Conditions: High-risk Diffuse Large B-cell Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 10
Healthy volunteers: no

Brief summary:
The study will estimate the MRD-negative response rate after treatment with blinatumomab in subjects with high-risk DLBCL who are MRD-positive following aHSCT. The clinical hypothesis is that the MRD-negative response rate will be greater than 10%. Achieving an MRD-negative response rate of 30% would be of scientific and clinical interest.

Detailed description:
This is a phase 2, multicenter, open-label, single arm estimation study in adult subjects with high-risk DLBCL in complete remission. The study will consist of up to a 28-day screening period, a run-in period of up to 24 months, a 12-week treatment period (8 weeks of blinatumomab treatment followed by a 4-week treatment free period), a 30-day safety follow-up visit after the last dose of blinatumomab, and a long-term follow-up period that begins after the safety follow-up visit is completed until 1 year from the first dose of blinatumomab. The study will enroll approximately 90 subjects in the screening period with biopsy proven, high-risk DLBCL that are positron emission tomography-computer tomography (PET-CT) negative 90 days (± 30 days) post aHSCT. During the run-in period subjects will be followed by clinic visits at regular interval for up to 24 months for monitoring of MRD status in plasma by a next generation sequencing (NGS)-based assay. It is estimated 30 subjects will be either MRD-positive at screening or become MRD-positive during the 24-month run-in period. The number of subjects enrolled may be altered in order to ensure that approximately 30 subjects are assigned to treatment with blinatumomab. Enrollment may be stopped, once approximately 30 subjects have been assigned to treatment with blinatumomab.

Arms:
arm 1: After a run-in period of up to 24 months to evaluate MRD status and assess eligibility for treatment assignment, participants received blinatumomab intravenous (IV) infusion at an initial dose of 9 μg/day for the first 7 days of treatment, escalated (dose-step) to 28 μg/day starting on Day 8 (Week 2), followed by a dose-step to 112 μg/day starting on Day 15 (Week 3) and continuing until completion of therapy (Day 57 of Cycle 1).

Cycle 1 of blinatumomab treatment is 12 weeks (84 days) in duration and includes 8 weeks (56 days) of blinatumomab IV infusion followed by a 4-week (28-day) treatment-free interval.

Interventions: intervention 1: Blinatumomab
Intervention descriptions: intervention 1: Blinatumomab is administered as a continuous IV infusion.

Protocol document:
Prot_000.pdf: 
Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 1 of 97 
CONFIDENTIAL 
 
 
Title:  A Phase 2 Open-Label Study to Determine the Effect of Blinatumomab on 
Minimal Residual Disease in Subjects With High-risk Diffuse Large B-cell 
Lymphoma Post-autologous Hematopoietic Stem-cell Transplantation 
Amgen Protocol Number (Blinatumomab) 20150291 
EudraCT Number: 2016-003255-30 
NCT Number: 03298412 
Clinical Study Sponsor: 
Amgen Inc 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Phone: +1-805-447-1000 
Key Sponsor Contact(s): 
 
Senior Medical Scientist, Clinical Research 
AMGEN Research (Munich) GmbH 
Staffelseestr. 2, 81477 München, Germany 
Telephone: 
 
Email: 
 
 
 
Global Clinical Trial Manager 
AMGEN Research (Munich) GmbH 
Staffelseestr. 2, 81477 München, Germany 
Telephone: 
 
Email: 
 
Date: 
26 January 2017 
Amendment 1: 
23 May 2017 
Amendment 2: 
24 August 2017 
Amendment 3 
18 July 2018 
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, Canadian sites, 
1-866-50-AMGEN; Amgen’s general number in the US (1-805-447-1000).  


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 2 of 97 
CONFIDENTIAL 
 
 
Investigator’s Agreement 
I have read the attached protocol entitled A Phase 2 Open-Label Study to Determine the 
Effect of Blinatumomab on Minimal Residual Disease in Subjects With High-risk Diffuse 
Large B-cell Lymphoma Post-autologous Hematopoietic Stem-cell Transplantation, 
dated 18 July 2018, and agree to abide by all provisions set forth therein.   
I agree to comply with the International Council on 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) 
• 
my sub investigators (including, if applicable, their spouses [or legal partners] and 
dependent children) at the start of the study and for up to one 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) 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 3 of 97 
CONFIDENTIAL 
 
 
Protocol Synopsis 
Title:  A Phase 2 Open-Label Study to Determine the Effect of Blinatumomab on Minimal 
Residual Disease in Subjects With High-risk Diffuse Large B-Cell Lymphoma Post-autologous 
Hematopoietic Stem-cell Transplantation 
Study Phase:  Phase 2 
Indication:  High-risk Diffuse Large B-cell Lymphoma (DLBCL) 
Primary Objective:  To determine minimal residual disease (MRD) negative rate following 
blinatumomab treatment in high-risk DLBCL subjects who are MRD-positive post-autologous 
hematopoietic stem-cell transplantation (aHSCT). 
Secondary Objective(s): 
• 
To describe the efficacy of blinatumomab in relation to progression-free survival (PFS), 
duration of MRD-negative status and overall survival (OS). 
• 
To evaluate the safety and tolerability of blinatumomab  
Hypotheses: The study will estimate the MRD-negative response rate after treatment with 
blinatumomab in subjects with high-risk DLBCL who are MRD-positive following aHSCT.  The 
clinical hypothesis is that the MRD-negative response rate will be > 10%.  Achieving an 
MRD-negative response rate of 30% would be of scientific and clinical interest.  
Primary Endpoint:  MRD-negative rate at the end of cycle 1 of blinatumomab 
Secondary Endpoint(s):   
• 
PFS 
• 
Duration of MRD-negative status 
• 
OS  
• 
Incidence, grade and severity of treatment emergent adverse events  
Study Design:   
This is a phase 2, multicenter, open-label, single arm estimation study in adult subjects with 
high-risk DLBCL in complete remission.  The study will consist of up to a 28-day screening 
period, a run-in period of up to 24 months, a 12-week treatment period (8 weeks of blinatumomab 
treatment followed by a 4-week treatment free period), a 30-day safety follow-up visit after the last 
dose of blinatumomab, and a long-term follow-up period that begins after the safety follow-up visit 
is completed until 1 year from the first dose of blinatumomab.  The study will enroll approximately 
90 subjects in the screening period with biopsy proven, high-risk DLBCL that are positron 
emission tomography-computer tomography (PET-CT) negative 90 days (± 30 days) post 
aHSCT.  During the run-in period subjects will be followed by clinic visits at regular interval for up 
to 24 months for monitoring of MRD status in plasma by a next generation sequencing 
(NGS)-based assay.  It is estimated 30 subjects will be either MRD-positive at screening or 
become MRD-positive during the 24-month run-in period.  The number of subjects enrolled may 
be altered in order to ensure that approximately 30 subjects are assigned to treatment with 
blinatumomab.  Enrollment may be stopped, once approximately 30 subjects have been assigned 
to treatment with blinatumomab. 
Sample Size:  Approximately 90 subjects will be enrolled in the study and approximately 
30 subjects will be assigned to treatment with blinatumomab.  
Summary of Subject Eligibility Criteria:  The study will enroll subjects age ≥ 18 years with 
refractory or relapsed biopsy-proven high-risk DLBCL (excluding DLBCL that represents 
transformation of indolent Non-Hodgkin’s Lymphoma (NHL).  Subjects must have received 
aHSCT, be PET-CT negative at 90 days post-aHSCT, have an Eastern Cooperative Oncology 
Group (ECOG) performance status ≤ 2, and have adequate organ function.  In addition, subjects 
must have available relapsed and/or diagnostic formalin-fixed paraffin-embedded (FFPE) tumor 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 4 of 97 
CONFIDENTIAL 
 
 
block or slide samples with successful identification of malignant clone sequences by the MRD 
assay at a central laboratory.  Finally, subjects must have an MRD plasma sample collected 
≤ 3 weeks after the post aHSCT PET-CT scan.  During the run-in period, enrolled subjects will be 
monitored for MRD status; MRD-positive subjects who are PET-CT negative and meet other 
part 2 eligibility criteria will be assigned to treatment with blinatumomab. 
For a full list of eligibility criteria, please refer to Section 4.1 through Section 4.2.2. 
Investigational Product 
Amgen Investigational Product Dosage and Administration:   
Blinatumomab will be supplied as 4 mL single-use sterile glass injection vials.  Blinatumomab is 
administered as a continuous intravenous (IV) infusion. 
Cycle 1 of blinatumomab treatment is 12 weeks (84 days) in duration and includes 8 weeks 
(56 days) of blinatumomab IV infusion followed by a 4-week (28-day) treatment-free interval.  The 
initial dose of blinatumomab will be 9 μg/day for the first 7 days of treatment.  Blinatumomab dose 
will then be escalated (dose-step) to 28 μg/day starting on day 8 (week 2) followed by a 
dose-step to 112 μg/day starting on day 15 (week 3) and continuing until completion of therapy 
(day 57 of cycle 1).  
Prior to initiation of blinatumomab and at each dose-step escalation, dexamethasone will be 
administered as described in Table 2. 
Procedures:  Written informed consent must be obtained from all subjects before any 
study-specific screening procedures are performed.  The following procedures will occur per the 
Schedule of Assessments (Table 4): medical history and prior therapies, demographics, physical 
examination, neurological examination, vital signs, body weight, height, ECOG performance 
status, electrocardiogram (ECG), recording of concomitant medications, review of adverse 
events, disease-related events, and serious adverse events.  Blood will be collected for local 
laboratory testing including: chemistry, hematology, coagulation, lactate dehydrogenase (LDH), 
creatinine clearance, hepatitis serology, human immunodeficiency virus testing, and C-reactive 
protein.  In females of childbearing potential, a urine or serum pregnancy test will be performed 
locally.  Central laboratory tests include: blood for MRD testing in plasma by NGS assay and 
anti-blinatumomab antibodies.  A relapsed and/or diagnostic FFPE tumor block/slides will be 
submitted for central laboratory MRD testing.  Finally, clinical tumor assessments and PET-CT 
imaging will be performed at various timepoints.  
For a full list of study procedures, including the timing of each procedure, please refer to 
Section 7 and the Schedule of Assessments Table 4.   
Statistical Considerations: 
General considerations 
The primary analysis set will include the first 30 subjects who received at least 1 dose of 
blinatumomab.  The primary analysis set will be used for the primary analysis.  The primary 
analysis will be triggered when the first 30 enrolled subjects have had the opportunity to complete 
cycle 1 of blinatumomab treatment. 
The full analysis set will include all subjects who received at least 1 dose of blinatumomab.  
Subjects who were treated beyond the required sample size of 30 subjects will be included in this 
analysis set.  The full analysis set will be used for the final analysis.  The final analysis will be 
conducted when the subjects in the Primary Analysis Set have had an opportunity to complete 
the long-term follow-up visit 1 year from the first dose of blinatumomab. 
Sample Size 
This is a single-arm estimation study.  It is assumed that an MRD-negative rate of 10% could be 
observed by chance in this study.  Therefore, if the assumed rate of MRD negativity is at least 
30%, then the sample size for this study (N = 30) is sufficient to demonstrate that, with 
95% confidence, the rate of achieving MRD negativity is greater than 10%.  This would also be 
sufficient to demonstrate evidence of clinical activity.  For more detail see Section 10.2. 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
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CONFIDENTIAL 
 
 
Primary endpoint 
MRD-negative rate is calculated as the number of subjects with MRD-negative status after 
treatment with blinatumomab divided by the total number of subjects in the respective analysis 
set.  Exact binomial 95% confidence intervals (CI) will be used to analyze MRD-negative rate. 
For a full description of statistical analysis methods, please refer to Section 10. 
Sponsor:  Amgen Inc. 
Data Element Standards 
Version(s)/Date(s):  
Version 5: 20 March 2015   


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
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CONFIDENTIAL 
 
