purpose of treatment as per the protocol or any standard of care treatment 
will not be considered an SAE. 
 
Prolongation of Hospitalization:  An event that occurs while the study patient is hospitalized and 
prolongs the patient’s hospital stay. 
 
Congenital Anomaly:  An anomaly detected at or after birth, or any anomaly that results in fetal 
loss. 
 
Persistent or Significant Disability/Incapacity:  An event that results in a condition that 
substantially interferes with the activities of daily living of a study patient.  Disability is not 
intended to include experiences of relatively minor medical significance such as headache, nausea, 
vomiting, diarrhea, influenza, or accidental trauma (e.g., sprained ankle). 
 
Important Medical Event Requiring Medical or Surgical Intervention to Prevent Serious 
Outcome:  An important medical event that may not be immediately life-threatening or result in 
death or hospitalization, but based on medical judgment may jeopardize the patient and may 
require medical or surgical intervention to prevent any of the outcomes listed above (i.e., death of 
patient, life-threatening, hospitalization, prolongation of hospitalization, congenital anomaly, or 
persistent or significant disability/incapacity).  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
8.1.8  Routine Reporting: AE reporting to the coordinating site at the time of the regularly 
scheduled time points listed in the Case Report Forms (CRFs). 
 

 
 
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8.2 
AE and SAE Reporting on Protocol 
 
8.2.1 Adverse Event Grading 
 
Grade Description 
0 
No AE (or within normal limits). 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
2 
Moderate; minimal, local or noninvasive intervention (e.g., packing cautery) 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 
 
8.3  
Known AEs List 
Known Risks and Side Effects Related to Blinatumomab Include Those Which Are: 
Very Common  
(In 100 people receiving 
blinatumomab, more than 10 
and up to 100 people may 
have) 
Common 
(In 100 people receiving 
blinatumomab, between 1 and 10 
people may have) 
Uncommon 
(In 1000 people receiving 
blinatumomab, between 1 
and 10 people may have) 
• Anemia (decreased red 
blood cells) which may 
require blood transfusion 
• Thrombocytopenia 
(decreased platelets, for 
clotting blood) 
• Leukopenia (decreased 
white blood cells) 
• Pyrexia (fever) 
• Infusion related reactions 
• Weight increased 
• Hypertension (high blood 
pressure) 
• Neutropenia (decreased 
neutrophils with fever 
• Increased hepatic 
enzymes (in the blood, 
which may be due to 
inflammation or damage 
to liver cells) 
• Tachycardia (rapid heart 
rate) 
• Edema (swelling of 
hands, legs, ankles, feet, 
face, or trunk) 
• Back pain 
• Leukopenia, Lymphopenia 
(decreased types of white blood 
cells)  
• Leukocytosis (increased white 
blood cells)  
• Lymphadenopathy (swelling in 
lymph nodes)  
• Hyperbilirubinemia (high levels of 
bilirubin in the blood)  
• Decreased immunoglobulins (in 
the blood, proteins made by the 
body’s immune system to fight 
against infections and foreign 
substances)  
• Increased alkaline phosphatase (in 
the blood can be due problems in 
your liver or in your bones)  
• Chills  
• Chest pain  
• Pain in the arms, legs and hands  
• Overdose, Accidental overdose  
• Weight increased  
• Hypertension (high blood pressure)  
• Flushing  
• Speech disorder  
• Cytokine storm, is a 
severe form of 
cytokine release 
syndrome which is 
described under the 
“Very Common” 
column. 
• Pancreatitis, 
inflammation of the 
pancreas that can be 
life-threatening or 
may even lead to 
death. Symptoms can 
include severe and 
persistent stomach 
pain, with or without 
nausea and vomiting.  
• Leukoencephalopathy, 
a rare, serious disorder 
of the white matter in 
the brain that can lead 
to severe disability 
and death and for 
which there is no 
known prevention, 

 
 
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Known Risks and Side Effects Related to Blinatumomab Include Those Which Are: 
Very Common  
(In 100 people receiving 
blinatumomab, more than 10 
and up to 100 people may 
have) 
Common 
(In 100 people receiving 
blinatumomab, between 1 and 10 
people may have) 
Uncommon 
(In 1000 people receiving 
blinatumomab, between 1 
and 10 people may have) 
• Bone pain 
• Headache 
• Insomnia (difficulty 
falling and/or staying 
asleep) 
• Cough 
• Rash 
• Hypotension (low blood 
pressure) 
• Infections in the blood  
including bacteria, fungi, 
viruses or infections in 
other organs. Serious 
infections can happen 
during and after treatment 
and can lead to death. 
Serious infections such as 
sepsis (infection in the 
bloodstream), and 
pneumonia (severe lung 
infection) have been 
reported in patients 
treated with 
blinatumomab. Your 
doctor may give you 
antibiotics to treat the 
infection or stop your 
treatment with 
blinatumomab 
• Infusion related reactions 
occur during or after the 
drug is given through the 
vein. Symptoms of 
infusion reaction may 
include headache, rash, 
itching, flushing, 
swelling, shortness of 
breath, nausea and 
sometimes vomiting. 
Severe infusion reactions 
can cause dizziness, 
severe skin reactions, 
• Dyspnea (difficulty breathing, 
wheezing or respiratory failure)  
• Hypersensitivity, allergic reactions 
to blinatumomab, including 
hypersensitivity, have been 
reported. Signs and symptoms of 
allergic reactions can be very 
similar to infusion reaction. If you 
have symptoms of an allergic 
reaction, you should contact the 
study doctor or his/her study staff 
immediately.  
• Hematophagocytic histiocytosis 
can occur with cytokine release 
syndrome, described under the 
“Very Common” column.  It is a 
life- threatening overactivity of 
your immune system caused by 
releasing large amounts of 
inflammatory cytokines. Your 
doctor may give you medications 
such as steroids and/or other 
medications to prevent or treat 
cytokine release syndrome.  
• Tumor lysis syndrome (a group of 
complications from release of large 
amounts of potassium, phosphate, 
and nucleic acid caused by the 
breakdown of tumor cells after 
cancer treatment). Tumor lysis 
syndrome may cause kidney 
failure, abnormal heart rhythm, and 
can even lead to death. Patients 
with moderate kidney failure 
showed an increased rate of tumor 
lysis syndrome compared with 
patients with mild kidney failure or 
normal kidney function. However, 
this did not lead to permanent 
discontinuation of treatment with 
blinatumomab. Your doctor may 
give you medicines before your 
treatment, or cure. 
Symptoms can include 
difficulty thinking, 
loss of balance, 
changes in speech or 
walking, weakness on 
one side of your body, 
or blurred or lost 
vision.  
• Capillary leak 
syndrome (leakage of 
fluid from small blood 
vessels into other 
body spaces that could 
cause swelling of the 
trunk, arms and legs)  
 

 
 
