Clinical trial NCT04506086
Conditions: B-precursor Acute Lymphoblastic Leukemia
Keywords: Blinatumomab Leukemia Acute lymphoblastic leukemia B-precursor Acute Lymphoblastic Leukemia Minimal/Measurable Residual Disease Bi-specific T-cell engager
Sponsor: Amgen
Start date: 2021-08-26; Completion date: 2024-09-16
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The study aims to determine the safety and feasibility of complete outpatient blinatumomab administration for subjects with minimal/measurable residual disease (MRD) of B-precursor Acute Lymphoblastic Leukemia (ALL).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Blinatumomab intervention 2: Current Wearable Heatlth Monitoring System (CWHMS)
Intervention descriptions: intervention 1: Participants will receive blinatumomab continuous IV infusion for a maximum of 4 cycles. Each cycle is 6 weeks in duration consisting of 4 weeks of treatment and 2 weeks of rest. intervention 2: The study will use the CWHMS device to monitor participants' vital signs while they are at home.

Protocol documents:
Prot_000.pdf: 
Product:  Blinatumomab 
Protocol Number:  20190014  
Date:  21 April 2022 
Page 1 of 108 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Title Page 
Protocol Title: 
A Phase 4, Multi-center Open-label Feasibility 
Study to Evaluate Outpatient Blinatumomab 
Administration in Adult Subjects with Minimal 
Residual Disease (MRD) of B-precursor Acute 
Lymphoblastic Leukemia (ALL) in Complete 
Hematologic Remission 
Short Protocol Title: 
Phase 4 Feasibility Study to Evaluate Outpatient 
Blinatumomab in Subjects with MRD of 
B-precursor ALL 
Protocol Number: 
20190014 
Investigational Product: 
Blinatumomab 
Trade Name: 
Blincyto 
Sponsor 
Name of Sponsor: 
Amgen 
Address: 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
Telephone Number: 
Phone: (805) 447-1000 
Protocol 
Approver 
Name: 
MD 
Function: 
Clinical Research Medical Director 
Telephone Number: 
Phone:
Email Address: 
Email:
Key 
Sponsor 
Contact 
Name: 
Address: 
Global Clinical Trial Manager 
Telephone Number: 
Email Address: 
EudraCT Number: 
TBD 
NCT Number: 
NCT04506086 
Protocol Version Date: 
Document 
Version 
Original 
Date 
 
08 November 2019 
Amendment 1 
08 April 2020 
Superseding 
Amendment 1 
28 September 2020 
Amendment 2 
21 April 2022 


Product:  Blinatumomab 
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Date:  21 April 2022 
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Data Elements Standards 
Version: 
6.0 
 
This protocol was developed, reviewed, and approved in accordance with Amgen’s 
standard operating procedures.  This format and content of this protocol is aligned with 
Good Clinical Practice:  Consolidated Guidance (International Council for 
Harmonisation [ICH] E6). 
Confidentiality Notice 
 
This document contains confidential information of Amgen Inc. 
This document must not be disclosed to anyone other than the site study staff and 
members of the institutional review board/independent ethics 
committee/institutional scientific review board or equivalent. 
The information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent 
of Amgen Inc. 
If you have questions regarding how this document may be used or shared, call 
the Amgen Medical Information number:  US sites, 1- 800-77-AMGEN; Amgen’s 
general number in the US, 1-805-447-1000. 


Product:  Blinatumomab 
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Investigator’s Agreement: 
I have read the attached protocol entitled A Phase 4, Multi-center Open-label Feasibility 
Study to Evaluate Outpatient Blinatumomab Administration in Adult Subjects with 
Minimal Residual Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia (ALL) in 
Complete Hematologic Remission, dated 21 April 2022, and agree to abide by all 
provisions set forth therein. 
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP), Declaration of Helsinki, and applicable 
national or regional regulations/guidelines.   
I agree to ensure that Financial Disclosure Statements will be completed by: me 
(including, if applicable, my spouse or legal partner and dependent children) and my 
subinvestigators (including, if applicable, their spouses or legal partners and dependent 
children) at the start of the study and for up to 1 year after the study is completed, if 
there are changes that affect my financial disclosure status. 
I agree to ensure that the confidential information contained in this document will not be 
used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Amgen Inc. 
 
_______________________________ 
Signature 
 
_______________________________ 
____________________________ 
Name of Investigator  
 
 
Date (DD Month YYYY) 
 
_______________________________ 
Title and Role of Investigator 
 
_______________________________ 
Institution Name 
 
_______________________________ 
Address and Telephone Number of Institution 
 


Product:  Blinatumomab 
Protocol Number:  20190014  
Date:  21 April 2022 
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Table of Contents 
Table of Contents ................................................................................................... 4 
1. 
Protocol Summary .................................................................................................. 8 
1.1 
Synopsis ..................................................................................................... 8 
1.2 
Study Schema ........................................................................................... 18 
1.3 
Schedule of Activities (SoA) ...................................................................... 20 
2. 
Introduction ........................................................................................................... 28 
2.1 
Study Rationale ......................................................................................... 28 
2.2 
Background ............................................................................................... 29 
2.2.1 
Disease ..................................................................................... 29 
2.2.2 
Brief history of Current Health and the platform ......................... 31 
2.2.3 
Amgen Investigational Product Background:  
Blinatumomab ........................................................................... 32 
2.3 
Benefit/Risk Assessment ........................................................................... 33 
3. 
Objectives and Endpoints ..................................................................................... 34 
4. 
Study Design  ....................................................................................................... 35 
4.1 
Design ....................................................................................................... 35 
4.2 
Number of Subjects ................................................................................... 36 
4.2.1 
Replacement of Subjects ........................................................... 36 
4.2.2 
Number of Sites ......................................................................... 36 
4.3 
Justification for Investigational Product Dose ............................................ 36 
4.4 
End of Study ............................................................................................. 36 
4.4.1 
End of Study Definition .............................................................. 36 
4.4.2 
Study Duration for Subjects ....................................................... 36 
5. 
Study Population .................................................................................................. 37 
5.1 
Inclusion Criteria ....................................................................................... 37 
5.2 
Exclusion Criteria ...................................................................................... 38 
5.3 
Subject Enrollment .................................................................................... 40 
5.4 
Screen Failures ......................................................................................... 40 
6. 
Treatments ........................................................................................................... 41 
6.1 
Treatment(s) Administered ........................................................................ 41 
6.1.1 
Investigational Products ............................................................ 41 
6.1.2 
Medical Devices ........................................................................ 43 
6.1.3 
Other Protocol-required Therapies ............................................ 44 
6.1.4 
Product Complaints ................................................................... 45 
6.1.5 
Excluded Treatments, Medical Devices, and/or 
Procedures During Study Period ............................................... 47 
6.2 
Dose Modification ...................................................................................... 47 
6.2.1 
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation ..................................... 47 


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6.2.1.1 
Amgen Investigational Product:  
Blinatumomab ......................................................... 47 
6.2.2 
Infusion Interruption/Dose Modification due to Adverse 
Events ....................................................................................... 47 
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules ....................... 49 
6.3 
Preparation/Handling/Storage/Accountability ............................................ 49 
6.4 
Treatment Compliance .............................................................................. 49 
6.5 
Drug Administration ................................................................................... 50 
6.6 
Prior and Concomitant Treatment ............................................................. 50 
6.6.1 
Prior Treatment ......................................................................... 50 
6.6.2 
Concomitant Treatment ............................................................. 50 
7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal ................................................................................... 51 
7.1 
Discontinuation of Study Treatment........................................................... 51 
7.2 
Subject Discontinuation/Withdrawal From the Study ................................. 52 
7.2.1 
Reasons for Removal From Study ............................................. 52 
7.2.2 
Lost to Follow-up ....................................................................... 53 
8. 
Study Assessments and Procedures .................................................................... 53 
8.1 
General Study Periods .............................................................................. 54 
8.1.1 
Screening, Enrollment, and/or Randomization ........................... 54 
8.1.2 
Treatment Period ....................................................................... 54 
8.1.3 
Long-term Follow-up .................................................................. 54 
8.1.4 
End of Study .............................................................................. 54 
8.2 
Description of General Study Assessments and Procedures ..................... 55 
8.2.1 
General Assessments ............................................................... 55 
8.2.1.1 
Informed Consent .................................................... 55 
8.2.1.2 
Demographics ......................................................... 55 
8.2.1.3 
Medical History/Current Medical 
Conditions ............................................................... 55 
8.2.1.4 
Physical Examination .............................................. 56 
8.2.1.5 
Physical Measurements .......................................... 56 
8.2.1.6 
Eastern Cooperative Oncology Group 
Performance Status................................................. 56 
8.2.1.7 
Primary Diagnosis/CR/MRD .................................... 56 
8.2.1.8 
Neurological History and Examination ..................... 56 
8.2.1.9 
Lumbar Puncture to Examine 
Cerebrospinal Fluid ................................................. 56 
8.2.1.10 
Intrathecal CNS Prophylaxis .................................... 57 
8.2.1.11 
Clinical Assessment ................................................ 57 
8.2.2 
Efficacy and Digital Health Tool Assessments ........................... 57 
8.2.2.1 
Digital Health Device Monitoring of Vital 
Signs During the Mandatory Monitoring 
Period ..................................................................... 57 


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8.2.3 
Data Collection and Use ............................................................ 58 
8.2.4 
Safety Assessments .................................................................. 58 
8.2.4.1 
Vital Signs ............................................................... 59 
8.2.4.2 
Electrocardiograms (ECGs) ..................................... 59 
8.2.4.3 
Vital Status .............................................................. 59 
8.2.5 
Adverse Events and Serious Adverse Events ............................ 59 
8.2.5.1 
Time Period and Frequency for Collecting 
and Reporting Safety Event Information .................. 60 
8.2.5.2 
Method of Detecting Adverse Events and 
Serious Adverse Events .......................................... 61 
8.2.5.3 
Follow-up of Adverse Events and Serious 
Adverse Events ....................................................... 61 
8.2.5.4 
Regulatory Reporting Requirements for 
Serious Adverse Events .......................................... 61 
8.2.5.5 
Safety Monitoring Plan ............................................ 62 
8.2.5.6 
Pregnancy and Lactation ......................................... 62 
8.2.5.7 
Adverse Device Effects ........................................... 62 
8.2.6 
Clinical Laboratory Assessments ............................................... 63 
8.2.6.1 
Pregnancy Testing .................................................. 64 
8.2.7 
Patient Reported Outcomes ...................................................... 64 
8.2.8 
Medical Resource Utilization ..................................................... 64 
9. 
Statistical Considerations ...................................................................................... 65 
9.1 
Statistical Hypotheses ............................................................................... 65 
9.2 
Sample Size Determination ....................................................................... 65 
9.3 
Analysis Sets, Subgroups, and Covariates ................................................ 65 
9.3.1 
Analysis Sets ............................................................................. 65 
9.3.2 
Covariates ................................................................................. 65 
9.3.3 
Subgroups ................................................................................. 66 
9.3.4 
Handling of Missing and Incomplete Data .................................. 66 
9.4 
Statistical Analyses ................................................................................... 66 
9.4.1 
Planned Analyses ...................................................................... 66 
9.4.1.1 
Interim Analysis ....................................................... 66 
9.4.1.2 
Primary Analysis ..................................................... 66 
9.4.1.3 
Final Analysis .......................................................... 67 
9.4.2 
Methods of Analyses ................................................................. 67 
9.4.2.1 
General Considerations ........................................... 67 
9.4.2.2 
Efficacy Analyses .................................................... 67 
9.4.2.3 
Safety Analyses ...................................................... 67 
9.4.2.4 
Other Analyses ........................................................ 68 
10. 
References ........................................................................................................... 69 
11. 
Appendices ........................................................................................................... 71 
11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms ...................... 72 


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11.2 
Appendix 2.  Clinical Laboratory Tests ...................................................... 75 
11.3 
Appendix 3.  Study Governance Considerations ....................................... 76 
11.4 
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting ....................................... 84 
11.5 
Appendix 5.  Contraceptive Guidance and Collection of 
Pregnancy and Lactation Information ........................................................ 95 
11.6 
Appendix 6.  Hepatotoxicity Stopping Rules:  Suggested Actions 
and Follow-up Assessments and Study Treatment Rechallenge 
Guidelines ............................................................................................... 102 
11.7 
Appendix 7.  Eastern Cooperative Oncology Group Performance 
Status (ECOG PS) Scale ........................................................................ 106 
11.8 
Appendix 8.  Protocol-specific Definitions ................................................ 107 
 
 
List of Tables 
Table 1-1.  Vital Signs and Clinical Monitoring ............................................................... 19 
Table 1-2.  Schedule of Activities ................................................................................... 20 
Table 2-1.  Prognostic Factors for Risk Stratification of Adult B-precursor ALL 
according to Gökbuget and Hoelzer 2009) .............................................. 30 
Table 6-1.  Study Treatments ........................................................................................ 42 
Table 6-2.  Infusion Interruptions/Dose Modifications Due to Adverse Events ............... 48 
Table 11-1.  Analyte Listing ........................................................................................... 75 
Table 11-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity ............................................ 103 
 
List of Figures 
Figure 1-1.  Study Schema ............................................................................................ 18 
Figure 11-1.  Electronic Serious Adverse Event Contingency Report Form 
(paper-based form) ................................................................................. 90 
Figure 11-2.  Pregnancy and Lactation Notification Forms ........................................... 100 
 


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1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  A Phase 4, Multi-center Open-label Feasibility Study to Evaluate 
Outpatient Blinatumomab Administration in Adult Subjects with Minimal Residual 
Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia (ALL) in Complete 
Hematologic Remission 
Short Protocol Title:  Phase 4 Feasibility Study to Evaluate Outpatient Blinatumomab 
in Subjects with MRD of B-precursor ALL 
Study Phase:  Phase 4 
Indication:  Adult subjects with MRD of B-precursor ALL 
Rationale 
This study aims to determine the safety and feasibility of complete outpatient 
blinatumomab administration for subjects with minimal/measurable residual disease 
(MRD) of B-precursor ALL.  Blinatumomab administration has been demonstrated to be 
efficacious in this population for converting subjects to MRD negative status.  However, 
the mechanism of action of T cell activation and cytokine production can result in 
potentially severe toxicity, specifically Cytokine Release Syndrome (CRS) and/or 
neurotoxicity (NT).  The incidence of these potentially severe side effects has been 
shown to be low.  In the BLAST study, 3 and 13 of subjects had severe CRS and NT 
respectively (Gökbuget et al, 2018).  
The objective of this study is to determine the safety and feasibility of complete 
outpatient blinatumomab administration for subjects with MRD of B-precursor ALL.  The 
study will use mobile electronic devices (tablet) to electronically communicate with the 
healthcare provider (HCP) or designee.  The designee will be any person selected 
by the principal investigator who has experience with and is trained on the 
management of patients with serious medical conditions (eg, acute leukemia), and 
who has received training on the protocol, the Current Health (CH) devices, and 
Current Wearable Health Monitoring System (CWHMS) outpatient monitoring.  
Examples of designees include sub-investigators, study nurses, or physician 
extenders (eg, nurse practitioners, physician assistants, etc).  A designee can also 
be trained medical personnel provided by CH who is trained on the protocol, the 
CH devices, and CWHMS outpatient monitoring.  If the Principal investigator 
selects a designee provided by CH, CH will document that the designee is trained 
on the protocol and devices, is qualified to triage health and technical alarms and 


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meets the above criteria.  The use of the term HCP, henceforth, will refer to the 
HCP or designee.  A Wi-Fi and cellular enabled platform will be used for the transfer 
of data and communication between subject and HCP to detect clinically important 
changes.  The data provided to the HCP will enable him/her to identify subjects at risk of 
developing grade 3 or 4 CRS, NT, or other serious adverse events (SAEs) requiring 
hospitalization during the mandatory device monitoring period (MDMP; see Section 3).  
The HCP can then direct such subjects to the appropriate medical facility for 
hospitalization if needed.  
Objective(s)/Endpoint(s) 
 
Objectives 
Endpoints 
Primary 
 
To determine the safety of outpatient 
blinatumomab administration, during the 
MDMP (defined as the first 3 days of 
cycle 1 and first 2 days of cycle 2 of 
outpatient blinatumomab infusion) 
 
Incidence of grade 3 and/or 
4 CRS, NT or any adverse event 
(AE) requiring hospitalization 
(SAE) during MDMP. 
Secondary 
 
To determine the time from first detection 
of grade 3 or 4 vital sign, or significant 
clinical change to therapeutic intervention 
(any measurable action taken by or 
performed on the subject due to onset of 
the clinical parameters described above) 
during the MDMP 
 
Time (in minutes) from first onset 
of fever, hypotension, hypoxia, 
other grade 3 or 4 vital sign 
including seizure or neurological 
change (grade 3-limiting self-care 
activities of daily living [ADL]) to 
therapeutic interventiona  
 
Evaluate the safety and tolerability of 
blinatumomab administered exclusively 
as an outpatient 
 
Overall incidence and severity of 
treatment-emergent adverse 
events (TEAE) and adverse 
events of interest in particular 
CRS and NT. 
 
Evaluate the impact of complete 
outpatient blinatumomab treatment on 
patient reported outcome (PRO), global 
health status (GHS), and quality of life 
(QoL). 
 
European Organisation for 
Research and Treatment of 
Cancer (EORTC) validated 
electronic version of QLQ-C30. 
 
Estimate healthcare resource utilization 
associated with treatment-related AEs 
 
TEAEs that resulted in 
hospitalizations 
 
TEAEs that resulted in surgeries. 
 
TEAEs that resulted in the use of 
concomitant medications 
 
TEAEs that resulted in the use of 
device/procedure intervention.  


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ADL  activities of daily living; AE  adverse event; CG  caregiver; CRS  cytokine release syndrome; 
EMS  Emergency Medical Service; EORTC  European Organisation for Research and Treatment of 
Cancer; GHS  global health status; HCP  Health Care Provider; IV  intravenous; MDMP  mandatory 
device monitoring period; NT  neurotoxicity; PO  by mouth; PRO  patient reported outcomes; 
QLQ-30  Quality of Life of Cancer Patients; QoL  quality of life; SAE  serious adverse event; 
TEAE  treatment-emergent adverse event. 
a Therapeutic intervention is any measurable action taken by the subject or performed on the subject as a 
result of the onset of the clinical parameters described.  Such actions may include: Advice from HCP to 
immediately call EMS or dial 911, discontinuation of the blinatumomab infusion, subject taking an oral 
medication, subject receiving a medication or intervention by any emergency or hospital medical services, 
intervention such as administering any medication (IV or PO or PR) or IV fluids or oxygen etc.  Time to 
therapeutic intervention (TTI) is the measured time between the delivery of the device alert or unscheduled 
contact with HCP by subject/CG to report a change to the time of initiation of the therapeutic intervention 
as defined.   
Background and Rationale 
This study aims to determine the safety and feasibility of complete outpatient 
blinatumomab administration.  Blinatumomab is a novel bispecific T-cell engaging (BiTE) 
single-chain antibody construct that links CD3 T lymphocytes with CD19 B cells.  This 
may result in a significant degree of T cell-mediated immune activation in subjects, 
which has correlated with efficacy but also with notable toxicity.  The result is a 
heightened T-cell activation and release of pro inflammatory cytokines and the clinical 
manifestation of CRS.  Along with CRS, another potentially severe toxicity observed is 
NT.  Subjects may show signs of encephalopathy with varying degrees of severity and 
may experience delirium, aphasia, lethargy, difficulty concentrating, agitation, tremor, 
seizures, and, rarely, cerebral edema.   
Minimal/measurable residual disease is defined as the presence of leukemic cells not 
detectable by microscopy ( 5) measured either by polymerase chain reaction (PCR) 
or flow cytometry.  After achieving hematologic remission, the presence of MRD 
portends a poor prognosis for patients.  In the Amgen trial MT103-203 (BLAST), 78 of 
subjects with MRD of B-precursor ALL achieved a complete MRD response to 
blinatumomab therapy.  In this trial, 4 subjects (3) had CRS (Common Terminology 
Criteria for Adverse Events [CTCAE] v4 grade 1, n  2; grade 3, n  2), all during 
cycle 1.  Twelve (10) and 3 subjects (3) had grade 3 and 4 NT, respectively.  
Moreover, subjects with relapsed/refractory B-precursor ALL treated with blinatumomab 
in the Amgen trial 00103311 (TOWER) similarly had a low incidence of CRS and NT.  In 
the 00103311 study the incidence of grade  3 CRS and NT were 4.9 and 9.4, 
respectively with 1 and 4.9 of subjects having their treatment discontinued due to 
CRS and NT, respectively (Kantarjian et al, 2017).  
The current recommendation for blinatumomab treatment for subjects with MRD of 
B-precursor ALL is continuous intravenous infusion (CiVI) for 28 days, with the first 


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3 days in cycle 1 and the first 2 days in cycle 2 administered in the inpatient setting.  
This recommendation for hospitalization is primarily for safety concerns of CRS, NT, or 
other severe adverse events (AEs). 
This study aims to determine the safety and feasibility of complete outpatient 
blinatumomab administration for subjects with MRD of B-precursor ALL.  The study will 
use the CWHMS that is comprised of CH wearable device worn on the subject's upper 
arm, an axillary temperature patch, a blood pressure cuff, a Wifi hub, tablet, a mobile 
phone provisioned to the HCP, and a platform will also be used to monitor subjects’ 
vital signs while they are at home.   
This study will include the following: 
 
Remote monitoring using CWHMS to measure vital signs and mobile electronic 
devices (tablet) to electronically communicate these vital signs with the HCP. 
 
The use of a Wi-Fi and cellular enabled platform for the transfer of data and 
communication between subject and HCP, to identify subjects at risk of developing 
grade 3 or 4 CRS, NT or other SAEs requiring hospitalization during the MDMP.  
This subject group may require immediate escalation of care and/or hospitalization 
once the digital monitoring system identifies changes. 
Design 
During screening, subjects and caregivers will be trained on the CWHMS and assessed 
for compliance (Table 1-1, panel 1).  Once enrolled, subjects will receive 2 complete 
cycles of blinatumomab in the outpatient setting in accordance with the monitoring and 
intervention guidelines (Table 1-1., panels 2 and 3).   
After the end of cycle 2 clinical assessment visit, some subjects may continue to receive 
2 additional (optional) cycles of outpatient blinatumomab.  There will be no CWHMS 
outpatient monitoring during the optional cycles 3 and 4.  For the purpose of this study, 
the MDMP is defined as the first 3 days of cycle 1 (72 hours) and the first 2 days of cycle 
2 (48 hours) of blinatumomab infusion for subjects with MRD of B-precursor ALL. 
The end of study visit will occur 30 days (3 days) after the last dose of blinatumomab is 
administered (Figure 1-1).   
During the MDMP, the CWHMS will measure vital signs.  These vital signs include pulse 
rate, respiratory rate, oxygen saturation, and axillary temperature.  The CWHMS will 
measure respiratory rate intermittently (sampling every 30 seconds).  The subjects will 


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take intermittent blood pressure (BP) measurements (using a subject-usable BP device) 
every 3 hours during the MDMP.  The schedule for BP measurements may be extended 
by HCP (up to but not exceeding every 6 hours) after the first 24 hours of MDMP.  The 
BP device will be provided and will directly transmit the BP reading via the monitoring 
platform to the CH Patients Application on the study provisioned mobile phone.  
Threshold vital sign values will be established, and an immediate alert will be generated 
and transmitted to the monitoring platform once the preset threshold values are 
surpassed and sustained for at least 10 minutes (Table 1-1).  Except for blood 
pressure, an alert will be triggered within 1 minute upon being received. 
In addition, subject and caregiver will be trained on the usual side effects of 
blinatumomab infusion (fever, erythematous skin rash, chills, confusion, headache, 
tremor, myalgia, lethargy, somnolence, seizure), and have direct (phone and video) 
contact with HCP or emergency services if any expected or unexpected side effects 
occur.  The caregiver is expected to be a spouse or close relative such as a child but 
can be any adult ( 18 years) willing and able to participate in the subject’s care.  The 
caregiver will remain in the home with the subject for the entire MDMP.  The caregiver 
will be trained to use and have access to the tablet for communication with the HCP, if 
necessary.  
The HCP and the staff will also be trained on the infusion, usual side effects and 
response algorithm (Table 1-1).  The HCP will be trained in the treatment of patients 
with ALL and the use of blinatumomab.  The HCP will carry the study provisioned 
mobile phone at all times during the MDMP.  The study provisioned mobile phone 
will have cellular connection to the subject’s tablet and the CWHMS and will receive vital 
signs refreshed every 30 seconds for the entire MDMP.  Blood pressure will be 
performed manually by the subject (or caregiver) every 3 hours and the result 
electronically delivered to the study provisioned mobile phone.  In addition to the 
continuous feed of vital signs, an audible alarm will sound every time the vital signs 
exceed the preset threshold and is consistent for at least 10 minutes.  In addition, an 
audible alarm will sound if there is no data transfer for 15 minutes.  
It is not intended that the CWHMS will allow the HCP to identify patients experiencing 
neurotoxicity.  The CWHMS is intended to provide remote monitoring of vital signs.  
Knowing a subject’s vital signs will give the HCP an overall picture of the subject’s 
disposition.  In addition to vital signs monitoring, the CWHMS includes the functionality 
for video calling between the HCP and the subject.  This allows the HCP to visually 


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assess the patient for early symptoms of mild neurotoxicity such as kinetic tremor 
(assessed by finger-nose test), ataxia, appearance of disorientation to time or place, 
impaired attention or short-term memory with preserved alertness, impaired naming, 
paraphasic errors, or verbal perseveration.  The HCP will also test the patient’s ability to 
name objects, follow simple commands, and communicate their needs.  The HCP will 
evaluate expressive aphasia by evaluating the subjects’ ability to communicate 
spontaneously (for example HCP may instruct subject to “look directly on the video 
screen and tell me how you are feeling today”) or in naming a common household object 
provided by caregiver.  Healthcare professional will evaluate apraxia by the subject’s 
ability to write a standard sentence (for example “Today is Tuesday January 1, 2001”).  
HCP will test receptive aphasia by the subject’s ability to follow a simple command (for 
example “Lift your right hand and touch your nose”). 
In addition, the caregiver will be present with the patient for the entire MDMP and will be 
able to communicate and participate with the HCP during the video call assessment.  
The HCP will use this video call assessment to determine if the patient’s symptoms (as 
defined for neurotoxicity in Section 11.8) necessitate immediate transfer to hospital.  The 
HCP will schedule video calls with the patients a minimum of every 12 hours (eg, 8 am 
and 8 pm) daily during the MDMP.  The frequency may be increased if there are any 
concerns by the HCP. 
The monitoring system also provides the functionality for the patient or caregiver to 
activate an "I don't feel well" button on the device tablet in the event of the subject 
experiencing any neurological symptoms.  Activating the button immediately generates 
an alarm and notifies the HCP and allows for an immediate video call assessment to be 
initiated.  Healthcare professional will advise transfer of subject to an inpatient facility 
if any of the neurological symptoms are greater than mild in severity.  In addition, as part 
of screening, patients and caregivers will be trained to activate the “I don’t feel well” 
button for any moderate symptoms of speech disorders, disturbances in consciousness, 
deterioration of hand writing, confusion or disorientation.  
Subjects will be trained to resend the “I don’t feel well” signal if no response from the 
HCP is received in 5 minutes.  If there is still no response after another 5 minutes, 
10 minutes total from the initial alarm, then the subject or caregiver is to call Emergency 
Medical Service (EMS) or dial 911 immediately.  Likewise, if the HCP responds to any 
alarm generated from the subject and the subject or caregiver does not answer within 
10 minutes, then the HCP will make 1 attempt to call the subject’s personal phone.  If the 


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Date:  21 April 2022 
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subject or caregiver is still not reachable, the HCP will have EMS dispatched to the 
subject’s location immediately.   
The study provisioned mobile phone is configured so that a loud audible alarm is 
made and repeated every 5 minutes until the HCP responds or if no data is transferred 
for 15 minutes. 
The HCP will then use the compendium of vital sign’s absolute value and/or deviation 
from baseline (provided by the CWHMS) and the subject’s clinical status (provided by 
direct subject/caregiver telephone and video contact), to make decisions on urgency of 
response, appropriate intervention and subject disposition. 
During MDMP, any device malfunction that results in lack of data transmission (eg, 
from the CH wearable device, axillary temperature patch) for 15 minutes will generate 
an alarm to the HCP.  The HCP will contact the patient immediately via the video calling 
functionality to assess the patient’s safety, clinical status, and any specific 
circumstances associated with the device malfunction (eg, device inadvertently 
dislodged, low battery charge, intermittent loss of signal transmission etc).  If the HCP 
has any concern of patient safety, HCP will advise the patient to immediately go to the 
hospital.  
Patients are provided with a full set of replacement devices to be used in case of a 
malfunction.  In addition, a manual oral thermometer will be provided to the patients, as 
needed or directed by the HCP.  In the case of a device malfunction and the HCP 
decides that the patient is safe via the video conference, the HCP will direct the patient 
to switch to the replacement device(s) immediately.  In addition, HCP may contact 
Current Health’s 24/7 help hotline for device support and troubleshooting for assistance.  
It is recommended that the HCP remain in contact with the subject until device 
malfunction is resolved.  If these interventions by HCP fail to resolve the device 
malfunction, then HCP will advise the patient to proceed immediately to the hospital.  
Only United States (US) Food and Drug Administration (FDA) cleared vital sign 
monitoring devices and platform will be used.  During the MDMP, subjects will be 
required to live no more than 1-hour transportation by car from an advanced medical 
care facility.  An advanced medical care facility is 1 with staff trained to manage acutely 
ill patients such as those who may be developing CRS.  Subjects will be allowed to stay 
at a hotel or other outpatient hospital housing facilities to fulfil the 1-hour transportation 
requirement.  Subjects will be trained to call emergency medical services for any 
concerns or for any delay in communication with the HCP.  