 
Study Design and Treatment Schema 
 
 
Day 1 
Cycle 1 
Blinatumomab 
Cycle 1: 8 weeks of IV 
infusion (9 µg/d x 7d; 
28 µg/d x 7d; 
112 µg/d x 42d) followed 
by 4 week treatment-free 
interval  
Screening (Up to 28 days) 
Enrollment (n = 90) 
Safety Follow-up 
Run-in Period
a 
Treatment Period  
Long-term Follow-upd 
MRD Monitoring 
up to 24 months  
Treatment Assignment n = 30 
Run-in 2: 
Treatment 
Assignment  
(-7 days) 
Run-in 1 
(MRD 
Monitoring) 
MRD-positive/ 
PET-CT negative 
(at any time after 
enrollment)
b 
Day 71 
30 d after the 
last dose of IP 
EOS 
Footnotes defined on the next page 
MRD Monitoringc 


Product:  Blinatumomab 
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CONFIDENTIAL 
 
 
EOS = end of study; IP = investigational product; MRD = minimal residual disease; PET-CT = positron emission tomography/computed tomography 
a Run-in period is up to 24 months in duration.  During the run-in period, enrolled subjects that are MRD-negative/PET-CT negative will be followed at 3, 5, 7 and 
9 months and thereafter every 3 months (± 1 week) up to 24 months for monitoring of MRD status by next generation sequencing.  
b At any time after enrollment and during the run-in period subjects who turn MRD-positive/ PET-CT negative and that meet all other part 2 eligibility criteria will be 
assigned to treatment with blinatumomab.  Subjects that do not display MRD positivity at the end of the 24-month run-in period will end the study. 
c MRD status will be assessed at cycle 1 day 1 prior to blinatumomab infusion, on cycle 1 days 15 and 43, the end of the blinatumomab infusion (day 57), and 2 weeks 
after the end of the blinatumomab infusion (day 71 + 3 days). 
d Long-term follow-up period will be 1 year from the first dose of blinatumomab.  Subjects will be followed via clinic visit every 3 months (± 2 weeks) until relapse and 
from this point onwards via telephone contact for overall survival. 
 
 
 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 8 of 97 
CONFIDENTIAL 
 
 
Study Glossary 
Abbreviation or Term 
Definition/Explanation 
ALL 
acute lymphoblastic leukemia 
ALT 
alanine aminotransferase  
ALP 
alkaline phosphatase 
ANC 
absolute neutrophil count 
AST  
aspartate aminotransferase   
aHSCT 
autologous hematopoietic stem-cell transplantation 
alloHSCT 
allogeneic hematopoietic stem cell transplantation 
CI 
confidence interval 
CNS 
central nervous system 
CORAL 
Collaborative Trial in Relapsed Aggressive Lymphoma 
CR 
complete response 
CRF  
case report form 
CRS 
cytokine release syndrome 
CSF 
cerebral spinal fluid 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CT-DNA 
cell-free circulating tumor DNA  
DILI 
drug-induced liver injury 
DLBCL 
Diffuse Large B-Cell Lymphoma 
DLT 
dose limiting toxicity 
DRT 
data review team 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
electronic data capture 
End of Follow-up 
defined as when the last subject completes the last protocol-specified 
assessment in the study   
End of Study for 
Individual Subject 
defined as the last day that protocol-specified procedures are 
conducted for an individual subject 
End of Study (primary 
completion) 
The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection 
of data for the primary endpoint, for the purposes of conducting the 
primary analysis, whether the study concluded as planned in the 
protocol or was terminated early 
End of Study (end of 
trial) 
The date when the last subject is assessed or receives an intervention 
for evaluation in the study (ie, last subject last visit), following any 
additional parts in the study (eg, long-term follow-up), as applicable.  
End of Treatment 
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 9 of 97 
CONFIDENTIAL 
 
 
Abbreviation or Term 
Definition/Explanation 
EOI 
Events of interest 
ESMO 
European Society for Medical Oncology 
EU 
European Union 
FFPE 
formalin-fixed paraffin-embedded 
FISH 
Fluorescent in-situ hybridization 
GCP 
Good Clinical Practice 
Heart rate 
number of cardiac cycles per unit of time 
HRT 
hormonal replacement therapy 
ICH 
International Council on Harmonisation 
ICF 
Informed Consent Form 
Ig 
Immunoglobulin 
INR 
international normalized ratio 
IPIM 
Investigational Product Instruction Manual 
IPI/aaIPI 
international prognostic index/age-adjusted international prognostic 
index 
IRB/IEC 
institutional review board/independent ethics committee 
IV 
intravenous 
KM 
Kaplan-Meier 
LDH 
lactate dehydrogenase 
MRD 
minimal residual disease 
MRI 
magnetic resonance imaging 
NCCN 
National Comprehensive Cancer Network 
NCIC CTG 
National Cancer Institute of Canada Clinical Trial Group 
NGS 
next generation sequencing 
NHL 
Non-Hodgkin’s Lymphoma 
OS 
overall survival 
PET 
positron emission tomography 
PFS 
progression-free survival 
PR Interval 
PR interval is measured from the beginning of the P wave to the 
beginning of the QRS complex in the heart's electrical cycle as 
measured by ECG 
QRS interval 
QRS interval is the interval between the Q wave and the S wave in the 
heart's electrical cycle as measured by ECG; represents the time it 
takes for the depolarization of the ventricles 
QT interval 
QT interval is a measure of the time between the start of the Q wave 
and the end of the T wave in the heart's electrical cycle as measured 
by ECG. 
QTc interval 
QT interval corrected for heart rate using accepted methodology  


Product:  Blinatumomab 
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Abbreviation or Term 
Definition/Explanation 
R-CHOP 
Rituximab, cyclophosphamide, doxorubicin, vincristine, and 
prednisone 
R-DHAP 
rituximab, dexamethasone, cytarabine, cisplatin 
R-GDP 
rituximab, gemcitabine, dexamethasone, cisplatin 
R-ICE 
rituximab, ifosfamide, carboplatin and etoposide 
Source Data 
information from an original record or certified copy of the original 
record containing patient information for use in clinical research.  The 
information may include, but is not limited to, clinical findings, 
observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial.  Source data are contained in 
source documents (original records or certified copies).  (ICH 
Guideline [E6]).  Examples of source data include subject 
identification, randomization identification, and stratification value. 
Study day 1 
defined as the first day that protocol-specified investigational products 
are administered to the subject 
TBL 
total bilirubin 
ULN 
upper limit of normal 


Product:  Blinatumomab 
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TABLE OF CONTENTS 
Protocol Synopsis ............................................................................................................ 3 
Study Design and Treatment Schema ............................................................................. 6 
Study Glossary ................................................................................................................ 8 
1. 
OBJECTIVES ....................................................................................................... 16 
1.1 
Primary ..................................................................................................... 16 
1.2 
Secondary ................................................................................................. 16 
1.3 
Exploratory ................................................................................................ 16 
2. 
BACKGROUND AND RATIONALE ...................................................................... 16 
2.1 
Disease ..................................................................................................... 16 
2.2 
Minimal Residual Disease ......................................................................... 18 
2.3 
Amgen Investigational Product Background .............................................. 20 
2.4 
Rationale ................................................................................................... 21 
2.5 
Clinical Hypotheses ................................................................................... 22 
2.6 
Benefit/Risk Assessment ........................................................................... 22 
3. 
EXPERIMENTAL PLAN ........................................................................................ 24 
3.1 
Study Design ............................................................................................. 24 
3.2 
Number of Sites ........................................................................................ 25 
3.3 
Number of Subjects ................................................................................... 25 
3.4 
Replacement of Subjects .......................................................................... 26 
3.5 
Estimated Study Duration .......................................................................... 26 
3.5.1 
Study Duration for Subjects ....................................................... 26 
3.5.2 
End of Study .............................................................................. 26 
4. 
SUBJECT ELIGIBILITY ........................................................................................ 26 
4.1 
Inclusion and Exclusion Criteria – Part 1 ................................................... 27 
4.1.1 
Inclusion Criteria – Part 1 .......................................................... 27 
4.1.2 
Exclusion Criteria – Part 1 ......................................................... 28 
4.2 
Inclusion and Exclusion Criteria – Part 2 ................................................... 29 
4.2.1 
Inclusion Criteria – Part 2 .......................................................... 29 
4.2.2 
Exclusion Criteria – Part 2 ......................................................... 30 
5. 
SUBJECT ENROLLMENT .................................................................................... 30 
5.1 
Treatment Assignment .............................................................................. 31 
6. 
TREATMENT PROCEDURES .............................................................................. 31 
6.1 
Classification of Product(s), Medical Device(s) and/or 
Combination Product(s) ............................................................................. 31 
6.2 
Investigational Product .............................................................................. 31 
6.2.1 
Amgen Investigational Product Blinatumomab ........................... 31 
6.2.1.1 
Dosage, Administration, and Schedule .................... 32 


Product:  Blinatumomab 
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6.2.1.2 
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation ........................................................ 34 
6.2.1.3 
Permanent Discontinuation of 
Blinatumomab ......................................................... 37 
6.2.2 
Study Stopping Rules ................................................................ 38 
6.3 
Other Protocol-required Therapies ............................................................ 38 
6.3.1 
Dexamethasone Premedication ................................................. 38 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules ....................................... 39 
6.4.1 
Criteria for Withholding and/or Permanent 
Discontinuation of Amgen Investigational Product and 
Other Protocol-required Therapies Due to Potential 
Hepatotoxicity............................................................................ 39 
6.4.2 
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity ............................................................. 41 
6.5 
Concomitant Therapy ................................................................................ 41 
6.6 
Medical Devices ........................................................................................ 42 
6.7 
Product Complaints ................................................................................... 42 
6.8 
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period .................................................................................. 43 
6.9 
Contraceptive Requirements ..................................................................... 43 
6.9.1 
Female Subjects ........................................................................ 44 
6.9.2 
Unacceptable Methods of Birth Control for Female 
Subjects .................................................................................... 44 
7. 
STUDY PROCEDURES ....................................................................................... 45 
7.1 
Schedule of Assessments ......................................................................... 45 
7.2 
General Study Procedures ........................................................................ 50 
7.2.1 
Screening/Enrollment ................................................................ 50 
7.2.2 
Rescreening .............................................................................. 50 
7.2.3 
Run-in Period ............................................................................ 51 
7.2.4 
Treatment .................................................................................. 51 
7.2.5 
Safety Follow-up Visit ................................................................ 52 
7.2.6 
Long-term Follow-up .................................................................. 52 
7.3 
Description of General Study Procedures ................................................. 53 
7.3.1 
Informed Consent ...................................................................... 53 
7.3.2 
Demographics ........................................................................... 53 
7.3.3 
Medical History .......................................................................... 53 
7.3.4 
Prior Therapies .......................................................................... 53 
7.3.5 
Performance Status ................................................................... 54 
7.3.6 
Physical Measurements ............................................................ 54 
7.3.7 
Vital Signs ................................................................................. 54 
7.3.8 
Physical Exam ........................................................................... 54 
7.3.9 
Neurological Examination .......................................................... 54 