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Known Risks and Side Effects Related to Blinatumomab Include Those Which Are: 
Very Common  
(In 100 people receiving 
blinatumomab, more than 10 
and up to 100 people may 
have) 
Common 
(In 100 people receiving 
blinatumomab, between 1 and 10 
people may have) 
Uncommon 
(In 1000 people receiving 
blinatumomab, between 1 
and 10 people may have) 
difficulty breathing or 
swallowing, a decrease in 
blood pressure, and could 
be life threatening. Signs 
and symptoms of infusion 
reaction can be very 
similar to cytokine 
release syndrome. 
• Cytokine release 
syndrome is when your 
body releases substances 
called cytokines during 
the blinatumomab 
infusion. This can cause 
fever, chills, headache, 
decreased blood pressure, 
increased liver enzymes, 
nausea, and vomiting. 
Cytokine release 
syndrome symptoms 
generally are mild to 
moderate but 
occasionally can be 
serious or life- 
threatening or may even 
lead to death. Your 
doctor may give you 
medications such as 
steroids and/or other 
medications to prevent or 
treat cytokine release 
syndrome.  
treatment to help prevent tumor 
lysis syndrome.  
• Nervous system problems such as 
tremor (shaking), dizziness, 
seizures, somnolence (changes in 
alertness), paresthesia (abnormal 
skin sensation such as burning, 
prickling, tingling), hypoaesthesia 
(numbness), aphasia (difficulty 
speaking or slurred speech), 
cognitive disorder (difficulty 
understanding words), 
encephalopathy (loss of 
consciousness, brain malfunction), 
memory impairment (memory 
loss), confusion and/or 
disorientation, or loss of balance. 
These nervous system problems 
can be serious, or life-threatening 
or may even lead to death. Patients 
with a medical history of 
neurologic signs and symptoms 
had a higher rate of neurologic 
events (such as tremor, dizziness, 
confusion, encephalopathy and 
poor coordination). Your doctor 
will be closely monitoring you and 
may give you medications such as 
steroids and/or other medications 
to treat nervous system problems 
or stop your treatment with 
blinatumomab. 
 
 
 
8.4   
What & When to Report: Adverse events and Serious Adverse Events that meet the 
below criteria are to be collected. Use the CTCAE (Version 5.0) to code and grade AEs. These 
AEs are to be documented from the time the patient initiates protocol therapy until the patient 
meets off study criteria. The time frame for reporting of AEs depends on the grade, expectedness, 
attribution, and date of event in relation to the date of the patient’s first and last protocol treatment 
dose. Grade 1 and 2 AEs do not need to be reported.  
 

 
 
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Reporting Requirements for AEs that occur between Blinatumomab Day 1 until ≤ 30 Days post 
last dose of Blinatumomab OR until patient starts a new, non-protocol therapy (whichever 
occurs first): 
 
 
Grade 3 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
Unexpected or 
Expected 
Unexpected or 
Expected 
Unrelated, 
Unlikely 
Routine 
No report 
(Exception: 
Routine 
Report Grade 
3 infection) 
Expedited  
(Exception Grade 4 
hematological AEs to 
be routine reported) 
 
Expedited 
Possible, 
Probable, 
Definite 
Routine 
No report 
(Exception: 
Routine 
Report Grade 
3 infection) 
Expedited 
(Exception Grade 4 
hematological AEs to 
be routine reported) 
 
Expedited 
 
Reporting Requirements for AEs that occur between > 30 Days post last dose of Blinatumomab OR 
occur after the start of a new, non-protocol therapy (whichever occurs first) until patient meets Off 
Study criteria: 
 
 
Grade 3 
Grade 4 
Grade 5 
 
Unexpected Expected 
Unexpected or 
Expected 
Unexpected or 
Expected 
Unrelated, 
Unlikely 
Routine 
No report 
(Exception: 
Routine 
Report Grade 
3 infection) 
Routine* 
 
Routine* 
Possible, 
Probable, 
Definite 
Routine 
No report 
(Exception: 
Routine 
Report Grade 
3 infection) 
Expedited 
(Exception Grade 4 
hematological AEs to 
be routine reported) 
 
Expedited 
* Grade 4 and Grade 5 events that occur > 30 days post last dose of protocol therapy (or after the start of 
a new non-protocol therapy) and are considered unrelated or unlikely related to protocol therapy only 
require ROUTINE reporting (i.e. patient has recovered from protocol therapy).  
 
How to Report: 
• Routine Reporting – Complete the AE CRF and submit according to the schedule in the CRF 
instructions to crconc@mcw.edu.  
• Expedited Reporting – Complete the SAE CRF and email within 5 calendar days to 
crconc@mcw.edu.  
 
Coordinating Site’s Responsibilities: 
• Routine Reporting – To collect all data from participating sites and to submit data into 

 
 
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OnCore for DSMC review at regular intervals. 
• Expedited Reporting – To collect all data from participating sites, follow-up with 
participating sites for additional information as needed, and to submit data into OnCore for 
DSMC review within 5 calendar days. The coordinating site will submit reports to the CHW 
IRB according to policy. All participating sites should submit any events to the local IRB per 
local policy. 
 
8.5 
Unanticipated Problem Involving Risk to Subject or Other (UPIRSO) 
 
The investigator and his or her team will follow the CHW IRB policies related to unanticipated 
problems involving risks to subjects or others.  
 
8.6  
Time Period and Grade of AE Capture 
 
The period of AE capture will include from the beginning of any study procedures through 30 days 
following the end of the study treatment OR occur after the start of a new, non-protocol therapy 
(whichever occurs first) until patient meets Off Study criteria. 
 
The criteria for grading toxicities and criteria for dose modifications will be according to CTCAE 
(Version 5.0). 
 
8.7  
Monitoring and Recording an Adverse Event  
 
8.7.1 Reporting Source: AEs may be spontaneously reported by the patient and/or in response to 
an open question from study personnel or revealed by observation, physical examination or other 
diagnostic procedures.  
 
8.7.2 Prior to the Trial: Planned hospital admissions or surgical procedures for an illness or 
disease that existed before the patient was enrolled in the trial are not to be considered AEs unless 
the condition deteriorated in an unexpected manner during the trial (e.g., surgery was performed 
earlier or later than planned).  
 
8.7.3 Pretreatment Events Following Signed Informed Consent: For serious pretreatment 
events, the investigator must determine both the intensity of the event and the relationship of the 
event to study procedures.  
 
8.7.4 Treatment Events: For serious AEs, the investigator must determine both the intensity of 
the event and the relationship of the event to study drug administration.  
 
8.7.5 Not Serious AEs: For non-serious AEs, the investigator must determine both the intensity 
of the event and the relationship of the event to study drug administration. 
 
8.8  
Follow-Up of Adverse Events 
 
All adverse events will be followed with appropriate medical management 30 days following the 
last dose of the study drug or treatment or until they are resolved, if they are related to the study 
treatment. 
 
8.9  
Subject Complaints 

 
 
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If a complaint is received by anyone on the study staff, it will be discussed with the study staff and 
will be addressed on a case-by-case basis. The PI will be notified of any complaints. Complaints 
will be reported to the IRB if indicated.  
 
If the subject has questions about his or her rights as a study subject, wants to report any problems 
or complaints, obtain information about the study or offer input, the subject can contact the 
Children’s Hospital of Wisconsin Institutional Review Board (CHW IRB), whose purpose is to 
see that the rights and welfare of research participants are adequately protected, and that risks are 
balanced by potential benefits.  A member of this committee is available to speak to you if you 
have any questions or complaints at 414-337-7133   This information is provided to the subject in 
their consent.  
 