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Subjects will be provided with a dedicated in-house Wi-Fi device (home hub) for the sole 
purpose of uninterrupted transmission of vital signs and for communication including 
video contact with the HCP.  Subjects and caregivers should contact their HCP for 
support with any technical issues relating to the CWHMS.  The HCP will have 
access to a 24/7 help hotline for any technical issues relating to the CWHMS.  
Subjects will not have access to this hotline, they will need to contact HCP who 
can contact the hotline. 
Sites would be given the option to utilize nursing triaging services provisioned by 
CH to act as their designee to acknowledge and respond to health and technical 
alarms during a subject's MDMP.  Details are discussed in Section 8.2.2.1.  
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3.  There will be no outpatient digital monitoring during the 
optional cycles 3 and 4.   
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects.”  Approximately 
45 subjects will participate in this study.  Refer to Section 9.2 for sample size 
considerations. 
Summary of Subject Eligibility Criteria 
Adult subjects with B-cell precursor (BCP) ALL with minimal/measurable residual 
disease (MRD) defined as a bone marrow (BM) blast count  5 
For a full list of eligibility criteria, please refer to Section 5.1 to Section 5.2. 
Treatments 
Investigational Product 
Amgen Investigational Product Dosage and Administration:  Blinatumomab is 
administered as a CiVI. 
A single cycle of blinatumomab treatment is 6 weeks in duration, which includes 4 weeks 
of blinatumomab CiVI followed by a 2-week treatment-free interval.  The treatment-free 
interval may be prolonged by up to 7 days, if deemed necessary by the investigator.  For 
subjects 45 kg, blinatumomab will be administered at a dose of 28 g/day for all 
4 weeks of continuous treatment.  Subjects  45 kg will be administered blinatumomab 
15 g/m2/day (max 28 g/day). 


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Non-investigational Product 
Non-Amgen Non-investigational Product Dosage and Administration:  
Dexamethasone 
Premedication with dexamethasone (or prednisone):  Dexamethasone 16 mg (or 
equivalent prednisone 100mg) intravenously (IV): up to 6 hours before start of treatment 
in each treatment cycle.  Subjects 45 kg will have 2 additional 8 mg doses (subjects 
 45 kg will receive 2 doses of 5 mg/m2 rounded to the nearest mg) of oral 
dexamethasone to use as needed for treatment of CRS symptoms only if instructed by 
HCP.  It will be recommended that hospitalization be strongly considered for subjects 
who require interruption of blinatumomab for  4 hours. 
Procedures 
Written informed consent must be obtained from all subjects before any study-specific 
screening procedures are performed.  Study-specific procedures will occur according to 
the Schedule of Assessments (Table 1-2)  
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 8.2 and the Schedule of Activities in Table 1-2. 
Statistical Considerations 
Sample Size Considerations:   
The planned enrollment for this study is approximately 45 patients.  The sample size is 
based on feasibility rather than on statistical considerations.  Given a true probability of a 
primary endpoint event of 38, the expected 95 upper confidence limit with 
45 subjects would be 53.5.  The 38 subject incidence rate is based on the SAE rate 
in first 3 days of cycle 1 and first 2 days of cycle 2 from the previous MRD study 
(BLAST).  Based on these assumptions, we expect to observe approximately 
17 subjects who will experience the primary endpoint which should provide an initial 
indication of the timeliness of the therapeutic intervention when outpatient blinatumomab 
in administered in conjunction with remote digital monitoring. 
Planned Analyses: 
Interim Analyses:  Safety data will be reviewed on an ongoing basis.  A data review team 
(DRT), internal to Amgen but external to the study team, will assess safety after every 
fifth non-replaceable subject has been dosed and given an opportunity to 
complete MDMP.  Refer to Section 4.2.1 for details on replacement of subjects.  


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Primary analysis: The primary analysis will occur when all subjects end the study.  
Final Analysis: The primary analysis will also be the final analysis.  
Descriptive statistics for demographic and safety will be summarized as appropriate.  For 
categorical variables, the number and percentage of subjects in each category will be 
summarized.  Continuous variables will be summarized by n, mean, standard deviation, 
median, Q1 (25th percentile), Q3 (75th percentile), minimum, and maximum values. 
For a full description of statistical analysis methods, please refer to Section 9. 
Statistical Hypotheses 
No formal statistical hypothesis will be tested. 
Sponsor Name:  Amgen 
 


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Protocol Number:  20190014  
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FORM-001520, v.24, 21 May 2019 
 
 
 
 
1.2 
Study Schema 
Figure 1-1.  Study Schema 
 


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FORM-001520, v.24, 21 May 2019 
 
 
 
 
Table 1-1.  Vital Signs and Clinical Monitoring 
 
BP  blood pressure; HCP  healthcare professional; IP  Investigational product 
AMG 103 20190014 VS and Clinical Monitoring 


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FORM-001520, v.24, 21 May 2019 
 
 
 
 
1.3 
Schedule of Activities (SoA) 
Table 1-2.  Schedule of Activities 
PROCEDURE 
Screening  
( 21 days) 
cycle 1 (C1) 
cycle 2 (C2) 
cycle 
3 (C3) 
cycle 
4 (C4) 
EOS 
Notes 
Study Day 
within Cycle 
D-
21 to 
D-1 
D-14
 to 
D-7 
D-
3 to 
D1 D1 D2 D3 D4 
D29 
( 7 d
ays) 
D1 D2 D3 
D29 
( 3 days) 
End of C2 
Clinical 
Assessment 
(D29) 
(C3, 
optional 
cycle) 
(C4, 
optional 
cycle) 
(30 days  
3 days post last 
dose 
blinatumomab) 
 
GENERAL ASSESSMENTS 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The ICF must be signed before any study-
specific procedures are performed.   
ELIGIBILITY CHECK 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/ 
Current medical 
conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG PS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary 
diagnosis/CR/M
RD 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects must have a diagnosis of MRD of 
B-precursor ALL in complete hematologic 
remission.  Standard of care procedures such 
as bone marrow aspiration/biopsy including 
MRD assessment and lumbar puncture are 
not considered study-specific and are to be 
performed no more than 14 days prior to 
informed consent.  Any additional BM 
procedure performed during the screening 
period to qualify the subject for 
participation in trial must be approved by 
the medical monitor. 
Physical 
examination  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Neurological 
Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Neurological 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 7 
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FORM-001520, v.24, 21 May 2019 
 
 
 
 
Table 1-2.  Schedule of Activities 
PROCEDURE 
Screening  
( 21 days) 
cycle 1 (C1) 
cycle 2 (C2) 
cycle 
3 (C3) 
cycle 
4 (C4) 
EOS 
Notes 
Study Day within Cycle 
D-
21 to 
D-1 
D-14 
to 
D-7 
D-
3 to 
D1 D1 D2 D3 D4 
D29 
( 7 d
ays) 
D1 D2 D3 
D29 
( 3 days) 
End of C2 
Clinical 
Assessment 
(D29) 
(C3, 
optional 
cycle) 
(C4, 
optional 
cycle) 
(30 days   
3 days post last 
dose 
blinatumomab) 
 
ELIGIBILITY CHECK (continued) 
Vital signs 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Vital signs to be assessed in clinic 
per standard of care.  At screening, 
3 blood pressure assessments (at 
least 30 minutes apart) must be 
taken using the CWHMS to 
establish a baseline BP for the 
subject. 
Height, weight, BSA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Glomerular filtration rate 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Calculation of glomerular filtration 
rate required only if serum 
creatinine  1.5x ULN 
Lumbar puncture/CSF 
prophylaxis 
X 
 
 
 
 
 
 
(X) 
 
 
 
 
 
 
 
 
If screening CSF demonstrates 
leukemic blasts, subjects must 
receive intrathecal treatment and 
demonstrate negative CSF before 
starting treatment. 
(X):  Required if screening CSF 
demonstrates leukemic blasts.   
Subjects required to stay 
within 1 hour of advanced 
care facility during 
monitoring period 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
Subjects may stay in a hotel or 
other outpatient hospital dwelling 
facilities to meet criteria. 
There will be no data transmission 
to HCP while subjects are 
transported to home from the 
outpatient facility; vital sign data will 
be stored but not transmitted in real 
time. 
Caregiver available 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
 
Adequate Cellular service 
available during monitoring 
period 
X 
 
 
X 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
There will be no data transmission 
to HCP while subjects are 
transported to home from the 
outpatient facility.  Vital sign data 
will be stored but not transmitted in 
real time. 
Page 2 of 7 
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Protocol Number:  20190014  
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FORM-001520, v.24, 21 May 2019 
 
 
 
 
Table 1-2.  Schedule of Activities 
PROCEDURE 
Screening  
( 21 days) 
cycle 1 (C1) 
cycle 2 (C2) 
cycle 
3 (C3) 
cycle 
4 (C4) 
EOS 
Notes 
Study Day within Cycle 
D-
21 to 
D-1 
D-14
 to 
D-7 
D-
3 to 
D1 D1 D2 D3 D4 
D29 
( 7 d
ays) 
D1 D2 D3 
D29 
( 3 days) 
End of C2 
Clinical 
Assessment 
(D29) 
(C3, 
optional 
cycle) 
(C4, 
optional 
cycle) 
(30 days   
3 days post 
last dose 
blinatumomab) 
 
LABORATORY ASSESSMENTS 
CBC including differential 
X 
 
X 
 
 
 
 
 
(X) 
 
 
 
 
 
 
 
X:  To be completed and reviewed 
within 3 days of C1D1.  If done at 
start of screening must be repeated 
within 3 days of starting C1D1.  Can 
be completed up to 3 days before 
C1D1. 
(X):  Must be repeated before starting 
C2D1.  May be completed up to 
48 hours prior to C2D1 and starting 
blinatumomab infusion.   
Coagulation 
PT/INR 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Chemistry 
Electrolytes 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
BUN/Creatinine 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Total and direct bilirubin 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
AST 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
ALT 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
ALP 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
LDH 
X 
 
X 
 
 
 
 
 
(X) 
 
 
 
 
 
 
 
X:  Must be completed up to 3 days 
before C1D1. 
(X):  Must be repeated on C2D1 up 
to 48 hours prior to starting 
blinatumomab infusion).   
Uric acid 
X 
 
X 
 
 
 
 
 
(X) 
 
 
 
 
 
 
 
X:  Must be completed up to 3 days 
before C1D1. 
(X):  Must be repeated on C2D1 
within 48 hours prior to starting 
blinatumomab infusion 
Lipase 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amylase 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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FORM-001520, v.24, 21 May 2019 
 
 
 
 
Table 1-2.  Schedule of Activities 
PROCEDURE 
Screening  
( 21 days) 
cycle 1 (C1) 
cycle 2 (C2) 
cycle 
3 (C3) 
cycle 
4 (C4) 
EOS 
Notes 
Study Day within Cycle 
D-
21 to 
D-1 
D-14 
to 
D-7 
D-
3 to 
D1 D1 D2 D3 D4 
D29 
( 7 d
ays) 
D1 D2 D3 
D29 
( 3 days) 
End of C2 
Clinical 
Assessment 
(D29) 
(C3, 
optional 
cycle) 
(C4, 
optional 
cycle) 
(30 days   
3 days post last 
dose 
blinatumomab) 
 
Clinical Chemistry (continued) 
Serum and/or Urine 
pregnancy test (females of 
childbearing potential only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional on-treatment pregnancy 
testing may be performed at the 
investigator’s discretion if there is 
suspicion that a female subject is 
pregnant or per local laws and 
regulations.  A highly sensitive 
(urine or serum) pregnancy test 
should be completed at 
screening and within 7 days of 
initiation of investigational 
product for females of 
childbearing potential. 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow MRD 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
According to institution practice. 
DIGITAL HEALTH 
Eligibility for home 
monitoring and wearables 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CWHMS kits delivered to 
site 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Monitoring device kits will be sent 
to site at site initiation.  Each kit will 
have duplicate devices and an oral 
thermometer to be used as needed. 
Subject home monitoring 
device training. 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Caregiver eligibility and 
device monitoring training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol Number:  20190014  
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FORM-001520, v.24, 21 May 2019 
 
 
 
 
Table 1-2.  Schedule of Activities 
PROCEDURE 
Screening  
( 21 days) 
cycle 1 (C1) 
cycle 2 (C2) 
cycle 
3 (C3) 
cycle 
4 (C4) 
EOS 
Notes 
Study Day within Cycle 
D-
21 to 
D-1 
D-14 
to 
D-7 
D-
3 to 
D1 D1 D2 D3 D4 
D29 
( 7 d
ays) 
D1 D2 D3 
D29 
( 3 days) 
End of C2 
Clinical 
Assessment 
(D29) 
(C3, 
optional 
cycle) 
(C4, 
optional 
cycle) 
(30 days   
3 days post last 
dose 
blinatumomab) 
 
DIGITAL HEALTH 
PI/Site device monitoring 
training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Site training will be completed at 
initiation and during the screening 
period for the first subject is 
enrolled.  Training may be required 
for first subject only.  Any 
subsequent training will be 
requested ad hoc 
Subject home trial period 
of CWHMS assessed for 
24-48 hours to determine 
eligibility. 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Recommend to be completed at 
least 1 week prior to start of 
treatment (during screening, 
subjects should test wearing of 
devices and data transmittal for a 
minimum of 24 hours).   
During this screening device testing 
period, the study doctor will not be 
monitoring the device.  The subject 
or caregiver must immediately 
contact the study doctor directly if 
the subject is feeling unwell during 
the screening period. 
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Protocol Number:  20190014  
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FORM-001520, v.24, 21 May 2019 
 
 
 
 
Table 1-2.  Schedule of Activities 
PROCED
URE 
Screening  
( 21 days) 
cycle 1 (C1) 
cycle 2 (C2) 
cycle 
3 (C3) 
cycle 
4 (C4) 
EOS 
Notes 
Study Day 
within 
Cycle 
D-
21 to 
D-1 
D-14 
to 
D-7 
D-
3 to 
D1 D1 D2 D3 D4 
D29 
( 7 d
ays) 
D1 D2 D3 
D29 
( 3 days) 
End of C2 
Clinical 
Assessment 
(D29) 
(C3, 
optional 
cycle) 
(C4, 
optional 
cycle) 
(30 days   
3 days post last 
dose 
blinatumomab) 
 
DIGITAL HEALTH (continued) 
Mandatory 
Device 
Monitoring 
Period 
(MDMP) 
 
 
 
X 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
During the MDMP, subjects will wear the 
CWHMS (Current Health wearable device and 
axillary temperature patch) continuously 
24 hours a day.  Subjects must constantly 
remain within range of the (provided) home hub 
WiFi device for the first 24 hours of the study.  
Subjects may go out of range of the home hub 
WiFi device for a maximum of 60 mins after the 
first 24 hours only after first notifying HCP.  Both 
subject and HCP should be able to 
communicate via their devices even in the 
absence of an alert.  Vital sign data will be 
stored but not transmitted in real time during 
these 60 minutes.  Vital signs measured 
continuously: pulse rate, axillary temperature, 
oxygen saturation.  Respiratory rate are taken 
every 30 secs.  BP is intermittently taken by 
subjects every 3 hours (mandatory for the first 
24 hours).  If subject is stable, HCP may change 
BP measurement up to every 6 hours for the 
remainder of the MDMP.  HCP must authorize 
the change in BP measurement frequency.  
HCP will have scheduled neurological 
assessments via video call at least every 
12 hours during the MDMP (eg, 8 am and 8 pm) 
daily.  All data from home monitoring devices 
will be collected electronically.  A source 
document report will be provided on the 
monitoring platform containing the median of 
device vital signs taken once every 3 hours.  
These will be recorded in the eCRF.  No digital 
monitoring data will be collected during the 
optional cycles 3 and 4. 
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Protocol Number:  20190014  
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FORM-001520, v.24, 21 May 2019 
 
 
 
 
Table 1-2.  Schedule of Activities 
PROCEDURE 
Screening  
( 21 days) 
cycle 1 (C1) 
cycle 2 (C2) 
cycle 
3 (C3) 
cycle 
4 (C4) 
EOS 
Notes 
Study Day within 
Cycle 
D-
21 to 
D-1 
D-14 
to 
D-7 
D-
3 to 
D1 D1 D2 D3 D4 
D29 
( 7 d
ays) 
D1 D2 D3 
D29 
( 3 days) 
End of C2 
Clinical 
Assessment 
(D29) 
(C3, 
optional 
cycle) 
(C4, 
optional 
cycle) 
(30 days   
3 days post last 
dose 
blinatumomab) 
 
DIGITAL HEALTH (continued) 
Removal and return of 
monitoring devices 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
Subjects will receive 1 monitoring 
device kit for each cycle.  A new kit 
will be given to each subject for cycle 
2 
PROTOCOL-SPECIFIED PROCEDURES 
Blinatumomab 
treatment 
 
 
 
Continuously throughout the 28-day infusion period for each cycle 
 
Enrollment should occur within 
21 days of signing ICF.   
Subjects will spend the first 5 hours of 
infusion in the outpatient department 
for C1D1 and 1-2 hours for C2D1.   
EORTC QLQ-C30 
X 
 
 
(X) 
 
  
 
 
X 
  
 
 
 
 
 
 
(X):  First EORTC QLQC30 can be 
completed at screening or C1D1 
(predose). 
 
EORTC QLQC30 will also be done at 
C2D1 
 
 
Concomitant 
medications 
  Continuously from Screening through end of study  → 
 
Adverse events 
 
 
 
 Report from cycle 1 day 1 treatment through end of study  → 
 
Serious adverse 
events 
 Report from Signing of Informed Consent  through end of study→ 
 
Adverse device effects 
  Continuously from Screening through end of study  → 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
(X) 
X 
In case of premature treatment 
discontinuation, subjects will be 
required to complete the end of study 
visit approximately 30 ( 3) days after 
the last dose of blinatumomab. 
Only safety and survival data to be 
collected. 
(X): To be collected on day 1 to 
determine eligibility to receive optional 
cycles 
Page 7 of 7 


Product:  Blinatumomab 
Protocol Number:  20190014  
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FORM-001520, v.24, 21 May 2019 
 
 
 
 
ALL = acute lymphoblastic leukemia; ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; BM  
bone marrow; BP = blood pressure; BSA = body surface area; BUN = blood urea nitrogen; C = cycle; CBC = complete blood count; CR = complete remission; CSF = cerebrospinal fluid; 
CWHMS = Current Wearable Health Monitoring System; D = day; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group Performance Status; EORTC QLQ-C30 = 
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; EOS = end of study; HCP = healthcare provider; ICF = informed consent form; INR = 
international normalized ratio; LDH = lactate dehydrogenase; MDMP = mandatory device monitoring period; MRD = minimal/measurable residual disease; PI = principal investigator; PT = 
prothrombin time; PRO = Patient Reported Outcomes; ULN = upper limit of normal 
 


Product:  Blinatumomab 
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FORM-001520, v.24, 21 May 2019 
 
2. 
Introduction 
2.1 
Study Rationale 
This study aims to determine the safety and feasibility of complete outpatient 
blinatumomab administration for subjects with minimal/measurable residual disease 
(MRD) of B-precursor acute lymphoblastic leukemia (ALL).  Blinatumomab 
administration has been demonstrated to be efficacious in this population for converting 
subjects to MRD negative status.  However, the mechanism of action of T cell activation 
and cytokine production can result in potentially severe toxicity, specifically cytokine 
release syndrome (CRS) and/or neurotoxicity (NT).  The incidence of these potentially 
severe side effects has been shown to be low.  In the BLAST study, 3 and 13 of 
subjects had severe CRS and NT respectively (Gökbuget et al, 2018). 
The objective of this study is to determine the safety and feasibility of complete 
outpatient blinatumomab administration for subjects with MRD of B-precursor ALL.  The 
study will use mobile electronic devices (tablet) to electronically communicate with the 
healthcare professional (HCP) or designee.  The designee will be any person 
selected by the principal investigator who has experience with and is trained on 
the management of patients with serious medical conditions (eg, acute leukemia), 
and who has received training on the protocol, the Current Health (CH) devices, 
and Current Wearable Health Monitoring System (CWHMS) outpatient monitoring.  
Examples of designees include sub-investigators, study nurses, or physician 
extenders (eg, nurse practitioners, physician assistants, etc).  A designee can also 
be trained medical personnel provided by CH who is trained on the protocol, the 
CH devices, and CWHMS outpatient monitoring.  If the Principal investigator 
selects a designee provided by CH, CH will document that the designee is trained 
on the protocol and devices, is qualified to triage health and technical alarms and 
meets the above criteria.  The use of the term HCP, henceforth, will refer to the 
HCP or designee.  A Wi-Fi and cellular enabled platform will be used for the transfer 
of data and communication between subject and HCP to detect clinically important 
changes.  The data provided to the HCP will enable him/her to identify subjects at risk of 
developing grade 3 or 4 CRS, NT, or other serious adverse events (SAEs) requiring 
hospitalization during the mandatory device monitoring period (MDMP; see Section 3).  
The HCP can then direct such subjects to the appropriate medical facility for 
hospitalization if needed.   


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The population for this study (MRD of B-precursor ALL) are expected to have a low 
incidence of severe CRS and NT and a reasonable target population to evaluate the 
feasibility of complete outpatient blinatumomab administration. 
This study will use the CH system and platform for outpatient monitoring.  Subjects who 
are in a high-acuity environment, such as an operating room (OR) or intensive care unit 
(ICU), or those who are acutely ill and may develop immediate and life-threatening 
arrhythmias are excluded from the CH platform and will not be enrolled into this study.  
The primary endpoint of this study is the incidence of grade 3 or 4 CRS, NT or any 
adverse event (AE) requiring hospitalization during the MDMP.  The CH devices will 
detect abnormal vital signs or changes in baseline vital signs to allow the HCP to 
determine if subjects are developing CRS.  In addition, the CH device contains 
functionality for video calling between the HCP and the patient to allow the HCP to 
visually assess the patient for early symptoms of mild neurotoxicity.  The vital signs are 
all monitored by the CWHMS with performance assessed and cleared by the United 
States (US) Food and Drug Administration (FDA) as non-inferior to both Draeger and 
Philips vital signs monitoring equipment.  Thus, the CH devices are appropriate and 
applicable for the monitoring of abnormal vital signs in the home environment. 
2.2 
Background 
2.2.1 
Disease 
B-precursor ALL is a malignant disease of lymphatic progenitor cells in the bone marrow 
or sites of lymphatic system.  Immature lymphoblasts proliferate in the bone marrow and 
may infiltrate other organs.  As a consequence, the normal hematopoiesis in the bone 
marrow is suppressed.  Acute lymphoblastic leukemia is a rare malignant disease with 
an overall incidence of 1.1/100 000 per year.  Acute lymphoblastic leukemia has a 
bimodal distribution with an early peak at 4 to 5 years of age (incidence of 
4.5/100 000 per year) followed by a second gradual increase at 50 years (incidence of 
2/100 000 per year).  It represents 80 of acute childhood leukemia and 20 of acute 
leukemia cases in adults (Pui and Evans 1998; Jabbour et al, 2005; Larson 2005; 
Howlader et al, 2012). 
A 75 of adult subjects with ALL is of B-cell lineage and approximately 25 is derived 
from T-cell lineage.  The majority of subjects with B-cell lineage ALL have an immature 
immunophenotype and are classified as B-precursor ALL.  CD19 is expressed in all 
subtypes of B-ALL (Bassan et al, 2004).  The Philadelphia chromosome (Ph) represents 


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the most frequent cytogenetic aberration in adult ALL and is found in 20-30 of subjects 
with B-precursor ALL. 
Adult ALL can be stratified into risk groups that are the basis for risk adapted treatment 
strategies.  A selection of prognostic factors in B-precursor ALL is displayed in 
Table 2-1: 
Table 2-1.  Prognostic Factors for Risk Stratification of Adult B-precursor ALL 
according to Gökbuget and Hoelzer 2009) 
Parameter 
Favorable 
Adverse 
WBC at diagnosis 
 30 000/l 
 30 000/l 
Immunophenotype 
 
Pro-B-ALL 
Cytogenetics/Molecular genetics 
 
t (9;22)/bcr-abl 
t (4;11)/ALL1-AF4 
Time to CR 
Early 
Late ( 3-4 weeks) 
MRD after induction and 
consolidation 
Negative ( 10-4) 
Positive ( 10-4) 
Age 
 25 years,  35 years 
 35 years,  55 years, 
 70 years 
ALL  acute lymphoblastic leukemia; CR  complete remission; MRD  minimal/measurable residual 
disease; WBC white blood cell count 
A white blood cell count (WBC) of  30 000/l at diagnosis and younger age are 
favorable factors in adult ALL.  Additionally, a short interval until achievement of a 
complete remission (CR) and a complete molecular remission following induction (MRD 
negative;  1 leukemic cell in 104 bone marrow cells is detectable) are favorable factors.  
Outcome of therapy in adult patients with ALL has improved substantially over the last 
10 years with CR rates of 85 to 90 and overall survival (OS) rates of 40 to 50 
(Gökbuget and Hoelzer, 2010).  Pediatric protocols have been the guideline to develop 
treatment regimens for adult ALL.  These regimens consist of 3 phases: induction, 
consolidation, and maintenance therapy.  Generally, the therapeutic “state of the art” 
modalities for adult leukemia can be summarized as outlined below (Gökbuget and 
Hoelzer, 2011). 
 