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7.3.10 
Electrocardiogram ..................................................................... 55 
7.3.11 
Clinical Tumor Assessment ....................................................... 55 
7.3.12 
Radiographic Assessment ......................................................... 55 
7.3.13 
Lumbar Puncture to Examine Cerebro Spinal Fluid ................... 56 
7.3.14 
Vital Status ................................................................................ 56 
7.4 
Laboratory Procedures .............................................................................. 56 
7.4.1 
Pregnancy Tests ....................................................................... 57 
7.4.2 
Minimum Residual Disease Testing ........................................... 58 
7.5 
Antibody Testing Procedures .................................................................... 58 
7.6 
Biomarker Development ............................................................................ 58 
7.7 
Sample Storage and Destruction ............................................................... 59 
8.
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY .................. 60
8.1 
Subjects’ Decision to Withdraw ................................................................. 60 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion ...................................... 61 
8.3 
Reasons for Removal From Run-in, Treatment, or Study .......................... 61 
8.3.1 
Reasons for Removal From Run-in ........................................... 61 
8.3.2 
Reasons for Removal From Treatment ...................................... 62 
8.3.3 
Reasons for Removal From Study ............................................. 62 
9.
SAFETY DATA COLLECTION, RECORDING, AND REPORTING ....................... 62
9.1 
Definition of Safety Events ........................................................................ 62 
9.1.1 
Disease-related Events ............................................................. 62 
9.1.2 
Adverse Events ......................................................................... 63 
9.1.3 
Serious Adverse Events ............................................................ 64 
9.2 
Safety Event Reporting Procedures .......................................................... 65 
9.2.1 
Reporting Procedures for Disease-related Events ....................    65 
9.2.2 
Adverse Events ......................................................................... 65 
9.2.2.1 
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria ............................ 65 
9.2.2.2 
Reporting Procedures for Serious Adverse 
Events ..................................................................... 66 
9.2.2.3 
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ................... 67 
9.2.2.4 
Serious Adverse Events That are not to be 
Reported by the Sponsors to Regulatory 
Agencies in an Expedited Manner ........................... 68 
9.3 
Pregnancy and Lactation Reporting .......................................................... 68 
10.
STATISTICAL CONSIDERATIONS ...................................................................... 69
10.1 
Study Endpoints, Analysis Sets, and Covariates ....................................... 69 
10.1.1 
Study Endpoints ........................................................................ 69 
10.1.1.1 
Primary Endpoint ..................................................... 69 
10.1.1.2 
Secondary Endpoint(s) ............................................ 69 


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10.1.1.3 
Exploratory Endpoint(s) ........................................... 69 
10.1.2 
Analysis Sets ............................................................................. 69 
10.1.2.1 
Full Analysis Set ...................................................... 69 
10.1.2.2 
Primary Analysis Set ............................................... 69 
10.1.2.3 
Target Dose Analysis Set ........................................ 70 
10.1.2.4 
Pre-treatment Analysis Set ...................................... 70 
10.1.2.5 
DLT Analysis Set ..................................................... 70 
10.1.3 
Covariates and Subgroups ........................................................ 70 
10.1.4 
Handling of Missing and Incomplete Data .................................. 71 
10.2 
Sample Size Considerations ..................................................................... 71 
10.3 
Planned Analyses ..................................................................................... 71 
10.3.1 
Interim Analyses ........................................................................ 71 
10.3.2 
Data Review Team .................................................................... 72 
10.3.3 
Primary Analysis ........................................................................ 72 
10.3.4 
Final Analysis ............................................................................ 73 
10.4 
Planned Methods of Analysis .................................................................... 73 
10.4.1 
General Considerations ............................................................. 73 
10.4.2 
Primary Efficacy Endpoint .......................................................... 74 
10.4.3 
Secondary Efficacy Endpoint(s) ................................................. 74 
10.4.4 
Safety Endpoints ....................................................................... 74 
10.4.4.1 
Adverse Events ....................................................... 74 
10.4.4.2 
Disease Related Events .......................................... 75 
10.4.4.3 
Laboratory Test Results .......................................... 75 
10.4.4.4 
Vital Signs ............................................................... 75 
10.4.4.5 
Electrocardiogram ................................................... 76 
10.4.4.6 
Antibody Formation ................................................. 76 
10.4.4.7 
Exposure to Investigational Product ........................ 76 
10.4.4.8 
Exposure to Concomitant Medication ...................... 76 
11. 
REGULATORY OBLIGATIONS ............................................................................ 76 
11.1 
Informed Consent ...................................................................................... 76 
11.2 
Institutional Review Board/Independent Ethics Committee ........................ 77 
11.3 
Subject Confidentiality ............................................................................... 78 
11.4 
Investigator Signatory Obligations ............................................................. 79 
11.5 
Regulatory and Ethical Considerations ...................................................... 79 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS .................................................. 79 
12.1 
Protocol Amendments and Study Termination .......................................... 79 
12.2 
Study Documentation and Archive ............................................................ 80 
12.3 
Study Monitoring and Data Collection ....................................................... 80 
12.4 
Investigator Responsibilities for Data Collection ........................................ 82 
12.5 
Language .................................................................................................. 82 
12.6 
Publication Policy ...................................................................................... 82 


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12.7 
Compensation ........................................................................................... 83 
13. 
REFERENCES ..................................................................................................... 84 
14. 
APPENDICES ...................................................................................................... 87 
List of Tables 
Table 1.  Infusion Interruptions/Dose Modifications Due to Adverse Events .................. 35 
Table 2.  Dexamethasone Pre-dose Treatment and for Events ..................................... 39 
Table 3.  Conditions for Withholding and/or Permanent Discontinuation of 
Amgen Investigational Product and Other Protocol-required 
Therapies Due to Potential Hepatotoxicity .............................................. 41 
Table 4.  Schedule of Assessments ............................................................................... 46 
Table 5.  Analyte Listing ................................................................................................ 57 
Table 6.  Disease-related Events by System Organ Class ............................................. 62 
Table 7.  Stopping Boundary With Posterior Probability of 90% and DLT Limit 
of 25% .................................................................................................... 72 
Table 8.  Operating Characteristics With Batch Size of 10 Subjects .............................. 72 
List of Appendices 
Appendix A.  Additional Safety Assessment Information ................................................ 88 
Appendix B.  Sample eSerious Event Contingency Form .............................................. 90 
Appendix C.  Pregnancy and Lactation Notification Worksheets .................................... 93 
Appendix D.  International Prognostic Index for Diffuse Large B-cell 
Lymphoma .............................................................................................. 95 
Appendix E.  Response Assessment per the Lugano Classification .............................. 96 
Appendix F.  Eastern Cooperative Oncology Group Performance Status ...................... 97 


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1. 
OBJECTIVES 
1.1 
Primary 
To determine minimal residual disease (MRD) negative rate following blinatumomab 
treatment in high-risk Diffuse Large B-cell Lymphoma (DLBCL) subjects who are 
MRD-positive post-autologous hematopoietic stem cell transplantation (aHSCT). 
1.2 
Secondary 
• 
To describe the efficacy of blinatumomab in relation to progression-free survival 
(PFS), duration of MRD-negative status, and overall survival (OS) 
• 
To evaluate the safety and tolerability of blinatumomab 
1.3 
Exploratory 
• 
To describe the incidence of anti-blinatumomab antibody 
• 
To describe the MRD-negative rate over time following blinatumomab treatment  
• 
To describe rate, features and outcomes of allogeneic hematopoietic stem cell 
transplantation (alloHSCT) following treatment with blinatumomab 
• 
To describe the relationship between clinical and baseline parameters and response 
to blinatumomab treatment 
• 
To describe MRD status relative to clinical relapse 
• 
To describe MRD status prior to treatment with blinatumomab in positron emission 
tomography (PET)-computed tomography (CT) negative high-risk DLBCL subjects 
following aHSCT: 
− 
To describe MRD-positive status post aHSCT 
− 
To describe the rate and timing of MRD-negative to MRD-positive change at 
screening and during the run-in period   
2. 
BACKGROUND AND RATIONALE 
2.1 
Disease 
The annual incidence of Non-Hodgkin’s Lymphoma (NHL) in Europe and the United 
States is estimated to be 15 to 20 cases/100.000 (Fisher and Fisher, 2004).  DLBCL is 
the most common lymphoid malignancy in adults, accounting for 31% of all NHL in 
Western countries and 37% of all B-cell tumors worldwide (Swerdlow et al, 2008).  The 
peak incidence of DLBCL is in the seventh decade (Martelli et al, 2013), with incidences 
increasing from 0.3 in 100.000 per year (35 to 39 years) to 26.6 in 100.000 per year 
(80 to 84 years) (Tilly and Dreyling, 2009). 
According to the World Health Organization classification, DLBCL corresponds to a 
group of lymphoid malignancies composed of large cells with vesicular nuclei, prominent 
nucleoli, basophilic cytoplasm, and an unusually high proliferation rate.  DLBCL is 
biologically and clinically heterogeneous, with subgroups defined by morphology, 


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immunophenotype, genetic alterations, and transcriptional patterns.  Although most 
cases arise de novo, some cases of DLBCL are progression or transformation of less 
aggressive lymphoma (eg, chronic lymphocytic leukemia or follicular lymphoma) 
(Hartge and Wang, 2004).  Despite this heterogeneity, and with the exception of the 
primary Central Nervous System (CNS) DLBCL, DLBCL are generally treated in a 
similar way (Gisselbrecht et al, 2010). 
The choice of the frontline treatment for patients with DLBCL is based on the individual 
International Prognostic Index (IPI) score and age.  This leads to 3 major subgroups of 
DLBCL patients: elderly patients (> 60 years, age-adjusted IPI [aaIPI] = 0 to 3), young 
patients with low risk (≤ 60 years, aaIPI = 0-1) and young patients with high risk 
(≤ 60 years, aaIPI = 2-3; Martelli et al, 2013).  Rituximab, cyclophosphamide, 
doxorubicin, vincristine, and prednisone (R-CHOP) given every 14 or 21 days is the 
cornerstone of first-line therapy for DLBCL (National Comprehensive Cancer Network 
[NCCN] Guidelines® and European Society for Medical Oncology [ESMO] Guidelines 
[Tilly et al, 2015]), particularly for elderly patients and younger patients with low risk 
features.  For elderly patients, the introduction of a so called pre-phase consisting of 
vincristine and prednisone may help reduce toxicities.  For localized disease involved 
field radiotherapy is commonly added to R-CHOP. 
Young patients with high-risk features represent the greatest current challenge in the 
front-line treatment of DLBCL.  Around 30% of these patients are refractory to frontline 
R-CHOP therapy.  In addition, poor prognostic genetic abnormalities that are present in 
some DLBCL cases, including myc rearrangement in approximately 10% of patients, are 
associated with poor outcome following standard therapy with R-CHOP 
(Savage et al, 2009).  Moreover, myc rearrangement with BCL2 (or BCL6) translocation, 
known as double-hit lymphomas (DHL), are also associated with dismal clinical outcome 
following R-CHOP (Green et al, 2012).  These DHLs progress rapidly and are refractory 
to therapy.   
Despite the improvements observed since the introduction of rituximab into frontline 
treatments, 10% to 20% of patients with low IPI and 30 to 50% of patients with high IPI 
will relapse.   
Patients with DLBCL who do not respond to frontline therapy, or who experience relapse 
after a remission, are generally considered incurable unless able to receive either 
high-dose chemotherapy with aHSCT or alloHSCT (Robinson et al, 2016).  aHSCT is 
currently recommended in patients who experienced primary induction failure, high-risk 