A product complaint is a verbal, written or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately contact the sponsor and report 
the event. Whenever possible, the associated product should be maintained in accordance with the 
label instructions pending further guidance from a sponsor representative. Product complaints in 
and of themselves are not Reportable Events. If a product complaint results in an SAE, an SAE 
form should be completed.  
 
8.10 
Routine Reporting Procedures for AEs 
 
Reporting to CHW Institutional Review Board 
 
The principal investigator must report events to the CHW IRB within five business days of his/her 
awareness of the event.  
 
Reporting to Amgen 
 
All Suspected Unexpected Serious Adverse Reactions (SUSARs) are to be reported to Amgen 
within 24 hours of reporting to a regulatory authority. A line‐listing of SAEs needs to be provided 
to Amgen safety every 6 months. 
 
Please see the table below which outlines reporting information.  
 
 
Event Type 
Report Recipients  
PI/Study Chair/ 
Coordinating 
Center 
Institutional 
Review 
Board 
DSMC 
 
 
CTO 
Regulatory 
Office 
Other 
Serious Adverse Event ASAP 
5 days (or 
annual CPR) 
5 days 
ASAP 
 
Unanticipated 
Problems Involving 
Risks to Subjects of 
Others 
ASAP 
5 days (or 
annual CPR) 
5 days 
ASAP 
 
Evidence of Causal 
Relationship between 
Drug and AE 
ASAP 
5 days (or 
annual CPR) 
5 days 
ASAP 
 

 
 
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Event Type 
Report Recipients  
PI/Study Chair/ 
Coordinating 
Center 
Institutional 
Review 
Board 
DSMC 
 
 
CTO 
Regulatory 
Office 
Other 
Dose-Limiting 
Toxicity 
ASAP 
5 days (or 
annual CPR) 
5 days 
ASAP 
 
CPR, continuing progress report 
 
9.0   
REPORTING AND DOCUMENTING RESULTS (MEASUREMENT OF EFFECT) 
 
Adverse Event information and reporting is in Section 8. 
 
9.1 
Evaluation of Efficacy (or Activity) 
 
9.1.1 Definitions 
 
Evaluable for Toxicity:  All patients will be evaluable for toxicity from the time of their first 
exposure to Blinatumomab. 
 
Evaluable for Objective Response:  Only those subjects who have measurable disease present at 
baseline, have received at least one therapy cycle and have had their disease re-evaluated will be 
considered evaluable for response. These subjects will have their response classified according to 
the definitions stated below. (Note:  Subjects who exhibit objective disease progression prior to 
the end of Cycle 1 will also be considered evaluable.) 
 
9.2 
Bone Marrow Response Criteria 
 
Complete Remission, MRD Negative (CR MRD) 
 
• A bone marrow with < 5% blasts by morphology (hematologic complete remission); 
AND  
• MRD < 0.01% by flow;  
AND 
• No evidence of circulating blasts or extramedullary disease;  
AND 
• Recovery of peripheral counts (ANC > 500/µL and PLT count > 50,000 µL).  
• Qualifying marrow and peripheral counts should be performed within 1 week of each 
other 
 
Complete Remission (CR) 
 
• A bone marrow with < 5% blasts by morphology (hematologic complete remission); 
AND  
• No evidence of circulating blasts or extramedullary disease;  
AND 
• Recovery of peripheral counts (ANC > 500/µL and PLT count > 50,000 µL).  
• Qualifying marrow and peripheral counts should be performed within 1 week of each 
other. 

 
 
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Complete Response with Incomplete Count Recovery (CRi) 
 
• A bone marrow with < 5% blasts by morphology (hematologic complete remission); 
AND  
• No evidence of circulating blasts or extramedullary disease;  
AND  
• Insufficient recovery of absolute neutrophil counts (ANC < 500/µL), and or insufficient 
recovery of platelets (PLT counts < 50,000/ul),  
 
Partial Remission (PR) 
 
• Complete disappearance of circulating blasts and one of the following:  
• A decrease of at least 50% of blasts in the bone marrow with > 5% and ≤ 20% blasts 
by morphology with recovery of peripheral counts (ANC > 500/µL and PLT count          
> 50,000 µL) 
 
Note: only patients who entered the study with ≥ 20% blasts in the marrow may be assessed 
as PR 
 
Stable Disease (SD) 
 
Patient does not satisfy the criterion for either CR, CRi, PR or disease progression. 
 
Progressive Disease (PD) 
 
An increase of at least 25% in the absolute number of bone marrow or circulating leukemic cells, 
development of new sites of extramedullary disease, or other laboratory or clinical evidence of 
progression of disease. 
 
Not Evaluable (NE) 
 
Aplastic or severely hypoplastic marrow without any blast percentage. Bone marrow 
aplasia/hypoplasia is defined as overall marrow cellularity less than 10-20%. In this instance, 
marrow evaluation should be repeated every 1-2 weeks until response determination can be made. 
 
Relapse 
 
After documentation of remission, one bone marrow aspirate and/or biopsy showing ≥ 5% 
leukemic blasts or pathological evidence of extramedullary disease. 
 
9.3 
Evaluation of Safety 
 
Analyses will be performed for all patients having received at least one dose of study drug. The 
study will use the CTCAE (Version 5.0) for reporting of nonhematologic adverse events and 
modified criteria for hematologic adverse events. See Section 8. 
 
10.0   STATISTICAL CONSIDERATIONS 
 

 
 
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10.1   Study Endpoints/Efficacy Variables 
 
 
10.1.1  Primary Efficacy Variables 
 
The primary efficacy variable is the percent of subjects that remain in Complete Remission (CR) 
and become Flow Cytometry-MRD negative (FC-MRD negative) < 0.01% (Flow Cytometry 
performed at the University of Washington, Brent Wood, MD or local lab if applicable) after 
completion of 1 or 2 cycles of blinatumomab. 
 
10.1.2 Secondary Efficacy Variables 
 
• The percent of subjects that remain in CR, achieve MRD negative by Flow Cytometry           
(< 0.01%) and by molecular High-Throughput Deep Sequencing (HTS-MRD negative) 
(MRD undetectable) (Adaptive Technologies, Seattle, WA) after completion of 1 to 2 
cycles of Blinatumomab. 
 
10.2  Study Design 
 
This is an open label non-blinded Phase 2 study of up to 35 children, adolescent and young adults 
with B-ALL and MRD ≥ 0.01%. The study will continue until there are at least 25 evaluable 
subjects who are FC-MRD negative (< 0.01%) or 35 subjects are recruited.  
 
 
10.3   Determination of Sample Size and Accrual Rate 
 
10.3.1   Sample Size and Power Estimate 
 
Blinatumomab has been evaluated in children with relapsed/refractory B-ALL. Among the 70 
pediatric patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) 
achieved complete remission (CR) within the first two cycles, 14 (52% of 70 or 20% overall) of 
whom achieved complete MRD negative response. If we were to receive this response our 95% CI 
would be 9.8%, with 35 patients. In our patients who will be in a complete remission (< 5% blasts) 
at the time of receiving blinatumomab, we expect a higher response rate than what was reported 
in the pediatric trial for relapse/refractory patients. For 35 subjects, with the widest margin for a 
one-sided CI of 0.15 when the proportion is 0.5 we will have a reasonable estimate.  
 