4- to 5 drug induction regimens using vincristine and prednisone, adding 
anthracyclines, cyclophosphamide, asparaginase (or a combination of these 
agents) to achieve CR 


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 
Intensified consolidation therapy based on cyclical administration of cytarabine, 
anthracyclines, methotrexate, asparaginase and repeated induction to reduce the 
level of MRD  
 
Protracted maintenance therapy (about 2 years) using methotrexate combined 
with mercaptopurine; allogeneic stem cell transplantation in first CR in high-risk 
patients: Allogeneic hematopoietic stem cell transplantation (HSCT) is the most 
intensive option of consolidation in first CR of high-risk patients.  
Progress in therapy and optimized risk stratification, which enabled patient-tailored 
treatment, were important factors contributing to improvement of treatment outcome.  
In spite of the success in upfront treatment, the outcome in most adults with recurring 
disease irrespective of their prior treatment is dismal, as they cannot be rescued using 
currently available therapy (Fielding et al, 2007).  Thus, prevention of relapse is the 
major treatment goal in patients resistant or intolerant to chemotherapy.  
2.2.2 
Brief history of Current Health and the platform 
Current Wearable Health Monitoring System is an FDA-cleared platform for wireless 
and wearable health monitoring of patients at home and hospital.  The CH product was 
launched on the US market in December 2018 after attainment of FDA clearance.  
Current Health’s FDA cleared indications for use are as follows: 
The CWHMS is intended for reusable bedside, mobile and central multi-parameter, 
physiologic patient monitoring of adult patients in professional healthcare facilities, such 
as hospitals or skilled nursing facilities, or their own home.  It is intended for monitoring 
of patients by trained HCPs.  The CWHMS is intended to provide visual and audible 
physiologic multi-parameter alarms. 
The CWHMS is intended for continuous monitoring of the following parameters in adults: 
 
Pulse rate 
 
Respiratory rate 
 
Axillary temperature 
 
Oxygen saturation 
 
Skin temperature (not evaluated for this study) 
 
Movement (not evaluated for this study) 


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The CWHMS is intended for intermittent or spot-check monitoring, in adults, of: 
 
Respiratory rate (every 30 secs) 
 
Non-invasive blood pressure (BP) 
 
Lung function & spirometry (not collected for this study) 
 
Weight (not collected for this study) 
The CWHMS generates intermittent respiration rates by sampling every 30 seconds.  
This means every 30 seconds new respiration rates will be available for use in the alarm 
system and for presentation on the dashboard.  This functionality was assessed using 
physician-underscored end tidal CO2.   
The CWHMS acts as a hub with seamless, wireless integrations.  Data flows directly 
through the CH wearable via integrated third-party devices such as the axillary 
temperature monitor and the BP monitor. 
For this study, pulse rate, axillary temperature, respiratory rate, oxygen saturation and 
BP will be monitored and collected.  The CWHMS is not intended for use in high-acuity 
environments, such as ICUs or ORs, or for use on acutely ill cardiac patients with the 
potential to develop life threatening arrhythmias eg, very fast atrial fibrillation and is not 
intended for peripheral capillary oxygen saturation (SpO2) monitoring in conditions of 
high motion or low perfusion.  These excluded patients and conditions will not be eligible 
for this study. 
Additional information about the CWHMS and integrated platform is described in 
Section 6.1.2 and the approved device manual. 
2.2.3 
Amgen Investigational Product Background:  Blinatumomab 
Blinatumomab is a CD19-directed bispecific single-chain antibody construct designed to 
link B cells and T cells resulting in T-cell activation and a cytotoxic T-cell response 
against CD19 expressing cells.  As stated previously blinatumomab is approved for the 
treatment of MRD of B-precursor ALL and has shown efficacy in the recently completed 
BLAST trial (Gökbuget et al, 2018).  The approval for blinatumomab recommends that 
the initiation of cycle 1 (first 3 days) and of cycle 2 (first 2 days) be given while patients 
are admitted to hospital.  In this investigational study we are testing the hypothesis that 
blinatumomab can be given as an outpatient for the entire 28 days if subjects are 
monitored during the initiation days.  The blinatumomab infusion, doses, and indication 
for use will be consistent with the approved label. 


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2.3 
Benefit/Risk Assessment 
Results from pivotal Study M103-203 and supportive Study M103-202 showed similar 
high (up to 80) MRD response rates after blinatumomab treatment in subjects with ALL 
in complete hematologic remission ( 5 bone marrow blasts) who were MRD positive 
at the start of blinatumomab treatment baseline.  Minimal/measurable residual disease 
response is a strong prognostic factor for relapse after achieving CR regardless of 
treatment choice or risk classification system (Lussana et al, 2016; 
van Dongen et al, 2015; Gökbuget et al, 2012; Gökbuget and Hoelzer, 2011; 
Bassan et al, 2009; Brüggemann et al, 2006).  At the time of relapse, the strongest 
prognostic factors for OS are duration of initial remission and age (Oriol et al, 2010; 
Fielding et al, 2007; Thomas et al, 1999).   
A published meta-analysis of 16 studies in adults with ALL solidified the association 
between MRD-negative status and improved clinical outcomes (event-free survival [EFS] 
and OS) that has up to this point been based largely on reports of individual studies with 
variable sample sizes.  Of particular interest, EFS and OS for subjects who are 
MRD negative were shown to be remarkably consistent across a variety of subgroups 
(eg, MRD detection by flow cytometry vs polymerase chain reaction (PCR), MRD 
assessment after induction vs after consolidation, definition of MRD positivity, Ph status, 
and B-cell or T-cell phenotype) (Berry et al, 2017).   
The key safety factors that have been identified in clinical trials are NT, CRS, and 
medication errors.  Most AEs occurred within the first few weeks of the first cycle and 
were mitigated by appropriate measures such as temporary interruption without 
negatively affecting therapeutic benefit.  Based on the short half-life of blinatumomab, in 
the presence of an AE, blinatumomab can be rapidly discontinued and cleared, which 
may enhance the ability to manage the AE effectively.  In addition, the rate of severe 
AEs, in particular, CRS, are low enough to warrant the evaluation of complete outpatient 
administration of blinatumomab.  This is particularly so in the MRD positive population, 
who by definition have low tumor burden.  Moreover, the CH system is FDA cleared to 
accurately assess vitals and transmit vital signs efficiently to an HCP.  In addition to 
benefit of MRD treatment, full administration of outpatient blinatumomab may be more 
convenient for patients. 
The above benefit risk assessment supports the conduct of this clinical trial.  Reference 
should be made to the Investigator’s Brochure for further data on blinatumomab.  


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Training material will be provided by CH with further information on the digital devices 
used in the study. 
3. 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
 
To determine the safety of outpatient 
blinatumomab administration, during the 
MDMP (defined as the first 3 days of 
cycle 1 and first 2 days of cycle 2 of 
outpatient blinatumomab infusion) 
 
Incidence of grade 3 and/or 
4 CRS, NT or any adverse event 
(AE) requiring hospitalization 
(SAE) during MDMP. 
Secondary 
 
To determine the time from first detection 
of grade 3 or 4 vital sign, or significant 
clinical change to therapeutic intervention 
(any measurable action taken by or 
performed on the subject due to onset of 
the clinical parameters described above) 
during the MDMP 
 
Time (in minutes) from first onset 
of fever, hypotension, hypoxia, 
other grade 3 or 4 vital sign 
including seizure or neurological 
change (grade 3-limiting self-care 
activities of daily living [ADL]) to 
therapeutic interventiona  
 
Evaluate the safety and tolerability of 
blinatumomab administered exclusively 
as an outpatient 
 
Overall incidence and severity of 
treatment-emergent adverse 
events (TEAE) and adverse 
events of interest in particular 
CRS and NT. 
 
Evaluate the impact of complete 
outpatient blinatumomab treatment on 
patient reported outcome (PRO), global 
health status (GHS), and quality of life 
(QoL). 
 
European Organisation for 
Research and Treatment of 
Cancer (EORTC) validated 
electronic version of QLQ-C30. 
 
Estimate healthcare resource utilization 
associated with treatment-related AEs 
 
TEAEs that resulted in 
hospitalizations 
 
TEAEs that resulted in surgeries. 
 
TEAEs that resulted in the use of 
concomitant medications 
 
TEAEs that resulted in the use of 
device/procedure intervention.  
ADL  activities of daily living; AE  adverse event; CG  caregiver; CRS  cytokine release syndrome; 
EMS  Emergency Medical Service; EORTC  European Organisation for Research and Treatment of 
Cancer; GHS  global health status; HCP  Health Care Provider; IV  intravenous; MDMP  mandatory 
device monitoring period; NT  neurotoxicity; PO  by mouth; PRO  patient reported outcomes; 
QLQ-30  Quality of Life of Cancer Patients; QoL  quality of life; SAE  serious adverse event; 
TEAE  treatment-emergent adverse event. 


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a Therapeutic intervention is any measurable action taken by the subject or performed on the subject as a 
result of the onset of the clinical parameters described.  Such actions may include: Advice from HCP to 
immediately call EMS or dial 911, discontinuation of the blinatumomab infusion, subject taking an oral 
medication, subject receiving a medication or intervention by any emergency or hospital medical services, 
intervention such as administering any medication (IV or PO or PR) or IV fluids or oxygen etc.  Time to 
therapeutic intervention (TTI) is the measured time between the delivery of the device alert or unscheduled 
contact with HCP by subject/CG to report a change to the time of initiation of the therapeutic intervention 
as defined.   
4. 
Study Design  
4.1 
Design 
This study aims to determine the safety and feasibility of complete outpatient 
blinatumomab administration for subjects with MRD of B-precursor ALL using CWHMS 
to measure vital signs and transmit the vital signs to the HCP, mobile electronic devices 
(tablet) to electronically communicate with the HCP, and a Wi-Fi and cellular enabled 
platform for the transfer of data and communication between subject and HCP to detect 
clinically important changes.  The data provided to the HCP will enable him/her to 
identify subjects at risk of developing grade 3 or 4 CRS, NT, or other SAEs requiring 
hospitalization during the MDMP.  The HCP can then direct such subjects to the 
appropriate medical facility for hospitalization if needed.   
During screening, subjects and caregivers will be trained on the CWHMS and assessed 
for compliance (Table 1-1-panel 1).  Once enrolled, subjects will receive 2 complete 
cycles of blinatumomab in the outpatient setting in accordance with the monitoring and 
intervention guidelines (Table 1-1-panels 2 and 3). 
After the end of cycle 2 clinical assessment visit, some subjects may continue to receive 
2 additional (optional) cycles of outpatient blinatumomab.  There will be no CWHMS 
outpatient monitoring during the optional cycles 3 and 4.  For the purpose of this 
study, the MDMP is defined as the first 3 days of cycle 1 (72 hours) and the first 
2 days of cycle 2 (48 hours) of blinatumomab infusion for subjects with MRD of 
B-precursor ALL.  
The end of study visit will occur 30 days ( 3 days) after the last dose of blinatumomab 
is administered (Figure 1-1).  
This may coincide with the end of cycle 2 clinical assessment for subjects ending after 
cycle 2 or after cycle 3 or 4 if subjects and PI’s choose to receive the optional 
consolidation cycles 3 and/or 4. 
The overall study design is described by a study schema in Section 1.2.  The endpoints 
are defined in Section 3. 


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4.2 
Number of Subjects 
Approximately 45 adult subjects will be enrolled in the study, with MRD of B-precursor 
ALL in complete hematologic remission.   
Subjects in this clinical investigation shall be referred to as “subjects.”  For the sample 
size justification, see Section 9.2. 
4.2.1 
Replacement of Subjects 
Subjects will be replaced for analysis if the outpatient monitoring during 
blinatumomab infusion is not established.   
 
Subjects removed from investigational product (IP) due to disease progression. 
Replacement status is only applicable for internal data analysis. 
4.2.2 
Number of Sites 
Approximately 25 investigative sites in the US will be included in the study.  Sites that do 
not enroll subjects within 12 months of site activation may be closed. 
4.3 
Justification for Investigational Product Dose 
The blinatumomab dosing regimen selected for this study is 28 µg/day for subject’s 
 45 kg (or 15 g/m2/day to a max of 28 g/day for subjects  45 kg) under continuous 
intravenous infusion (CiVI) for a period of 28 days per treatment cycle, followed by a 
14-day infusion free interval, as per approved dosing.   
4.4 
End of Study 
4.4.1 
End of Study Definition 
End of Study:  The end of study date is defined as the date when the last subject 
across all sites is assessed or receives an intervention for evaluation in the study (ie, last 
subject last visit). 
4.4.2 
Study Duration for Subjects 
For an individual subject the length of participation includes a 21-day screening period, 
up to a 5.5-month treatment period (assumes 2 complete cycles in the outpatient setting 
plus 2 additional optional cycles in the outpatient setting), and an end of study visit 
(30 days  3 days after the last dose of study treatment).  
For subjects who complete the protocol from the date of first dose through the end of 
study visit, the entire duration of the study will take approximately 8 months to complete.  


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5. 
Study Population 
Investigators will be expected to maintain a screening log of all potential study 
candidates that includes limited information about the potential candidate (eg, date of 
screening). 
Eligibility criteria will be evaluated during screening. 
Before any study-specific activities/procedures, the appropriate written informed consent 
must be obtained (see Section 11.3). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions will not be provided. 
5.1 
Inclusion Criteria 
Subjects are eligible for study participation only if all of the following criteria are met: 
101 
Subject has provided informed consent prior to initiation of any study-specific 
activities/procedures OR subject’s legally acceptable representative has provided 
informed consent prior to any study-specific activities/procedures being initiated 
when the subject has any kind of condition that, in the opinion of the Investigator, 
may compromise the ability of the subject to give written informed consent. 
102 
Age  18 years 
103 
B-cell precursor (BCP) ALL with minimal/measurable residual disease 
defined as hematologic CR with less than 5 bone marrow blasts and 
meets clinical eligibility criteria to receive blinatumomab as outlined below. 
105 
Hematologic criteria for remission as defined below: 
 
< 5 bone marrow blasts.  
 
Absolute neutrophil count  1.0 x109 / L  
 
Platelets  50 x109/L (transfusion permitted)  
 
Hemoglobin level  90 g/L (transfusion permitted)  
106 
Renal and hepatic function as defined below: 
 
Total bilirubin  3 x ULN unless related to Gilbert’s or Meulengracht disease 
 
Serum creatinine  1.5 x ULN.  If serum creatinine  1.5 x ULN, then 
measure Glomerular Filtration Rate (GFR); subject will be eligible only if 
measured GFR is within normal limits. 
107 
Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. 
108 
Negative pregnancy test in women of childbearing potential. 
109 
Ability and willingness to wear and comply with the instructions for the use of and 
monitoring of the digital monitoring devices as outlined in informed consent. 
110 
Subject resides within 1 hour of ground transportation to an advanced medical 
care facility for the duration of the MDMP 


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111 
Adequate cellular service available during MDMP 
Caregiver Eligibility Requirements 
112 
Presence of an adult ( 18 years) caregiver(s) in the same dwelling, for 
24 hours/day for the entire MDMP.  Caregiver will be expected to have access to 
transportation. 
113 
Ability and willingness to participate in the health management of the subject and 
to assist with the requirements of remote digital monitoring devices during the 
blinatumomab infusion within the MDMP 
5.2 
Exclusion Criteria 
Subjects will not be eligible for study participation if any of the following criteria apply: 
Disease Related 
201 
Presence of circulating blasts 
202 
Presence of extramedullary disease 
203 
History of relevant central nervous system (CNS) pathology or current relevant 
CNS pathology (seizure, paresis, aphasia, cerebrovascular 
ischemia/hemorrhage, severe brain injuries, dementia, Parkinson’s disease, 
cerebellar disease, organic brain syndrome, psychosis, or coordination or 
movement disorders 
204 
Current infiltration of cerebrospinal fluid (CSF) by ALL.  If screening CSF 
demonstrates leukemic blasts, subjects must receive intrathecal treatment and 
demonstrate negative CSF before enrollment and starting blinatumomab infusion. 
205 
Current autoimmune disease or history of autoimmune disease with potential 
CNS involvement 
206 
Allogeneic HSCT within 12 weeks before blinatumomab treatment 
207 
Active acute or chronic graft versus host disease (GvHD) requiring systemic 
treatment with immunosuppressive medication 
208 
Systemic chemotherapy within 2 weeks prior to study treatment (except for 
intrathecal prophylaxis) 
209 
Radiotherapy within 4 weeks prior to study treatment 
210 
Known hypersensitivity to blinatumomab or to any component of the product 
formulation 
211 
Active malignancy other than ALL with the exception of basal cell or squamous 
cell carcinoma of the skin, or carcinoma in situ of the cervix. 
212 
History of other malignancy within the past 2 years, with the following 
exception[s]: 
 
Malignancy treated with curative intent and with no known active disease 
present for  2 years before enrollment and felt to be at low risk for 
recurrence by the treating physician. 
 
Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease. 
 
Adequately treated cervical carcinoma in situ without evidence of disease. 


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 
Adequately treated breast ductal carcinoma in situ without evidence of 
disease. 
 
Prostatic intraepithelial neoplasia without evidence of prostate cancer. 
 
Adequately treated urothelial papillary non-invasive carcinoma or carcinoma 
in situ. 
213 
Currently receiving treatment with an investigational device or drug study or less 
than 30 days since ending treatment on an investigational device or drug 
study(ies) 
214 
Active uncontrolled infection requiring therapy 
215 
Known infection or chronic infection with hepatitis B virus (hepatitis B surface 
antigen [HBsAg] positive) or hepatitis C virus (HCV) (anti-HCV positive) 
216 
Known positive test for human immunodeficiency virus (HIV) 
217 
Any concurrent disease or medical condition deemed to interfere with the 
conduct of the study and remote digital monitoring as judged by the investigator 
218 
Any acutely ill cardiac patients with the potential to develop life threatening 
arrhythmias eg, very fast atrial fibrillation 
219 
Subjects with no cellular signal in their home 
220 
Subjects with bi-lateral upper arm tattoos directly under the area of CWHMS 
application (CH wearable device) 
221 
Subjects with a known allergy to any of the device component materials 
222 
Subjects with open wounds on both arms directly under the area of CWHMS 
application (CH wearable device) or with injuries to both arms 
223 
Subjects with an upper arm circumference of less than 20 cm or greater than 
50 cm 
224 
Subjects with an implantable defibrillator 
225 
Subjects unwilling to wear the CWHMS (CH wearable device, axillary 
temperature patch) during the MDMP in cycles 1 and 2 
226 
Subjects with excessive scarring directly under the area of CWHMS (CH 
wearable device) application 
227 
Subjects who cannot have their BP measured in both arms (or wrists) eg due to 
atrio-venous shunt, risk of lymphedema or peripherally inserted central catheter 
line 
Other Exclusions 
228 
Female subject is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 48 hours after the last dose of 
protocol-specified therapy. 
229 
Female subjects of childbearing potential unwilling to use 1 highly effective 
method of contraception during treatment and for an additional 48 hours after the 
last dose of protocol-specified therapy.  Refer to Section 11.5 for additional 
contraceptive information. 
230 
Female subjects of childbearing potential with a positive pregnancy test assessed 
at Screening by a serum pregnancy test and/or urine pregnancy test. 


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231 
Subject likely to not be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures (eg, PROs) to 
the best of the subject and investigator’s knowledge. 
5.3 
Subject Enrollment 
Before subjects begin participation in any study-specific activities/procedures, Amgen 
requires a copy of the site’s written institutional review board/independent ethics 
committee (IRB/IEC) approval of the protocol, informed consent form, and all other 
subject information and/or recruitment material, if applicable (see Section 11.3). 
The subject or the subject’s legally acceptable representative must personally sign and 
date the IRB/IEC and Amgen approved informed consent before commencement of 
study-specific procedures. 
Each subject who enters into the screening period for the study (entry is defined as the 
point at which the subject signs the informed consent) receives a unique subject 
identification number before any study-related activities/procedures are performed.  The 
subject unique identification number will be assigned manually.  This number will be 
used to identify the subject throughout the clinical study and must be used on all study 
documentation related to that subject.  The medical devices will be returned to CH after 
assigned use. 
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened. 
A subject is considered enrolled when the investigator decides that the subject 
has met all eligibility criteria.  The investigator is to document this decision and 
date in the subject’s medical record and in/on the enrollment case report form 
(CRF). 
Sites that do not enroll subjects within 12 months of site initiation may be closed. 
5.4 
Screen Failures 
Screen failures are defined as subjects who consent to participate in the clinical study 
but are not subsequently enrolled in the study.  A minimal set of screen failure 
information will be collected that includes demography, screen failure details, eligibility 
criteria, and any SAEs. 
Individuals who do not meet the criteria for participation in this study (screen failure) may 
be rescreened.   


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Subjects who are unable to complete or meet eligibility at the initial screening will be 
permitted to re-screen once.  Re-screen subjects must first be registered as a screen 
failure manually, and subsequently registered as re-screen.  Once the subject is 
registered as re-screened, a new 21-day screening window will begin.  Sites may need 
to repeat CR and MRD testing so that eligibility assessments are within 5 weeks of 
starting blinatumomab infusion.  Subjects will retain the same subject identification 
number assigned at the original screening.   
For subjects who fail screening because of an inability to wear or are unsuitable for the 
device, the assigned monitoring medical devices will be returned to CH. 
Refer to Section 8.1.1. 
6. 
Treatments 
Study treatment is defined as any investigational product(s), procedure or process, 
non-investigational product(s), placebo, or medical device(s) intended to be 
administered to a study subject according to the study protocol.  The investigational 
nature of this study is in using blinatumomab in a complete outpatient setting.  Both 
blinatumomab and the CWHMS are approved for use and will be used for an approved 
indication. 
The modular Investigational Product Instruction Manual (IPIM), a document external to 
this protocol, contains detailed information regarding the storage, preparation, 
destruction, and administration of each treatment shown in Table 6-1 below. 
6.1 
Treatment(s) Administered 
6.1.1 
Investigational Products 


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Table 6-1.  Study Treatments 
Study Treatment Name 
Amgen Investigational Product:a 
Blinatumomab; Blincyto 
Dosage Formulation 
38.5 g powder for solution for infusion, single use 
vials 
Unit Dose Strength(s)/ 
Dosage Level(s) and Dosage 
Frequency 
28 g/day as a CiVI per cycle for up to 4 cycles.  
Dose for subjects  45 kg: 15 g/m²/day (max 
28 g/day).  1 cycle consists of 6 weeks (4 weeks 
CiVI and 2 weeks infusion-free interval) 
Route of Administration 
CiVI 
Accountability 
The number of vials dispensed, date dispensed, date, 
and lot number of investigational product (IP) are to 
be recorded.   
Dosing Instructions (24 to 48 hours) 
To prepare Blinatumomab for IV infusion, the 
lyophilized powder is reconstituted with sterile water 
for injection resulting in a concentration of 
12.5 g/mL.  The reconstituted solution is added to 
an infusion bag containing 0.9 NaCl and a product 
specific stabilizer (IV Solution Stabilizer [IVSS]).  The 
IVSS functions to prevent adsorption of 
blinatumomab to surfaces of the infusion 
components. 
IV infusion method: Blinatumomab infusion for 
solution will be prepared in IV bags for CiVI and 
delivered through infusion lines with an in-line 0.2 m 
filter that is compatible with the IP as described in the 
IPIM. 
The daily blinatumomab dose may be up to 10 
lower or higher, in order to account for possible pump 
inaccuracies. 
7-day CiVI Dosing Instructions 
To prepare blinatumomab for IV infusion, the 
lyophilized powder is reconstituted with sterile 
water for injection resulting in a concentration of 
12.5 g/mL.  The reconstituted solution is added 
to an infusion bag containing Bacteriostatic 
0.9 Sodium Chloride and a product specific 
stabilizer (IVSS).  The IVSS functions to prevent 
adsorption of blinatumomab to surfaces of the 
infusion components. 
IV infusion method:  blinatumomab infusion for 
solution will be prepared in IV bags for CiVI and 
delivered through infusion lines with no in-line 
0.2 µm filter as described in the IPIM. 
The daily blinatumomab dose may be up to 10 
lower or higher, in order to account for possible 
pump inaccuracies. 
CiVI  continuous intravenous infusion; IM  intramuscular; IP  Investigational Product; 
IPIM  Investigational Product Instruction Manual; IV  intravenous; IVSS  intravenous solution stabilizer 
a Blinatumomab will be manufactured and packaged by Amgen and distributed using Amgen clinical study 
drug distribution procedures.


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6.1.2 
Medical Devices 
The medical devices provided by Amgen for use in this study include: 
 
Infusion pump and infusion line 
 
The CWHMS 
These devices are non-Amgen non-investigational devices.  Descriptions of the devices 
are provided in the approved device manual, and the CH User Manual. 
Blinatumomab must be administered in the outpatient setting using infusion pumps 
approved for use by the appropriate regulatory authorities.  
Blinatumomab solution for infusion will be prepared in intravenous (IV) bags for IV 
infusion and delivered through infusion lines that are compatible with the IP as described 
in the IPIM.  The blinatumomab final solution for infusion should not come into contact 
with the pump at any time.  Additional details for the use of the above-mentioned 
medical devices are provided in the IPIM.  
Infusion pumps, IV bags and tubing, and ancillary materials (eg, syringes, sterile 
needles, alcohol prep pads) may be provided by Amgen if site is unable to provision.  
Additional non-investigational medical devices that are commercially available are not 
provided or reimbursed by Amgen.  The investigator overseeing the conduct of the study 
at each respective institution will be responsible for obtaining these supplies.  If site 
supplies are used, then the Investigator will be responsible for obtaining and maintaining 
these supplies. 
Current Wearable Health Monitoring System (CWHMS) 
The central component of the CWHMS is the CH wearable device that is worn on the 
subject’s upper arm.  The CH Wearable device monitors a subject’s pulse rate, 
respiratory rate, skin temperature, oxygen saturation, step count and activity levels at a 
maximum rate of every 2 seconds.  For this study, the following vital signs will be 
collected and evaluated: pulse rate, respiratory rate, axillary temperature, and oxygen 
saturation. 
The CH Wearable device also integrates with an axillary temperature sensor, via 
Bluetooth, to measure axillary temperature.  This temperature sensor will be used in this 
study.  In addition, the subject tablet will allow capture of systolic and diastolic BP via a 
Bluetooth integration with an approved and integrated BP monitor which the subject 
applies to their other arm/wrist to capture the BP. 


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The CH wearable device transmits encrypted data over WiFi/cellular.   
The subject is also provided with a tablet.  This tablet allows capture of electronic patient 
reported outcomes (ePROs), specifically European Organisation for Research and 
Treatment of Cancer (EORTC) Quality of Life of Cancer Patients (QLQ-C30) for this 
study (see Section 8.2.8), as well as video calls with their HCP. 
The CH platform generates an alert based on pre-specified alarming thresholds.  This 
alert is sent via push notification to a mobile application installed on the study 
provisioned mobile phone of the subject’s HCP.  The HCP can also use this application 
to review subject vital sign trends and history.  A similar application is also provided for 
access via an internet browser.  
In response to an alert, the HCP may schedule (or as needed make) a video call to the 
subject.  (In addition, subject may initiate a call to the HCP if needed).  This is via the 
tablet that the subject is provided and the application installed on the study provisioned 
mobile phone.  This allows the HCP to immediately and conveniently assess the 
subject’s condition and make an appropriate intervention.  
6.1.3 
Other Protocol-required Therapies 
All other protocol-required therapies including dexamethasone, that are commercially 
available are not provided or reimbursed by Amgen (except if required by local 
regulation).  The investigator will be responsible for obtaining supplies of these 
protocol-required therapies.  Additional details regarding these protocol-required 
therapies are provided in the IPIM. 
Dexamethasone Premedication 
Premedication with dexamethasone (or prednisone) is required before each 
blinatumomab treatment cycle for prophylaxis of CRS.  Dexamethasone 16mg (or 
equivalent prednisone 100 mg) should be given up to 6 hours prior to the start of 
blinatumomab infusion for each cycle.  Dexamethasone will be the recommended steroid 
for this study.  Subjects  45 kg will have 2 additional 8mg doses (subjects < 45 kg will 
receive 2 doses of 5 mg/m2 rounded to the nearest mg) of oral dexamethasone to use as 
needed for treatment of CRS symptoms only if instructed by HCP.  It will be 
recommended that hospitalization be strongly considered for subjects who require 
interruption of blinatumomab for  4 hours. 