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first complete remission/first partial remission, high risk IPI or relapse, improved risk 
stratification for example via c-myc and BCL2 analysis and interim PET positivity may 
advance patient selection for aHSCT, particularly in clinical trials (Bhatt and Vose, 2014). 
aHSCT is preceded by a course of salvage chemotherapy in order to demonstrate 
chemosensitivity.  The efficacy of salvage regimens have been compared in 2 large, 
multicenter randomized trials: Collaborative Trial in Relapsed Aggressive Lymphoma 
(CORAL [R-DHAP vs R-ICE]) and National Cancer Institute of Canada Clinical Trial 
Group (NCIC CTG) LY.12 (R-DHAP vs R-GDP) (Gisselbrecht et al, 2010; 
Crump et al, 2014).  A third trial, ORCHARRD (Ofatumumab Versus Rituximab Salvage 
Chemoimmunotherapy Followed by aHSCT in Relapsed or Refractory DLBCL), tested 
an alternative anti-CD20 agent, ofatumomab, versus rituximab in combination with 
DHAP (van Imhoff et al, 2014).  The CORAL study demonstrated no differences in 
response rates when using either R-ICE (rituximab, ifosfamide, carboplatin, etoposide) 
or R-DHAP (rituximab, dexamethasone, cytarabine, cisplatin) followed by aHSCT.  For 
the approximately 50% of patients who underwent aHSCT, 3-year PFS was 53%.  
Outcomes including OS were particularly poor for patients that had received prior 
rituximab or had relapsed within one year of diagnosis or had high risk secondary aaIPI 
(long-term disease free survival of below 20%) (Gisselbrecht et al, 2010).  A single 
center study evaluated patients with relapsed/refractory DLBCL proceeding to high-dose 
chemotherapy with aHSCT, assessing salvage therapy outcome with interim PET as 
pre-aHSCT risk factor.  At 3 years, patients achieving a Deauville response of 1 to 3 to 
salvage, experienced superior PFS and OS rates of 77% and 86%, respectively, 
compared with patients achieving Deauville 4 who achieved 49% and 54%, respectively, 
with the majority of relapses occurring within the first 6 months (Sauter et al, 2015). 
The only curative option for relapse after aHSCT is alloHSCT (generally using 
reduced-intensity conditioning alloHSCT), which is considered in a selected group of 
patients with relapsed DLBCL (Friedberg, 2011).  However, patients rarely achieve the 
necessary disease control required to undergo alloHSCT and this treatment is 
associated with a high treatment-related mortality rate (up to ~25%) (Lazarus et al, 
2010).  Therefore, it is of high interest to prevent relapse post aHSCT. 
2.2 
Minimal Residual Disease 
MRD is emerging as a valuable approach to assess treatment efficacy, provide a 
prognosis, in which the introduction of MRD monitoring has fundamentally transformed 
cancer patient management.  MRD status guides treatment decisions for neoplasms 


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such as acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia and chronic 
myeloid leukemia.  For example, persistence of MRD after induction chemotherapy has 
been demonstrated to be a major negative prognostic factor for B-lineage ALL and an 
early indicator of chemorefractory disease (Conter et al, 2010; van der Velden et al, 
2007; Bassan et al, 2009; Borowitz et al,2008; Raff et al, 2007; Brüggemann et al, 
2006).  More than 90% of patients with MRD after chemotherapy have a hematologic 
relapse (Gökbuget et al, 2012).  The only curative option for patients with MRD-positive 
ALL is alloHSCT however, the prognosis is still not optimal (Bader et al, 2009). 
While MRD monitoring is well-established for ALL, chronic myeloid leukemia and acute 
promyelocytic leukemia, MRD monitoring in other malignancies including lymphomas is 
evolving.  Some of the challenges include selection of the appropriate methodology for 
assessment of MRD.  Techniques such as flow cytometry or PCR may be used to 
measure MRD in bone marrow samples with greater sensitivity than microscopy.  MRD 
can be monitored as part of standard monitoring bone marrow aspiration.  Such 
monitoring is not informative in diseases like DLBCL because they do not consistently 
involve a single accessible anatomic site.  Random sampling of clinically uninvolved 
lymph nodes is unfeasible and presumably insensitive.  An additional complexity of 
PCR-based methodologies relates to the sequence stability of the target genes in B cells 
that are capable of ongoing hypermutation. 
In first complete remission, the commonly used radiographic method of surveillance with 
or without isotopic imaging has not been shown to improve survival, lacks sensitivity and 
specificity, and exposes patients to radiation (Avivi et al, 2013; Cheah et al, 2013; 
Huntington et al, 2015; Thompson et al, 2014; Ghielmini et al, 2013; Cheson et al, 2014; 
Hicks et al, 2013).  Multiple societies and guidelines recommend against routine 
surveillance imaging.  Rarely are asymptomatic recurrences detected by routine 
surveillance as relapse in patients with DLBCL most likely originate from the persistence 
of MRD below the detection limit of the current imaging technology.  
Technical advances in DNA sequencing have also uncovered an interesting biologic 
feature: the shedding of tumor DNA into the plasma fraction of peripheral blood induced 
by apoptosis and necrosis of the malignant cells (Jahr et al, 2001; Leon et al, 1977). 
Cell-free circulating tumor DNA (CT-DNA) can be detected by the more sensitive 
methodologies such as next generation sequencing (NGS).  The VDJ regions of the 
immunoglobulin genes contain unique sequences that are markers of the unique disease 
clones present in each patient.  Two studies have aimed to assess whether CT-DNA 


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encoding the clonal immunoglobulin gene sequence, could be detected in the plasma of 
patients with DLBCL and, used to predict clinical disease recurrence after frontline 
treatment (Kurtz et al, 2015; Roschewski et al, 2014).  A Cox proportional hazards model 
showed that the hazard ratio for clinical disease progression was 228 (95% confidence 
intervals [CI]: 51–1022) for patients who had detectable CT-DNA during surveillance 
compared with patients with undetectable CT-DNA (p<0·0001).  Surveillance CT-DNA 
had a positive predictive value of 88.2% (95% CI 63.6 to 98.5) and a negative predictive 
value of 97.8% (92.2 to 99.7) and identified risk of recurrence at a median of 3.5 months 
(range 0 to 200) before evidence of clinical disease.  Another study demonstrated that 
detection of molecular disease in the plasma often preceded PET-CT detection of 
relapse in patients initially achieving remission.  Given its high specificity, NGS based 
detection of CT-DNA from plasma has potential clinical utility for surveillance after 
complete response (CR) (Kurtz et al, 2015).  Surveillance CT-DNA identifies patients at 
risk of recurrence before clinical evidence of disease in most patients and results in a 
reduced disease burden at relapse.  Interim CT-DNA is a promising biomarker to identify 
patients at high-risk of treatment failure (Roschewski et al, 2014).  A recently published 
clinical trial with panobinostat with or without rituximab in relapsed/refractory DLBCL 
retrospectively examined early changes in CT-DNA as a potential predictive biomarker.  
The investigators observed changes in CT-DNA as early as after 15 days of therapy and 
a clear association with response, with very high specificity and positive predictive value.  
No patients with an increase in CT-DNA responded and all patients who responded had 
a significant drop in CT-DNA after 15 days of therapy, which also had an impact on OS 
and PFS.  Thus, MRD monitoring by assessment of CT-DNA dynamics may provide an 
indication of treatment outcome in clinical trials. 
2.3 
Amgen Investigational Product Background 
Blinatumomab (BLINCYTO®, AMG 103) is a member of a novel class of bispecific 
antibody constructs called “bispecific T-cell engagers” or BiTE® (Schlereth et al, 2006; 
Dreier et al, 2003) with dual binding specificities.   T cells are bound by its anti-CD3 
moiety, whereas B lymphoblasts and cells are bound by the anti-CD19 moiety.  This 
unique feature of blinatumomab allows it to transiently connect malignant cells with 
T cells, thereby inducing T-cell mediated killing of the bound malignant cell.  In 
preclinical models, blinatumomab-mediated T-cell activation involves the transient 
release of inflammatory cytokines and proliferation of T cells.  The subsequent serial 
lysis of multiple malignant cells by a single blinatumomab-activated T cell closely 
resembles a natural cytotoxic T-cell reaction. 


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Blinatumomab is approved in multiple regions for the treatment of Philadelphia 
chromosome-negative relapsed or refractory B-cell precursor ALL.  Additionally, 
confirmation of clinical benefit is a condition of approval in multiple countries.   
CD19 is highly expressed throughout B-cell development and is present on > 90% of 
B-cell lineage cancers, including DLBCL.  The efficacy of blinatumomab has been 
evaluated in subjects with B-cell precursor ALL and multiple histologies of NHL, 
including DLBCL.  Refer to Investigators Brochure for efficacy and safety information 
with the use of blinatumomab as well as for additional information related to the physical, 
chemical, and pharmaceutical properties and formulation(s). 
2.4 
Rationale 
The current study in high-risk DLBCL subjects who are MRD-positive post-aHSCT will 
provide an opportunity to further define blinatumomab’s safety and efficacy profile.  
DLBCL tumors are aggressive but potentially curable malignancies in subjects with 
limited disease, with a 5-year PFS ranging from 80 to 85%.  However, there is a subset 
of subjects with high-risk DLBCL that do substantially worse with only a 25 to 50% PFS 
at 5 years, and most of these subjects relapse within the first year.  In addition, at 
relapse, high-risk DLBCL subjects historically do very poorly with salvage therapy, 
including aHSCT.  The concept of increasing depth of response by eradication of MRD 
has been widely established in hematological malignancies.  In DLBCL, data on clinical 
relevance of MRD is evolving.  MRD detection via immunoglobulin high-throughput 
sequencing of CT-DNA was predictive for relapse in 2 retrospective studies.  MRD 
occurred after a median of 3.5 months in one study and was followed by clinical relapse.  
The other study confirmed the occurrence of MRD followed by clinical relapse.  Early 
detection of disease recurrence via MRD prior to clinical relapse provides the option for 
early intervention.  A potential clinical benefit of intervention in MRD-positive DLBCL, 
however, has not been investigated yet. 
This study focuses on an unmet medical need in subjects with high-risk DLBCL who 
underwent aHSCT and are currently in CR with detectable MRD in the circulation to 
improve their PFS by increasing the depth of their responses by eradicating MRD.  This 
study is designed to investigate if preemptive treatment with blinatumomab of subjects 
that are MRD-positive post-aHSCT will improve subject outcomes and can be 
administered with a favorable safety profile.  In addition, this study may contribute to 
understanding the relevance of the concept of MRD in order to intervene early when 
disease is limited and help to improve overall outcomes in DLBCL. 


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Based on experience with blinatumomab in previous studies, this study will use the 
stepwise dosing regimen (9/28/112 µg/day) for relapsed/refractory DLBCL.  In the 
previous NHL study, bone marrow clearance was achieved at doses of 15 µg/m²/d 
(translating into 28 µg/d) while eradication of extramedullary disease needed dose 
escalation to 60 µg/m²/d (translating into 112 µg/d).  Although MRD will be detected in 
blood, the location of disease is presumed to be in extramedullary sites.  MRD 
assessments at intermediate dose-step and interim timepoints during cycle 1 treatment 
will be performed to help inform the appropriate choice of dosing regimen in the DLBCL 
MRD setting. 
The single-agent activity of blinatumomab observed in heavily pre-treated subjects 
coupled with the need for new agents earlier in the course of treatment of high-risk 
subjects provides a strong rationale for testing blinatumomab in the setting of MRD 
positivity post aHSCT. 
2.5 
Clinical Hypotheses 
The study will estimate the MRD-negative response rate after treatment with 
blinatumomab in subjects with high-risk DLBCL who are MRD-positive following aHSCT.  
The clinical hypothesis is that the MRD-negative response rate will be greater than 10%.  
Achieving an MRD-negative response rate of 30% would be of scientific and clinical 
interest. 
2.6 
Benefit/Risk Assessment 
Subjects with high-risk DLBCL represent the greatest challenged population in front-line 
treatment of DLBCL.  Approximately 30% to 50% subjects with high risk will relapse.  
Autologous hematopoietic stem-cell transplant is recommended in subjects who 
experience primary induction failure and high-risk first complete remission/first partial 
remission (Robinson et al, 2016).  In spite of the improved therapies, for a significant 
portion (approximately 50%) of the subjects who undergo aHSCT, the 3-year 
progression-free survival remains low at 53% (Gisselbrecht et al, 2010).  The treatment 
options become very limited after aHSCT.  Allogeneic HSCT, a therapy with a high 
treatment-related mortality rate (up to approximately 25%), is the only curative option for 
relapse after aHSCT, but the majority of patients are not able to achieve disease control 
which is a prerequisite for undergoing alloHSCT.  There is a significant unmet need for 
the DLBCL subjects who have undergone aHSCT. 
Treating subjects with MRD-positive, high-risk DLBCL post aHSCT presents a potential 
benefit because these subjects have a high risk of disease relapse.  Once relapsed, the 


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chances of survival are low and the adverse events associated with other treatment 
options severe. 
Known toxicities due to the use of blinatumomab include neurologic events and cytokine 
release syndrome (CRS), which, in some cases, may be life-threatening.  These events 
may be severe and require temporary interruption or permanent discontinuation of 
blinatumomab treatment. 
Furthermore, there is a risk that the MRD assay could result in a false positive.  As such, 
in this study, this would lead to the administration of 1 cycle of blinatumomab treatment 
to a patient who is actually MRD-negative, thus exposing a patient to the treatment risks 
without receiving incremental benefit.  Since blinatumomab has not been studied directly 
in DLBCL subjects who are MRD-negative, this risk is based on available safety data in 
subjects who achieved complete MRD response (MRD-negative) and continued to 
receive blinatumomab in Study MT103-203, a phase 2 study evaluating the efficacy and 
safety of blinatumomab in adult subjects with MRD-positive ALL.  The 
treatment-emergent adverse events from Study MT 103-203 provided information to 
estimate the potential risk to MRD-negative subjects who may receive blinatumomab 
treatment due to a false positive MRD result.  Of the 64 MRD-negative subjects, 89.1% 
of subjects experienced at least 1 treatment-emergent adverse event, 29.7% of subjects 
experienced grade 3 treatment-emergent adverse events, and 18.8% experienced 
grade 4 treatment-emergent adverse events.  There were no grade 5 events among 
these subjects.  The majority of the treatment-emergent adverse events experienced by 
subjects who received blinatumomab in a second cycle after achieving MRD-negativity 
in the first cycle of treatment were mild, and none had a fatal outcome.   
Experience to-date has shown that adverse events associated with high tumor burden at 
baseline, such as CRS and neurologic events, appear to become less frequent and 
severe with reduction of tumor burden.  As such, the high unmet medical need in the 
patient population and the potential for benefit outweighs the risks that may be 
associated with participating in this study. 