It is expected that the study will complete recruitment in 30 to 36 months. If there is an 80% rate 
of MRD negative (< 0.01%) subjects, a total of 25 evaluable subjects will be recruited. The 95% 
confidence interval will be (0.59,0.93) for 25 patients. If we must recruit 35 total subjects, we 
would expect that the proportion will be no less than 0.67 with a 95% CI of (0.47,0.83). 
 
We expect ~40% (10 patients) will be HTS-MRD negative (undetectable MRD). With 25 
evaluable subjects recruited the 95% CI would be (0.21,0.61). 
 
10.3.2   Accrual Estimates  
 
We expect to have 8-10 eligible subjects per year with about 6 to 8 consenting per year. Thus, the 
time to accrual will be 30 to 36 months. 
 
10.4   Interim Analyses, Missing Data and Stopping Rules 

 
 
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A planned interim analysis will be performed upon enrolling 12 evaluable subjects. Using a 
Fleming 2-stage design with a target accrual goal of 25 subjects, our null hypothesis is that the 
response rate is less than or equal to 0.400 versus the alternative that it is greater. Success for this 
study will be a response rate of at least 67% MRD negativity (< 0.01%). At the first stage we have 
12 evaluable subjects and the cumulative number of successes, R, will be compared to the 
acceptance value and rejection value numbers for that stage. If R ≤ 4, the study committee will 
reevaluate the study and determine if changes to the protocol design are necessary.  If R ≥ 10, then 
there is a very high chance of success. Similarly, after 25 evaluable subjects are recruited, if               
R < 15 we would not have met our 60% threshold. The type I error rate would be 0.0333. The 
power, calculated at a response rate of 0.670, is 0.8071. The calculation is done using PASS 15. 
 
Missing Data: The dropout pattern will be plotted and summarized. Subjects who dropout before 
the first cycle of blinatumomab is completed will not have an MRD assessment. Subjects that are 
not MRD negative (≥ 0.01%) at the end of the first cycle, proceed to a second cycle of 
blinatumomab, but dropout before the second cycle is completed will not have a final MRD 
assessment. Our primary outcome is the number of subjects who can achieve FC-MRD negativity 
(< 0.01%) after one or two cycles of blinatumomab.  Hence the primary assessment is the 
proportion of subjects achieving FC-MRD negativity and completing these treatments.  
However, secondary outcomes will include:  
• The proportion of subjects achieving FC-MRD negativity (< 0.01%) after completing the 
first cycle of blinatumomab. 
• The proportion of subjects achieving HTS-MRD negativity (MRD undetectable) after 
completing the first cycle of blinatumomab. 
• The proportion of subjects achieving FC-MRD negativity (< 0.01%) out of all subjects 
recruited.  
• The proportion of subjects achieving HTS-MRD negativity (MRD undetectable) out of all 
subjects recruited.  
 
Patients who drop out or are removed from the study due to an adverse symptom profile will be 
reported as a safety outcome. Characteristics of these will be summarized. The occurrence of toxic 
death (TD) at any time during protocol therapy will be a primary endpoint for safety monitoring 
and a stopping rule. A population toxic death rate that exceeds p0=0.10 will be considered 
unacceptable. Operationally, this criterion will be satisfied if the following fractions of TDs out of 
total patients treated are exceeded: ≥ 1/5, ≥ 2/12, ≥ 3/20, ≥ 4/28, and so on as dictated by this rule. 
If this criterion is satisfied at any time the cause and circumstances of these deaths will be reviewed 
with the study committee and with the Data and Safety Monitoring Committee to determine 
whether modifications to or termination of the study is warranted. 
 
10.5 
Analyses Plans 
 
The primary objective is to determine the efficacy of giving blinatumomab immediately prior to 
HCT as “bridging therapy” to eliminate MRD (as measured by flow cytometry) in children, 
adolescents and young adults with relapse, refractory or persistent MRD B-ALL. 
 
10.6   Analysis Population 
 

 
 
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This will include all subjects who have completed at least one course of blinatumomab and for 
whom there is an assessment of MRD. This will be the primary efficacy analysis group since 
we will assess the ability to proceed for HCT.  
 
All Enrolled Cases:  This will include all subjects enrolled. If any dropout or die they will be 
 
included in the MRD positive group. This is a less enriched group and will be mainly used for 
 
assessment of feasibility of the treatment.  
 
Per Protocol Cases:  The per-protocol population will be defined as the subset of the observed 
cases (OC) who completed all treatments and who did not have any major protocol violations (such 
as lack of compliance to the study medication schedule). The definitions of these protocol 
violations will be finalized before the database closure and will be documented in the analysis 
plan. The analysis of this group will be exploratory.  
 
10.7    Primary Analysis (or Analysis of Primary Endpoints) 
 
10.7.1 Endpoints to be Collected 
 
• FC-MRD: minimal residual disease measured by flow cytometry at the end of each cycle 
of blinatumomab. 
• HTS-MRD: minimal residual disease measured by high throughput sequencing at the end 
of each cycle of blinatumomab. 
• Severe Adverse Events: Grade 3 and 4 adverse events attributed to blinatumomab. 
• Toxic death rate: deaths attributed to blinatumomab treatment prior to HCT. 
 
10.7.2 Primary Endpoint  
 
The proportion of subjects who are FC-MRD negative (< 0.01%) will be summarized with 95% 
CI. 
 
10.7.3 Secondary Analysis (or Analysis of Secondary Endpoints) 
 
10.7.3.1 Secondary Endpoints 
 
• The proportion who are HTS-MRD negative (MRD undetectable) will be summarized with 
95% CI. 
 
10.7.4 Other Analyses/Assessments 
 
We will summarize by and compare the subgroups of those who are MRD negative by Flow 
Cytometry AND HTS will be compared to those subjects who are MRD negative by only Flow 
Cytometry (HTS MRD positive) by demographics and by # of cycles (incomplete, 1 or 2). For 
comparison of continuous data, we will use a t-test or non-parametric Mann Whitney test, if needed 
due to distribution. For categorical data we will use a Fisher exact test.  
 
 
10.7.5    Evaluation of Safety 

 
 
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Safety population:  The safety population will consist of all subjects who have received any 
amount of blinatumomab, whether withdrawn prematurely or not.  
 
All information on AEs and SAEs will be listed by patient and will be summarized. The SAE 
report will include event term(s), serious criteria, and the sponsor-investigator’s or sub-
investigator’s determination of both the intensity of the event(s) and the relationship of the event(s) 
to study drug administration. Intensity for each SAE, including any lab abnormalities, will be 
determined by using the NCI CTCAE (Version 5.0) as a guideline whenever possible.  
 
Frequencies will be presented for the categorical variables (e.g., race) and descriptive statistics 
will be presented for continuous variables (e.g., weight, age). 
 
10.7.6    Adverse Events of Special Interest (Immediately Reportable to the Sponsor) 
 
Adverse events of special interest are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 8.4 for reporting 
instructions). Adverse events of special interest for this study are as follows: Cytokine Release 
Syndrome (CRS) and Neurological Adverse Events. 
 
11.0    DATA AND SAFETY MONITORING PLAN (DSMP) 
 
Please refer to the MCWCC DSMC Charter.  
 