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Intrathecal CNS Prophylaxis Before Treatment  
Lumbar puncture and CSF analysis must be performed during screening to determine 
the presence of CSF lymphoblasts.  Cerebrospinal fluid evaluation done as part of 
standard of care within 2 weeks of screening may be used.  If CSF is positive, subjects 
must receive intrathecal chemotherapy as per site standard of care and a negative CSF 
must be documented prior to starting protocol-specified blinatumomab therapy.  Subjects 
with persistent positive CSF will not be eligible.  A repeat CSF on cycle 1 day 29 (prior to 
starting cycle 2 day 1) will be required only for subjects with positive CSF in screening.   
6.1.4 
Product Complaints 
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug, combination product, or device after it is released for 
distribution to market or clinic by either (1) Amgen or (2) distributors or partners for 
whom Amgen manufactures the material.  This includes all components distributed 
with the drug, such as packaging drug containers, delivery systems, labeling, and 
inserts. 
This includes any investigational/non-investigational product(s), device(s) or 
combination product(s) provisioned and/or repackaged/modified by Amgen.  Amgen 
will collect product complaints for blinatumomab and the wearables included in the 
CWHMS. 
Any product complaint(s) associated with investigational product(s), 
non-investigational product(s), device(s), or combination products supplied by 
Amgen are to be reported. 
For non-investigational products like IV Solution Stabilizer (IVSS), product complaints 
are to be reported according to the instructions provided in modular IPIM.  
There are no combination product(s) provided by Amgen on this study.  
For Pump Complaints, guidance will also be provided in the IPIM.  
For CH wearable device complaints, these will be triaged through the HCP, who after 
assessing that the subject is safe, will directly contact the current health support 
system (current health 24/7 help hotline, email).  
Current Health defines a complaint as any indication of the failure or deficiency of the 
product to meet customer, healthcare professional, user or subjects’ expectations.  This 


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includes deficiencies related to performance eg, the product operating in some way that 
does not comply with the indications for use or accompanying labelling, safety, 
appearance, quality, reliability or effectiveness. 
A complaint may be received through a number of mechanisms including written, oral, 
electronic or through return of a product. 
In this study, during the MDMP, the patient must report all complaints related to the 
CWHMS to the HCP.  The HCP will then triage the complaint and when he/she is 
satisfied that the subject is safe, the HCP will directly contact the current health 
support system (current health 24/7 help hotline, email).  At any time that the 
complaint of a device is considered to be risking the safety of the subject by preventing 
the transmission of vital signs and/or information the HCP will direct the subject to the 
nearest health care facility or emergency room. 
If a complaint is received by Amgen related to the CH product (including accompanying 
peripherals), it should be reported to CH within 24 hours.  The following information 
should be provided: 
1. Date and time of complaint 
2. The serial number of the specific product  
3. The nature of the complaint 
4. When and where the event took place including as much context as possible 
5. Any concomitant subject conditions that may be relevant  
6. Any other relevant information 
If a complaint is received by the CH support desk and relates to Amgen drugs or 
products, this will be reported to Amgen as per a procedure to be agreed with Amgen. 
If a complaint is received by CH that relates to any of the associated devices, CH will 
engage with the device manufactures to provide the complaint so that they can manage 
as per their own internal procedures.   
Current Health will investigate and evaluate all complaints leading to one of a number of 
possible outcomes: 
 
No further action required along with the reason and rationale for this 
 
A product improvement is required which will be managed via change control 
 
A corrective action/preventive action (CAPA) is required 


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Current Health will determine whether a regulatory report is required.  Current Health will 
provide mandatory device reports to the US FDA based on the following guidelines: 
 
Within 30 days of death, serious injury or malfunction 
Within 5 days event requiring remedial action immediately to prevent an unreasonable 
risk of substantial harm to the public health. 
6.1.5 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following medications are not permitted during a subject’s participation (including 
the induction, consolidation, and/or maintenance treatment) of this study: 
 
Any anti-tumor therapy other than the protocol-specified therapy (ie, radiation 
therapy, immunotherapy, cytotoxic and/or cytostatic drugs); 
 
Chronic systemic ( 7 days) high-dose corticosteroid therapy (dexamethasone 
 24 mg/day or equivalent); any other immunosuppressive therapies (except for 
transient use of corticosteroids); 
 
Any other investigational agent. 
6.2 
Dose Modification 
6.2.1 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation 
6.2.1.1 
Amgen Investigational Product:  Blinatumomab 
The reason for dose change of blinatumomab is to be recorded on each subject’s 
CRF(s).  There will be no dose change while the subject is receiving blinatumomab 
during the MDMP.  Infusion may be interrupted by the investigator for any AE.  If the AE 
is persistent and not responsive to the investigator’s intervention for  4 hours, the 
subject should be directed to the nearest hospital for evaluation. 
6.2.2 
Infusion Interruption/Dose Modification due to Adverse Events 
Sites will administer blinatumomab as per the local regulatory approved guidelines.  
Common Terminology Criteria for Adverse Events (CTCAE) v5.0 will be used to grade 
toxicities.  Grade 1 and grade 2 events will be managed symptomatically with temporary 
discontinuation of the blinatumomab (if considered necessary by the investigator).  The 
investigator will intervene in accordance with the alert algorithm for other AEs. 


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Table 6-2.  Infusion Interruptions/Dose Modifications Due to Adverse Events 
Toxicity 
Grade or 
Adverse 
Event 
Instructions for Treatment Interruption and Restart 
 
 
Subjects Greater Than or Equal 
to 45 kg 
Subjects Less Than 45 kg 
Cytokine 
Release 
Syndrome 
3 
 
Interrupt blinatumomab.  
 
Administer dexamethasone 
8 mg every 8 hours IV or 
PO for up to 3 days and 
taper thereafter over 
4 days. 
 
When CRS is 
resolved, restart 
blinatumomab at 
9 g/day, and 
escalate to 28 g/day 
after 7 days if the 
toxicity does not recur.  
 
Interrupt blinatumomab.  
 
Administer dexamethasone 
5 mg/m2 (maximum 8 mg) 
every 8 hours IV or PO for 
up to 3 days and taper 
thereafter over 4 days.  
 
When CRS is resolved, 
restart blinatumomab at 
5 g/m2/day and escalate to 
15 g/m2/day after 7 days if 
the toxicity does not recur. 
4 
Discontinue BLINCYTO permanently.  Administer dexamethasone 
as instructed for grade 3 CRS. 
Neurologic 
Toxicity 
3 
Administer dexamethasone 
as instructed for grade 3 CRS.  
Withhold blinatumomab until no 
more than grade 1 (mild) and for 
at least 3 days, then restart 
blinatumomab at 9 g/day.  
Escalate to 28 g/day after 
7 days if the toxicity does not 
recur.  If the toxicity occurred at 
9 g/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 g/m2/day.  
Escalate to 15 g/m2/day after 
7 days if the toxicity does not 
recur.  If the toxicity occurred at 
5 g/m2/day, or if the toxicity 
takes more than 7 days to 
resolve, discontinue 
blinatumomab permanently. 
4 
Discontinue blinatumomab permanently. 
Seizurea  
Administer dexamethasone as instructed for grade 3 CRS. 
Administer anti-seizure medication.  Permanently discontinue 
BLINCYTO if seizure occurs at 9 ug or if second seizure occurs 
after restart. 
Page 1 of 2 
Footnotes defined on last page of this table 


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Table 6-2.  Infusion Interruptions/Dose Modifications Due to Adverse Events 
Toxicity 
Grade or 
Adverse 
Event 
Instructions for Treatment Interruption and Restart 
Other 
clinically 
relevant 
adverse 
events  
3 
Withhold blinatumomab until no 
more than grade 1 (mild), then 
restart blinatumomab at 
9 g/day.  Escalate to 28 g/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 g/m2/day.  Escalate to 
15 g/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 
Consider discontinuing blinatumomab permanently. 
Page 2 of 2 
a Obtain brain MRI and perform cerebrospinal fluid (CSF) analysis, if indicated, and if there are no 
contraindications. 
CRS  cytokine release syndrome; IV  intravenous(ly); PO  oral. 
Grade scale is based on Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). 
Source: Blinatumomab USPI  
6.2.3 
Hepatotoxicity Stopping and Rechallenge Rules 
Refer to Section 11.6 for details regarding drug-induced liver injury guidelines, as 
specified in the Guidance for Industry Drug-Induced Liver Injury:  Premarketing Clinical 
Evaluation, July 2009.  
6.3 
Preparation/Handling/Storage/Accountability 
Guidance and information on drug accountability for the investigational product 
and/or device will be provided to the site.  Guidance and information for digital health 
devices provided for this study will be included in a study guide. 
6.4 
Treatment Compliance 
Compliance with using the devices can be determined from the data transmitted by the 
device.  Health and technical alarms will confirm if data is not being transmitted from 
the devices.  The subject will be instructed to call HCP immediately if alert is received 
that data is not being transmitted from the devices.  The HCP are advised to contact the 
subject immediately if data is not being received.  Assessing compliance with 
blinatumomab therapy per protocol and per IPIM will be performed by the study centers 
and clinical research associates.  If a subject fails to comply with the instructions for use 
of the device, the subject will receive re-education/re-training on use of the device.  If the 
subject fails to comply a second time, then the subject will be removed from the study 
and it will be recommended that the subject be admitted to the hospital for the remainder 
of the MDMP as per the product label. 


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6.5 
Drug Administration 
The drug administration should not be interrupted, if possible.  In case of infusion 
interruption, due to any technical or logistic reason, the interruption should be as short 
as possible, and the infusion restarted at the earliest time possible.  Every interruption 
longer than 1 hour should be documented.  Administration of dexamethasone 
premedication will occur as described in Section 6.1.3.  If the infusion is interrupted, if 
possible, the total infusion time should equal 28 days in each cycle. 
A dose of up to 10 higher than the intended blinatumomab dose (per day) may not 
require specific intervention.  In case of overdose or medication error, the infusion 
should be immediately stopped.  Routine supportive and symptomatic care according to 
standard medical practice is recommended.  Once the subject is stabilized and no 
clinically relevant safety findings due to blinatumomab are observed, resumption of 
blinatumomab at a correct dose can be considered after consultation with the Amgen 
medical monitor. 
For blinatumomab, a dose of greater than 10 higher than the intended dose will be 
considered clinically important and classified as a serious adverse event under the 
criterion of “other medically important serious event” per Section 11.4.  If the overdose 
results in additional AEs, the subject should be followed carefully until all signs of toxicity 
are resolved and the AEs should be recorded/reported per Section 11.4 of the protocol. 
6.6 
Prior and Concomitant Treatment 
6.6.1 
Prior Treatment 
Prior therapies that were being taken from initial diagnosis through the informed consent 
should be collected.  For prior therapies being taken for the disease under study, collect 
therapy name, indication, dose, unit, frequency, start date, and stop date.  For all other 
prior therapies, collect therapy name, start date, and stop date. 
6.6.2 
Concomitant Treatment 
Throughout the study, investigators may prescribe any concomitant medications 
or treatments deemed necessary to provide adequate supportive care except for 
those listed in Section 6.1.5. 
For concomitant therapies being taken on study, collect therapy name, indication, dose, 
unit, frequency, route, start date, and stop date. 


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7. 
Discontinuation of Study Treatment and Subject 
Discontinuation/Withdrawal 
Subjects have the right to withdraw from investigational product and/or other 
protocol-required therapies, protocol procedures, or the study as a whole at any time 
and for any reason without prejudice to their future medical care by the physician or at 
the institution. 
The investigator and/or sponsor can decide to withdraw a subject(s) from 
investigational product, device, and/or other protocol-required therapies, protocol 
procedures, or the study as a whole at any time prior to study completion for the reasons 
listed in Section 7.1 and Section 7.2.1. 
7.1 
Discontinuation of Study Treatment 
Subjects (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  If this occurs, the 
investigator is to discuss with the subject the appropriate processes for discontinuation 
from investigational product or other protocol-required therapies and must discuss 
with the subject the possibilities for continuation of the Schedule of Activities (see Table 
1-2) including different options of follow-up (eg, in person, by phone/mail, through 
family/friends, in correspondence/communication with other treating physicians, from the 
review of medical records) and collection of data, including endpoints, adverse events, 
and device-related events, as applicable and must document this decision in the 
subject’s medical records.  Subjects who have discontinued investigational product 
and/or other protocol-required therapies or procedures should not be automatically 
removed from the study.  Whenever safe and feasible, it is imperative that subjects 
remain on-study to ensure safety surveillance and/or collection of outcome data. 
Subjects may be eligible for continued treatment with Amgen IP(s) and/or other 
protocol-required therapies by a separate protocol or as provided for by the local 
country’s regulatory mechanism, based on parameters consistent with Section 11.3. 
Reasons for early removal from protocol-required IP(s) or procedural assessments may 
include any of the following: 
 
decision by Sponsor  
 
lost to follow-up 
 
death 


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 
adverse event 
 
subject request 
 
ineligibility determined 
 
protocol deviation 
 
non-compliance 
 
pregnancy 
 
disease progression 
 
failure to comply with the instructions for the CWHMS 
7.2 
Subject Discontinuation/Withdrawal From the Study 
Withdrawal of consent for a study means that the subject does not wish to receive 
further protocol-required therapies or procedures, and the subject does not wish to or is 
unable to continue further study participation.  Subject data up to withdrawal of consent 
will be included in the analysis of the study, and where permitted, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study and must document the 
subject’s decision to withdraw in the subject’s medical records.   
If a subject wishes to discontinue participation from the study during the MDMP, the 
investigator will establish that the subject is safe and without any abnormal vital signs.  If 
the subject is not stable, they will be instructed to go to the nearest emergency room.  If 
the subject is stable, the devices will be turned off, monitoring will be discontinued, and 
devices will be returned.  The investigator will recommend that the subject be admitted 
to the hospital for the remainder of the MDMP as per the product label.  After 
discontinuation, subjects will be required to complete the end of study visit approximately 
30 (3) days after the last dose of blinatumomab. 
Refer to the Schedule of Activities (Table 1-2) for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to be 
completed.  The subject is required to return all medical devices upon discontinuation of 
study treatment. 
7.2.1 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
 
decision by Sponsor 


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 
withdrawal of consent from study 
 
death 
 
lost to follow-up 
7.2.2 
Lost to Follow-up 
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit: 
 
The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or is able to 
continue in the study. 
 
In cases in which the subject is deemed lost to follow-up, the investigator or 
designee must make every effort to regain contact with the subject (where possible, 
3 telephone calls and, if necessary, a certified letter to the subject’s last known 
mailing address or local equivalent methods).  These contact attempts are to be 
documented in the subject’s medical record. 
 
If the subject continues to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up.  
 
For subjects who are lost to follow-up, the investigator can search publicly available 
records where permitted to ascertain survival status.  This ensures that the data 
set(s) produced as an outcome of the study is/are as comprehensive as possible. 
The subject is required to return all medical devices upon discontinuation of study 
treatment. 
8. 
Study Assessments and Procedures 
Study procedures and their time points are summarized in the Schedule of Activities 
(see Table 1-2).  
As protocol waivers or exemptions are not allowed if an enrolled subject is subsequently 
determined to be ineligible for the study, this must be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the subject is to continue or 
discontinue study treatment. 
Adherence to the study design requirements, including those specified in the Schedule 
of Activities, is essential and required for study conduct. 


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8.1 
General Study Periods 
8.1.1 
Screening, Enrollment, and/or Randomization 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy for any disallowed therapy.  After the subject has 
signed the informed consent form, the site will register the subject and screen the 
subject in order to assess eligibility for participation.  The screening window is up to 
21 days. 
All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, (see Section 5.4) as applicable. 
If a subject has not met all eligibility criteria at the end of the screening period, the 
subject will be registered as a screen fail.  Screen fail subjects may be eligible for 
re-screening 1 time.  
Rescreen subjects must first be noted as screen failures and subsequently noted as 
rescreens.  Once the subject is registered as rescreened, a new 21-day screening 
window will begin.  Subjects will retain the same subject identification number assigned 
at the original screening.  If the rescreening period begins more than 21 days after the 
original signing of the informed consent form, all screening procedures, including 
informed consent, must be repeated.  The period between bone marrow evaluation and 
determination of CR, and signing of informed consent must not be greater than 14 days.   
8.1.2 
Treatment Period 
Visits will occur per the Schedule of Activities (Table 1-2).  The date and time of the first 
dose of blinatumomab is defined as day 1, hour 0.  All subsequent doses and study 
visits will be scheduled based on the day 1 date and time. 
8.1.3 
Long-term Follow-up 
Not applicable. 
8.1.4 
End of Study 
All subjects will complete an end of study (EOS) visit approximately 30 ( 3) days after 
the last dose of blinatumomab.  If a subject starts a new treatment for their disease 
within 30 ( 3) days of their last dose of blinatumomab therapy, an EOS visit should be 
conducted immediately prior to starting any new treatment, including HSCT conditioning 
regimens.  Serious adverse events (and any concomitant medications associated with 


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SAEs observed by the investigators or reported by the subjects that occur within 
30 ( 3) days following cessation of treatment if the subject initiates new anticancer 
therapy (whichever is earlier) will be reported, followed, and recorded.  End of study 
assessments will occur per the Schedule of Activities (Table 1-2).  No digital tools will be 
provided by the study after cycle 2 day 2; subjects will continue with standard of care per 
investigator and site. 
8.2 
Description of General Study Assessments and Procedures 
The sections below provide a description of the individual study procedures for required 
time points. 
8.2.1 
General Assessments  
8.2.1.1 
Informed Consent 
All subjects or their legally authorized representative must sign and personally date the 
IRB/IEC approved informed consent before any study-specific procedures are 
performed.  Confirmation that the informed consent form has been signed must occur 
before any study-specific procedures are performed.  All subjects who are enrolled and 
receive protocol-specified therapy should be reconsented with any updated versions of 
IRB/IEC approved informed consents during study participation as applicable and per 
institutional guidelines. 
8.2.1.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
accordance with local law in order to study their possible association with subject safety 
and treatment effectiveness. 
8.2.1.3 
Medical History/Current Medical Conditions 
The Investigator or designee will collect a complete medical and surgical history that 
started 3 years prior to screening through time of signing of informed consent.  In 
addition, any non-serious Adverse Event that is observed between the signing of the 
Informed Consent Form to enrolment/pre-dose cycle 1 day 1 should be captured as 
Medical History.  Medical history will include information on the subject's concurrent 
medical conditions.  Record all findings on the medical history CRF.  In addition to the 
medical history above, all history related to the subject’s diagnosis of MRD positivity will 
be recorded.  The current toxicity grade will be collected for each condition that has not 
resolved. 


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8.2.1.4 
Physical Examination  
Physical examination will be performed as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
8.2.1.5 
Physical Measurements 
Physical measurements include height, weight, body surface area (BSA). 
8.2.1.6 
Eastern Cooperative Oncology Group Performance Status  
The subject’s performance status will be assessed per the Schedule of Activities see 
(Table 1-2), using the ECOG PS score (see Section 11.7). 
8.2.1.7 
Primary Diagnosis/CR/MRD 
Standard of care procedures such as bone marrow aspiration/biopsy including MRD 
assessment and lumbar puncture are not considered study-specific and are to be 
performed no more than 14 days prior to informed consent as outlined in the Schedule 
of Activities (Table 1-2).  Any additional bone marrow (BM) procedure performed 
during the screening period to qualify the subject for participation in trial must be 
approved by the medical monitor.  
8.2.1.8 
Neurological History and Examination 
The Investigator or designee will collect a complete neurological history that started 
3 years prior to screening through time of signing of informed consent.  Neurological 
history will include information on the subject's concurrent medical conditions.   
A neurological examination will be performed as outlined in the Schedule of Activities 
(Table 1-2).  Subjects will be specifically queried for neurological symptoms observed in 
the interval since the last extended neurological examination.  Abnormalities of the 
following should be recorded:  level of consciousness, orientation, vision, cranial nerves 
and brain stem functions, pyramidal and extra pyramidal motor system, reflexes, muscle 
tone and trophic findings, coordination, sensory system, neuropsychological findings (eg, 
speech, cognition, and emotion). 
8.2.1.9 
Lumbar Puncture to Examine Cerebrospinal Fluid 
A lumbar puncture will be performed as outlined in the Schedule of Activities (Table 1-2) 
to assess for possible leukemic involvement.  Cerebrospinal fluid, cell count, glucose, 
and protein, will be measured at the local laboratory as part of the examination.  
Additional investigations of the CSF should be performed as clinically appropriate.  
If an Ommaya reservoir is in place and there is no evidence of blockage of CSF flow in 
the spinal canal, withdrawal of a sample through the Ommaya reservoir is permitted.   


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8.2.1.10 
Intrathecal CNS Prophylaxis 
Please refer to Section 6.1.3 for mandatory intrathecal CNS prophylaxis guidelines. 
8.2.1.11 
Clinical Assessment 
A clinical assessment will be performed at the end of cycle 2, as specified in the 
Schedule of Activities see (Table 1-2). 
8.2.2 
Efficacy and Digital Health Tool Assessments 
All efficacy assessments will be evaluated per the Schedule of Activities see (Table 1-2). 
8.2.2.1 
Digital Health Device Monitoring of Vital Signs During the Mandatory 
Monitoring Period 
During the MDMP, subjects will wear the CWHMS (CH wearable device and axillary 
temperature patch) continuously 24 hours a day.  Subjects must constantly remain 
within range of the (current health provided) home hub WiFi device for the first 
24 hours of the study.  After the first 24 hours, subjects may be allowed to remove 1 or 
all of the devices for a maximum of 1 hour per day only after first notifying HCP.  This 
will allow subjects to attend to personal activities such as taking a bath or shower.  
Subject must be clinically stable with normal vitals and no evidence of NT prior to the 
start of the 60-minute period.  This break must be coordinated with the HCP, as no data 
will be transmitted during this period.  It is recommended that subjects use this time to 
charge the CH wearable device.  It is also strongly encouraged that the subjects 
charge the CH wearable device at approximately the same time each day.   
Vital signs (pulse rate, respiratory rate, oxygen saturation, and axillary temperature) 
will be measured continuously using CWHMS, as specified in the Schedule of Activities 
(Table 1-2).  There will be no data transmission to HCP while subjects are transported to 
home from the outpatient facility.  Vital sign data will be stored but not transmitted in real 
time. 
Non-invasive BP will also be performed as specified in the Schedule of Activities (Table 
1-2).  Vital signs will be available as a constant live feed to the HCP for the entire 
MDMP.  Health and technical alarms/alerts will indicate when a vital sign is outside of 
the preset parameters.  Details of the data that will be monitored using the digital health 
devices are described in detail in Section 6.1.2. 
Sites will be given the option to utilize a nursing triaging service provisioned by 
CH to act as their designee to acknowledge and respond to health and technical 


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alarms during a subject's MDMP.  This service can be requested by the site on a 
subject-by-subject basis.  
If a site elects to use this nursing triage service as their designee during the 
MDMP, the nursing triage staff provided will be licensed nurses who are trained 
on the protocol, trained on use and management of the CWHMS, and will be able 
to support the site with management of health and technical alarms 24 hours a 
day during MDMP.  The nursing triage staff will follow Schmitt-Thompson phone 
triage clinical protocols which are currently being utilized in 95 of medical call 
centers in North America.  
Sites would have the option to utilize this service for all, some, or none of their 
subjects.  Should a site decide to utilize the nursing triaging services, the nursing 
staff would have access to and would be monitoring the CH monitoring platform 
for subject health and technical alarms during MDMP.  Triage nurses would be the 
first point of contact for subjects and for the management of health and technical 
alarms during MDMP.  Nurses will follow triage protocols and will manage and 
silence alerts that are within their training and remit. 
If, per protocol, the alert cannot be resolved by the triage nurses, the nurse will 
then escalate all medical concerns and alerts immediately to the HCP and/or 
designee via the HCPs direct phone number for clinical symptom management 
and intervention.  Investigators or designee will still be responsible for arranging 
and conducting every 12-hour neurotoxicity checks via videocall with the 
subjects.  In addition, the HCP may initiate contact with the patient at other times 
as he finds necessary.  
8.2.3 
Data Collection and Use 
The digital health tools used in this study will collect data beyond what is specified for 
analysis in this protocol.  Digital Health is capable of collecting pulse rate, respiratory 
rate, axillary temperature, skin temperature, oxygen saturation, step count and activity 
levels, and noninvasive BP.  The tablet provided by the digital health vendor will also 
support collection of subject responses to QLQ-C30. 
8.2.4 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Activities 
see (Table 1-2). 


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8.2.4.1 
Vital Signs 
The following measurements must be performed:  systolic/diastolic BP, heart rate, 
respiratory rate, and temperature.  Vital signs performed in the clinic should be 
performed as per hospital standard.  Subject must be in a rested and calm state for at 
least 5 minutes before BP assessments are conducted.  The position selected for a 
subject should be the same that is used throughout the study and documented on the 
vital sign CRF.  The temperature location selected for a subject should be the same that 
is used throughout the study and documented on the vital signs CRF.  Record all 
measurements on the vital signs performed in the clinic on the vital signs CRF.  Vital 
signs recorded using the digital health monitoring devices will be collected as described 
in Section 6.1.2. 
8.2.4.2 
Electrocardiograms (ECGs) 
Subject must be in supine position in a rested and calm state for at least 5 minutes 
before ECG assessment is conducted.  If the subject is unable to be in the supine 
position, the subject should be in most recumbent position as possible.  The ECG must 
include the following measurements:  heart rate (HR), QRS, QT, QTc, and PR intervals.  
The investigator [or (eg, designated site physician, central reader)] will review all ECGs.  
Once signed, the original ECG tracing will be retained with the subject's source 
documents.  At the request of the sponsor, a copy of the original ECG will be made 
available to Amgen. 
8.2.4.3 
Vital Status 
Vital status must be obtained for all subjects within the limits of local law.  This includes 
subjects who may have discontinued study visits with or without withdrawing consent 
and should include interrogation of public databases, if necessary.  If deceased, the date 
and reported cause of death should be obtained. 
8.2.5 
Adverse Events and Serious Adverse Events 
The method of recording, evaluating, and assessing causality of adverse events, 
adverse device effects, and serious adverse events and the procedures for 
completing and transmitting serious adverse event reports are provided in 
Section 11.4. 


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8.2.5.1 
Time Period and Frequency for Collecting and Reporting Safety 
Event Information 
8.2.5.1.1 
Adverse Events 
The adverse event grading scale to be used for this study will be the CTCAE v5 and is 
described in Section 11.4. 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after enrollment through the end of 
study visit are reported using the Events CRF. 
8.2.5.1.2 
Serious Adverse Events 
The investigator is responsible for ensuring that all serious adverse events observed 
by the investigator or reported by the subject that occur from signing of the informed 
consent through the end of study visit are reported using the Events CRF. 
All serious adverse events will be collected, recorded and reported to the sponsor or 
designee within 24 hours of the investigator’s awareness of the event, as indicated in 
Section 11.4.  The investigator will submit any updated serious adverse event data to 
the sponsor within 24 hours of it being available. 
Since the criteria for grade 4 in the CTCAE grading scale differs from the regulatory 
criteria for serious adverse events, if adverse events correspond to grade 4 CTCAE 
toxicity grading scale criteria (eg, laboratory abnormality reported as grade 4 
without manifestation of life-threatening status), it will be left to the investigator’s 
judgment to also report these grade 4 abnormalities as serious adverse events.  For 
any adverse event that applies to this situation, comprehensive documentation of 
the event’s severity must be recorded in the subject medical records. 
8.2.5.1.3 
Serious Adverse Events After the Protocol-Required Reporting 
Period 
If the investigator becomes aware of serious adverse events suspected to be 
related to investigational product after the protocol-required reporting period (as 
defined in Section 8.2.5.1.2) is complete, then these serious adverse events will be 
reported to Amgen within 24 hours following the investigator’s awareness of the event 
on the Events CRF. 
After the End of Study, there is no requirement for the investigator to actively 
monitor study subjects who were treated in this study.  However, if the 
investigator becomes aware of serious adverse events suspected to be related to 


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investigational product, then these serious adverse events will be reported to 
Amgen within 24 hours following the investigator’s awareness of the event. 
Serious adverse events reported outside of the protocol-required reporting period will be 
captured within the safety database as clinical trial cases and handled accordingly based 
on relationship to investigational product.  
If further safety related data is needed to fulfill any regulatory reporting 
requirements for a reportable event, then additional information may need to be 
collected from the subject’s records after the subject ends the study. 
8.2.5.1.4 
Reporting a Safety Endpoint as a Study Endpoint 
Safety endpoints that are study endpoints are reported on the Events CRF.  All 
endpoints that also meet the criteria of serious adverse event must also be transmitted 
to safety within 24 hours of the investigator’s knowledge of the event (refer to Section 
11.4).  
8.2.5.2 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting adverse events and/or serious 
adverse events.  Open-ended and non-leading verbal questioning of the subject is the 
preferred method to inquire about adverse event occurrence. 
8.2.5.3 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial adverse event/serious adverse event report, the investigator is required 
to proactively follow each event at subsequent visits/contacts.  All adverse events and 
serious adverse events will be followed until resolution, stabilization, until the event is 
otherwise explained, or the subject is lost to follow-up (as defined in Section 7.2.2).  
Further information on follow-up procedures is given in Section 11.4. 
All new information for previously reported serious adverse events must be sent to 
Amgen within 24 hours following awareness of the new information.  If specifically 
requested, the investigator may need to provide additional follow-up information, such as 
discharge summaries, medical records, or extracts from the medical records.  
Information provided about the serious adverse event must be consistent with that 
recorded on the Events CRF. 
8.2.5.4 
Regulatory Reporting Requirements for Serious Adverse Events 
If subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 


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Prompt notification by the investigator to the sponsor of serious adverse events is 
essential so that legal obligations and ethical responsibilities towards the safety of 
subjects and the safety of a study treatment under clinical investigation are met.  
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation.  The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators. 
Individual safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded 
to investigators as necessary. 
An investigator who receives an individual safety report describing a serious adverse 
event or other specific safety information (eg, summary or listing of serious adverse 
events) from the sponsor will file it along with the Investigator’s Brochure and will notify 
the IRB/IEC, if appropriate according to local requirements. 
8.2.5.5 
Safety Monitoring Plan 
Subject safety will be routinely monitored as defined in Amgen’s safety surveillance and 
signal management processes. 
8.2.5.6 
Pregnancy and Lactation 
Details of all pregnancies and/or lactation in female subjects and female partners of 
male subjects will be collected after the start of study treatment and through an 
additional 48 hours after the last dose of protocol-required therapies. 
If a pregnancy is reported, the investigator is to inform Amgen within 24 hours of learning 
of the pregnancy and/or lactation and is to follow the procedures outlined in 
Section 11.5.  Amgen Global Patient Safety will follow-up with the investigator regarding 
additional information that may be requested. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs. 
Further details regarding pregnancy and lactation are provided in Section 11.5. 
8.2.5.7 
Adverse Device Effects 
In order to fulfill regulatory reporting obligations worldwide, the investigator is 
responsible for the detection and documentation of any adverse device effects that occur 
during the study with such devices. 