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3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This is a phase 2, multicenter, open-label, single arm estimation study in adult subjects 
with high-risk DLBCL that are PET-CT negative post aHSCT.  The study will consist of 
the following periods: 
• 
Screening period (up to 28 days) 
• 
Run-in period of up to 24 months to evaluate MRD status and assess eligibility for 
treatment assignment 
• 
Treatment period of 12 weeks (which includes 8 weeks of treatment with 
blinatumomab followed by a 4-week treatment-free period) 
• 
Safety follow-up visit 30 days after the last dose of blinatumomab 
• 
Long-term follow-up period that begins after the safety follow-up visit is completed 
until 1 year from the first dose of blinatumomab.  
The study will enroll approximately 90 subjects with relapsed/refractory, biopsy-proven, 
high-risk DLBCL who are PET-CT negative at 90 days (± 30 days) post aHSCT 
(see Section 4.1 Part 1 Inclusion and Exclusion criteria).  During the run-in period, 
subjects will be followed by clinic visits at 3, 5, 7, and 9 months, and thereafter every 
3 months (± 1 week) up to 24 months for monitoring of MRD status in plasma by 
NGS-based assay.  Subjects who remain MRD-negative by the end of the 24-month 
run-in period will end the study.  It is expected that approximately 30 subjects will be 
MRD-positive either at screening or become MRD-positive during the 24-month run-in 
period.  The number of subjects enrolled may be altered in order to ensure that 
approximately 30 subjects are assigned to treatment with blinatumomab.  Enrollment 
may be stopped once approximately 30 subjects have been assigned to treatment with 
blinatumomab. 
Subjects who are MRD-positive at enrollment or become MRD-positive during the run-in 
period, and who meet all other part 2 eligibility criteria (see Section 4.2), will be assigned 
to treatment with blinatumomab. 
Blinatumomab will be administered as a continuous intravenous (IV) infusion.  Cycle 1 
will be 12 weeks (84 days) in duration, which includes 8 weeks (56 days) of 
blinatumomab IV infusion followed by a 4-week (28 day) treatment-free interval.  
Blinatumomab will be dosed at 9 µg/day for 7 days, followed by 28 µg/day for 7 days and 
112 µg/day for 42 days. 


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MRD status will be assessed at cycle 1 day 1 prior to blinatumomab infusion, on cycle 1 
days 15 and 43, the end of the blinatumomab infusion (day 57), and 2 weeks after the 
end of the blinatumomab infusion (day 71 + 3 days) to evaluate disease status.  A 
PET-CT will be performed only if a subject remains MRD-positive (day 57 of cycle 1 
assessment) after blinatumomab or has clinical signs and symptoms of disease 
progression. 
A safety follow-up visit will occur 30 days (+ 3 days) after the last dose of blinatumomab 
for assessment of disease-related events, adverse events, and serious adverse events.  
A long-term follow-up period to assess disease status and OS begins at completion of 
the safety follow-up visit and continues for 1 year from the first dose of blinatumomab.  
Subjects will be followed via clinic visit every 3 months (± 2 weeks) for MRD assessment 
and by institutional standard of care disease evaluation (PET-CT or CT) until relapse at 
which time the subject will be followed for survival via telephone contact.   
A Data Review Team (DRT) will monitor the study for safety on a regular basis 
(see Section 10.3.1).  
The overall study design is described by a study schema at the end of the protocol 
synopsis section. 
The study endpoints are defined in Section 10.1.1. 
3.2 
Number of Sites 
Approximately 35 sites in North America, Australia, and Europe will participate in the 
study.  During the conduct of the study, additional countries, regions or sites may be 
added if necessary.  Sites that do not enroll subjects within 6 months of site initiation 
may be closed.   
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
Approximately 90 subjects will be enrolled in the study.  It is expected that approximately 
30 subjects will be MRD-positive at screening or become MRD-positive during the 
24-month run-in period.  The number of subjects enrolled may be altered in order to 
ensure that approximately 30 subjects are assigned to treatment with blinatumomab.  
Enrollment may be stopped once approximately 30 subjects have been assigned to 
treatment with blinatumomab. 
For sample size considerations see Section 10.2. 


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3.4 
Replacement of Subjects 
Subjects who are withdrawn or removed from treatment or the study will not be replaced. 
3.5 
Estimated Study Duration 
3.5.1 
Study Duration for Subjects 
The total study duration for an individual subject will vary from approximately 
1 to 3 years.  This includes a 28-day screening period, a run-in period of up to 
24-months, a 12-week treatment period (8 weeks of treatment with blinatumomab 
followed by a 4-week treatment free period), a 30-day safety follow-up and a long term 
follow-up period that begins after the safety follow-up period until 1-year from the first 
dose of blinatumomab. 
3.5.2 
End of Study 
Primary Completion:  The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the final collection of data for the 
primary endpoint, for the purposes of conducting the primary analysis, whether the study 
concluded as planned in the protocol or was terminated early. 
The primary completion date is the date when data for the primary endpoint are last 
collected for the purposes of conducting the primary analysis.  
If the study concludes prior to the primary completion date originally planned in the 
protocol (ie, early termination of the study), then the primary completion will be the date 
when the last subject is assessed or receives an intervention for evaluation in the study 
(ie, last subject last visit). 
End of Study:  The end of study date is defined as the date when the last subject is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (ie, long-term follow-up), as applicable. 
4. 
SUBJECT ELIGIBILITY 
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).   
Part 1 eligibility criteria will be evaluated during screening to establish enrollment in the 
study.  Part 2 eligibility criteria will be evaluated in order to assign subjects to treatment 
with blinatumomab.  Part 2 eligibility will be assessed at any time after enrollment and 
through the run-in period at the time when MRD status becomes positive 
(see Section 5). 


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Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1). 
4.1 
Inclusion and Exclusion Criteria – Part 1 
4.1.1 
Inclusion Criteria – Part 1 
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 at time of informed consent 
103 
Biopsy-proven DLBCL excluding DLBCL that represents transformation of 
indolent NHL  
Note: Lymphoblastic Lymphoma and Burkitt Lymphoma histology are not eligible 
104 
Subject has ≥ 1 characteristic feature of high-risk DLBCL: 
• 
High-risk first complete remission (defined as interim PET-CT positive or 
< complete remission to frontline chemotherapy AND achieved complete 
remission to platinum-containing salvage) 
• 
Relapse within 1 year of diagnosis 
• 
Secondary aaIPI > 1 (see Appendix D) 
• 
Partial response/partial metabolic response after minimum of 2 cycles of 
platinum-containing salvage chemotherapy 
• 
C-myc rearrangement 
105 
aHSCT with high-dose chemotherapy following first (or later) salvage treatment. 
106 
PET-CT negative (Deauville score ≤ 3) 90 days (± 30 days) post aHSCT 
107 
Available relapsed and/or diagnostic pathology formalin-fixed paraffin-embedded 
(FFPE) tumor block or slide samples at the time of enrollment including the 
successful identification of malignant clone sequences by the central laboratory.  
108 
MRD plasma sample collected ≤ 3 weeks after the post aHSCT PET-CT scan  
109 
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. 
110 
Adequate organ function determined ≤ 3 weeks prior to enrollment defined as 
follows: 
Hematological: 
• 
Absolute neutrophil count (ANC) ≥ 1.0 x 109/L 
• 
Platelet count  ≥ 75 x 109/L 
• 
Hemoglobin ≥ 8 g/dL 


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Renal: 
• 
Creatinine clearance ≥ 50 mL/min Cockcroft-Gault equation 
Hepatic: 
• 
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 
< 3 x upper limit of normal (ULN) 
• 
Total bilirubin < 2 x ULN (unless Gilbert’s Disease or if liver involvement with 
lymphoma) 
111 
Subject will be available to complete all protocol-required study visits or 
procedures, and/or to comply with all required study procedures to the best of the 
subject’s and investigator’s knowledge including but not limited to: 
• 
Completion of up to a 24-month run-in period  
• 
Completion of all regularly scheduled study visits including blood draws for 
MRD assessment, clinical disease state assessment, PET-CT scans (ie, at 
time of MRD positivity or relapse), assignment to treatment with 
blinatumomab 
4.1.2 
Exclusion Criteria – Part 1 
201 
Clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, 
stroke, severe brain injury, dementia, Parkinson’s disease, cerebellar disease, 
organic brain syndrome, and psychosis 
202 
Evidence of CNS involvement with DLBCL at disease evaluation obtained 
prior to starting blinatumomab 
203 
Current autoimmune disease or history of autoimmune disease with potential of 
CNS involvement 
204 
Prior anti-CD19 directed therapies 
205 
Prior alloHSCT 
206 
Received radiation ≤ 2 weeks prior to enrollment 
207 
Infection with human immunodeficiency virus or chronic infection with hepatitis B 
virus (hepatitis B surface antigen positive) or hepatitis C virus (anti-hepatitis C 
virus positive) 
208 
History of malignancy other than DLBCL within the past 3 years with the following 
exceptions: 
• 
Malignancy treated with curative intent and with no known active disease 
present for ≥ 3 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 noninvasive carcinoma or carcinoma in 
situ 
209 
Subject has known hypersensitivity to immunoglobulins or any of the products or 
components to be administered during dosing. 
210 
History or evidence of any other clinically significant disorder, condition or 
disease (with the exception of those outlined above) that, in the opinion of the 
investigator or Amgen physician, if consulted, would pose a risk to subject safety 
or interfere with the study evaluation, procedures or completion. 
211 
Women who are pregnant or breastfeeding or planning to become pregnant or 
breastfeed while receiving blinatumomab and for an additional 48 hours after the 
last treatment dose of blinatumomab.  (Females of child bearing potential should 
only be included after a negative highly sensitive urine or serum pregnancy test.)  
212 
Women of childbearing potential unwilling to use an acceptable method of 
effective contraception while receiving blinatumomab and for an additional 
48 hours after last dose of blinatumomab.   
Note: The pregnancy, breastfeeding and contraceptive requirements are specific to 
blinatumomab.  The investigator is responsible for providing the subject (male 
and female) with pregnancy and breastfeeding (female only) avoidance 
requirements for other medications given during the study.  
213 
Currently receiving treatment in another investigational device or drug study or 
less than 30 days since ending treatment on another investigational device or 
drug study.  Other investigational procedures while participating in this study are 
excluded. 
4.2 
Inclusion and Exclusion Criteria – Part 2 
4.2.1 
Inclusion Criteria – Part 2 
112 
MRD-positive assessment (by NGS analysis) at enrollment or at any time during 
the run-in 1 period 
113 
PET-CT negative (defined by Deauville criteria ≤ 3) at run-in 2 performed 
≤ 3 weeks from MRD test result available to the site at run-in 1.  Historical 
PET-CT are allowed if performed ≤ 6 weeks from day 1 (first dose of 
blinatumomab) and subject has no clinical signs or symptoms suggestive of 
disease progression (eg, increase in lactate dehydrogenase [LDH] not otherwise 
explained)  