 
11.1 
Data and Safety Management Overview 
 
The Medical College of Wisconsin (MCW) Data Safety Monitoring Committee (DSMC) and the 
Children’s Hospital of Wisconsin Institutional Review Board (CHW IRB) will approve protocol-
specific DSM plans. A local,  investigator-initiated trial will be required to be continuously 
monitored by the principal investigator of the study with (biannual, monthly) safety and progress 
reports submitted to the DSMC.  
 
11.1.1  Study Team 
 
The study team minimally consists of the principal investigator, the clinical research coordinator, 
regulatory specialist, and the study biostatistician. While subjects are on treatment, the principal 
investigator will meet regularly with the research coordinator and the study biostatistician to 
review study status (attendees and time periods should be modified so as to make sense within the 
context of the study). This review will include but not be limited to reportable SAEs and UPIRSOs 
and an update of the ongoing study summary that describes study progress in terms of the study 
schema. The appropriateness of further subject enrollment and the specific intervention for a next 
subject enrollment is addressed. SAE and any AEs requiring assigning of attribution are discussed 
and recorded via email or by physician signature on applicable documentation. 
 
The CHW CTO DVL, Leukemia/Lymphoma, and HCT groups meet weekly to discuss upcoming 
protocols, SAEs, existing patients, and new patients.  Individual SAEs are discussed with the 
attending provider as needed. 
 
11.1.2 Quality Assurance  

 
 
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This protocol will be reviewed internally every six months by MCW CTSI staff. Approximately 
30% of subject files will be selected randomly for review (max 5 subjects at each monitoring 
timepoint). Consent, eligibility and objective based data will be reviewed for those files selected. 
One file will be selected randomly for a comprehensive review at each quality assurance review 
timepoint. Regulatory will also be reviewed each time.  
 
11.1.3 Clinical Trials Office 
 
The MCWCC CTO provides administrative assistance and support to the DSMC.  
 
11.1.4 DSMC 
 
The Pediatric CTO places the highest priority on ensuring the safety of patients participating in 
clinical trials. Every cancer interventional trial conducted at CHW includes a plan for safety and 
data monitoring. 
 
More information can be found related to the MCWCC Data and Safety Monitoring Plan at the 
MCWCC website (Data and Safety Monitoring Plan).  
 
This study will be reviewed by the Medical College of Wisconsin Cancer Center Data and Safety 
Monitoring Committee (MCWCC DSMC). A summary of the MCWCC DSMC activities are as 
follows:  
• Review the clinical trial for data integrity and safety  
• Review all unexpected Grade 3, and all Grade 4, and 5 adverse events (with the exception of 
Grade 4 hematological AEs, which can be routine reported), as well as any others requiring 
expedited reporting as defined in this protocol. (Grades 4 & 5 events must be reported to the 
DSMC within 5 calendar days of study staff’s knowledge.) 
• Review all DSM reports  
• Submit a summary of any recommendations related to study conduct  
• Terminate the study if deemed unsafe for patients  
 
A copy of the MCWCC Data and Safety Monitoring Plan and membership roster will be 
maintained in the study research file and updated as membership changes. The committee will 
review reports from the study PI twice annually (or more frequently if needed) and provide 
recommendations on trial continuation, suspension or termination as necessary.  
 
Any available DSMC letters will be submitted to the IRB of record as required. 
 
11.2 
Monitoring 
 
The PI at each participating center is responsible for monitoring this study for accuracy of data 
and protocol compliance at their institution.  Patient eligibility will be confirmed by Dr. Michael 
Burke before each patient is enrolled. 
 
The PI, data coordinators, and research nurses are responsible for review and maintenance of all 
patient records at their individual institution to ensure data integrity and protocol adherence. 
The site PI will permit study-related monitoring, audits, and inspections by the MCW 

 
 
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compliance groups, as necessary.  The investigator will make available all study related 
documents (i.e. source documents, regulatory documents, data collection instruments, study data, 
etc.).  The investigator will ensure the capability for inspections of applicable study-related 
facilities (i.e. pharmacy, diagnostic laboratory, etc.) will be available for trial related monitoring, 
audits, or regulatory inspections. 
 
12.0    REGULATORY COMPLIANCE, ETHICS AND STUDY MANAGEMENT 
 
12.1 
Ethical Standard 
 
This study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and all applicable 
regulatory requirements. 
 
12.2 
Regulatory Compliance 
 
This study will be conducted in compliance with: 
• The protocol 
• Federal regulations, as applicable, including: 21 CFR 50 (Protection of Human 
Subjects/Informed Consent); 21 CFR 56 (Institutional Review Boards) and §312 
(Investigational New Drug Application; and 45 CFR 46 Subparts A (Common Rule), B 
(Pregnant Women, Human Fetuses and Neonates), C (Prisoners), and D (Children), 
GCP/ICH guidelines, and all applicable regulatory requirements. The IRB must comply 
with the regulations in 21 CFR §56 and applicable regulatory requirements. 
 
12.3 
Pre-Study Documentation  
 
Prior to implementing this protocol at the Pediatric CTO, the protocol, informed consent form, 
HIPAA authorization, and any other information pertaining to participants must be approved by 
the CHW IRB.  
 
The clinical investigation will not begin until the following conditions have been met, as 
applicable: 
• The FDA has determined that the study under the Investigational Drug Application (IND) 
is allowed to proceed 
OR 
• The Investigator has received a letter from FDA stating that the study is exempt from IND 
requirements 
OR 
• The study meets all of the following IND Exempt requirements (as applicable): 
o The drug product is lawfully marketed in the United States 
o The investigation is not intended to be reported to FDA as a well-controlled study in 
support of a new indication and there is no intent to use it to support any other 
significant change in the labeling of the drug 
o In the case of a prescription drug, the investigation is not intended to support a 
significant change in the advertising for the drug 
o The investigation does not involve a route of administration, dose, patient population, 
or other factor that significantly increases the risk (or decreases the acceptability of the 

 
 
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risk) associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)) 
o The investigation is conducted in compliance with the requirements for review by an 
IRB (21 CFR part 56) and with the requirements for informed consent (21 CFR part 
50) 
o The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the 
investigation is not intended to promote or commercialize the drug product).  
 
12.4 
Institutional Review Board 
 
The protocol, the proposed informed consent form, and all forms of participant information related 
to the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the 
CHW IRB.  
 
Prior to obtaining CHW approval, the protocol must be approved by the Medical College of 
Wisconsin Cancer Center Scientific Review Committee. The initial protocol and all protocol 
amendments must be approved by the IRB prior to implementation.  
 
12.5 
Informed Consent Process 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Extensive discussion of risks 
and possible benefits of this therapy will be provided to the subjects and their families. Consent 
forms describing in detail the study interventions/products, study procedures and risks are given 
to the subject and written documentation of informed consent is required prior to starting 
intervention/administering study product. 
 
Consent forms will be IRB-approved and the subject (and Legally Authorized Representative, if 
necessary) will be asked to read and review the document. Upon reviewing the document, the 
investigator will explain the research study to the subject and answer any questions that may arise. 
In accordance with 46 CR 46.111, the subject will sign and date the informed consent document 
prior to any procedures being done specifically for the study.  
 