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Further details regarding adverse device effects can be found in Section 11.4. 
An adverse device effect is any adverse event related to the use of a combination 
product (definition of combination product is provided in Section 11.4) or medical 
device.  Adverse device effects include, but are not limited to, adverse events 
resulting from insufficient or inadequate instructions for use, adverse events resulting 
from any malfunction of the device, or adverse events resulting from use error or from 
intentional misuse of the device. 
All adverse device effects are to be reported as adverse events following the same 
reporting periods and procedures. 
The CH will provide the monitoring devices and related training to the sites.  The 
sites will then provide the monitoring devices and the training to the subjects.  A 
24/7 help hotline is available for any CWHMS related issues.  The CH hotline will 
be trained on how to report product related device incidents (with or without 
associated AE) and product complaints to the site as per the approved protocol 
design.  All monitoring device related complaints/AEs will be reported in the 
Clinical Trial Database and relayed to the CH for reporting since all the defined 
monitoring devices are part of their 510k clearance. 
Product complaints are described in Section 6.1.4. 
8.2.6 
Clinical Laboratory Assessments 
Refer to Section 11.2 for the list of clinical laboratory tests to be performed and to the 
Schedule of Activities (Table 1-2) for the timing and frequency.  
The investigator is responsible for reviewing laboratory test results and recording any 
clinically relevant changes occurring during the study in the Events CRF.  The 
investigator must determine whether an abnormal value in an individual study subject 
represents a clinically significant change from the subject’s baseline values.  In general, 
abnormal laboratory findings without clinical significance (based on the investigator's 
judgment) are not to be recorded as adverse events.  However, laboratory value 
changes that require treatment or adjustment in current therapy are considered adverse 
events.  Where applicable, clinical sequelae (not the laboratory abnormality) are to be 
recorded as the adverse event. 
All protocol-required laboratory assessments, as defined in Section 11.2, must be 
conducted in accordance with the Schedule of Activities (Table 1-2).  


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8.2.6.1 
Pregnancy Testing 
A highly sensitive (urine or serum) pregnancy test should be completed at 
screening and within 7 days of initiation of investigational product for females of 
childbearing potential. 
Note:  Females who have undergone a bilateral tubal ligation/occlusion should 
have pregnancy testing per protocol requirements.  (If a female subject, or the 
partner of a male subject, becomes pregnant it must be reported on the Pregnancy 
Notification Form, see Figure 11-2).  Refer to Section 11.5 for contraceptive 
requirements. 
Additional on-treatment pregnancy testing may be performed at the investigator’s 
discretion or as required per local laws and regulations. 
8.2.7 
Patient Reported Outcomes 
Patient reported outcomes will be assessed with the EORTC QLQ-C30, which is a 
commonly used instrument and validated for cancer patients across tumor types.  The 
instrument is scored using guidelines recommended by the EORTC.  The QLQ-C30 
contains an overall global health status (GHS)/quality of life (QoL) scale, 5 functional 
domains (physical, emotional, cognitive, social, and role functioning), and 9 symptom 
scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties).  Each domain/scale is scored from zero 
to 100; higher scores indicate better QoL, better functioning, or more severe symptoms, 
respectively. 
8.2.8 
Medical Resource Utilization 
Medical resource utilization data, associated with medical encounters, will be collected in 
the CRF by the investigator and study-site personnel for all subjects throughout the 
study.  Protocol-mandated procedures, tests, and encounters are excluded.  
The data collected may be used to conduct exploratory economic analyses and will 
include: 
 
Number of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient) 
 
Use of concomitant medications associated with treatment-related AEs 


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9. 
Statistical Considerations 
9.1 
Statistical Hypotheses 
No formal hypotheses will be tested.  For the primary and secondary objectives, 
analyses will be descriptive and include estimations. 
9.2 
Sample Size Determination 
The planned enrollment for this study is approximately 45 patients.  The sample size is 
based on feasibility rather than on statistical considerations.  Given a true probability of a 
primary endpoint event of 38, the expected 95 upper confidence limit with 
45 subjects would be 53.5.  The 38 probability is based on the SAE rate in first 
3 days of cycle 1 and first 2 days of cycle 2 from the previous MRD study 
(BLAST).  Based on these assumptions, we expect to observe approximately 
17 subjects who will experience the primary endpoint which should provide an initial 
indication of the timeliness of the therapeutic intervention when outpatient blinatumomab 
in administered in conjunction with remote digital monitoring. 
9.3 
Analysis Sets, Subgroups, and Covariates 
9.3.1 
Analysis Sets 
Safety Analysis Set (SAS) 
All enrolled subjects who receive at least 1 dose of blinatumomab.  The analysis of 
secondary safety and resource utilization endpoints will be conducted on the SAS. 
Primary Analysis Set (PAS) 
All subjects in the SAS who were not replaced (see Section 4.2.1).  The analysis of 
primary and key secondary endpoint will be conduct on the PAS. 
Patient Reported Outcomes Analysis Set 
The Patient Reported Outcomes (PRO) Analysis Set will include all subjects in the SAS 
with a non-missing baseline and at least 1 non-missing post-baseline result for EORTC 
QLQ-C30.  Subjects will be included in the analysis of each EORTC QLQ-C30 for which 
they have non-missing data. 
9.3.2 
Covariates 
The relationship between covariates and safety endpoints may be explored if 
appropriate. 


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9.3.3 
Subgroups 
The subgroup analysis may be performed but could be limited by the small sample size 
of the study. 
9.3.4 
Handling of Missing and Incomplete Data 
Subjects will be replaced for analysis if the outpatient monitoring during 
blinatumomab infusion is not established.   
 
Subjects are removed from IP due to disease progression. 
Replacement status is only applicable for internal data analysis. 
Details on handling of missing and incomplete data are described in the statistical 
analysis plan. 
9.4 
Statistical Analyses 
The statistical analysis plan will be developed and finalized before database lock.  Below 
is a summary of the timing and methods for the planned statistical analyses.  To 
preserve study integrity, the final analysis will be conducted and reported following the 
end of study, as defined in Section 4.4.1. 
9.4.1 
Planned Analyses 
9.4.1.1 
Interim Analysis 
Safety data will be reviewed on an ongoing basis.  A data review team (DRT), internal to 
Amgen but external to the study team, will assess after every fifth non-replaceable 
subject has been dosed and given an opportunity to complete MDMP.  Refer to 
Section 4.2.1 for details on replacement of subjects.  Based on their reviews, the 
DRT will make recommendations to Amgen regarding the continuation of the study.  
There will be no formal guidelines to stop for safety.  The DRT will consist of 3 or more 
members including 2 or more clinicians with relevant specialties and 1 or more 
statisticians.  The DRT will be supported by an independent statistician who is 
responsible for preparing reports that describe the ongoing clinical study data.  Details 
regarding the responsibilities of the DRT and the independent statistician will be 
described in the DRT Charter. 
9.4.1.2 
Primary Analysis 
The primary analysis will occur when all subjects complete the end of study Visit 30 days 
( 3 days) after the last dose of up to 4 cycles of blinatumomab or withdraw from the 
study.  


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9.4.1.3 
Final Analysis 
The primary analysis will also be the final analysis.  
9.4.2 
Methods of Analyses 
9.4.2.1 
General Considerations 
Descriptive statistics for demographic and safety will be summarized as appropriate.  
For categorical variables, the number and percentage of subjects in each category will 
be summarized.  Continuous variables will be summarized by n, mean, standard 
deviation, median, Q1 (25th percentile), Q3 (75th percentile), minimum, and maximum 
values.  
9.4.2.2 
Efficacy Analyses 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable 
Secondary 
Not applicable 
Exploratory 
Not applicable. 
 
9.4.2.3 
Safety Analyses 
9.4.2.3.1 
Analyses of Primary Safety Endpoint(s) 
 
Endpoint 
Statistical Analysis Methods 
Primary 
Subject incidence rate of primary endpoint (grade 3 or 4 CRS, NT or 
any adverse event resulting in hospitalization during MDMP) will be 
summarized and accompanied by 2-sided 95% exact binomial 
confidence intervals (Clopper and Pearson, 1934).  
Key 
Secondary 
Time from first onset of the key secondary endpoint event to 
therapeutic intervention will be summarized as continuous variable 
with count of non-missing, mean, median, standard deviation, 
minimum and maximum for those experiencing the endpoint.  Type of 
therapeutic intervention will be tabulated with n (see Section 9.4.2.4).  
If there are events that prevent the occurrence of therapeutic 
intervention, censoring based approach such as Kaplan-Meier may be 
used. 
Secondary 
The statistical analysis methods for adverse event and other safety 
endpoints are described in Section 9.4.2.3.2 through Section 9.4.2.3.4. 
Exploratory 
Not applicable 
 
9.4.2.3.2 
Adverse Events 
Subject incidence of all treatment-emergent adverse events will be tabulated by 
system organ class and preferred term.  Tables of fatal adverse events, serious 


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adverse events, adverse events leading to discontinuation from investigational 
product or other protocol-required therapies, and significant treatment-emergent 
adverse events (including adverse events of interest [EOIs]) will also be provided.  
These analyses will be performed using subjects in the SAS.  Analysis will be repeated 
for treatment-emergent adverse events during MDMP using the PAS. 
Subject incidence of device-related events, if applicable, will be tabulated by system 
organ class and preferred term. 
9.4.2.3.3 
Laboratory Test Results 
Summary statistics over scheduled visits for actual values and changes from baseline of 
selected laboratory parameters will be presented.  In addition, shift tables between the 
post-baseline and baseline values for selected laboratory parameters will be provided.  
Subject incidence of potential cases of Hy’s Law will be summarized. 
9.4.2.3.4 
Vital Signs 
A summary of the subject incidence with abnormal changes in vital signs will be 
presented for subjects in the SAS.  Vital signs to include: BP, respiratory rate, pulse 
rate, and axillary temperature. 
9.4.2.3.5 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to blinatumomab for 
subjects in the SAS.  The duration of therapy and the cumulative dose will be 
summarized.  The number and percent of subjects with dose modifications (eg, dose 
changes, dose interruptions) and reason for modification will be summarized.  Analysis 
will be repeat for exposure during MDMP. 
9.4.2.3.6 
Exposure to Other Protocol-required Therapy 
Descriptive statistics will be produced to describe the exposure to required 
pre-medication (dexamethasone) in the SAS. 
9.4.2.3.7 
Exposure to Concomitant Medication 
Number and proportion of subjects receiving therapies of interest will be summarized by 
preferred term as coded by the World Health Organization Drug dictionary in the SAS. 
9.4.2.4 
Other Analyses 
The analysis of PRO endpoint will be described in the statistical analysis plan finalized 
before database lock. 


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10. 
References 
Bassan R, Gatta G, Tondini C, et al, Adult acute lymphoblastic leukaemia. Crit Rev 
Oncol Hematol. 2004; 50:223-261. 
Bassan R, Spinelli O, Oldani E, et al,  Improved risk classification for risk-specific 
therapy based on the molecular study of minimal residual disease (MRD) in adult acute 
lymphoblastic leukemia (ALL).  Blood.  2009;113:4153-4162.  
Berry DA, Zhou S, Higley H, et al,  Association of minimal residual disease with clinical 
outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis.  JAMA 
Oncol.  2017;e170580 doi:10.1001/jamaoncol.2017.0580. 
Brüggemann M, Raff T, Flohr T, et al, Clinical significance of minimal residual disease 
quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 
2006; 107(3):1116-1123. 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika. 1934;26(4):404-413. 
Fielding AK, Richards SM, Chopra R et al.: Outcome of 609 adults after relapse of ALL; 
an MRC UKALL12/ECOG 2993 study. Blood.2007;109:944-950. 
Gökbuget N, Hoelzer D. Salvage therapy of adult acute lymphoblastic leukemia. In: 
Faderl S, Kantarjian H, eds. Leukemias: Principles and Practice of Therapy. Oxford, UK 
Wiley-Blackwell; 2011; ch17. 
Gökbuget N, Hoelzer D. Salvage therapy of adult acute lymphoblastic leukemia. In: 
Faderl S, Kantarjian H (eds.). Leukemias: Principles and Practice of Therapy 2010. 
Gökbuget N, Hoelzer D. Treatment of Adult Acute Lymphoblastic Leukemia. Seminars in 
Hematology. 2009; 46(1):64-75. 
Gökbuget N, Kneba M, Raff T, et al, Adults with acute lymphoblastic leukemia and 
molecular failure display a poor prognosis and are candidates for stem cell 
transplantation and targeted therapies. Blood. 2012;120(10):2032-2041. 
Gökbuget N, Dombret H, Bonifacio M, et al,  Blinatumomab for minimal residual disease 
in adults with B-cell precursor acute lymphoblastic leukemia.  Blood. 
2018;131(14):1522-1531. 
Howlader N, Noone AM, Krapcho M, et al (eds), SEER Cancer Statistics Review, 
1975-2009 (Vintage 2009 Populations), National Cancer Institute.  Bethesda, MD, 
http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data 
submission, posted to the SEER website, 2012. 
Jabbour EJ, Faderl S, Kantarjian HM. Adult acute lymphoblastic leukemia. Mayo Clin 
Proc. 2005;80:1517-1527. 
Kantarjian H, Stein A, Gökbuget N, et al,  Blinatumomab versus Chemotherapy for 
Advanced Acute Lymphoblastic Leukemia.  N Engl J Med.  2017;376:836-847. 
Larson RA. Acute lymphoblastic leukemia: Older patients and newer drugs. Hematology 
Am Soc Hematol Educ Program. 2005;131-136. 
Lee DW, Santomasso BD, Locke FL, et al,  ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells.  Biol 
Blood Marrow Transplant.  2018;25(4):625-638. 


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Lussana F, Intermesoli T, Gianni F, et al,  Achieving molecular remission before 
allogeneic stem cell transplantation in adult patients with Philadelphia 
chromosome-positive acute lymphoblastic leukemia:  impact on relapse and long-term 
outcome.  Biol Blood Marrow Transplant.  2016;22:1983-1987. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP.  
Toxicity and response criteria of the Eastern Cooperative Oncology Group.  Am J Clin 
Oncol.  1982;5(6):649-655. 
Oriol A, Vives S, Hernández-Rivas JM, et al,  Outcome after relapse of acute 
lymphoblastic leukemia in adult patients included in 4 consecutive risk-adapted trials by 
the PETHEMA Study Group.  Haematologica.  2010;95:589-596. 
Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med. 1998;339:605-615. 
Thomas DA, Kantarjian H, Smith TL, et al,  Primary refractory and relapsed adult acute 
lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage 
therapy.  Cancer.  1999;86(7):1216-1230. 
van Dongen JJM, van der Velden VHJ, Brüggemann M, Orfao A.  Minimal residual 
disease diagnostics in acute lymphoblastic leukemia:  need for sensitive, fast, and 
standardized technologies.  Blood.  2015;125(26):3996-4009. 
 


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11. 
Appendices 
 


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11.1 
Appendix 1.  List of Abbreviations and Definitions of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ADL 
activities of daily living 
AE 
adverse event 
ALL 
acute lymphoblastic leukemia 
Anti-HCV 
hepatitis C virus antibody 
BCP 
B-cell precursor 
BiTE 
bispecific T-cell engaging 
BM 
bone marrow 
BP 
blood pressure 
BSA 
body surface area 
CAPA 
corrective action/preventative action 
CFR 
U.S. Code of Federal Regulations 
CH 
Current Health 
CiVI 
continuous intravenous infusion 
CNS 
central nervous system 
CR 
complete remission 
CRF 
case report form 
CRS 
cytokine release syndrome 
CSF 
cerebrospinal fluid 
CTCAE 
Common Terminology Criteria for Adverse Events 
CWHMS 
Current Wearable Health Monitoring System 
DILI 
drug induced liver injury 
DRT 
data review team 
ECG 
electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EDC 
electronic data capture 
EFS 
event-free survival 
EMS 
Emergency Medical Service 
EOI 
events of interest 
EOS 
end of study 
EORTC 
European Organisation for Research and Treatment of Cancer 
ePRO 
electronic patient reported outcomes 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 


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GHS 
global health status 
GvHD 
graft versus host disease 
HCP 
healthcare provider 
HBsAg 
Hepatitis B Surface Antigen 
HIV 
human immunodeficiency virus 
HR 
heart rate 
HRT 
hormonal replacement therapy 
HSCT 
hematopoietic stem cell transplantation 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ICU 
intensive care unit 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IP 
investigational product 
IPIM 
Investigational Product Instruction Manual 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
IVSS 
IV solution stabilizer 
MDMP 
mandatory monitoring period 
MRD 
minimal/measurable residual disease 
NT 
neurotoxicity 
OR 
operating room 
OS 
overall survival 
PAS 
primary analysis set 
PCR 
polymerase chain reaction 
Ph 
Philadelphia chromosome 
PO 
oral(ly) 
PRO 
Patient reported outcomes 
QLQ-C30 
Quality of Life of Cancer Patients 
QoL 
quality of life 
SAE 
serious adverse event 
SAS 
Safety Analysis Set 
SBP 
systolic blood pressure 
SpO2 
peripheral capillary oxygen saturation 
TBL 
total bilirubin 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
US 
United States 


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WBC 
white blood cell count 
 


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11.2 
Appendix 2.  Clinical Laboratory Tests 
The tests detailed in Table 11-1 will be performed by the local laboratory.  
Protocol-specific requirements for inclusion or exclusion of subjects are detailed in 
Section 5.1 to 5.2 of the protocol. 
Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations. 
Table 11-1.  Analyte Listing 
Local 
Laboratory: 
Chemistry 
Local 
Laboratory: 
Coagulation 
Local 
Laboratory: 
Urinalysis 
Local Laboratory: 
Hematology 
Other Labs 
Sodium 
Potassium 
Chloride 
Albumin 
Total Calcium 
BUN 
Creatinine 
Glomerular 
filtration rate 
Uric acid 
Total bilirubin 
Direct bilirubin 
ALP 
LDH 
AST (SGOT) 
ALT (SGPT) 
Amylase 
Lipase 
PT/INR 
aPTT 
Blood 
Protein 
Glucose 
RBC 
Hemoglobin 
Hematocrit 
Platelets 
WBC 
Differential 
• Absolute 
Neutrophils 
• Neutrophils 
• Segmented 
Neutrophils 
• Bands/stabs 
• Eosinophils 
• Basophils 
• Blasts 
• Lymphoblasts 
• Lymphocytes 
• Monocytes  
• Myeloblasts 
• Promyelocytes 
• Myelocytes 
• Metamyelocytes 
• Atypical 
lymphocytes 
Bone marrow 
histology and MRD 
CSF analytes  
• CSF Glucose 
• CSF Protein 
• CSF White Blood 
Cells 
• CSF Blasts 
 
Local Laboratory: 
Serum and/or Urine 
Pregnancy 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
BUN = blood urea nitrogen; CSF = cerebrospinal fluid; INR = international normalized ratio; LDH = 
lactate dehydrogenase; MRD = minimal/measurable residual disease; PT = prothrombin time; aPTT = 
activated partial thromboplastin time; RBC = red blood cell count; SGOT = serum glutamic-oxaloacetic 
transaminase; SGPT - serum glutamic-pyruvic transaminase; WBC = white blood cell count 
 


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11.3 
Appendix 3.  Study Governance Considerations 
Data Review Team 
A data review team (DRT) is a group internal to Amgen, but external to the 
blinatumomab product team(s).  The DRT will review accumulating safety data from the 
ongoing clinical trial to ensure no avoidable increased risk for harm to subjects.  DRT 
review meetings will be triggered after the first occurrence of primary endpoint events 
and every 5 additional events thereafter 
In order to maintain trial integrity, the unblinded data reviewed by the DRT will be 
restricted and not accessible by the Amgen product team.   
The DRT is composed of members that are external to the study team and include a 
clinician, a safety physician, and a biostatistician.  Membership, procedures, and 
meeting timing will be described in detail in the study DRT charter. 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with: 
 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines 
 
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
 
Applicable ICH laws and regulations 
The protocol, protocol amendments, informed consent form (ICF), Investigator’s 
Brochure, and other relevant documents (eg, subject recruitment advertisements) must 
be submitted to an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
by the investigator and reviewed and approved by the IRB/IEC.  A copy of the written 
approval of the protocol and ICF must be received by Amgen before recruitment of 
subjects into the study and shipment of Amgen investigational product (IP). 
Amgen may amend the protocol at any time.  The investigator must submit and, where 
necessary, obtain approval from the IRB/IEC for all subsequent protocol amendments 
and changes to the informed consent document.  The investigator must send a copy of 
the approval letter from the IRB/IEC and amended protocol Investigator’s Signature 
page to Amgen prior to implementation of the protocol amendment at their site. 


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The investigator will be responsible for the following: 
 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
 
Obtaining annual IRB/IEC approval/renewal throughout the duration of the study.  
Copies of the investigator’s reports and the IRB/IEC continuance of approval must be 
sent to Amgen 
 
Notifying the IRB/IEC of serious adverse events (SAEs) occurring at the site, 
deviations from the protocol or other adverse event reports received from Amgen, in 
accordance with local procedures 
 
Overall conduct of the study at the site and adherence to requirements of Title 21 of 
the U.S. Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, and all 
other applicable local regulations 
Recruitment Procedures 
For sites that do not screen and/or enroll subjects, the Clinical Monitor will address 
concerns and identify any recruitment barriers with the investigator.  Any potential 
subject recruitment materials used in this study must be submitted, reviewed and 
approved to the site IRB.  
Informed Consent Process 
The written ICF is to be prepared in the language(s) of the potential patient population. 
The investigator or his/her delegated representative will explain to the subject, or his/her 
legally authorized representative, the aims, methods, anticipated benefits, and potential 
hazards of the study before any protocol-specific screening procedures or any IP(s) 
is/are administered, and answer all questions regarding the study.   
Subjects must be informed that their participation is voluntary.  Subjects or their legally 
authorized representative (defined as an individual or other body authorized under 
applicable law to consent, on behalf of a prospective subject, to the subject’s 
participation in the clinical study) will then be required to sign a statement of informed 
consent that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 
Health Insurance Portability and Accountability Act requirements, where applicable, and 
the IRB/IEC or study site.  


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The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the ICF. 
The acquisition of informed consent is to be documented in the subject’s medical 
records, and the ICF is to be signed and personally dated by the subject or a legally 
acceptable representative and by the person who conducted the informed consent 
discussion.  Subject withdrawal of consent or discontinuation from study treatment 
and/or procedures must also be documented in the subject’s medical records; refer to 
Section 7. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
The original signed ICF is to be retained in accordance with institutional policy, and a 
copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative.  If a potential subject is illiterate or visually impaired and does not have a 
legally acceptable representative, the investigator must provide an impartial witness to 
read the ICF to the subject and must allow for questions.  Thereafter, both the subject 
and the witness must sign the ICF to attest that informed consent was freely given and 
understood.  (Refer to ICH GCP guideline, Section 4.8.9). 
A subject who is rescreened is not required to sign another ICF if the rescreening occurs 
within 21 days from the previous ICF signature date.   
The ICF will contain a separate section that addresses the use of all data collected by 
the digital health tools for optional future research.  The investigator or authorized 
designee will explain to each subject the objectives of the future research.  Subjects will 
be told that they are free to refuse to participate and may withdraw their agreement at 
any time and for any reason during the storage period.  A separate signature will be 
required to document a subject’s agreement to allow any collected data to be used for 
future research.  Subjects who decline to participate will not provide this separate 
signature. 
Data Protection/Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen. 


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Subject will be assigned a unique identifier by the sponsor.  Any subject records or 
datasets that are transferred to the sponsor will contain the identifier only; subject names 
or any information which would make the subject identifiable will not be transferred.  
On the case report form (CRF) demographics page, in addition to the unique subject 
identification number, include the age at time of enrollment. 
For SAEs reported to Amgen, subjects are to be identified by their unique subject 
identification number, initials (for faxed reports, in accordance with local laws and 
regulations), and age (in accordance with local laws and regulations). 
Documents that are not submitted to Amgen (eg, signed ICFs) are to be kept in 
confidence by the investigator, except as described below. 
In compliance with governmental regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  Direct access 
includes examining, analyzing, verifying, and reproducing any records and reports that 
are important to the evaluation of the study.   
The investigator is obligated to inform and obtain the consent of the subject to permit 
such individuals to have access to his/her study-related records, including personal 
information. 
Publication Policy 
To coordinate dissemination of data from this study, Amgen may facilitate the formation 
of a publication committee consisting of several investigators and appropriate Amgen 
staff, the governance and responsibilities of which are set forth in a Publication Charter.  
The committee is expected to solicit input and assistance from other investigators and to 
collaborate with authors and Amgen staff, as appropriate, as defined in the Publication 
Charter.  Membership on the committee (both for investigators and Amgen staff) does 
not guarantee authorship.  The criteria described below are to be met for every 
publication. 
Authorship of any publications resulting from this study will be determined on the basis 
of the Uniform Requirement for Manuscripts Submitted to Biomedical Journals 
International Committee of Medical Journal Editors Recommendations for the Conduct of 
Reporting, Editing, and Publications of Scholarly Work in Medical Journals, which states:  


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Authorship credit is to be based on:  (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or revising it critically for important intellectual content; (3) final approval of the version to 
be published; and (4) agreement to be accountable for all aspects of the work in 
ensuring that questions related to the accuracy or integrity of any part of the work are 
appropriately investigated and resolved.  Authors need to meet conditions 1, 2, 3, and 4. 
When a large, multicenter group has conducted the work, the group is to identify the 
individuals who accept direct responsibility for the manuscript.  These individuals must 
fully meet the criteria for authorship defined above.  Acquisition of funding, collection of 
data, or general supervision of the research group, alone, does not justify authorship.  All 
persons designated as authors must qualify for authorship, and all those who qualify are 
to be listed.   Each author must have participated sufficiently in the work to take public 
responsibility for appropriate portions of the content.  All publications (eg, manuscripts, 
abstracts, oral/slide presentations, book chapters) based on this study must be 
submitted to Amgen for review.  The Clinical Trial Agreement among the institution, 
investigator, and Amgen will detail the procedures for, and timing of, Amgen’s review of 
publications. 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of multicenter 
studies, the coordinating investigator. 
The coordinating investigator, identified by Amgen, will be any or all of the following: 
 
A recognized expert in the therapeutic area 
 
An Investigator who provided significant contributions to either the design or 
interpretation of the study 
 
An Investigator contributing a high number of eligible subjects 
Data Quality Assurance 
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data, centrally or 
adjudicated data).  The investigator is responsible for verifying that data entries are 
accurate and correct by physically or electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  


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The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.   
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
Clinical monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable 
from source documents; that the safety and rights of subjects are being protected; and 
that the study is being conducted in accordance with the currently approved protocol and 
any other study agreements, ICH GCP, and all applicable regulatory requirements per 
the sponsor’s monitoring plan.  
The investigator agrees to cooperate with the clinical monitor to ensure that any 
problems detected in the course of these monitoring visits, including delays in 
completing CRFs, are resolved. 
The Amgen representative(s) and regulatory authority inspectors are responsible for 
contacting and visiting the investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global Research and Development 
Compliance and Audit function (or designees).  Inspection of site facilities (eg, 
pharmacy, protocol-required therapy storage areas, laboratories) and review of 
study-related records will occur to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
All written information and other material to be used by subjects and investigative staff 
must use vocabulary and language that are clearly understood. 
Source Documents 
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form. 
Source documents provide evidence for the existence of the subject and substantiate 
the integrity of the data collected.  Source documents are filed at the investigator’s site. 


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Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.  Source documents may also include data captured in the CRF 
entries if the CRF is the site of the original recording (ie, there is no other written or 
electronic record of data, such as paper questionnaires for a patient reported outcomes 
[PRO]). 
Data reported on the CRF or entered in the electronic CRF that are transcribed from 
source documents must be consistent with the source documents or the discrepancies 
must be explained.  The investigator may need to request previous medical records or 
transfer records, depending on the study.  Also, current medical records must be 
available. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities. 
Elements to include: 
 
Subject files containing completed CRFs, ICFs, and subject identification list 
 
Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the IRB/IEC 
and Amgen 
 
Investigational product-related correspondence including Proof of Receipts, 
Investigational Product Accountability Record(s), Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement, as 
applicable 
 
Medical device documentation, as applicable 
Retention of study documents will be governed by the Clinical Trial Agreement. 
Study and Site Closure 
Amgen or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable 
laws, regulations, and GCP.  