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114 
Adequate organ function determined ≤ 7 days prior to treatment assignment with 
blinatumomab as follows: 
Hematological: 
• 
ANC ≥ 1.0 x 109/L 
• 
Hemoglobin ≥ 8 g/L 
• 
Platelet count ≥ 75 x 109/L 
Renal: 
• 
Creatinine clearance ≥ 50 mL/min Cockcroft-Gault equation 
Hepatic: 
• 
AST and ALT < 3 x ULN 
• 
Total bilirubin < 2 x ULN (unless Gilbert’s Disease or if liver involvement 
with lymphoma) 
4.2.2 
Exclusion Criteria – Part 2 
214 
Subject has active infection requiring systemic therapy 
215 
Any change in the part 1 eligibility criteria during the run-in period. 
5. 
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 11.2). 
All subjects or legally acceptable representatives must personally sign and date the 
Amgen approved informed consent form before commencement of study-specific 
activities/procedures. 
A subject is considered enrolled when the investigator decides that the subject has met 
all Part 1 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). 
Each subject who enters into the screening period for the study (defined as the point at 
which the subject or subject’s legally acceptable representative signs the informed 
consent form) receives a unique subject identification number before any study-related 
activities/procedures are performed.  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 subject identification number must remain constant throughout the entire 


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clinical study; it must not be changed after initial assignment, including if a subject is 
rescreened. 
Subjects not meeting Part 1 eligibility criteria are permitted to rescreen 1 additional time 
after failing the first screening. 
Part 2 eligibility criteria will be evaluated at any time after enrollment through the 
24-month run-in period at the time when MRD status becomes positive 
(see Section 4.2).  Subjects who do not meet Part 2 eligibility criteria will end the study. 
5.1 
Treatment Assignment 
Subjects who meet Part 2 eligibility criteria will be assigned to treatment with 
blinatumomab. 
The treatment assignment date is to be documented in the subject’s medical record and 
on the enrollment CRF. 
6. 
TREATMENT PROCEDURES 
6.1 
Classification of Product(s), Medical Device(s) and/or Combination 
Product(s) 
The Amgen Investigational Product used in this study includes: blinatumomab. 
Non-investigational medical device(s) (ie, medical device[s] not under study) will be 
described in Section 6.6. 
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of blinatumomab.  
6.2 
Investigational Product 
6.2.1 
Amgen Investigational Product Blinatumomab 
Blinatumomab will be manufactured and packaged by Amgen Inc. and distributed using 
Amgen clinical study drug distribution procedures. 
Blinatumomab will be supplied in a single-use glass injection vials as a sterile, 
preservative-free, white to off-white, lyophilized powder for reconstitution and 
administration by continuous IV infusion.  Each vial contains blinatumomab with 
additional excipients and buffers including citric acid monohydrate, trehalose dihydrate, 
lysine hydrochloride and polysorbate 80, pH 7. 
To prepare blinatumomab for IV infusion, the lyophilized powder is reconstituted with 
sterile water for injection.  The reconstituted solution is added to an infusion bag 
containing 0.9% NaCl and a product-specific stabilizer (IV Solution Stabilizer).  The 


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IV Solution Stabilizer functions to prevent adsorption of blinatumomab to surfaces of the 
infusion components.  The IV Solution Stabilizer is supplied in 10 mL single-use glass 
injection vials as a sterile, preservative-free, clear, colorless-to-slightly-yellow liquid 
concentrate.  
Sterile water for injection and supplies required for reconstitution and injection of 
blinatumomab will not be provided to clinical sites. 
For information surrounding the use of a continuous infusion pump, refer to Section 6.6 
Medical Devices. 
6.2.1.1 
Dosage, Administration, and Schedule 
Blinatumomab will be administered as a continuous IV infusion. 
Cycle 1 of blinatumomab treatment is 12 weeks (84 days) in duration and includes 
8 weeks (56 days) of blinatumomab IV infusion followed by a 4-week (28-day) 
treatment-free interval.   
The initial dose of blinatumomab will be 9 μg/day for the first 7 days of treatment.  
Blinatumomab dose will then be escalated (dose-step) to 28 μg/day starting on day 8 
(week 2), followed by a dose-step up to 112 μg/day starting on day 15 (week 3) and 
continuing until completion of therapy (day 57 for cycle 1). 
To evaluate disease status, MRD status (CT-DNA) will be assessed at cycle 1 day 1 
prior to blinatumomab infusion, on cycle 1 days 15 and 43, the end of the blinatumomab 
infusion (day 57), and 2 weeks after the end of the blinatumomab infusion (day 71 + 3 
days).  A PET-CT will be performed only if subject remains MRD-positive at the day 57 
assessment or has clinical signs and symptoms of disease progression.  
Prior to initiation of blinatumomab and each dose-step escalation, dexamethasone will 
be administered as described in Table 2.  
The daily blinatumomab dose may be up to 10% lower or higher in order to account for 
possible pump inaccuracies.  A dose of up to 10% higher than the intended dose may 
not require specific intervention.  The effects of overdose of blinatumomab are not 
known.  In case of overdose or medication error, the infusion should be immediately 
stopped.  Consultation with the Amgen medical monitor is strongly recommended for 
prompt reporting of clinically apparent or laboratory adverse events possibly related to 
overdose.  If the overdose results in an adverse event, the subject should be followed 
carefully until all signs of toxicity are resolved, and consultation with the Amgen medical 


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monitor is also strongly recommended even if there are no adverse events, in order to 
discuss the minimal duration of dose interruption.  The adverse event(s) should be 
recorded/reported per Section 9.  Resumption of blinatumomab should adhere to the 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, Permanent 
Discontinuation Section 6.2.1.2. 
The dosing, start and stop date and time, and lot number of blinatumomab is to be 
recorded on each subject’s CRF.  
6.2.1.1.1 
Inpatient Dosing 
Subjects should be monitored in a hospital for a minimum of 72 hours following initiation 
of therapy and for a minimum of 48 hours at each dose-step increase because of the 
potential adverse events associated with T-cell distribution and potential cytokine 
release effects triggered by the administration of blinatumomab.  Nurses/physicians 
trained in emergency medicines should be available for immediate intervention in case 
of complications.   
6.2.1.1.2 
Outpatient Dosing 
After a subject meets the minimum criteria for inpatient administration and monitoring as 
described above, and if subject is deemed stable by the investigator, administration of 
blinatumomab IV infusion may continue as an outpatient.  See Section 6.2.1.2.1 
regarding monitoring following dose interruptions. 
In the outpatient setting, either the subject will return to the study site for changes of 
infusion bag or the subject will be visited by a well-trained ambulatory home-care service 
provider at specific intervals to change the infusion bag.  The subject and the home 
health care provider will be trained and will receive written instructions for storage of the 
IV bags.  For the home health care provider study-specific requirements and recording 
source documentation must be completed before any study-related tasks are started.  A 
comprehensive list of all home health care services, including but not limited to the 
storage, handling, and administration of blinatumomab, as well as mandatory procedural 
and data collection requirements, will be separately provided in a home health care 
manual.  Following each visit, this information will be documented on the home health 
care services visit worksheet and forwarded to the investigator.  In case of any adverse 
event in the outpatient setting, the home health care provider should directly contact the 
investigator at the study center for further management.  Any unexpected or unusual 
events, as well as deviations, will be communicated promptly to the investigator.  The 
home health care professionals provide 24-hour emergency on-call service.  In addition, 


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the subject will visit the study site for the examinations according to the schedule of 
assessments (Table 4). 
6.2.1.2 
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation  
6.2.1.2.1 
Infusion Interruption Due to Technical/Logistical Reasons 
The administration of blinatumomab 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 continued at the earliest time possible.  Every 
interruption longer than 1 hour should be documented.  If the interruption is longer than 
4 hours, restart of the infusion should be performed in the hospital, under the supervision 
of the investigator.  The subject should be observed overnight for possible side effects 
after the restart.  Administration of dexamethasone premedication prior to resumption of 
blinatumomab infusion after a treatment interruption of more than 4 hours is described in 
Table 2. 
The reason for dose change of blinatumomab is to be recorded on each subject’s CRF. 


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6.2.1.2.2 
Infusion Interruptions/Dose Modifications Due to Adverse Events 
Table 1.  Infusion Interruptions/Dose Modifications Due to Adverse Events 
Toxicity 
Grade or 
Adverse 
Event 
Instructions for Treatment Interruption and Restart 
Cytokine 
Release 
Syndrome 
3 
• Interrupt blinatumomab until the event improves to grade ≤ 1 
and administer corticosteroids (refer to Table 2)  
• Restart no less than 72 hours after the initial observation of the 
grade 3 event at the following dose levels: 
o 
If event occurred at 112 µg/day, resume at 28 µg/day 
o 
If event occurred at 9 or 28 µg/day, resume at 9 µg/day 
• Escalate up 1 dose level after 7 days if toxicity does not reoccur. 
Increase dose stepwise at 7-day intervals to target dose of 
112 µg/day if toxicity does not reoccur. 
• Permanently discontinue if: 
o 
Initial grade 3 CRS does not improve to grade ≤ 1 within 
7 days, OR 
o 
Grade 3 CRS reoccurs at the lower dose level within 
7 days of reinitiation OR 
o 
Grade 3 CRS reoccurs at a dose of 9 µg/day without prior 
dose-step escalation 
4 
• Permanently discontinue blinatumomab  
Neurologic 
Events 
3 
• Interrupt blinatumomab until the event improves to grade ≤ 1 
and administer corticosteroids (refer to Table 2)  
• Restart no less than 72 hours after the initial observation of the 
grade 3 event at the following dose levels: 
o 
If event occurred at 112 µg/day, resume at 28 µg/day 
o 
If event occurred at 28 µg/day, resume at 9 µg/day 
• Escalate up 1 dose level after 7 days if toxicity does not reoccur. 
Increase dose stepwise at 7-day intervals to target dose of 
112 µg/day if toxicity does not reoccur. 
• Permanently discontinue if: 
o 
Initial grade 3 neurologic event occurred at 9 µg/day, OR 
o 
Initial grade 3 neurologic event does not improve to grade 
≤ 1 within 7 days, OR 
o 
Grade 3 neurologic event reoccurs at the lower dose level 
within 7 days of re-initiation, OR 
o 
Grade  3 neurologic event reoccurs at a dose of 9 µg/day   
4 
• Permanently discontinue blinatumomab 
Seizurea  
• 
Interrupt blinatumomab, administer corticosteroids (refer to 
Table 2) and anti-seizure medication per local practice 
• For restart, refer to grade 3 neurologic events above for dose 
level rules for re-instituting infusion 
• Do not re-initiate blinatumomab until 7 days after the last seizure 
and after therapeutic levels of anti-seizure medication are likely 
to have been achieved 
• 
Permanently discontinue if a second seizure occurs with 
re-initiation of blinatumomab at any dose 
Page 1 of 2 
Footnotes defined on last page 