A witness should only sign when required, per CHW IRB policy. If a witness signs the document 
when not required, the study staff should document in the legal medical record (or note to file) the 
relationship to the patient and why a witness signed. (i.e., “Although not required, the subject’s 
spouse was present during the consenting process and signed as the witness.” Or “Although not 
required, hospital staff was present for consenting process and signed as a witness.”) 
 
The subjects will have the opportunity to discuss the study with their surrogates or think about it 
prior to agreeing to participate. The subjects may withdraw consent at any time throughout the 
course of the trial.  
 
A copy of the informed consent document will be given to the subjects for their records. The rights 
and welfare of the subjects will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. If there are 
changes to the consent form, all revisions will be reviewed with study subject at the next 
appropriate opportunity. Subjects that require re-consenting will be defined in the IRB approved 
amendment submission. The process for obtaining informed consent will again be performed. 
Study subjects will not be re-consented for continuing reviews. The Pediatric CTO will follow the 

 
 
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CHW IRB’s policy for subjects who demonstrate limited English proficiency or limited literacy. 
 
After the subject’s visit in which the consent is signed, it is documented in the clinic chart that the 
consent has been signed and that all questions have been answered to the subject’s satisfaction 
after adequate time for review of the consent. It is also documented that a copy of the consent is 
given to the subject. The original consent is kept with the subject’s study file, and a copy of the 
signed consent is sent to the Medical Records Office to be scanned into EPIC, the legal medical 
record. 
 
12.6  Subject Confidentiality and Access to Source Documents/Data 
 
Subject confidentiality must be contained at all material submitted to the key sponsor contact. The 
following rules are to be applied:  
• Subjects will be identified by a unique identification number  
• Date of birth or year of birth/age at time of enrollment will be reported according with local 
laws and regulations  
 
For reporting of serious adverse events, subjects will be identified by their respective subject 
identification number, initials and data of birth (as per their local reporting requirements for both 
initials and date of birth). 
 
Per federal regulations and ICH/GCP guidelines, investigators and institutions are required to 
permit authorization to the sponsor, CRO, IRB/IEC and regulatory agencies to subject’s original 
source documents for verification of study data. The investigator is responsible for informing 
potential subjects that such individuals will have access to their medical records which includes 
personal information. 
 
12.7  Protection of Human Subjects 
 
12.7.1 Protection from Unnecessary Harm 
 
Each clinical site is responsible for protecting all subjects involved in human experimentation. 
This is accomplished through the IRB mechanism and the informed consent process. The IRB 
reviews all proposed studies involving human experimentation and ensures that the subject’s rights 
and welfare are protected and that the potential benefits and/or the importance of the knowledge 
to be gained outweigh the risks to the individual. The IRB also reviews the informed consent 
document associated with each study in order to ensure that the consent document accurately and 
clearly communicates the nature of the research to be done and its associated risks and benefits. 
 
12.7.2 Protection of Privacy 
 
As noted, patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, they will 
be asked to sign informed consent documents. The original signed document will become part of 
the patient’s medical records, and each patient will receive a copy of the signed document.  
 
12.8 
Changes in the Protocol 
 
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documented in the form of an amendment. The amendment must be signed by the investigator and 
approved by IRB prior to implementation.  
 
If the protocol is amended, the investigators agreement with the amendment and the IRB/IEC 
approval of the amendment must be obtained. Documentation acknowledging approval from both 
parties are to be submitted to the key sponsor contact. 
 
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval. In this circumstance, however, the 
Investigator must then notify the IRB in writing within five working days after implementation.  
 
The IRB may provide, if applicable regulatory authority(ies) permit, expedited review and 
approval/favorable opinion for minor change(s) in ongoing studies that have the 
approval/favorable opinion of the IRB. The investigator will submit all protocol modifications to 
the sponsor and the regulatory authority(ies) in accordance with the governing regulations. 
 
Both CHW and the investigator reserve the right to terminate the investigators participation in the 
study as per the terms of the agreement in the study contract. The investigator is to provide written 
communication to the IRB/IEC of the trial completion or early termination and provide CHW with 
a copy of the correspondence.  
 
12.9 
Investigator Compliance  
 
The investigator will conduct the study in compliance with the protocol given approval/favorable 
opinion by the IRB and the appropriate regulatory authority(ies).  
 
Onsite Audits/Monitoring 
 
Auditing is essential to ensure that research conducted at the Pediatric CTO is of the highest quality 
and meets regulatory agency standards.  
 
Regulatory authorities, the IRB, and/or sponsor may request access to all source documents, data 
capture records, and other study documentation for on-site audit or inspection. Direct access to 
these documents must be guaranteed by the investigator, who must provide support at all times for 
these activities. 
 
The key sponsor contact, monitors, auditors or regulatory inspectors are responsible for contacting 
and visiting the investigator for the purpose of inspecting the facilities and verifying source 
documents and records assuring that subject confidentially is respected.  
 
The monitor is responsible for source document verification of CRF data at regular intervals during 
the study. Protocol adherence, accuracy and consistency of study conduct and data collection with 
respect to local regulations will be confirmed. Monitors will have access to subject records as 
identified in Section 13.4.  
 
By signing the investigator agreement, the investigator agrees to cooperate with the monitor to 
address and resolve issues identified during monitoring visits.  
 
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would include, but is not limited to, an inspection of the facility (ies), review of subject and study 
related records, and compliance with protocol requirements as well as ICH GCP and applicable 
regulatory policies.  
 
All data will be collected in an electronic CRF system. All entries must be completed in English 
and concomitant medications should be identified by trade names. For further details surrounding 
the completion of CRFs, please refer to the CRF completion guidelines. 
 
13.0    DATA HANDLING AND RECORD KEEPING 
 
13.1 
Overview 
 
Every effort is made to uphold the integrity of the project, the research, the institution, and the 
researchers involved. Data collection guidelines and methodologies are carefully developed before 
the research begins. Investigators focus on the following to ensure data integrity:  well-trained data 
collectors/recorders to ensure consistency and quality, well-designed data collection protocols and 
ongoing monitoring. In this way, study rigor and validity are maintained. Data is protected from 
physical damage as well as from tampering, loss or theft. This project’s data management is a 
multidisciplinary activity that includes investigators, research coordinators and nurses, data 
mangers, support personnel, biostatisticians and database programmers. Quality control will be 
applied to each stage of data handling to ensure that all data are reliable and have been processed 
correctly.  
 
13.2 
Data Management Responsibilities 
 
13.2.1 Principal Investigator 
 
The principal investigator oversees the management of patient records/case report forms and 
ensures that a) complete and accurate data will be obtained and provided to the sponsor; b) patient 
records are maintained to include history, prescribed medication and investigational product(s), 
measurements, exams, evaluations and adverse events; c) corrections are applied to clinical 
research data according to principles of good research practice (i.e., single-line delete, date and 
initial). He or she will ensure that there is correlation between the case report forms and the source 
documents.  
 
13.2.2 Research Coordinator  
 
A research coordinator creates, collects and organizes clinical trial documentation. He or she 
ensures that source documentation and data abstraction and entry are being done at protocol 
specified time points. 
 
13.2.3 Research Nurse/Medical Staff 
 
The research nurse and medical staff documents protocol-required care or assessment of the 
subject’s outcomes, adverse events and compliance to study procedures. 
 