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Both Amgen and the Investigator reserve the right to terminate the Investigator’s 
participation in the study according to the Clinical Trial Agreement.  The investigator is to 
notify the IRB/IEC in writing of the study’s completion or early termination and send a 
copy of the notification to Amgen. 
Subjects may be eligible for continued treatment with Amgen IP(s) by an extension 
protocol or as provided for by the local country’s regulatory mechanism.  However, 
Amgen reserves the unilateral right, at its sole discretion, to determine whether to supply 
Amgen IP(s) and by what mechanism, after termination of the study and before the 
product(s) is/are available commercially. 
Compensation 
Any arrangements for compensation to subjects for injury or illness that arises in the 
study are described in the Compensation for Injury section of the Informed Consent that 
is available as a separate document. 
 


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11.4 
Appendix 4.  Safety Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up and Reporting 
Definition of Adverse Event 
Adverse Event Definition 
 
An adverse event is any untoward medical occurrence in a clinical study subject 
irrespective of a causal relationship with the study treatment.   
 
Note:  An adverse event can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or 
exacerbated) temporally associated with the use of a treatment, combination 
product, medical device or procedure. 
 
Note:  Treatment-emergent adverse events (TEAEs) will be defined in the 
Statistical Analysis Plan (SAP). 
 
Events Meeting the Adverse Event Definition 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, electrocardiogram, radiological scans, vital signs 
measurements), including those that worsen from baseline, that are considered 
clinically significant in the medical and scientific judgment of the investigator (ie, 
not related to progression of underlying disease). 
 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication.  Overdose per se will not be reported as an 
adverse event/serious adverse event unless it is an intentional overdose taken 
with possible suicidal/self-harming intent.  Such overdoses are to be reported 
regardless of sequelae. 
 
For situations when an adverse event or serious adverse event is due to primary 
tumor type being studied report all known signs and symptoms.  Death due to 
disease progression in the absence of signs and symptoms should be reported as 
the primary tumor type (eg, metastatic pancreatic cancer).  Note: The term 
“disease progression” should not be used to describe the adverse event. 
 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as adverse event or serious adverse event if they fulfill the definition of 
an adverse event or serious adverse event.  Also, “lack of efficacy” or “failure of 
expected pharmacological action” also constitutes an adverse event or serious 
adverse event. 
 


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Events NOT Meeting the Adverse Event Definition 
 
Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that 
leads to the procedure is the adverse event. 
 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
Definition of Serious Adverse Event 
A Serious Adverse Event is defined as any untoward medical occurrence that, 
meets at least 1 of the following serious criteria: 
Results in death (fatal) 
Immediately life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are an adverse 
event.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the adverse event is to be considered serious.  Hospitalization for elective 
treatment of a pre-existing condition that did not worsen from baseline is not 
considered an adverse event. 
Results in persistent or significant disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.  This definition is not intended to include experiences of relatively 
minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (eg, sprained ankle) which may interfere 
with or prevent everyday life functions but do not constitute a substantial disruption. 
Is a congenital anomaly/birth defect 


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Other medically important serious event 
Medical or scientific judgment is to be exercised in deciding whether serious adverse 
event reporting is appropriate in other situations such as important medical events 
that may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the subject or may require medical or surgical intervention to prevent 
1 of the other outcomes listed in the above definition.  These events are typically to be 
considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
Definition of Adverse Device Effect 
The detection and documentation procedures for adverse device effects described in 
this protocol apply to all medical devices provided for use in the study (see Section 6.1.2 
for the list of medical devices). 
Adverse Device Effect Definition 
An adverse device effect is any adverse event related to the use of a combination 
product or medical device.  Adverse device effects include, but are not limited to, 
adverse events resulting from insufficient or inadequate instructions for use, adverse 
events resulting from any malfunction of the device, or adverse events resulting from 
use error or from intentional misuse of the device. 
A combination product is a product composed of any combination of a drug, a 
device, and a biological product.  Each drug, device, and biological product 
included in a combination product is referred to as a “constituent part” of the 
combination product. 
Recording Adverse Events and Serious Adverse Events 
Adverse Event and Serious Adverse Event Recording 
 
When an adverse event or serious adverse event occurs, it is the responsibility 
of the investigator to review all documentation (eg, hospital progress notes, 
laboratory, and diagnostics reports) related to the event. 


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 
The investigator will then record all relevant adverse event/serious adverse 
event information in the Event case report form (CRF). 
 
The investigator must assign the following mandatory adverse event attributes: 
o Adverse event diagnosis or syndrome(s), if known (if not known, signs or 
symptoms); 
o Dates of onset and resolution (if resolved); 
o Did the event start prior to first dose of investigational product; 
o Assessment of seriousness; 
o Severity (or toxicity defined below); 
o Assessment of relatedness to IP [blinatumomab], or other protocol-required 
therapies or devices [Current Wearable Health Monitoring System 
(CWHMS)]; 
o Action taken; and 
o Outcome of event. 
 
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record a single event for each level of severity on the Events CRF. 
 
It is not acceptable for the investigator to send photocopies of the subject’s 
medical records to sponsor/responsible contact research organization in lieu of 
completion of the Events CRF page. 
 
If specifically requested, the investigator may need to provide additional follow-up 
information, such as discharge summaries, medical records, or extracts from the 
medical records.  In this case, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records before 
submission to Amgen. 
 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the adverse event/serious 
adverse event. 
Evaluating Adverse Events and Serious Adverse Events 
Assessment of Severity 
The investigator will make an assessment of severity for each adverse event and 
serious adverse event reported during the study.  The assessment of severity will be 
based on:  
The Common Terminology Criteria for Adverse Events, version 5.0 which is available 
at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 


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Assessment of Causality 
 
The investigator is obligated to assess the relationship between investigational 
product (blinatumomab), protocol-required therapies, device(s) [ie, CWHMS], 
and/or study-mandated procedure and each occurrence of each adverse 
event/serious adverse event. 
 
Relatedness means that there are facts or reasons to support a relationship 
between investigational product (blinatumomab) and the event. 
 
The investigator will use clinical judgment to determine the relationship. 
 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated. 
 
The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
 
For each adverse event/serious adverse event, the investigator must document 
in the medical notes that he/she has reviewed the adverse event/serious 
adverse event and has provided an assessment of causality. 
 
There may be situations in which a serious adverse event has occurred and the 
investigator has minimal information to include in the initial report.  However, it is 
very important that the investigator always make an assessment of causality for 
every event before the initial transmission of the serious adverse event data. 
 
The investigator may change his/her opinion of causality in light of follow-up 
information and send a serious adverse event follow-up report with the updated 
causality assessment. 
 
The causality assessment is 1 of the criteria used when determining regulatory 
reporting requirements. 
 
Follow-up of Adverse Event and Serious Adverse Event 
 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 
Amgen to elucidate the nature and/or causality of the adverse event or serious 
adverse event as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health 
care professionals. 
 
If a subject is permanently withdrawn from protocol-required therapies because of 
a serious adverse event, this information must be submitted to Amgen. 
 
If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Amgen with a copy of any post-mortem 
findings including histopathology. 
 
New or updated information will be recorded in the originally completed Events 
CRF. 


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 
The investigator will submit any updated s data to Amgen within 24 hours of 
receipt of the information. 
Reporting of Serious Adverse Event 
Serious Adverse Event Reporting via Electronic Data Collection Tool 
 
The primary mechanism for reporting serious adverse event will be the electronic 
data capture (EDC) system.  
 
If the EDC system is unavailable for more than 24 hours, then the site will report 
the information to Amgen using a paper-based Serious Adverse Event 
Contingency Report Form (also referred to as the electronic Serious Adverse 
Event (eSAE) Contingency Report Form (see Figure 11-1) within 24 hours of the 
investigator’s awareness of the event. 
 
The site will enter the serious adverse event data into the electronic system as 
soon as it becomes available. 
 
After the study is completed at a given site, the EDC system will be taken off-line to 
prevent the entry of new data or changes to existing data. 
 
If a site receives a report of a new serious adverse event from a study subject or 
receives updated data on a previously reported serious adverse event after the 
EDC system has been taken off-line, then the site can report this information on 
the paper-based Serious Adverse Event Contingency Report Form (see 
Figure 11-1). 
 
Once the study has ended, serious adverse event(s) suspected to be related 
to investigational product will be reported to Amgen if the investigator 
becomes aware of a serious adverse event.  The investigator should use the 
paper-based Serious Adverse Event Contingency Report Form to report the 
event.  
Adverse Device Effects:  Recording, Evaluating and Reporting 
 
Any adverse event resulting from an adverse device effect that occur during the 
study will be documented in the subject’s medical records, in accordance with the 
investigator’s normal clinical practice, and on the Events CRF page. 
 
It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical devices [ie, CWHMS] provided by CH) at the time of the 
initial report and describes any corrective or remedial actions taken to prevent 
recurrence of the incident. 


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Figure 11-1.  Electronic Serious Adverse Event Contingency Report Form 
(paper-based form) 
 
General Instructions 
The protocol will provide instruction on what types of events to report for the study. This form is to 
be used ONLY to report events that must be captured in the Amgen safety database. *Indicates a 
mandatory field. 
Types of Events to be reported on this form  
 
Serious Adverse Events (regardless of causal relationship to IP)  
   
1. Site Information  
Site Number* – Enter your assigned site number for this study  
Investigator*, Country*, Reporter*, Phone No., and Fax No. – Enter information requested   
2. Subject Information  
Subject ID Number* – Enter the entire number assigned to the subject  
Age at event onset, Sex, and Race – Enter the subject’s demographic information  
End of Study date – If the subject has already completed the study or terminated the study early, enter 
the End of Study date  
If you are submitting follow-up information to a previous report, provide the serious adverse event 
term for the previous report as well as the start date for the initial event.   
3. Serious Adverse Event 
Provide the date the Investigator became aware of this Information 
Serious Adverse Event Diagnosis or Syndrome* –   
➢ If the diagnosis is known, it should be entered. Do not list all signs/symptoms if they are 
included in the diagnosis.  
➢ If a diagnosis is not known, the relevant signs/symptoms should be entered.  
➢ If the event is fatal, the cause of death should be entered and autopsy results should be 
submitted, when available.   
Date Started* – Enter date the adverse event first started (not the date on which the event met serious 
criteria) rather than the date of diagnosis or hospitalization. This is a mandatory field. 
Date Ended – Enter date the adverse event ended and not the date when the event no longer met 
serious criteria.  If the event has not ended at the time of the initial report, a follow-up report should be 
completed when the end date is known.  If the event is fatal, enter the date of death as the end date. 
If event occurred before the first dose of Investigational Product (IP)/drug under study, add a 
check mark in the corresponding box. 
Is event serious?* – Indicate Yes or No. This is a mandatory field. 
Serious Criteria Code* – This is a mandatory field for serious events. Enter all reasons why the 
reported event has met serious criteria: 
➢ Immediately life-threatening – Use only if the subject was at immediate risk of death from the 
event as it occurred.  Emergency treatment is often required to sustain life in this situation. 
➢ If the investigator decides an event should be reported in an expedited manner, but it does not 
meet other serious criteria, “Other Medically Important Serious Event” may be the appropriate 
serious criterion. 
Relationship to IP – The Investigator must determine and enter the relationship of the event to the IP at 
the time the event is initially reported. This is a mandatory field. 
Relationship to Amgen device* – The Investigator must determine and enter the relationship of the 
event to the Amgen device (eg, prefilled syringe, auto-injector) at the time the event is initially reported. If 
the study involves an Amgen device, this is a mandatory field. This question does not apply to 
non-Amgen devices used in the study (eg, heating pads, infusion pumps) 
Outcome of Event* – Enter the code for the outcome of the event at the time the form is completed. 
This is a mandatory field.  
➢ Resolved – End date is known 
➢ Not resolved / Unknown – End date is unknown 
➢ Fatal – Event led to death 
If event is related to a study procedure, such as a biopsy, radiotherapy or withdrawal of a current drug 
treatment during a wash-out period, add a check mark to the corresponding box. This does not include 
relationship to IP or concomitant medication – only diagnostic tests or activities mandated by the 


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protocol. 
4. Hospitalization 
If the subject was hospitalized, enter admission and discharge dates.  Hospitalization is any in-patient 
hospital admission for medical reasons, including an overnight stay in a healthcare facility, regardless of 
duration.  A pre-existing condition that did not worsen while on study which involved a hospitalization for 
an elective treatment, is not considered an adverse event.  Protocol specified hospitalizations are 
exempt.   
 
At the top of Page 2, provide your Site Number and the Subject ID Number in the designated section. 
5. IP Administration including Lot # and Serial # when known / available. 
Blinded or open-label – If applicable, indicate whether the investigational product is blinded or open-
label 
Initial Start Date – Enter date the product was first administered, regardless of dose.  
Date of Dose Prior to or at the time of the Event – Enter date the product was last administered prior 
to, or at the time of, the onset of the event.  
Dose, Route, and Frequency at or prior to the event – Enter the appropriate information for the dose, 
route and frequency at, or prior to, the onset of the event.  
Action Taken with Product – Enter the status of the product administration.   
6. Concomitant Medications  
Indicate if there are any medications.  
Medication Name, Start Date, Stop Date, Dose, Route, and Frequency – Enter information for any 
other medications the subject is taking.  Include any study drugs not included in Section 5 (Product 
Administration) such as chemotherapy, which may be considered co-suspect.  
Co-suspect – Indicate if the medication is co-suspect in the event  
Continuing – Indicate if the subject is still taking the medication  
Event Treatment – Indicate if the medication was used to treat the event    
7. Relevant Medical History  
Enter medical history that is relevant to the reported event, not the event description. This may include 
pre-existing conditions that contributed to the event allergies and any relevant prior therapy, such as 
radiation.  Include dates if available.   
8. Relevant Laboratory Tests   
Indicate if there are any relevant laboratory values.  
For each test type, enter the test name, units, date the test was run and the results.  
9. Other Relevant Tests  
Indicate if there are any tests, including any diagnostics or procedures.  
For each test type, enter the date, name, results and units (if applicable).   
At the top of Page 3, provide your Site Number and the Subject ID Number in the designated section.  
10. Case Description  
Describe Event – Enter summary of the event.  Provide narrative details of the events listed in Section 
3.  Include any therapy administered, such as radiotherapy; (excluding medications, which will be 
captured in Section 6). If necessary, provide additional pages to Amgen.  
Complete the signature section at the bottom of page 3 and fax the form to Amgen.  If the reporter 
is not the investigator, designee must be identified on the Delegation of Authority form 
 


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11.5 
Appendix 5.  Contraceptive Guidance and Collection of Pregnancy 
and Lactation Information 
Study-specific contraception requirements for females of childbearing potential are 
outlined in Section 5.2. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to the fetus if they become pregnant during treatment and for 
an additional 48 hours after the last dose of protocol-required therapies. 
Additional medications given during the study may alter the contraceptive requirements.  
These additional medications may require female subjects to use highly effective 
methods of contraception and/or for an increased length of time.  The investigator must 
discuss these contraceptive changes with the subject. 
Female subjects of childbearing potential must agree to practice true sexual abstinence 
(refrain from sexual intercourse) or use an acceptable method of effective birth control 
during treatment and for an additional 48 hours after the last dose of study drug. 
Definition of Females of Childbearing Potential 
A female is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile.  Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy. 
Females in the following categories are not considered female of childbearing potential: 
 
Premenopausal female with 1 of the following: 
o Documented hysterectomy; 
o Documented bilateral salpingectomy; or 
o Documented bilateral oophorectomy. 
Note:  Site personnel documentation from the following sources is acceptable:  1) 
review of subject’s medical records; 2) subject’s medical examination; or 3) subject’s 
medical history interview. 
 
Premenarchal female 
 
Postmenopausal female 
o A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a postmenopausal state in 


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women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to 
use 1 of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment 
Contraception Methods for Female Subjects 
Highly Effective Contraceptive Methods 
Note: Failure rate of < 1% per year when used consistently and correctly. 
 
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation (oral, intravaginal, or transdermal) 
 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
 
Intrauterine device  
 
Intrauterine hormonal-releasing system  
 
Bilateral tubal ligation/occlusion 
 
Vasectomized partner (provided that partner is the sole sexual partner of the female 
subject of childbearing potential and that the vasectomized partner has received 
medical assessment of the surgical success) 
 
Sexual abstinence (defined as refraining from heterosexual intercourse during the 
entire period of risk associated with the study treatments; the reliability of sexual 
abstinence must be evaluated in relation to the duration of the trial and the preferred 
and usual lifestyle of the subject) 
Male Subjects 
Male subjects of reproductive potential must agree to avoid impregnating a partner while 
receiving study drug and for 48 hours after the last dose of study drug. 
Unacceptable Methods of Birth Control for Female Subjects 
Birth control methods that are considered unacceptable in clinical trials include: 
 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
 
Withdrawal (coitus interruptus) 
 
Spermicides only 


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 
Lactational amenorrhea method 
Collection of Pregnancy Information 
Female Subjects Who Become Pregnant 
 
Investigator will collect pregnancy information on any female subject who becomes 
pregnant while taking protocol-required therapies through an additional 48 hours 
after the last dose of protocol-required therapies. 
 
Information will be recorded on the Pregnancy Notification Form (see Figure 11-2).  
The form must be submitted to Amgen Global Patient Safety within 24 hours of 
learning of a subject’s pregnancy.  (Note: Sites are not required to provide any 
information on the Pregnancy Notification Form that violates the country or regions 
local privacy laws). 
 
After obtaining the female subject’s signed authorization for release of pregnancy 
and infant health information, the investigator will collect pregnancy and infant health 
information and complete the pregnancy questionnaire for any female subject who 
becomes pregnant while taking protocol-required therapies through an additional 
48 hours after the last dose of protocol-required therapies.  This information will be 
forwarded to Amgen Global Patient Safety.  Generally, infant follow-up will be 
conducted up to 12 months after the birth of the child (if applicable). 
 
Any termination of pregnancy will be reported to Amgen Global Patient Safety, 
regardless of fetal status (presence or absence of anomalies) or indication for 
procedure.  
 
While pregnancy itself is not considered to be an adverse event or serious adverse 
event, any pregnancy complication or elective termination of a pregnancy for 
medical reasons will be reported as an adverse event or serious adverse event.  
Abnormal pregnancy outcomes (eg, spontaneous abortions, stillbirth, fetal 
death, congenital anomalies) will be reported as an adverse event or serious 
adverse event.  Note that an elective termination with no information on a fetal 
congenital malformation or maternal complication is generally not considered an 
adverse event, but still must be reported to Amgen as a pregnancy exposure case. 
 
Any serious adverse event occurring as a result of a post-study pregnancy which is 
considered reasonably related to the study treatment by the investigator, will be 
reported to Amgen Global Patient Safety as described in Section 11.4.  While the 
investigator is not obligated to actively seek this information in former study subjects, 
he or she may learn of a serious adverse event through spontaneous reporting.  


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 
Any female subject who becomes pregnant while participating will discontinue study 
treatment (see Section 7.1 for details). 
Male Subjects With Partners Who Become Pregnant or Were Pregnant at the Time 
of Enrollment 
 In the event a male subject fathers a child during treatment, and for an 
additional 48 hours after discontinuing protocol-required therapies, the 
information will be recorded on the Pregnancy Notification Form.  The form 
(see Figure 11-2) must be submitted to Amgen Global Patient Safety within 
24 hours of the site’s awareness of the pregnancy.  (Note: Sites are not 
required to provide any information on the Pregnancy Notification Form that 
violates the country or regions local privacy laws). 
 Males with pregnant partners or whose partners become pregnant during 
treatment and for an additional 48 hours must practice sexual abstinence or 
use a condom through 48 hours. 
 The investigator will attempt to obtain a signed consent for release of 
pregnancy and infant health information directly from the pregnant female 
partner to obtain additional pregnancy information. 
 After obtaining the female partner’s signed consent for release of pregnancy 
and infant health information, the investigator will collect pregnancy outcome 
and infant health information on the pregnant partner and her baby and 
complete the pregnancy questionnaires.  This information will be forwarded to 
Amgen Global Patient Safety. 
 Generally, infant follow-up will be conducted up to 12 months after the birth of 
the child (if applicable).  
 Any termination of the pregnancy will be reported to Amgen Global Patient 
Safety regardless of fetal status (presence or absence of anomalies) or 
indication for procedure. 
Collection of Lactation Information 
 
Investigator will collect lactation information on any female subject who breastfeeds 
while taking protocol-required therapies through an additional 48 hours after the last 
dose of protocol-required therapies. 


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 
Information will be recorded on the Lactation Notification Form (see below) and 
submitted to Amgen Global Patient Safety within 24 hours of the investigator’s 
knowledge of event. 
 
Study treatment will be discontinued if female subject breastfeeds during the study 
as described in exclusion criterion 228. 
 
With the female subjects signed authorization for release of mother and infant health 
information, the investigator will collect mother and infant health information and 
complete the lactation questionnaire on any female subject who breastfeeds while 
taking protocol-required therapies through an additional 48 hours after discontinuing 
protocol-required therapies. 


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Figure 11-2.  Pregnancy and Lactation Notification Forms
Amgen Proprietary - Confidential
Pregnancy Notification Form
5HSRUWWR$PJHQDWUSTO fax: +1-888-814-8653, Non-US fax: +44 (0)207-136-1046 or email (worldwide): svc-ags-in-us@amgen.com
1. Case Administrative Information
Protocol/Study Number: 20190014
Study Design:  X Interventional      
Observational (If Observational:  
Prospective
Retrospective)
2. Contact Information
Investigator Name
_
Site #
Phone (
)
_
Fax (_    _)
Email
Institution
Address 
3. Subject Information
Subject ID #
_
Subject Gender:
Female
Male
Subject age (at onset):       (in years)
4. Amgen Product Exposure
Amgen Product
Dose at time of 
conception
Frequency
Route
Start Date
mm
/dd
/yyyy
Was the Amgen product (or study drug) discontinued?
Yes
No
If yes, provide product (or study drug) stop date: mm 
/dd
/yyyy
Did the subject withdraw from the study?
Yes
No
5. Pregnancy Information
Pregnant femal)Cs last menstrual period (LMP)
mm
/ dd______/ yyyy
Unknown
N/A
Estimated date of delivery   mm
/ dd
_/ yyyy
If N/A, date of termination (actual or planned) mm
/ dd _/ yyyy
Has the pregnant female already delivered?
Yes
No
Unknown
N/A
If yes, provide date of delivery: mm 
/ dd
/ yyyy
Was the infant healthy?
Yes
No
Unknown
N/A
If any Adverse Event was experienced by the infant, provide brief details:
Form Completed by:
Print Name: 
Title: 
Signature: 
Date: 
FORM-115199                                                                                       Version 1.0                                                                         Effective Date: 24-Sept-2018


Product:  Blinatumomab
Protocol Number:  20190014
Date:  21 April 2022
Page 101 of 108
CONFIDENTIAL 
FORM-001520, v.24, 21 May 2019
Amgen Proprietary - Confidential
Lactation Notification Form
5HSRUWWR$PJHQDWUSTO fax: +1-888-814-8653, Non-US fax: +44 (0)207-136-1046 or email (worldwide): svc-ags-in-us@amgen.com
1. Case Administrative Information
Protocol/Study Number: 20190014
Study Design:  X Interventional      
Observational (If Observational:  
Prospective
Retrospective)
2. Contact Information
Investigator Name
Site #
Phone (
)
Fax (
)
Email
Institution
Address 
3. Subject Information
Subject ID #
Subject age (at onset):       (in years)
4. Amgen Product Exposure
Amgen Product
Dose at time of 
breast feeding
Frequency
Route
Start Date
mm
/dd
/yyyy
Was the Amgen product (or study drug) discontinued?
Yes
No
If yes, provide product (or study drug) stop date: mm 
/dd
/yyyy
Did the subject withdraw from the study?
Yes
No
5. Breast Feeding Information
Did the mother breastfeed or provide the infant with pumped breast milk while actively taking an Amgen product?
Yes
No
If No, provide stop date: mm
/dd
/yyyy
Infant date of birth: mm
/dd
/yyyy
Infant gender:
Female
Male
Is the infant healthy?
Yes
No
Unknown
N/A
If any Adverse Event was experienced by the mother or the infant, provide brief details:
  Form Completed by:
Print Name: 
Title: 
Signature:  
Date: 
FORM-115201                                                                                      Version 1.0                                                                           Effective Date: 24-Sept-2018


Product:  Blinatumomab 
Protocol Number:  20190014  
Date:  21 April 2022 
Page 102 of 108 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
11.6 
Appendix 6.  Hepatotoxicity Stopping Rules:  Suggested Actions and 
Follow-up Assessments and Study Treatment Rechallenge 
Guidelines 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], 
aspartate aminotransferase [AST], alanine aminotransferase [ALT], total bilirubin [TBL]) 
and/or international normalized ratio (INR) and/or signs/symptoms of hepatitis (as 
described below) may meet the criteria for withholding or permanent discontinuation of 
Amgen IP or other protocol-required therapies, as specified in the Guidance for Industry 
Drug-Induced Liver Injury:  Premarketing Clinical Evaluation, July 2009. 
Criteria for Withholding and/or Permanent Discontinuation of Amgen 
Investigational Product and Other Protocol-required Therapies Due to Potential 
Hepatotoxicity 
The following stopping and/or withholding rules apply to subjects for whom another 
cause of their changes in liver biomarkers (TBL, INR and transaminases) has not been 
identified.  
Important alternative causes for elevated AST/ALT and/or TBL values include, but are 
not limited to: 
 
Hepatobiliary tract disease 
 
Viral hepatitis (eg, hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, herpes 
simplex virus, varicella, toxoplasmosis, and parvovirus) 
 
Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia 
 
Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and dietary 
supplements, plants and mushrooms 
 
Heritable disorders causing impaired glucuronidation (eg, Gilbert’s syndrome, 
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, indinavir, 
atazanavir) 
 
Alpha-1 antitrypsin deficiency 
 
Alcoholic hepatitis 
 
Autoimmune hepatitis 
 
Wilson’s disease and hemochromatosis 
 
Nonalcoholic fatty liver disease including steatohepatitis 
 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
 
Cytokine release syndrome (CRS) 


Product:  Blinatumomab 
Protocol Number:  20190014  
Date:  21 April 2022 
Page 103 of 108 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
If investigational product(s) (IPs) is/are withheld, the subject is to be followed for possible 
drug induced liver injury (DILI) according to recommendations in the last section of this 
appendix.  
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (see next section in this appendix). 
Table 11-2.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity 
Analyte 
Temporary Withholding 
Permanent Discontinuation 
TBL 
> 3x ULN  
at any time 
> 2x ULN 
 
 
OR 
INR 
-- 
> 1.5x (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8x ULN at any time 
> 5x ULN but < 8x ULN for  2 weeks 
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring schedule 
> 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (such as 
right upper quadrant pain/tenderness, 
fever, nausea, vomiting, and jaundice) 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
> 3x ULN (when baseline was < ULN) 
 
OR 
 
ALP 
> 8x ULN at any time 
-- 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = 
international normalized ratio; TBL = total bilirubin; ULN = upper limit of normal 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
The decision to rechallenge the subject is to be discussed and agreed upon 
unanimously by the subject, investigator, and Amgen. 
If signs or symptoms recur with rechallenge, then Amgen IP and other protocol-required 
therapies, as appropriate is to be permanently discontinued.  Subjects who clearly meet 
the criteria for permanent discontinuation (as described in Table 11-2) are never to be 
rechallenged. 