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Table 1.  Infusion Interruptions/Dose Modifications Due to Adverse Events 
Toxicity 
Grade or 
Adverse 
Event 
Instructions for Treatment Interruption and Restart 
Elevated 
liver 
enzymes 
NA 
• 
Interrupt blinatumomab (refer to Table 3) if any one of the 
following occurs: 
o 
TBL > 3 x ULN at any time 
o 
ALP > 8 x ULN at any time  
o 
AST or ALT > 8x ULN at any time  
o 
AST or ALT > 5x ULN but < 8 x ULN for ≥ 2 weeks 
o 
AST or ALT > 3 x ULN with clinical signs or symptoms that 
are consistent with hepatitis (eg, RUQ abdominal 
pain/tenderness, fever, nausea, vomiting, jaundice) 
• 
Permanently discontinue blinatumomab if: 
o 
TBL > 2 x ULN OR INR > 1.5 (for subjects not on 
anticoagulant therapy) 
AND 
o 
AST or ALT > 3 x ULN (when baseline was < ULN)  
AND 
o 
no other cause for the combination of the above laboratory 
abnormalities is immediately apparent 
Refer to Section 6.4 for additional details 
Other 
clinically 
relevant 
adverse 
events  
3 
• 
Interrupt blinatumomab until event improves to grade ≤ 1 (refer 
to Table 2)  
• 
Restart no less than 72 hours after the initial observation of the 
grade 3 event at the following dose levels: 
o 
If event occurred at 112 µg/day, resume at 28 µg/day 
o 
If event occurred at 9 or 28 µg/day, resume at 9 µg/day 
• 
Escalate up 1 dose level after 7 days if toxicity does not reoccur. 
Increase dose stepwise at 7-day intervals to target dose of 
112 µg/day if toxicity does not reoccur. 
• 
Permanently discontinue blinatumomab if: 
o 
Initial grade 3 event does not improve to grade ≤ 1 within 
14 days, OR 
o 
Grade 3 event reoccurs at the lower dose level within 7 days 
of re-initiation OR  
o 
Grade 3 event reoccurs at a dose of 9 µg/day without 
prior -dose-step escalation  
4 
• 
Permanently discontinue blinatumomab 
Page 2 of 2 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
CRS = cytokine release syndrome; NA = not applicable; TBL= total bilirubin; ULN = upper limit of normal; 
MRI = magnetic resonance imaging 
Grade scale is based on Common Terminology Criteria for Adverse Events version 4.0. 
a Obtain brain MRI and perform cerebro spinal fluid (CSF) analysis, if there are no contraindications 


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Restart of an infusion after interruption for an adverse event should be performed under 
supervision of the investigator.  Before blinatumomab is restarted, premedication with 
dexamethasone must be administered as described in Table 2.  
6.2.1.3 
Permanent Discontinuation of Blinatumomab 
Blinatumomab will be permanently discontinued for: 
Disease Progression 
Cytokine Release Syndrome 
• 
Initial grade 3 CRS that does not improve to grade ≤ 1 within 7 days 
• 
Grade 3 CRS that reoccurs at the lower dose level within 7 days of reinitiation 
• 
Grade 3 CRS reoccurs at a dose of 9 µg/day without prior dose-step escalation 
• 
Grade 4 CRS 
Neurologic Events 
• 
Initial grade 3 neurologic event occurred at 9 µg/day 
• 
Initial grade 3 neurologic event does not improve to grade ≤ 1 within 7 days 
• 
Grade 3 neurologic event that reoccurs at the lower dose level within 7 days of 
reinitiation 
• 
Grade 3 neurologic event reoccurs at a dose of 9 µg/day 
• 
Grade 4 neurologic event 
• 
A second seizure occurs after reinitiation of blinatumomab at any dose 
Elevated Liver Enzymes 
• 
Total bilirubin (TBL) > 2 x ULN OR international normalized ratio (INR) > 1.5 (for 
subjects not on anticoagulant therapy) AND 
• 
AST/ALT > 3 x ULN (when baseline  was < ULN) AND 
• 
No other cause of combination of the above laboratory abnormalities is immediately 
apparent 
Other Clinical Relevant Adverse Events 
• 
Initial grade 3 event does not improve to grade ≤ 1 within 14 days (with the exception 
of delay in restart due to logistical difficulties, in which case the restart may be 
postponed for an additional 7 days) 
• 
Grade 3 event reoccurs at the lower dose level within 7 days of reinitiation 
• 
Grade 3 event reoccurs at a dose of 9 µg/day without prior dose-step escalation 
• 
Dose limiting toxicities (DLTs) as described in Section 6.2.2 
Subjects who permanently discontinue study treatment due to adverse event should 
continue with other study procedures, including response assessment, as appropriate. 


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6.2.2 
Study Stopping Rules 
The DLT evaluation period will be the entire duration of cycle 1 of blinatumomab 
treatment.  For subjects who are removed from study treatment for reasons other than 
an adverse event/toxicity, ie, disease progression, they will be considered DLT evaluable 
if they have received at least 7 days of the target dose of blinatumomab. 
The occurrence of any of the following toxicities will be considered a DLT, if judged by 
the investigator to be related to blinatumomab administration: 
• 
grade 5 toxicity 
• 
grade 4 non-hematologic toxicity (non-laboratory) 
• 
grade 4 hematologic toxicity lasting ≥ 7 days (excluding lymphopenia) 
• 
grade 4 laboratory abnormalities lasting ≥ 7 days (excluding lymphopenia) 
• 
any permanent discontinuation of blinatumomab as described in Section 6.2.1.3 
The stopping rules will use a Bayesian approach to terminate the study if the posterior 
probability that the DLT rate is greater than 25% is > 90% (Section 10.3.1). 
6.3 
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. 
6.3.1 
Dexamethasone Premedication 
Mandatory premedication with dexamethasone is required before the treatment cycle 
and at each dose-step for the prevention of CRS and neurologic events resulting from 
blinatumomab treatment.  Dexamethasone premedication will also be required before 
restarting blinatumomab after a dose interruption due to an adverse event or 
technical/logistical issue.  Refer to Table 2 for details.  Collect dose, unit, frequency, 
route, start date, stop date and reason for dose change. 


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Table 2.  Dexamethasone Pre-dose Treatment and for Events 
Treatment Phase 
Target Subjects 
Dexamethasone Dose 
Pre-dose dexamethasone 
prior to blinatumomab 
treatment cycle and before 
each dose-step increase 
All subjects assigned to 
treatment 
 
Dexamethasone 20 mg IV: within 
1 hour prior to start of treatment in 
treatment cycle, and within 1 hour 
prior to dose-step increase. 
Infusion interruption/dose 
modification due to 
adverse event or 
interruption due to 
technical/logistical event 
Subjects who interrupt 
treatment > 4 hours 
Dexamethasone 20 mg IV: within 
1 hour prior to restart of treatment 
In case of signs of CRS 
Subjects with signs of CRS 
Dexamethasone orally or IV at a 
dose maximum of 3 doses of 
8 mg/day (24 mg/day) for up to 
3 days.  The dose should then be 
reduced step-wise over 4 days. 
Infusion interruption/dose 
modification due to 
neurologic events 
Subjects with neurologic 
event 
Dexamethasone should be 
administered at a dose of at least 
24 mg/day for up to 3 days.  
Dexamethasone will then be 
reduced step-wise over 4 days. 
CRS = cytokine release syndrome; IV = intravenous 
6.4 
Hepatotoxicity Stopping and Rechallenge Rules 
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
ALT, 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 investigational product or other protocol-required therapies as specified in the 
Guidance for Industry Drug-Induced Liver Injury (DILI):  Premarketing Clinical 
Evaluation, July 2009. 
6.4.1 
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) 


Product:  Blinatumomab 
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• 
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-one antitrypsin deficiency 
• 
Alcoholic hepatitis 
• 
Autoimmune hepatitis 
• 
Wilson’s disease and hemochromatosis 
• 
Nonalcoholic Fatty Liver Disease including Steatohepatitis (NASH) 
• 
Non-hepatic causes (eg, rhabdomylosis, hemolysis) 
If investigational product(s) is/are withheld, the subject is to be followed according to 
recommendations in Appendix A for possible DILI.  
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 (Section 6.4.2). 


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Table 3.  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 
> 3 x ULN at any time 
> 2 x ULN 
 
 
OR 
INR 
-- 
> 1.5 (for subjects not on 
anticoagulation therapy) 
 
OR 
AND 
AST/ALT 
> 8 x ULN at any time 
 
> 5 x ULN but < 8 x ULN for 
≥ 2 weeks 
 
> 5 x ULN but < 8 x ULN and unable 
to adhere to enhanced monitoring 
schedule 
 
> 3 x ULN with clinical signs or 
symptoms that are consistent with 
hepatitis (such as right upper 
quadrant pain/tenderness, fever, 
nausea, vomiting, jaundice). 
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or TBL values 
 
> 3 x ULN (when baseline was 
< ULN) 
 
OR 
 
ALP 
> 8 x 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 
6.4.2 
Criteria for Rechallenge of Amgen Investigational Product and Other 
Protocol-required Therapies After Potential Hepatotoxicity 
If signs or symptoms recur with rechallenge, then blinatumomab and other 
protocol-required therapies, as appropriate should be permanently discontinued.  
Subjects who clearly meet the criteria for permanent discontinuation (as described in 
Table 3) should never be rechallenged. 
6.5 
Concomitant Therapy 
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.8. 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community 
standards of medical care.   


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Concomitant therapies are to be collected from enrollment through the safety follow-up 
period.  All concomitant medication will be recorded on the CRF including all 
prescription, over-the-counter, herbal supplements, and IV medications and fluids.  
Collect therapy name, indication, dose, unit, frequency, route, start date, and stop date.   
6.6 
Medical Devices 
Blinatumomab must be administered using infusion pumps approved for use by the 
appropriate regulatory authorities for the country in which the subject is undergoing 
treatment, in both the inpatient and outpatient setting. 
Blinatumomab infusion for solution will be prepared in bags for IV infusion and delivered 
through infusion lines that are compatible with the investigational product 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 and specific set of 
device specifications are provided in the IPIM. 
Other non-investigational medical devices may be used in the conduct of this study as 
part of standard care.  These other medical devices (eg, syringes, sterile needles, 
alcohol prep pads) that are commercially available are not usually provided or 
reimbursed by Amgen (except, for example, if required by local regulation).  The 
investigator will be responsible for obtaining supplies of these devices. 
6.7 
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(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material.  
This includes any drug(s), device(s) or combination product(s) provisioned and/or 
repackaged /modified by Amgen.  Drug(s) or device(s) includes investigational product.   
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported 
according to the instructions provided in the IPIM. 


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6.8 
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period 
The following treatments and/or procedures are excluded during the study:  
• 
Any antitumor therapy other than blinatumomab 
• 
Any other immunosuppressive therapies (except for transient use of corticosteroids) 
• 
Any other investigational agent 
• 
Cytotoxic and/or cytostatic drugs  
• 
Radiation therapy  
• 
Immunotherapy other than blinatumomab 
• 
Chronic systemic (> 7 days) high-dose corticosteroid therapy 
(dexamethasone > 24 mg/day or equivalent) 
6.9 
Contraceptive Requirements 
Female 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. 
Female in the following categories are not considered of child bearing potential: 
• 
Premenopausal female with one of the following: 
− 
Documented hysterectomy 
− 
Documented bilateral salpingectomy 
− 
Documented bilateral oophorectomy 
Note:  Site personnel documentation from the following sources is acceptable: 1) review 
of subject medical records, 2) subject medical examination, or 3) subject medical history 
interview. 
• 
Premenarchal female 
• 
Postmenopausal female 
− 
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  A high follicle stimulating hormone level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT).  However, in the absence of 12 months of amenorrhea, a single follicle 
stimulating hormone measurement is insufficient. 
− 
Females on HRT and whose menopausal status is in doubt will be required to 
use one 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. 