13.2.4 Biostatistician 
 
The biostatistician may assist in CRF development (content and design), dataset specifications 

 
 
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(annotation of CRFs and record layout) and validation. 
 
13.3 
Source Documents 
 
The investigator will maintain a list of qualified staff to whom study responsibilities have been 
delegated. These individuals authorized to fulfil these responsibilities should be outlined and 
included in the Delegation of Authority Form.  
 
Source documents are original documents, data and records for which the study data are collected 
and verified. Example of such source documents may include, but are not limited to, hospital 
records and patient charts, laboratory, pharmacy, radiology and records, subject diaries, 
microfiches, correspondence and death registries. Case report form entries may be considered as 
source data if the site of the original data collection is not available. However, use of the CRFs as 
source documentation as a routine practice is not recommended.  
 
The investigator and study staff are responsible for maintaining a comprehensive and centralize 
filing system of all subject records that are readily retrieved to be monitored and or audited at any 
time by the key sponsor contact, regulatory authorities and IRB/IECs. The filing system will 
include at minimum:  
• Subject content including assents/consents and subject identification lists  
• Protocols and protocol amendments, investigator brochure, copies of pre-study 
documentation, and all IRB/IEC and sponsor communication  
• Proof of receipt, experimental treatment flow records and experimental product related 
correspondence.  
 
Original source documents supporting entries into CRFs must be maintained at the site and readily 
available upon request. No study documents should be discarded without prior written agreement 
between CHW and the investigator. Should storage no longer be available to archive source 
documents or must be moved to an alternative location, the research staff should notify the key 
sponsor contact prior to the shipping the documents. 
 
All source documents will be written following ALCOA standards as follows:  
ALCOA Attribute 
Definition 
Attributable 
Clear who has documented the data. 
Legible 
Readable and signatures identifiable. 
Contemporaneous 
Documented in the correct time frame along with the flow of 
events. If a clinical observation cannot be entered when made, 
chronology should be recorded. Acceptable amount of delay 
should be defined and justified. 
Original  
Original, if not original should be exact copy; the first record 
made by the appropriate person. The investigator should have the 
original source document. 
Accurate 
Accurate, consistent and real representation of facts. 
Enduring 
Long-lasting and durable. 
Available and Accessible 
Easily available for review by treating physicians and during 
audits/inspections. The documents should be retrievable in 
reasonable time. 
Complete 
Complete until that point in time. 

 
 
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ALCOA Attribute 
Definition 
Consistent 
Demonstrate the required attributes consistently. 
Credible 
Based on real and reliable facts. 
Corroborated 
Data should be backed up by evidence. 
 
13.4 
Case Report Forms  
 
The principal investigator and/or his/her designee will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study. Study-specific Case 
Report Forms (CRFs) will document safety and treatment outcomes for safety monitoring and data 
analysis. All study data will be entered into OnCore® via standardized CRFs, in accordance with 
the study calendar, using single data entry with a secure access account. The Clinical Research 
Coordinator will complete the CRFs as soon as possible upon completion of the study visit; the 
investigator will review and approve the completed CRFs.  
 
The information collected on CRFs shall be identical to that appearing in original source 
documents. Source documents will be found in the patient’s medical records maintained by 
Pediatric CTO personnel. All source documentation should be kept in separate research folders for 
each patient. 
 
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The principal investigator will 
approve all completed CRFs to attest that the information contained on the CRFs is true and 
accurate.  
 
All source documentation and data will be available for review/monitoring by the MCWCC DSMC 
and regulatory agencies. 
 
13.5 
Study Record Retention 
 
The principal investigator is required to maintain adequate records of the disposition of the drug, 
including dates, quantity and use by subjects, as well as written records of the disposition of the 
drug when the study ends.  
 
The principal investigator is required to prepare and maintain adequate and accurate case histories 
that record all observations and other data pertinent to the investigation on each individual 
administered the investigational drug or employed as a control in the investigation. Case histories 
include the case report forms and supporting data including, for example, signed and dated consent 
forms and medical records including, for example, progress notes of the physician, the individual's 
hospital chart(s), and the nurses' notes. The case history for each individual shall document that 
informed consent was obtained prior to participation in the study. 
 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
sponsor-investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research study. 
In accordance with FDA regulations, the investigator shall retain records for a period of two years 
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is being investigated; or, if no application is to be filed or if the application is not approved for 
such indication, until two years after the investigation is discontinued and FDA is notified. 
 
The investigator will retain study records including source data, copies of case report forms, 
consent forms, HIPAA authorizations, and all study correspondence in a secured facility for 10 
years after the study file is closed with the IRB. 
 
In addition, the Pediatric CTO will keep a master log of all patients participating in the study with 
sufficient information to allow retrieval of the medical records for that patient.  Please contact the 
CTO before destroying any study related records. 
 
 
REFERENCES  
 
1. 
Society AC. Cancer Facts and Figures. American Cancer Society. 2007;Atlanta, GA. 
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Mateos MK, O'Brien TA, Oswald C, et al. Transplant-related mortality following allogeneic 
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Miglino M, Berisso G, Grasso R, et al. Allogeneic bone marrow transplantation (BMT) for adults 
with acute lymphoblastic leukemia (ALL): predictive role of minimal residual disease monitoring 
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Knechtli CJ, Goulden NJ, Hancock JP, et al. Minimal residual disease status before allogeneic 
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adolescents with acute lymphoblastic leukemia. Blood. 1998;92(11):4072-4079. 
5. 
Foster JH, Hawkins DS, Loken MR, Wells DA, Thomson B. Minimal residual disease detected 
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Bader P, Kreyenberg H, Henze GH, et al. Prognostic value of minimal residual disease 
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journal of the American Society of Clinical Oncology. 2009;27(3):377-384. 
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Pulsipher MA, Bader P, Klingebiel T, Cooper LJ. Allogeneic transplantation for pediatric acute 
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American Society for Blood and Marrow Transplantation. 2009;15(1 Suppl):62-71. 
8. 
Goulden N, Bader P, Van Der Velden V, et al. Minimal residual disease prior to stem cell 
transplant for childhood acute lymphoblastic leukaemia. British journal of haematology. 
2003;122(1):24-29. 
9. 
Krejci O, van der Velden VH, Bader P, et al. Level of minimal residual disease prior to 
haematopoietic stem cell transplantation predicts prognosis in paediatric patients with acute 
lymphoblastic leukaemia: a report of the Pre-BMT MRD Study Group. Bone marrow 
transplantation. 2003;32(8):849-851. 
10. 
Sramkova L, Muzikova K, Fronkova E, et al. Detectable minimal residual disease before 
allogeneic hematopoietic stem cell transplantation predicts extremely poor prognosis in children 
with acute lymphoblastic leukemia. Pediatric blood & cancer. 2007;48(1):93-100. 