Product:  Blinatumomab 
Protocol Number:  20190014  
Date:  21 April 2022 
Page 104 of 108 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Drug-induced Liver Injury Reporting and Additional Assessments 
Reporting 
To facilitate appropriate monitoring for signals of DILI, cases of concurrent AST or ALT 
and TBL and/or INR elevation, according to the criteria specified in the above, require 
the following: 
 
The event is to be reported to Amgen as a serious adverse event (SAE) within 
24 hours of discovery or notification of the event (ie, before additional etiologic 
investigations have been concluded) 
 
The appropriate case report form (CRF) (eg, Events CRF) that captures information 
necessary to facilitate the evaluation of treatment-emergent liver abnormalities is to 
be completed and sent to Amgen  
Other events of hepatotoxicity and potential DILI are to be reported as SAEs if they meet 
the criteria for a SAE defined in Section 11.4. 
Additional Clinical Assessments and Observation 
All subjects in whom IP(s) or protocol-required therapies is/are withheld (either 
permanently or conditionally) due to potential DILI as specified in Table 11-2 or who 
experience AST or ALT elevations > 3x upper limit of normal (ULN) or 2-fold increases 
above baseline values for subjects with elevated values before drug are to undergo a 
period of “close observation” until abnormalities return to normal or to the subject’s 
baseline levels.   
Assessments that are to be performed during this period include:  
 
Repeat AST, ALT, ALP, bilirubin (BIL) (total and direct), and INR within 24 hours  
 
In cases of TBL > 2x ULN or INR > 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve 
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the IP(s) or protocol-required therapies has/have been discontinued AND the 
subject is asymptomatic. 
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated TBL.  
The following are to be considered depending on the clinical situation: 
 
Complete blood count with differential to assess for eosinophilia 
 
Serum total immunoglobulin G (IgG), anti-nuclear antibody anti-smooth muscle 
antibody, and liver kidney microsomal antibody-1 to assess for autoimmune hepatitis 


Product:  Blinatumomab 
Protocol Number:  20190014  
Date:  21 April 2022 
Page 105 of 108 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
 
Serum acetaminophen (paracetamol) levels 
 
A more detailed history of:  
o Prior and/or concurrent diseases or illness 
o Exposure to environmental and/or industrial chemical agents  
o Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever 
o Prior and/or concurrent use of alcohol, recreational drugs and special diets 
o Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms 
 
Viral serologies 
 
Creatine phosphokinase, haptoglobin, lactate dehydrogenase and peripheral blood 
smear 
 
Appropriate liver imaging if clinically indicated 
 
Hepatology consult (liver biopsy may be considered in consultation with a 
hepatologist) 
Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  The 
“close observation period” is to continue for a minimum of 4 weeks after discontinuation 
of all IP(s) and protocol-required therapies. 
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs.  
 


Product:  Blinatumomab 
Protocol Number:  20190014  
Date:  21 April 2022 
Page 106 of 108 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
11.7 
Appendix 7.  Eastern Cooperative Oncology Group Performance 
Status (ECOG PS) Scale 
ECOG PS Scale 
Grade 
Descriptions 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (eg, light housework, office work). 
2 
Ambulatory and capable of all selfcare, but unable to carry out any work activities.  
Up and about more than 50 of waking hours. 
3 
Capable of only limited selfcare, confined to bed or chair more than 50 of 
waking hours. 
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or 
chair. 
5 
Dead 
Source:  Oken et al, 1982. 
 


Product:  Blinatumomab 
Protocol Number:  20190014  
Date:  21 April 2022 
Page 107 of 108 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
11.8 
Appendix 8.  Protocol-specific Definitions 
Cytokine Release Syndrome (CRS) 
A supraphysiologic response following the administration of blinatumomab therapy that 
results in the activation or engagement of endogenous or infused T cells and/or other 
immune effector cells.  Symptoms can be progressive, must include fever (  G1) at the 
onset, and may include hypotension, capillary leak (hypoxia) and end organ dysfunction. 
 
Source:  Lee et al, 2018. 
 
Fever 
Fever as defined in the Common Terminology Criteria for Adverse Events (CTCAE) 
v5.0 is “a disorder characterized by elevation of the body’s temperature above the upper 
limit of normal (ULN),” and a temperature  38.0C (100.4F) (for this study, axillary 
temperature  37.0C [99.4F]) is considered grade 1 fever. 
 
For this study, any temperature  38.0C (100.4F) maintained for a minimum of 
10 minutes will generate an alert.  As this study will rely on the fever scout the equivalent 
alert values from the fever scout will be set at  37.0C (99.4F). 
 
CTCAE v5.0 Fever 
1 38.0 - 39.0C (100.4 - 102.2F) 
2  39.0 - 40.0C (102.3 - 104.0F)  
3  40.0C ( 104.0F) for  24 hrs  
4  40.0C ( 104.0F) for  24 hrs  
 
Elevated Pulse Rate 
For this study, a pulse rate of  150 beats per minute maintained for a minimum of 
10 minutes will be considered severe and generate an alert. 
 
Elevated Respiratory Rate 
For this study, an elevated respiratory rate of  25 breaths per minute maintained for a 
minimum of 10 minutes is considered severe and will generate an alert. 
 


Product:  Blinatumomab 
Protocol Number:  20190014  
Date:  21 April 2022 
Page 108 of 108 
CONFIDENTIAL  
FORM-001520, v.24, 21 May 2019 
 
Hypoxia 
The CTCAE v5.0 defines hypoxia as “a disorder characterized by a decrease in the level 
of oxygen in the body.”  For this study hypoxia will be defined as an oxygen saturation of 
 92. 
 
Hypotension 
Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0) as “a 
disorder characterized by a blood pressure (BP) that is below the normal expected for an 
individual in a given environment.”  For this study hypotension will be defined as any 
systolic blood pressure (SBP) 100 mmHg or any change by 20 decrease below the 
baseline level established during screening for each subject. 
 
Neurotoxicity (NT) or Immune effector cell-associated neurotoxicity syndrome (ICANS)  
ICANS definition:  A disorder characterized by a pathologic process involving the central 
nervous system (CNS) following blinatumomab therapy that results in the activation or 
engagement of endogenous T cells and/or other immune effector cells.  Symptoms or 
signs can be progressive and may include aphasia, altered level of consciousness, 
impairment of cognitive skills, motor weakness, seizures or cerebral edema.  Symptoms 
may be manifested by expressive aphasia (limiting the ability to communicate 
spontaneously or difficulty naming objects), difficulty writing a standard 
sentence(apraxia), receptive aphasia (difficulty following commands) and/or poor 
concentration.  Headache is not considered part of ICANS.  For this study, any 
neurotoxicity (NT) is defined as outlined below. 
 
CTCAE v5.0  G3 neurological symptoms: 
 
Limits self-care activities of daily living (ADL). 
 
Any New-onset seizures (partial or generalized); multiple seizures despite medical 
intervention is CTCAE v5.0 G3. 
 
Severe receptive or expressive characteristics; impairing ability to read, write, 
communicate intelligibly 
 
Difficult to arouse 
 
Activities of Daily Living (ADL) 
Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc 
Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden. 
 


Product:  Blinatumomab 
Protocol Number:  20190014 
Date:  21 April 2022 
Page 1 of 3 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
Amendment 2 
Protocol Title:  A Phase 4, Multi-center Open-label Feasibility Study to Evaluate 
Outpatient Blinatumomab Administration in Adult Subjects with Minimal Residual 
Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia (ALL) in Complete 
Hematologic Remission 
Amgen Protocol Number Blinatumomab 20190014 
NCT Number:  NCT04506086 
Amendment Date: 
21 April 2022 
 
Rationale: 
The rationale for this amendment is to clarify the eligibility criteria to include all patients 
in complete remission (CR) with measurable residual disease of precursor B-cell acute 
lymphoblastic leukemia (PBC-ALL).  This will include all patients with PBC-ALL in 
morphological remission ie, bone marrow blast count less than 5.  The population of 
minimal/measurable residual disease (MRD) positive patients are difficult to capture.  
This is due to the low incidence PBC-ALL in adults in general and specifically those who 
relapse or are refractory (R/R ALL).  In addition, identifying only MRD positive patients 
within this small group who are otherwise eligible to be monitored at home is difficult.  
Moreover, MRD positivity is an independent risk factor of poor outcome.  The 
amendment will allow eligibility of all patients in morphologic complete remission (CR) 
but with molecular disease.   
In addition to provide clarifying language to permit clinical coverage of enrolled patients 
by approved designees of the Health Care Professional (HCP) or approved 
vendor/monitoring team by Current Health.  One of the barriers for site participation is 
the increase workload reported by investigators due to the study monitoring 
requirements.  In our experience, the majority of the initial alarms generated from the 
patient monitoring devices were not of an emergent clinical nature but occurred primarily 
in the early stages of set up and were technical.  A team of trained and licensed nurses 
have been established to provide assistance in monitoring the patients and responding 
to any alarms or patient questions.  They have been trained on the details of the 
protocol.  The monitoring team will have immediate access to the HCP as needed.  They 
will have a validated system with built in mitigation strategies.  This will allow more 
flexibility in a patient centric way as patients will have 24/7 access to the monitoring 


Product:  Blinatumomab 
Protocol Number:  20190014 
Date:  21 April 2022 
Page 2 of 3 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
team and decrease the monitoring demands of the HCP and his/her team without 
compromising patient safety. 
In addition, protocol amendment 2 will align with current template safety language. 
Other amendments include: 
 
Added the nursing triaging services as an option to be utilized by the sites/subjects. 
 
Updated the end of study (EOS) visit. 
 
Changed the serious adverse event (SAE) language in the study to outside of the 
protocol-required reporting period to SAE’s related to investigational product (IP) 
instead of all SAE’s regardless of causality since the study did not have a long-term 
follow-up (LTFU). 
 
Language was updated to include both HCP or HCP designee to include other 
medical professional 
 
Appendix 9 (Current Health Digital Health Platform) was deleted from the protocol 
and was made as a stand-alone study specific approved device manual. 
 
Language for SAE reporting period, reporting post EOS, outcome data for serious 
and non-serious events was updated per new protocol template to align with 
European Medicines Agency (EMA) regulations. 
 
Inclusion criteria was updated to include BCP-ALL in hematologic CR defined as less 
than 5 bone marrow blasts. 
 
Blinatumomab 7-day continuous intravenous infusion (CIVI) dosing instructions was 
added as some sites requested the 7-day bag.  The approved 7-day bag is more 
convenient to many sites, and other infusion bags would be a significant burden to 
their participation.   
 
Language was updated for bone marrow biopsy procedure.  Any additional bone 
marrow aspiration or biopsy procedure, outside of that required for eligibility will need 
to be approved by the medical monitor. 
 
Replacement status definition:  Subjects will be replaced for analysis if the outpatient 
monitoring during blinatumomab infusion is not established.   


Product:  Blinatumomab 
Protocol Number:  20190014 
Date:  21 April 2022 
Page 3 of 3 
Amgen Proprietary - Confidential 
FORM-492529,   Effective Date: 02 Mar 2020,  Version:6.0 
 
Blood pressure (BP) alert trigger:  To provide clarity as BP is the only vital sign in 
which an alert will not be triggered within 1 minute upon being received.  BP is 
measured manually every 3-6 hours by the patient. 
 
Reference to safety report form was removed to align with the new protocol template. 
 
Administrative updates were made per the new protocol template. 
 
Formatting errors were corrected throughout the protocol amendment. 


Product:  Blinatumomab 
Protocol Number:  20190014 
Date:  28 September 2020 
 
 
Amgen Proprietary - Restricted 
Page 1 of 1 
Superseding Amendment 1 
Protocol Title:  A Phase 4, Multi-center Open-label Feasibility Study to Evaluate 
Outpatient Blinatumomab Administration in Adult Subjects with Minimal Residual 
Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia (ALL) in Complete 
Hematologic Remission 
 
Amgen Protocol Number Blinatumomab 20190014 
 
Amendment Date: 
28 September 2020 
 
Rationale:  This protocol is being amended to make the following typographical corrections 
to Blinatumomab 20190014 Protocol v1.0 dated 08 April 2020 to align with the intended and 
US Food and Drug Administration requested MRD level for patient eligibility.  
 
Correct inclusion criteria 104 from Presence of MRD < 0.1% to Presence of MRD 
≥ 0.1% 
 
Correct inclusion criteria 106 from Serum creatinine ≤ 1.5x upper limit of normal 
(ULN) to Serum creatinine < 1.5x ULN 
 
Administrative and editorial edits 


Product:  Blinatumomab 
Protocol Number:  20190014 
Date:  08 April 2020 
 
 
Amgen Proprietary - Restricted 
Page 1 of 2 
Amendment 1 
Protocol Title:  A Phase 4, Multi-center Open-label Feasibility Study to Evaluate 
Outpatient Blinatumomab Administration in Adult Subjects with Minimal Residual 
Disease (MRD) of B-precursor Acute Lymphoblastic Leukemia (ALL) in Complete 
Hematologic Remission 
 
Amgen Protocol Number (AMG 103) 20190014 
 
Amendment Date: 
08 April 2020 
 
Rationale: 
This protocol is being amended in response to FDA comments received on the AMG 103 
20190014 Protocol v1.0 dated 8Nov2019. In addition, clarifications are being made as 
follows:  
 
FDA requirement to revise for the MRD inclusion criteria to be greater than or equal 
to 0.1% to reflect the approved population for blinatumomab.  
 
FDA requirement to add neurotoxicity monitoring clarification to include requirements 
for the HCP to conduct scheduled video calls with the patients and caregivers at 
minimum of every 12 hours (eg, 8AM and 8PM) daily during the mandatory device 
monitoring period (MDMP).  This frequency may be increased if any there are any 
concerns by the HCP. 
 
FDA requirement to clarify that respiration rate will be measured “intermittently/every 
30 seconds” instead of “continuously”. 
 
FDA requirement to add guidance language in the event of a device malfunction (eg, 
to delete the phrase “(without affecting patient safety) that cannot be resolved within 
1 to 2 hours during the MDMP). 
 
Defining the term CWHMS (Current Wearable Health Monitoring System) to match 
description & components mentioned in the 510k clearance, and updating protocol to 
utilize this term as applicable 
 
Updating QLQC30 collection timepoints to screening and at Cycle 2 Day 1 (after 
subject has completed 1 full cycle of blinatumomab) in order to make this more 
operationally feasible for subjects to complete the QLQC30 while the device tablet is 
in their possession.  
 
Updating optional sub study timepoints and clarifying guidance in the Optional 
Subject Experience Guide on safety reporting and how interviews will be conducted.  


Product:  Blinatumomab 
Protocol Number:  20190014 
Date:  08 April 2020 
 
 
Amgen Proprietary - Restricted 
Page 2 of 2 
 
Capturing "route" in Concomitant Medication language to match eCRF specifications 
 
Adding missing footnote to Table 6-2 (Infusion Interruptions/Dose Modifications Due 
to Adverse Events) that in the event of seizure “Obtain brain MRI and perform 
cerebrospinal fluid (CSF) analysis if indicated and if there are no contraindications 
 
Modifying Entry Criteria as follows: 
o Delete mention of systemic therapy in exclusion criteria 214 “Active 
uncontrolled infection requiring therapy”, as mention of systemic therapy in 
this criteria is thought to be too broad.  
o Editorial correction of lab units in inclusion criteria 105 
o Editorial correction of signage in inclusion criteria 106  
o Editorial correction to use the term CWHMS as applicable (eg, exclusion 
criterion 220, 222, 225, 226) 
 
Clarifying in to Section 8.2.1.3 that “In addition, any non-serious Adverse Event that 
is observed between the signing of the Informed Consent Form to enrolment / pre-
dose Cycle 1 Day 1 should be captured as Medical History” 
 
Correct Appendix 5 to reflect “Female subjects of childbearing potential must agree 
to practice true sexual abstinence (refrain from sexual intercourse) or use an 
acceptable method of effective birth control during treatment and for an additional 48 
hours after the last dose of study drug,” to be in line with blinatumomab contraceptive 
guidance for female subjects of childbearing potential. 
 
Incorporating editorial corrections, ie, administrative edits, typographical and 
formatting changes were made throughout the protocol. Updates have been 
implemented to align with the current template. 
 
Delete optional interview substudy to reduce procedural burden on subjects. 


Approval Signatures
Document Name:
Protocol Amendment blinatumomab 20190014 2
Document Description:
Protocol Amendment 2 Blinatumomab 20190014
Document Number:
CLIN-000072727
Approval Date:
22 Apr 2022
Type of Study Protocol:
Amendment
Protocol Amendment No.: 2
Document Approvals
Reason for Signing: Management
Name:
Date of Signature: 22-Apr-2022 02:28:31 GMT+0000

SAP_001.pdf: 
Product:  Blinatumomab 
Protocol Number:  20190014 
Date:  26 July 2022 
Page 1 of 33 
CONFIDENTIAL  
 
 
 
Statistical Analysis Plan 
 
Protocol Title: 
A Phase 4, Multi-center Open-label Feasibility Study 
to Evaluate Outpatient Blinatumomab Administration 
in Adult Subjects With Minimal Residual Disease 
(MRD) of B-precursor Acute Lymphoblastic 
Leukemia (ALL) in Complete Hematologic 
Remission 
Short Protocol Title: 
Phase 4 Feasibility Study to Evaluate Outpatient 
Blinatumomab in Subjects With MRD of B-precursor 
ALL 
Protocol Number: 
20190014 
NCT Number: 
NCT04506086 
Authors: 
Sponsor: 
Amgen 
One Amgen Center Drive 
Thousand Oaks, CA 91320 
SAP Date: 
Document Version 
Date 
Amendment 1.0 (v[2.0]) 
26 July 2022 
 


Product:  Blinatumomab 
Protocol Number:  20190014 
Date:  26 July 2022 
Page 2 of 33 
CONFIDENTIAL  
 
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
28Sep2020 
 
Amendment 1 (v2.0) 
26Jul2022 
Key updates are as mentioned 
below:  
 
Section 2.1: Updates to 
wording for primary and 
secondary endpoint  
 
Section 3.1: Updates to 
‘Study Design’ in consistency 
with PA2 
 
Removal of section 5 ‘Primary 
Completion’ Definition  
 
Removal of section 6.7 
‘Interim Analysis Set’ 
Definition  
 
Section 7.1: Updates to 
‘Interim (DRT) Analysis’ 
trigger criteria in consistency 
with PA2 
 
Section 8.3: Updates to 
‘Replacement of Subjects’ in 
consistency with PA2 
 
Section 9.4: Removal of 
‘Patients in 1st, 2nd or further 
remission’  
 
Section 9.6.2: Removal of 
TEAE summaries based on 
PAS 
 
Section 9.6.4: Removal of 
‘oxygen saturation’ from vital 
signs summary  
 
Section 9.6.2: Added analysis 
for secondary objective on 
estimation of healthcare 
resource utilization  
 
Section 10: Updated to 
include changes to protocol 
specified analysis 
 


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Table of Contents 
Table of Contents ................................................................................................... 3 
1. 
Introduction ............................................................................................................. 7 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 7 
2.1 
Objectives and Endpoints ............................................................................ 7 
2.2 
Hypotheses and/or Estimations ................................................................... 8 
3. 
Study Overview ...................................................................................................... 8 
3.1 
Study Design ............................................................................................... 8 
3.2 
Sample Size ................................................................................................ 9 
4. 
Covariates and Subgroups ................................................................................... 10 
4.1 
Planned Covariates ................................................................................... 10 
4.2 
Subgroups ................................................................................................. 10 
5. 
Definitions ............................................................................................................. 10 
6. 
Analysis Sets ........................................................................................................ 13 
6.1 
Full Analysis Set (FAS) ............................................................................. 13 
6.2 
Safety Analysis Set (SAS) ......................................................................... 13 
6.3 
Primary Analysis Set (PAS) ....................................................................... 14 
6.4 
Per Protocol Set ........................................................................................ 14 
6.5 
Patient-Reported Outcome (PRO) Analyses Set ....................................... 14 
6.6 
Pharmacokinetic/Pharmacodynamic Analyses Set .................................... 14 
7. 
Planned Analyses ................................................................................................. 14 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 14 
7.2 
Primary Analysis ....................................................................................... 14 
7.3 
Final Analysis ............................................................................................ 15 
8. 
Data Screening and Acceptance ........................................................................... 15 
8.1 
General Principles ..................................................................................... 15 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 15 
8.3 
Handling of Missing and Incomplete Data ................................................. 15 
8.4 
Detection of Bias ....................................................................................... 15 
8.5 
Outliers ..................................................................................................... 15 
8.6 
Distributional Characteristics ..................................................................... 16 
8.7 
Validation of Statistical Analyses ............................................................... 16 
9. 
Statistical Methods of Analysis.............................................................................. 16 
9.1 
General Considerations ............................................................................. 16 
9.2 
Subject Accountability ............................................................................... 16 
9.3 
Important Protocol Deviations ................................................................... 16 
9.4 
Demographic and Baseline Disease Characteristics ................................. 17 
9.5 
Efficacy Analyses ...................................................................................... 17 


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9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 17 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 17 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 17 
9.6 
Safety Analyses ........................................................................................ 18 
9.6.1 
Analyses of Primary and Key Secondary Safety 
Endpoint(s) ................................................................................ 18 
9.6.2 
Adverse Events ......................................................................... 20 
9.6.3 
Laboratory Test Results ............................................................ 21 
9.6.4 
Vital Signs ................................................................................. 22 
9.6.5 
Physical Measurements ............................................................ 22 
9.6.6 
Electrocardiogram ..................................................................... 22 
9.6.7 
Antibody Formation ................................................................... 22 
9.6.8 
Exposure to Investigational Product .......................................... 22 
9.6.9 
Exposure to Non-investigational Product ................................... 22 
9.6.10 
Exposure to Other Protocol-required Therapy ........................... 23 
9.6.11 
Exposure to Concomitant Medication ........................................ 23 
9.7 
Other Analyses ......................................................................................... 23 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 23 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 23 
9.7.3 
Analyses of Health Economic Endpoints ................................... 23 
9.7.4 
Analyses of Biomarker Endpoints .............................................. 24 
10. 
Changes From Protocol-specified Analyses.......................................................... 24 
11. 
Literature Citations / References ........................................................................... 25 
12. 
Prioritization of Analyses....................................................................................... 25 
13. 
Data Not Covered by This Plan............................................................................. 25 
14. 
Appendices ........................................................................................................... 26 
 


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List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALL 
Acute Lymphoblastic Leukemia 
BP 
Blood Pressure 
BSA 
Body Surface Area 
CG 
Caregiver 
CH 
Current Health 
CRF 
Case Report Form 
CRS 
Cytokine Release Syndrome 
CTCAE 
Common Terminology Criteria for Adverse Events 
CWHMS 
Current Wearable Health Monitoring System  
DRT 
Data Review Team 
ECG 
Electrocardiogram 
ECOG PS 
Eastern Cooperative Oncology Group Performance Status 
EOI 
Events of Interest 
EOS 
End of Study 
EORTC 
European Organisation for Research and Treatment of Cancer 
ePRO 
Electronic Patient-Reported Outcomes 
GHS 
Global Health Status 
HCP 
Healthcare Provider 
HR 
Heart Rate 
IgG 
Immunoglobulin G 
IP 
Investigational Product 
IV 
Intravenous(ly) 
MDMP 
Mandatory Device Monitoring Period 
MRD 
Minimal Residual Disease 
NT 
Neurotoxicity 
PAS 
Primary Analysis Set 
PO 
Oral(ly) 
PRO 
Patient-Reported Outcomes 
QLQ-30 
Quality of Life of Cancer Patients 
QoL 
Quality of Life 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 


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Abbreviation or Term 
Definition/Explanation 
SAS 
Safety Analysis Set 
SBP 
Systolic Blood Pressure 
SpO2 
Peripheral Capillary Oxygen Saturation 
TBL 
Total Bilirubin 
TEAE 
TTI 
Treatment-Emergent Adverse Event 
Time to Intervention 
ULN 
Upper Limit of Normal 
WBC 
White Blood Cell Count 
 


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1. 
Introduction 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol amendment 1 for Blinatumomab 
study 20190014, dated 21 April 2022.  The scope of this plan includes the interim 
analysis, and the primary analysis. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
To determine the safety of outpatient 
blinatumomab administration, during the 
MDMP (defined as the first 3 days of 
cycle 1 and first 2 days of cycle 2 of 
outpatient blinatumomab infusion) 
 
Grade 3 and/or 4 CRS, NT or any 
adverse event (AE) requiring 
hospitalization (SAE) during 
MDMP. 
Secondary 
 
To determine the time from first detection 
of grade 3 or 4 vital sign, or significant 
clinical change to therapeutic intervention 
(any measurable action taken by or 
performed on the subject due to onset of 
the clinical parameters described above) 
during the MDMP 
 
Time (in minutes) from first onset 
of fever, hypotension, hypoxia, 
other grade 3 or 4 vital sign 
including seizure or neurological 
change (grade 3-limiting self-care 
activities of daily living [ADL]) to 
therapeutic intervention. 
 
Evaluate the safety and tolerability of 
blinatumomab administered exclusively 
as an outpatient 
 
Treatment-emergent adverse 
events (TEAE) and adverse 
events of interest in particular 
CRS and NT. 
 
Evaluate the impact of complete 
outpatient blinatumomab treatment on 
patient-reported outcome (PRO), global 
health status (GHS), and quality of life 
(QoL). 
 
European Organisation for 
Research and Treatment of 
Cancer (EORTC) validated 
electronic version of QLQ-C30. 
 
Estimate healthcare resource utilization 
associated with treatment-related AEs 
 
Treatment-related TEAEs that 
resulted in hospitalizations. 
 
Treatment-related TEAEs that 
resulted in surgeries. 
 
Treatment-related TEAEs that 
resulted in the use of concomitant 
medications. 
 
Treatment-related TEAEs that 
resulted in the use of 
device/procedure intervention.  
ADL = activities of daily living; AE = adverse event; CG = caregiver; CRS = cytokine release syndrome; EMS 
= Emergency Medical Service; EORTC = European Organisation for Research and Treatment of Cancer; 
GHS = global health status; HCP = Health Care Provider; IV = intravenous; MDMP = mandatory device 
monitoring period; NT = neurotoxicity; PO = by mouth; PRO = patient-reported outcomes; QLQ-30 = Quality 
of Life of Cancer Patients; QoL = quality of life; SAE = serious adverse event; TEAE = treatment-emergent 
adverse event. 


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2.2 
Hypotheses and/or Estimations 
No formal hypotheses will be tested. For the primary and secondary objectives, analyses 
will be descriptive and include estimations. 
3. 
Study Overview 
3.1 
Study Design  
This study aims to determine the safety and feasibility of complete outpatient 
blinatumomab administration for subjects with MRD of B-precursor ALL. The study will 
use the CWHMS that is comprised of CH wearable device worn on the subject’s upper 
arm, an axillary temperature patch, a blood pressure cuff, a Wi-fi hub, tablet, a mobile 
phone provisioned to the HCP, and a platform will also be used to monitor subjects’ 
vital signs while they are at home.  
This study will include remote monitoring using CWHMS to measure vital signs and 
mobile electronic devices (tablet) to electronically communicate these vital signs with the 
HCP. 
The use of a Wi-Fi and cellular enabled platform for the transfer of data and 
communication between subject and HCP, to identify subjects at risk of developing 
grade 3 or 4 CRS, NT, or other SAEs requiring hospitalization during the MDMP. This 
subject group may require immediate escalation of care and/or hospitalization once the 
digital monitoring system identifies changes. 
Design 
During screening, subjects and caregivers will be trained on the CWHMS and assessed 
for compliance (Table 1, panel 1).  Once enrolled, Subjects will receive 2 complete 
cycles of blinatumomab completely in the outpatient setting in accordance with the 
monitoring and intervention guidelines (Table 1, panels 2 and 3).     
After the end of cycle 2 clinical assessment visit, some subjects may continue to receive 
2 additional (optional) cycles of outpatient blinatumomab. There will be no CWHMS 
outpatient monitoring during the optional cycles 3 and 4. For the purpose of this study, 
the MDMP is defined as the first 3 days of cycle 1 (72 hours) and the first 2 days of 
cycle 2 (48 hours) of blinatumomab infusion for subjects with MRD of B-precursor 
ALL. 
The end of study visit will occur 30 days ( 3 days) after the last dose of blinatumomab is 
administered (Figure 1). 


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During the MDMP, the CWHMS will measure vital signs.  These vital signs include 
pulse rate, respiratory rate, and axillary temperature. The CWHMS will measure 
respiratory rate (RR) intermittently (sampling every 30 seconds).  The subjects will take 
intermittent blood pressure (BP) measurements (using a subject-usable BP device) 
every 3 hours during the MDMP. The schedule for BP measurements may be extended 
by HCP (up to but not exceeding every 6 hours) after the first 24 hours of MDMP. The 
BP device will be provided and will directly transmit the BP reading via the monitoring 
platform to the CH Patients Application on the study provisioned mobile phone..  
Threshold vital sign values will be established, and an immediate alert will be generated 
and transmitted to the HCP device once the preset threshold values are surpassed and 
sustained for at least 10 minutes (Table 1).  Except for blood pressure, an alert will 
be triggered within 1 minute upon being received. 
The overall study design is described by a study schema in Figure 1. The endpoints are 
defined in Section 2.1.  There will be no outpatient digital monitoring during the optional 
cycles 3 and 4.   
Figure 1. Study Schema 
 
3.2 
Sample Size 
The planned enrollment for this study is approximately 45 patients. The sample size is 
based on feasibility rather than on statistical considerations.  Given a true probability of a 
primary endpoint event of 38%, the expected 95% upper confidence limit with 45 
subjects would be 53.5%. The 38% probability is based on the SAE rate in first 3 days of 
cycle 1 and first 2 days of cycle 2 from the previous MRD study (BLAST).  Based on 
these assumptions, we expect to observe approximately 17 subjects who will experience 


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the primary endpoint which should provide an initial indication of the timeliness of the 
therapeutic intervention when outpatient blinatumomab is administered in conjunction 
with remote digital monitoring. 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
No covariate analysis is planned for the study.  
4.2 
Subgroups 
Due to small sample size, subgroup analysis will not be performed.  
5. 
Definitions 
Age at Enrollment:  
Subject age at enrollment will be collected in years in the clinical database. 
Adverse Event During the MDMP 
Adverse event during the MDMP is defined as an adverse event that started within 72 
hours after the first dose of blinatumomab in cycle 1 and within 48 hours after the first 
dose of blinatumomab in cycle 2.  
For adverse events with missing start time, the adverse event during the MDMP is 
defined as an adverse event that started within 3 days after the first dose date of 
blinatumomab in cycle 1 and within 2 days after the first dose date of blinatumomab in 
cycle 2.  
Baseline  
The baseline value will be defined as the value measured on day 1 of the first cycle 
before start of the first infusion of blinatumomab. If a cycle 1 day 1 value is not available, 
the latest value before the day 1 of the start of blinatumomab infusion may be used.  
Cumulative Dose of Blinatumomab  
The cumulative dose in µg is defined as the following with summation over infusions: 
∑ Duration of infusion [days] for each dose received × dose received [µg/day]. 
Cumulative dose will be calculated within a cycle and across all cycles. 
Duration of Therapy 
For each infusion episode within a cycle, the duration of exposure will be calculated by 
subtracting the start date and time from the stop date and time. If either a start or stop 
time is missing, only the date portion will be used in calculating the duration of a specific 


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infusion. For each cycle, the duration will be the sum of the individual infusion durations 
within that cycle. For the entire study, the duration will be the sum of the durations 
across cycles. The duration will be rounded to the nearest day. 
End of Study 
The end of study date is defined as the date when the last subject across all sites is 
assessed or receives an intervention for evaluation in the study (i.e. last subject last 
visit). 
End of Study Visit  
The end of study visit will occur 30 days ( 3 days) after the last dose of blinatumomab 
is given.  The end of study visit will occur after cycle 3 or 4 for subjects who chose these 
optional cycles. End of study visit date for each subject will be recorded on the End of 
Study CRF page. 
Enrollment Date  
The date of enrollment is the date the subject has met all the eligibility criteria. This date 
will be documented in Subject Enrollment case report form (CRF) by investigator. 
EORTC Quality of Life Questionnaire (EORTC QLQ-C30) 
The EORTC QLQ-C30 is a 30-item questionnaire that assesses the health related 
quality of life of cancer subjects participating in clinical trials (see Table B.1). The 
EORTC QLQ-C30 forms a global health status (GHS)/quality of life (QoL) scale, 5 
functional domains (physical, role, emotional, cognitive and social), and 9 symptom 
domains (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, 
constipation, diarrhea, and financial difficulties). No question occurs in more than one 
scale (see Table B.1 & B.2). The score for each scale will be derived using the sum of 
the non-missing responses from all the associated questions and the corresponding 
range, assuming the number of items with non-missing scores meets the minimum 
requirement as specified in Table B.2, otherwise this scale score will be scored as 
missing. Range for a scale/item is defined as the maximum value – minimum value 
given in the questionnaire (see Table B.2). All of the scales/items measures will get 
mapped to a common range from 0 to 100. A high scale score represents a higher 
response level. Thus, a high score for the global health status/QoL scale represents a 
high QoL, a high score for a functional scale represents a high/healthy level of 
functioning; but a high score for a symptom scale/item represents a high level of 


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symptomatology/problems. The score will be calculated as follows (Aaronson et al 
1993): 
Raw score = RS = (Item1 + Item2 +…+ Itemn)/n (i.e., average) 
Score transformed to 0-100 scale: 
 
Global health status/QoL score = {(RS-1)/score range} × 100 
 
Functional scales score = {1 - (RS-1)/score range} × 100 
 
Symptom scales\items score = {(RS-1)/score range} × 100 
The score range is the difference between the maximum possible value of the RS and 
minimum possible value. 
If at least half of the items from the scale have been answered, then the missing items 
are imputed based on the average of those items that are answered. The single-item 
measures are not eligible for imputation. For scales missing more than half the items or 
for the single-item measures, the score will be set to missing (Aaronson et al 1993). 
Mandatory Device Monitoring Period (MDMP) 
For the purpose of this study, the mandatory device monitoring period (MDMP) is 
defined as the first three days of cycle 1 (72 hours) and the first 2 days of cycle 2 
(48 hours) of blinatumomab infusion. 
Therapeutic Intervention (TI)  
Therapeutic intervention is any measurable action taken by the subject or performed on 
the subject as a result of the onset of the clinical parameters described. Such actions 
may include:  
 
Advised subject to go to hospital/ER immediately 
 
Advised subject to call 911 immediately 
 
Advised to suspend blinatumomab 
 
Advised to take antipyretic (e.g. acetaminophen) 
 
Advised subject to take dexamethasone 
 
Advised to suspend blinatumomab and take antipyretic 
 
Advised to suspend blinatumomab and take dexamethasone 
 
Advised to take other medication 


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 
Other (if Other, describe the intervention) 
Time to Therapeutic Intervention (TTI) 
Time to therapeutic intervention is the time between the delivery of the device alert or 
unscheduled contact with HCP by subject/CG to report a change to the time of initiation 
of the therapeutic intervention.  
TTI will be calculated as duration (in minutes) from time of the device alert (alarm 
triggered) to the time of initiation of the therapeutic intervention (i.e. when HCP silenced 
the alarm and advised an intervention). 
If there is a case where the alarm is triggered, and the HCP advised an intervention, but 
event is not resolved and subject/CG presses the alarm again then that would be 
considered as a separate event (as alarm ID will be different) to calculate TTI. 
TTI will be calculated for all the valid alarm triggers which leads to an intervention. If the 
calculated TTI is considered incongruous (i.e. more than 15min.) then a query will be 
entered in DIIR log. 
All the scenarios defined below will be considered as invalid for calculation of TTI: 
 
If no intervention is required (e.g. technical issues) corresponding to an alarm. 
 
If intervention time is prior to the time of device alert (alarm triggered). 
Treatment-emergent Adverse Event  
Treatment-emergent Adverse Event is defined as adverse events starting on or after first 
dose of blinatumomab as determined by “Did event start before first dose of 
investigational product” equal to “No” or missing on the Events eCRF and up to the end 
of study visit.  
Any TEAE reported as serious will be considered as treatment-emergent serious 
adverse events (SAEs). Any AE or SAE reported post end of study visit by site will not 
be considered as treatment-emergent. 
6. 
Analysis Sets 
6.1 
Full Analysis Set (FAS) 
Full Analysis Set (FAS) will include all subjects enrolled into the study. 
6.2 
Safety Analysis Set (SAS) 
Safety analysis set will include all enrolled subjects who receive at least 1 dose of 
blinatumomab. The analysis of secondary safety and resource utilization endpoints will 
be conducted on the SAS. 


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6.3 
Primary Analysis Set (PAS) 
Primary analysis set will include all subjects in the SAS who were not replaced (see 
Section 8.3 for the criteria of subject replacement).  The analysis of primary and the key 
secondary endpoint will be conducted on the PAS. 
  
6.4 
Per Protocol Set 
Not applicable. 
6.5 
Patient-Reported Outcome (PRO) Analyses Set 
The Patient-Reported Outcomes (PRO) Analysis Set will include all subjects in the SAS 
with a non-missing baseline and at least 1 non-missing post-baseline result for EORTC 
QLQ-C30. Subjects will be included in the analysis of each EORTC QLQ-C30 score for 
which they have non-missing data. 
6.6 
Pharmacokinetic/Pharmacodynamic Analyses Set 
Not applicable. 
  
7. 
Planned Analyses 
7.1 
Interim Analysis and Early Stopping Guidelines 
Safety data will be reviewed on an ongoing basis.  A data review team (DRT), internal to 
Amgen but external to the study team, will assess safety after every fifth non-
replaceable subject has been dosed and given an opportunity to complete MDMP. 
Refer to Section 8.3 for details on replacement of subjects.  Based on their reviews, 
the DRT will make recommendations to Amgen regarding the continuation of the study.  
There will be no formal guidelines to stop for safety. The DRT will consist of 3 or more 
members including 2 or more clinicians with relevant specialties and 1 or more 
statisticians. The DRT will be supported by an independent statistician who is 
responsible for preparing reports that describe the ongoing clinical study data.  If a DRT 
meeting and subsequent meetings occur around the same time, the DRT chair can 
decide to combine into one meeting. This request should be made to the independent 
statistician approximately 1 week before the DRT meeting and be documented in the 
meeting minutes. Details regarding the responsibilities of the DRT and the independent 
statistician will be described in the DRT Charter. 
7.2 
Primary Analysis 
The primary analysis will occur when all subjects complete the end of study visit 30 days 
(3 days) after the last dose of up to 4 cycles of blinatumomab or withdraw from the 
study. 


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7.3 
Final Analysis 
The primary analysis will also be the final analysis.  
8. 
Data Screening and Acceptance 
8.1 
General Principles 
The objective of the data screening is to assess the quantity, quality, and statistical 
characteristics of the data relative to the requirements of the planned analyses. 
The data base will be subjected to edit checks outlined in the data validation 
specification plan by Clinical data management (CDM) department. Any outstanding 
data issue will be communicated to CDM for resolution before the database lock. 
8.2 
Data Handling and Electronic Transfer of Data 
The Amgen Global Study Operations-Data Management (GSO-DM) department will 
provide all data to be used in the planned analyses.  This study will use the RAVE 
database. 
Device data by Current Health will be provided to CDM in the agreed frequency. 
8.3 
Handling of Missing and Incomplete Data 
In general, missing data will be treated as missing, unless stated otherwise. Missing 
response for questions in EORTC QLQ-C30 PRO will be imputed as defined in section 5 
of this SAP.  
The handling of incomplete and partial dates for adverse events and concomitant 
medications are described in Appendix D. 
Subjects will be replaced for analysis if the outpatient monitoring during 
blinatumomab infusion is not established.   
8.4 
Detection of Bias 
If applicable, the methods to detect bias are described in the analyses of particular 
endpoints.  
8.5 
Outliers 
Any suspected outliers will be investigated by the study team and will be included in the 
database unless determined to be an error or there is supporting evidence or 
explanation to justify the exclusion.  Any outliers excluded from the analysis will be 
discussed in the Clinical Study Report (CSR), including the reasons for exclusion and 
the impact of their exclusion on the study. 


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8.6 
Distributional Characteristics 
The statistical assumptions for analysis methods will be assessed.  If the assumptions 
for the distributional characteristics are not met, these will be described, and further 
analyses may be carried out using data transformations or alternative analysis methods.  
The use of transformations or alternative analysis methods will be justified in the final 
study report. 
8.7 
Validation of Statistical Analyses 
Programs will be developed and maintained and output will be verified in accordance 
with current risk-based quality control procedures.   
Tables, figures, and listings will be produced with validated standard macro programs 
where standard macros can produce the specified outputs.   
The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.2 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Descriptive statistics for demographic and safety will be summarized as appropriate.  For 
categorical variables, the number and percentage of subjects in each category will be 
summarized.  Continuous variables will be summarized by n, mean, standard deviation, 
median, Q1 (25th percentile), Q3 (75th percentile), minimum, and maximum values.  
9.2 
Subject Accountability 
The number and percent of subjects who were screened, enrolled, received at least one 
dose of Blinatumomab, completed MDMP period, completed study, along with the 
reasons for discontinuing protocol-specified therapy and discontinuing study will be 
summarized. The number and percent of subjects infused will be tabulated by study site. 
Key study dates for the first subject infused, last subject infused, and data cut-off date 
for analysis will be presented. 
9.3 
Important Protocol Deviations 
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s initial visit and updated during the IPD reviews throughout the study 
prior to database lock. These definitions of IPD categories, subcategory codes, and 
descriptions will be used during the course of the study.  Eligibility deviations are defined 
in the protocol. 


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9.4 
Demographic and Baseline Disease Characteristics 
Demographic (i.e. age, age group [18 – 64, 65 – 74, 75 - 84, >=85], sex, race, and 
ethnicity) and baseline disease characteristics will be summarized using descriptive 
statistics for the Safety Analysis Set (SAS). If multiple races have been reported for a 
subject, the subject will be categorized as multiple race (as well as by combination of 
races). 
The baseline characteristics to be summarized include:  
 
B-ALL Subtype  
 
MRD status following induction therapy (negative, positive) 
 
ECOG performance status (see Appendix C) 
 
Physical measurement (Height, Weight, BSA) 
 
Number of prior lines of therapy 
 
Prior anti-cancer treatment regimen 
9.5 
Efficacy Analyses 
Not Applicable. 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
Not Applicable. 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
Not Applicable. 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
Not Applicable. 
 


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9.6 
Safety Analyses 
9.6.1 
Analyses of Primary and Key Secondary Safety Endpoint(s) 
 


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Endpoint 
Statistical Analysis Methods 
Primary 
Subject incidence rate of primary endpoint (grade 3 or 4 CRS, NT or 
any adverse event resulting in hospitalization during MDMP) will be 
summarized and accompanied by 2-sided 95% exact binomial 
confidence intervals (Clopper and Pearson, 1934). This endpoint will 
be analyzed using PAS and repeated using interim analysis set. 
Key 
Secondary 
TTI as defined in section 5 of SAP will be summarized as continuous 
variable with number of non-missing and valid TTI with mean, median, 
standard deviation, minimum and maximum.   
Number and percent of subjects who had received at least one 
therapeutic intervention (as defined in section 5 of SAP) will be 
summarized in total and by types of intervention. Total number of 
therapeutic interventions and type of therapeutic intervention will be 
tabulated. 
Number and percent of subjects with at least one alarm triggered will 
be summarized in total and by reasons of alarm trigger. Total number 
of alarms triggered and reasons for each alarm trigger (as specified 
below) will be tabulated. 
 
Technical 
 
Patient message 
 
Physiological – Axillary temperature 
 
Physiological – Systolic blood pressure 
 
Physiological – Spo2  
 
Physiological – Respiratory rate 
 
Physiological – Pulse rate 
Descriptive statistics for number of alarms triggered and therapeutic 
interventions received per person will also be presented. 
This endpoint will be analyzed using PAS and repeated using interim 
analysis set. 
 


Product:  Blinatumomab 
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9.6.2 
Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) version 25.0 or later will be 
used to code all events to a system organ class (SOC) and a preferred term (PT). 
Severity will be coded by using CTCAE version 5.0 or later. 
Subject incidence of all, serious, grade 3 and above, leading to withdrawal of 
investigational product, leading to interruption of investigational product, fatal, treatment-
related, treatment-related serious, and treatment-related grade 3 and above TEAEs will 
be tabulated by SOC and PT in descending order of frequency. In addition, treatment-
emergent adverse events will be summarized by SOC, PT, and grade; and by PT only in 
descending order of frequency.  
Treatment-emergent events of interest (EOIs) will be summarized by EOI category and 
preferred term. In addition, for each EOI category, the subject incidence of all, serious, 
grade 3 and above, grade 4 and above, fatal, leading to withdrawal of IP, leading to 
interruption of IP will be summarized. Time to onset, duration, number of resolved events 
for select EOIs (infection, neurologic events and CRS) will also be summarized. 
To support estimation of healthcare resource utilization associated with 
treatment-related AEs, the summary of subject incidence treatment related TEAEs 
will be provided for treatment related TEAEs that resulted in hospitalizations, 
treatment related TEAEs that resulted in surgeries, treatment related TEAEs that 
resulted in the use of concomitant medications, treatment related TEAEs that 
resulted in the use of device/procedure intervention (see SAP section 10 ‘Changes 
from Protocol-specified Analyses’ for details on updates to endpoints of 
secondary objective for estimation of healthcare resource utilization).  
The above analyses will be performed using subjects in the SAS.  
 


Product:  Blinatumomab 
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9.6.3 
Laboratory Test Results 
List of tests to be performed by the local laboratory for this study is as defined below. 
 
Summary statistics over scheduled visits for actual values, changes from baseline of 
selected laboratory parameters listed below will be presented. Shift tables between the 
post-baseline and baseline values for selected laboratory parameters will be also 
provided for subjects in the Safety Analysis Set. 
Summary statistics tables:  lymphocytes, neutrophils, WBC, platelets, hemoglobin, 
albumin, AST, ALT, bilirubin, corrected calcium, potassium, lipase, amylase, ALP, IgG, 
creatinine  
Shift tables: lymphocytes, hemoglobin, corrected calcium, potassium, neutrophils, WBC, 
platelets, albumin, AST, ALT, bilirubin, lipase, amylase, creatinine 
The subject incidence of potential cases of Hy’s Law will be summarized. See Appendix 
A as a guide for table shell. 


Product:  Blinatumomab 
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9.6.4 
Vital Signs 
Vital sign data are captured using both CWHMS during MDMP period and on eCRF 
during in-clinic visits (i.e. at screening, C2D1 and C2D29). Subject vital signs captured 
on eCRF will be summarized over time. A summary of the subject incidence with 
abnormal changes in vital signs will be presented for subjects in the SAS. Vital signs will 
include BP, Respiratory rate, Pulse rate and axillary temperature. 
Abnormal changes in vital signs will be defined as follows: 
 
Systolic BP <=100 mmHg or >=20% reduction from baseline 
 
Temperature >= 38.0o C (100.4o F) 
 
Respiratory rate <=10 or >=25 
 
Pulse rate <=60 or >=150 
9.6.5 
Physical Measurements 
Physical measurements (height, weight and BSA) will be summarized at baseline for all 
the subjects in SAS.  
9.6.6 
Electrocardiogram 
The electrocardiogram (ECG) measurements from this clinical study were performed as 
per standard of care for routine safety monitoring, rather than for purposes of 
assessment of potential QT interval corrected (QTc) effect.  Because these evaluations 
may not necessarily be performed under the rigorous conditions expected to lead to 
meaningful evaluation of QTc data; neither summaries nor statistical analyses will be 
provided, and these data would not be expected to be useful for meta-analysis with data 
from other trials. 
9.6.7 
Antibody Formation 
Not applicable 
9.6.8 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to blinatumomab for 
subjects in the SAS.  The duration of therapy and the cumulative dose will be 
summarized. 
The number and percent of subjects with dose modifications (eg, dose changes, dose 
interruptions) and reason for modification will be summarized.  Analysis will be repeated 
for exposure during MDMP. 
9.6.9 
Exposure to Non-investigational Product  
Not applicable. 


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9.6.10 
Exposure to Other Protocol-required Therapy 
Not Applicable. 
9.6.11 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving concomitant medications from study 
day 1 through EOS (30 days  3 days post last dose of Blinatumomab) will be 
summarized by preferred term as coded by the World Health Organization Drug 
(WHODRUG) dictionary in the SAS. 
9.7 
Other Analyses 
 Not Applicable   
9.7.1 
Analyses of Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Endpoints 
Not applicable. 
9.7.2 
Analyses of Clinical Outcome Assessments 
The Electronic Patient Reported Outcome (ePRO) will be assessed using EORTC QLQ-
C30 at screening and Cycle 2 Day 1. 
Descriptive statistics for the overall GHS/QoL domain, 5 functional domains, and 9 
symptom domains will be presented at baseline and Cycle 2 Day 1. Descriptive statistics 
for change from baseline will also be reported at Cycle 2 Day 1.  
Change from baseline at Cycle 2 Day 1 for GHS/QoL score will be categorized as 
follows (Kode and Chenna, 2019); 
Improved 
: 
Change >=10 
Stable  
: 
-10 < Change <10 
Deteriorated : 
. < Change <=-10 
Similar categorization with minimal important difference (MID) of 5 may also be reported. 
Counts and percentage of subjects within each category will be also be presented.  
9.7.3 
Analyses of Health Economic Endpoints 
Subject incidence rate of following endpoints: TEAEs that resulted in hospitalizations, 
TEAEs that resulted in surgeries, TEAEs that resulted in use of concomitant 
medications, TEAEs that resulted in use of device/procedure intervention will be 
summarized and accompanied by 2-sided 95% exact binomial confidence intervals 
(Clopper and Pearson, 1934). 


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9.7.4 
Analyses of Biomarker Endpoints 
Not applicable. 
10. 
Changes From Protocol-specified Analyses 
For estimation of secondary objective on healthcare resource utilization, the 
endpoints are updated to treatment-related TEAEs instead of the TEAEs in 
consistency with the objective. 
SAP Section 
Update 
Section 2.1 
a) The wording of below primary and secondary endpoints 
from protocol are modified in the SAP to clarify what 
endpoints are exactly evaluated at the subject level: 
 
Primary endpoint: Incidence of grade 3 and/or 4 CRS, 
NT or any adverse event (AE) requiring hospitalization 
(SAE) during MDMP 
 
Secondary endpoint: Overall incidence and severity of 
treatment-emergent adverse events (TEAE) and adverse 
events of interest in particular CRS and NT 
b) For estimation of secondary objective on healthcare 
resource utilization, the endpoints are updated to include 
‘treatment-related TEAEs’ instead of the ‘TEAEs’ in 
consistency with the objective. 
Section 8.3 
Subject replacement rule for analysis is updated to exclude the 
below criterion from protocol. Since the replacement rule is 
defined for analysis, an additional text on replacement status 
applicability for internal data analysis also excluded.  
Text from protocol section 4.2.1 excluded from SAP section 
8.3: 
 
Subjects are removed from treatment with IP due to disease 
progression. 
Replacement status is only applicable for internal data 
analysis. 
 


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11. 
Literature Citations / References 
Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organisation for Research 
and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international 
clinical trials in oncology. Journal of the National Cancer Institute. 1993; 85:365-376. 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika. 1934;26(4):404-413. 
Lee DW, Santomasso BD, Locke FL, et al.  ASTCT consensus grading for cytokine 
release syndrome and neurologic toxicity associated with immune effector cells.  Biol 
Blood Marrow Transplant.  2018;25(4):625-638. 
Kode V, Chenna S. ePRO: A View from Statistical Programmer, SESUG. 174-2019. 
12. 
Prioritization of Analyses 
Not applicable 
13. 
Data Not Covered by This Plan 
Not applicable. 


Product:  Blinatumomab 
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14. 
Appendices 
Appendix A Reference Values/Toxicity Graders 
Table 14-A.  Summary of Potential Hy's Law Cases 
(Safety Analysis Set) 
 
 
  
Blinatumomab 
(N  xxx) 
 
Pre-infusion - n/N1() 
ALT or AST 3xULN 
  
xx/xxx (xx.x) 
TBL 2xULN 
  
xx/xxx (xx.x) 
ALP 2xULN 
  
xx/xxx (xx.x) 
(ALT or AST) 3xULN & TBL 2xULN & ALP 2XULN any day 
  
xx/xxx (xx.x) 
(ALT or AST) 3xULN & TBL 2xULN & ALP 2XULN within one day 
  
xx/xxx (xx.x) 
 
On-study - n/N1() 
ALT or AST 3xULN 
  
xx/xxx (xx.x) 
TBL 2xULN 
  
xx/xxx (xx.x) 
ALP 2xULN 
  
xx/xxx (xx.x) 
(ALT or AST) 3xULN & TBL 2xULN & ALP 2XULN any day 
  
xx/xxx (xx.x) 
(ALT or AST) 3xULN & TBL 2xULN & ALP 2XULN within one day 
  
xx/xxx (xx.x) 
              Page 1 of 1 
nnumber of subjects who met criteria 
N1 number of subjects with available data 
ALPAlkaline Phosphatase; ALTAlanine Aminotransferase; ASTAspartate Aminotransferase; TBLTotal 
Bilirubin. 
 
 


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Appendix B Clinical Outcome Assessment Forms/Instruments 
Table 14-B-1. EORTC Quality of Life Questionnaire 
 
 


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Table 14-B-2. Correspondence of the EORTC QLQ-C30 questions to the scale 
Scale/Item Name 
(PARAM) 
Abbreviation 
 
Number of 
Items 
Item Range* 
Item 
numbers 
Minimum  of 
non-missing 
items needed 
Global health status/QoL 
 
Global health 
status/QoL 
QL2 
2 
6 
29, 30 
1 
Functional scales 
 
Physical 
functioning 
PF2 
5 
3 
1 to 5 
3 
Role functioning 
RF2 
2 
3 
6, 7 
1 
Emotional 
functioning 
EF 
4 
3 
21 to 24 
2 
Cognitive 
functioning 
CF 
2 
3 
20, 25 
1 
Social functioning 
SF 
2 
3 
26, 27 
1 
Symptom scales 
 
Fatigue 
FA 
3 
3 
10, 12, 18 
2 
Nausea and 
vomiting 
NV 
2 
3 
14, 15 
1 
Pain 
PA 
2 
3 
9, 19 
1 
Symptom Single items 
 
Dyspnoea 
DY 
1 
3 
8 
N/A 
Insomnia 
SL 
1 
3 
11 
N/A 
Appetite loss 
AP 
1 
3 
13 
N/A 
Constipation 
CO 
1 
3 
16 
N/A 
Diarrhoea 
DI 
1 
3 
17 
N/A 
Financial difficulties 
FI 
1 
3 
28 
N/A 
*Item range is the difference between the possible maximum and the minimum response to individual items 
 


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Appendix C Eastern Cooperative Oncology Group Performance Status (ECOG PS) 
Scale 
 


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Appendix D Handling of Dates, Incomplete Dates and Missing Dates for Adverse Events and Concomitant Medications  
The following data will be imputed using the following algorithm:  
 
Adverse Events  
 
Concomitant Medications 
Table 14-D-1.  Imputation Rules for Partial or Missing Start Dates 
 Start Date 
Stop Date 
Complete: 
yyyymmdd 
Partial:  
yyyymm 
Partial:  
yyyy 
missing 
 1st 
dose 
 1st 
dose 
 1st 
dose 
yyyymm 
 1st 
dose 
yyyymm 
 1st 
dose 
yyyy 
 1st 
dose 
yyyy 
Partial: 
yyyymm 
 1st 
dose 
yyyymm 
2 
1 
2 
1 
n/a 
1 
1 
 1st dose 
yyyymm 
2 
2 
2 
2 
2 
Partial: 
yyyy 
 1st dose 
yyyy 
3 
1 
3 
1 
n/a 
1 
1 
 1st dose 
yyyy 
3 
3 
3 
3 
3 
Missing 
4 
1 
4 
1 
4 
1 
1 
1  Impute the date of first dose 
2  Impute the first of the month 
3  Impute January 1 of the year 
4  Impute January 1 of the stop year 
Note: If the start date imputation leads to a start date that is after the stop date, then do not impute the start date. 


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Imputation rules for partial or missing stop dates: 
Initial imputation 
 
For partial stop date mmyyyy, impute the last of the month. 
 
For partial stop date yyyy, impute December 31 of the year. 
 
For completely missing stop date, do not impute. 
 
If the stop date imputation leads to a stop date that is after the death date, then impute the stop date as the death date. 
 
If the stop date imputation leads to a stop date that is before the start date, then there is a data error and do not impute the stop 
date. (ie. set the stop date as missing). 
Imputation rules for partial or missing death dates: 
 
If death year and month are available but day is missing: 
 
If mmyyyy for last contact date  mmyyyy for death date, set death date to the day after the last contact date. 
 
If mmyyyy for last contact date  mmyyyy for death date, set death date to the first day of the death month. 
 
If mmyyyy for last contact date  mmyyyy for death date, data error and do not impute. 
 
If both month and day are missing for death date or a death date is totally missing, do not impute. 
Note that the last contact date refers to the last contact (i.e. a visit or an assessment) with patient instead of family members. Last 
contact date would be derived from the latest patient visit/assessment date. 
 


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Appendix E Vital Signs and Clinical Monitoring 
Table 1. Vital Signs and Clinical Monitoring 
AMG 103 20190014 VS and Clinical Monitoring 
 
BP  blood pressure; HCP  healthcare professional; IP  Investigational product