 
 
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11. 
Eckert C, Henze G, Seeger K, et al. Use of allogeneic hematopoietic stem-cell transplantation 
based on minimal residual disease response improves outcomes for children with relapsed acute 
lymphoblastic leukemia in the intermediate-risk group. Journal of clinical oncology : official 
journal of the American Society of Clinical Oncology. 2013;31(21):2736-2742. 
12. 
Pulsipher MA, Langholz B, Wall DA, et al. The addition of sirolimus to tacrolimus/methotrexate 
GVHD prophylaxis in children with ALL: a Phase 3 Children's Oncology Group/Pediatric Blood 
and Marrow Transplant Consortium trial. Blood. 2014;123(13):2017-2025. 
13. 
Ko RH, Ji L, Barnette P, et al. Outcome of patients treated for relapsed or refractory acute 
lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium study. 
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 
2010;28(4):648-654. 
14. 
Pulsipher MA, Carlson C, Langholz B, et al. IgH-V(D)J NGS-MRD measurement pre- and early 
post-allotransplant defines very low- and very high-risk ALL patients. Blood. 2015;125(22):3501-
3508. 
15. 
Nguyen K, Devidas M, Cheng SC, et al. Factors influencing survival after relapse from acute 
lymphoblastic leukemia: a Children's Oncology Group study. Leukemia. 2008;22(12):2142-2150. 
16. 
Handgretinger R, Zugmaier G, Henze G, Kreyenberg H, Lang P, von Stackelberg A. Complete 
remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post-
transplant relapsed acute lymphoblastic leukemia. Leukemia. 2011;25(1):181-184. 
17. 
Klinger M, Brandl C, Zugmaier G, et al. Immunopharmacologic response of patients with B-
lineage acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-
bispecific BiTE antibody blinatumomab. Blood. 2012;119(26):6226-6233. 
18. 
Topp MS, Gokbuget N, Zugmaier G, et al. Long-term follow-up of hematologic relapse-free 
survival in a Phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 
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19. 
Topp MS, Kufer P, Gokbuget N, et al. Targeted therapy with the T-cell-engaging antibody 
blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute 
lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free 
survival. Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. 2011;29(18):2493-2498. 
20. 
von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/Phase II Study of Blinatumomab in 
Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. Journal of clinical 
oncology : official journal of the American Society of Clinical Oncology. 2016;34(36):4381-4389. 
21. 
Teachey DT, Rheingold SR, Maude SL, et al. Cytokine release syndrome after blinatumomab 
treatment related to abnormal macrophage activation and ameliorated with cytokine-directed 
therapy. Blood. 2013;121(26):5154-5157. 
 
 
 
 
 
 

 
 
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APPENDIX 1 
Performance Status Criteria 
 
Karnofsky Performance Scale 
For Patients 16 Years of Age and Older 
Percent 
Description 
100 
Normal, no complaints, no evidence of disease. 
90 
Able to carry on normal activity; minor signs or symptoms of disease. 
80 
Normal activity with effort; some signs or symptoms of disease. 
70 
Cares for self, unable to carry on normal activity or to do active work. 
60 
Requires occasional assistance but is able to care for most of his/her needs. 
50 
Requires considerable assistance and frequent medical care. 
40 
Disabled, requires special care and assistance. 
30 
Severely disabled, hospitalization indicated.  Death not imminent. 
20 
Very sick, hospitalization indicated. Death not imminent. 
10 
Moribund, fatal processes progressing rapidly. 
0 
Dead 
 
 
 
Lansky Performance Scale 
For Patients Less Than 16 Years of Age 
Lansky 
Score 
Play Score 
100 
Fully active, normal 
90 
Minor restrictions in physically strenuous activity 
80 
Active, but tires more quickly 
70 
Both greater restriction of and less time spent in play activity 
60 
Up and around, but minimal active play; keeps busy with quieter activities 
50 
Gets dressed but lies around much of the day, no active play but able to participate 
in all quiet play and activities 
40 
Mostly in bed; participates in quiet activities 
30 
In bed; needs assistance even for quiet play 
20 
Often sleeping; play entirely limited to very passive activities 
10 
No play; does not get out of bed 
0 
Unresponsive 
 
 
 
 
 
 
 
 
 

 
 
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APPENDIX 2 
Preparation of Blinatumomab 
 
Only trained staff may prepare the blinatumomab IV solution. Blinatumomab must be prepared in 
an ISO Class 5 containment device, ideally in an ISO Class 7 room as described in USP <797>, 
but ISO Class 7 is not required. Use aseptic technique and prepare blinatumomab IV solution under 
a qualified biological safety cabinet.  
 
The label on the IV bag must include the following:  
• 
Patient name and number  
• 
Name of the drug  
• 
Dose (mcg/day and volume/day)  
• 
Infusion rate  
• 
Expiration date and time  
• 
CAUTION: NEW DRUG – Limited by United States law to investigational use.  
• 
Bag number  
• 
Additional information as required by state, local, and country pharmacy regulations.  
 
Blinatumomab must be dispensed in an acceptable IV bag. Acceptable bags include those made 
of polyolefin/polyethylene, ethylene vinyl acetate (EVA), or PVC non-DEHP.  
 
The final IV solution must be prepared in the following sequential order (do not deviate from this 
order; refer to the table below for volume details):  
 
1. 
Reconstitute Blinatumomab Lyophilized Powder  
Blinatumomab 38.5 mcg/vial 
Add 3 mL of Sterile Water for Injection (SWFI) to the vial to yield 3.08 mL of Blinatumomab 
at a final concentration of 12.5 mcg/mL. 
 
a. Rotate the vial to dissolve all powder. Do not shake.  
b. The stability of the reconstituted vial is 4 hours at room temperature (22°C to 27°C) or 
24 hours refrigerated at 2° to 8°C.  
 
2. Add the appropriate amount of 0.9% NaCl into the IV bag  
 
3. Add the IV solution stabilizer for blinatumomab to the IV bag  
a.    Gently mix the contents of the bag to avoid foaming. Do not shake. 
b.    Discard remaining IV solution stabilizer vial.  
 
4. Add the calculated dose (mL) of blinatumomab into the solution in the IV bag  
a.    Rotate the IV bag to mix the solution thoroughly. Do not shake.  Avoid foaming the 
IV bag.  
b.    Visually inspect for floating particles or discoloration of the IV solution. If floaters or 
discoloration is present, do not use the prepared solution.  
c.    The total volume of blinatumomab IV solution will account for the volume of the IV 
infusion set for the inpatient or outpatient setting.  
 

 
 
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Patients Weighing Under 22 kg 
 
Due to the addition of bacteriostatic saline, 7-day infusion bags of Blinatumomab solution contain benzyl 
alcohol and are not recommended for use in any patients weighing less than 22 kg. 
 
Prepare Blinatumomab solution for infusion with preservative-free saline in 24-hour or 48-hour infusion 
bags for patients weighing less than 22 kg. 
 
Please Refer to the Current USPI for Preparation of the 
Infusion Bags and Volume Calculations 
 
Blinatumomab can be infused over 24 hours (preservative-free), 48 hours (preservative-free), or 7 days 
(with preservative). The choice between these options for the infusion duration should be made by the 
treating healthcare provider considering the frequency of the infusion bag changes and the weight of the 
patient. The administration of Blinatumomab as a 7-day infusion is not recommended for patients 
weighing less than 22 kg. 
 
Call 1-800-77-AMGEN (1-800-772-6436) if you have questions about the reconstitution and preparation 
of Blinatumomab. 
 
Blinatumomab Prescribing Information can be found here:  
https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-
com/blincyto/blincyto_pi_hcp_english.pdf