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6.9.1 
Female Subjects  
Female subjects of childbearing potential must agree to use one or acceptable method 
of effective contraception (as described in the table below) during treatment and for an 
additional 48 hours after the last dose of protocol-required therapies.   
Acceptable Methods of Effective Contraception for Female Subjects 
• 
Combined (estrogen and progestogen) or progestogen-only hormonal methods given via 
oral, intravaginal, transdermal, injectable, or implantable route 
• 
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 or female condom with or without spermicide 
• 
Cap, diaphragm or sponge with spermicide 
• 
Double barrier method: the male uses a condom and the female may choose either a 
cap, diaphragm, or sponge with spermicide.  (A female condom is not an option due to 
the risk of tearing when both partners use a condom.) 
If a female subject is suspected of being pregnant, the protocol-required therapies must 
be stopped immediately and may not be resumed until absence of pregnancy has been 
medically confirmed. 
6.9.2 
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, and lactational amenorrhea method. 
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to fetus if they become pregnant during treatment and for 
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 for an increased length of time.  In addition, male subjects 
may also be required to use contraception.  The investigator must discuss these 
contraceptive changes with the subject. 


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7. 
STUDY PROCEDURES 
7.1 
Schedule of Assessments 
 


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Table 4.  Schedule of Assessments 
Study Period 
Screen 
Run-ina 
Treatment 
Follow-up 
 
 
Run-in 1a Run-in 2 
Blinatumomab Cycle 1h 
Treatment 
Free 
interval 
Safety 
Long-term/
EOS 
Cycle Day (d) 
-28 d to 
-24 dn,o 
Up to 
28 d 
MRD 
monitor 
Treatment 
Assign     
(-7 d) 
1 
2 3 8 9 
10 
15 
16 
17 
22 
29 
36 
43 
50 
57 
71 
30 d after 
last dose 
of IPi 
Q3 
monthsj 
Cycle Week 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 to 12 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part 1 eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part 2 eligibility 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Assignment 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history & Prior 
therapies 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsb 
 
X 
 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG PS 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Concomitant 
medications 
 
 
←       Continuous from enrollment     → 
 
Anti-lymphoma 
therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurological Exam 
 
X 
 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam  
 
X 
 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical tumor 
assessment 
 
X 
 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Adverse Events 
 
 
 
 
←       Continuous from first dose of blinatumomab       → 
 
Disease Related 
Events 
 
 
 
 
←       Continuous from first dose of blinatumomab       → 
 
Page 1 of 3 
Footnotes defined on the last of this table 


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Table 4.  Schedule of Assessments 
Study Period 
Screen 
Run-ina 
Treatment 
Follow-up 
 
 
Run-in 1a Run-in 2 
Blinatumomab Cycle 1h 
Treatment 
Free interval 
Safety 
Long-term/
EOS 
Cycle Day (d) 
-28 d to  
-24 dn,o  
Up to 
28 d 
MRD 
monitor 
Treatment 
Assign    
(-7 d) 
1 2 3 8 9 10 
15 
16 
17 
22 
29 
36 
43 
50 
57 
71 
30 d 
after 
last 
dose 
of IPi 
Q3 
monthsj 
Cycle Week 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 to 12 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological AE 
 
 
 
 
←       Continuous from first dose of blinatumomab        → 
 
Serious AE 
←       Continuous from Informed Consent    → 
X j 
Local Labs/Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serology 
(HBsAg and HCVAb) 
and HIV testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry  
 
X 
 
X 
 
X X X X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Hematology  
 
X 
 
X 
 
X X X X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Coagulation  
 
 
 
X 
 
X  
X X 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
LDH 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
X 
Creatinine clearance c 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing d 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoglobulins (IgG, 
IgM, IgA) 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
CRP 
 
X 
 
 
X X  
X X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Lumbar puncture 
 
 
 
 
Only if  neurological event leading to interruption/discontinuation 
of IP or seizure e 
 
 
 
 
Neurological safety 
blood 
 
 
 
 
Only if  neurological event leading to interruption/discontinuation 
of IP or seizure 
 
 
 
 
Central Labs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-blinatumomab 
antibodies  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pathology tumor 
block/slides l 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
MRD testing  
Xp 
 
X 
 
X  
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Xm  
 
Xf 
Page 2 of 3 
Footnotes defined on the last of this table 


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Table 4.  Schedule of Assessments 
Study Period 
Screen 
Run-ina 
Treatment 
Follow-up 
 
 
Run-in 1a Run-in 2 
Blinatumomab Cycle 1h 
Treatment 
Free 
interval 
Safety 
Long-term/
EOS 
Cycle Day (d) 
-28 d to 
-24 dn,o 
Up to 
28 d 
MRD 
monitor 
Treatment
Assign   
(-7 d) 
1 2 3 8 9 10 
15 
16 
17 
22 
29 
36 
43 
50 
57 
71 
30 d 
after last 
dose of 
IPi 
Q3 
monthsj 
Cycle Week 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 to 12 
 
 
Radiographic  
Assessments 
PET-CT g 
 
 
 
X g 
 
 
 
 
 
 
 
 
 
X g 
 
X g 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinatumomab h 
 
 
 
 
← IV infusion → 
 
 
 
 
Page 3 of 3 
AE = adverse event; IV = intravenous; CT = computed tomography; CRP = C-reactive protein; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology 
Group performance status; HBsAg = hepatitis B surface antigen; HCVAb = hepatitis C virus antibody; HIV = human immunodeficiency virus; Ig = immunoglobulin; 
IP = investigational product; LDH = lactate dehydrogenase; MRD = minimal residual disease; PET = positron emission tomography; Q3 = every 3 months; EOS = end 
of study 
a Run-in period is up to 24 months in duration.  During the run-in 1 period enrolled subjects that are MRD-negative/PET-CT negative will be followed at 3, 5, 7, 
9 months and thereafter every 3 months (± 1 week) up to 24 months for MRD testing.  At enrollment or during the run-in 1 subjects that are MRD-positive will 
complete Run-in 2 assessments to determine part 2 eligibility and treatment assignment. 
b On days of hospitalization, obtain vital sign monitoring every 4 to 8 hours based on institutional standard of practice.  When subject is in the outpatient clinic, 
only obtain 1 baseline vital sign per visit. 
c Creatinine clearance is calculated by the Cockcroft-Gault equation 
d Pregnancy test must be performed within 72 hours from the start of run-in period and 72 hours prior to the first dose of blinatumomab (day [D] 1, cycle 1).  
e Lumbar puncture only required during treatment period if subject has a neurologic event leading to interruption/discontinuation or at seizure.  
f During the long term follow-up period an optional sample for MRD testing will be obtained at the time of suspicion of relapse and relapse. 
g  PET-CT must be performed at run-in 2 in subjects that are MRD positive during run-in 1.  Subjects that are MRD-positive at screening may qualify for treatment 
assignment with historical PET-CT negative results as long as PET-CT was performed ≤ 6 weeks from  day 1 cycle 1 (first dose of blinatumomab) and subject has no 
clinical signs or symptoms  suggestive of disease progression (eg, increase in LDH not otherwise explained).  Every attempt should be made to complete PET and 
CT within 3 days of each other, particularly during blinatumomab treatment. PET-CT at day 71 (+ 3 days) will only be performed if subject remains MRD+ at cycle 1 
day 57 or has clinical signs and symptoms of disease progression.  During the long-term follow-up period a PET-CT or CT will be obtained at time of relapse and as 
per institutional standards for surveillance. 
h Blinatumomab will be administered by continuous IV infusion.  Cycle 1 is 12 weeks (84 days) in duration and includes 8 weeks (56 days) of blinatumomab IV infusion 
followed by a 4-week (28-day) treatment-free interval (day 57 to 84).  Cycle 1 dosing is 9 µg/day x 7 days (days 1 to 7); 28 µg/day x 7 days (days 8 to 14); 112 µg/day 
x 42 days (15 to 56).  Subjects should be monitored in a hospital for a minimum of 72 hours following initiation of blinatumomab treatment and 48 hours at each 
dose-step of blinatumomab (see Section 6.2.1.1). 
i Safety follow-up visit to be completed 30 days (+ 3 days) after the last dose of blinatumomab   


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j Long-term follow-up begins after the safety follow-up visit and visits will occur every 3 months (± 2 weeks) for a maximum of 1 year from the first dose of 
blinatumomab, or until relapse at which time the subject will be followed for survival via telephone contact. 
k During the long-term follow-up only serious adverse events related to blinatumomab will be collected 
l Relapsed and/or diagnostic pathology tumor block/slides must be shipped for determination of malignant clone sequence at the time of enrollment.  During the 
long-term follow up an optional pathology tumor block/slides will be obtained at the time of relapse. 
m Visit must be completed within + 3 days of day 71. 
n The screen tests should be completed within the indicated window (ie, 28 to 24 days before enrollment), but the subject won’t be considered a screen fail 
if these tests are completed outside of this window. 
o An exception to the maximum 28-day screening period may be allowed at certain sites/countries with prior approval from Amgen to ensure sufficient time 
to obtain pathology tumor block/slides prior to enrollment.  However, all other screening procedures must be completed within the 28-day screening 
period. 
p The screening MRD test should be performed 28 to 24 days before enrollment and should be shipped to central laboratory together with the slides of 
tumor tissue without any delay.  


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7.2 
General Study Procedures 
The procedures performed and timing of each study visit are outlined in the Schedule of 
Assessments (Table 4).  It is very important to attempt to perform study procedures and 
obtain samples at the precise timepoints stipulated in the Schedule of Assessments 
(Table 4).  When it is not possible to perform the study visit at the exact timepoint, the 
visit may be performed within the acceptable visit windows if applicable.  Any missed 
visits, tests not done, or examinations that are not conducted must be reported as such 
on the CRFs.  Subsequent study visits should resume on the original schedule.  Missed 
assessments at prior visits should not be duplicated at subsequent visits. 
Details regarding each type of procedure are provided in subsequent sub-sections.  
Refer to the applicable supplemental central laboratory manual, IPIM, and study 
manuals for detailed collection and handling procedures. 
7.2.1 
Screening/Enrollment 
The screening period is up to 28 days.  Screening procedures are to be completed 
during the screening period at time points designated in the Schedule of Assessments 
(Table 4).   
Note: An exception to the maximum 28-day screening period may be allowed at 
certain sites/countries with prior approval from Amgen to ensure sufficient time to 
obtain pathology tumor block/slides prior to enrollment.  However, all other 
screening procedures must be completed within the 28-day screening period.   
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy or any disallowed therapy.  After signing the written 
informed consent form, the site will register the subject and screen the subject for part 1 
eligibility criteria.   
If a subject has not met all part 1 eligibility criteria at the end of the 28-day window, the 
subject will be registered as a screen fail (see Section 7.2.2).  Screen fail subjects may 
be eligible for re-screening once.  Subjects satisfying part 1 eligibility requirements will 
be enrolled. 
7.2.2 
Rescreening 
Subjects who are unable to complete or meet Part 1 eligibility criteria on initial screening 
will be permitted to rescreen once.  Rescreen subjects must first be registered as screen 
failed and subsequently registered as rescreened.  Subjects will retain the same subject 
identification number assigned at the original screening.  Once the subject is registered 


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as rescreened, a new 28-day screening window will begin.  If the rescreening period 
begins more than 30 days after the original signing of the informed consent form, 
informed consent must be repeated.   
7.2.3 
Run-in Period 
Once a subject is enrolled (ie, subject has met the Part 1 eligibility criteria) he/she will 
enter the run-in period.   
During the run-in period subjects who are MRD-negative/PET-CT negative will complete 
MRD monitoring visits (run-in visit 1) at 3, 5, 7, and 9 months, and thereafter every 
3 months (± 1 week) for up to 24 months (see Schedule of Assessments Table 4).  
Subjects who remain MRD-negative by the end of the 24-month run-in period will end 
the study.  Subjects who are MRD-positive at enrollment or become MRD-positive at any 
time during the run-in period will complete run-in 2 visit (treatment assignment visit).  
MRD-positive subjects that meet all other part 2 eligibility criteria (see Section 4.2) will 
be assigned to treatment with blinatumomab.  Subjects who do not meet Part 2 eligibility 
criteria will end the study. 
In order to confirm part 2 eligibility and treatment assignment, all procedures during 
run-in visit 2 (see Table 4) should be initiated immediately after confirmation of MRD 
positivity (except as noted below), and completed within 7 days from the first dose of 
blinatumomab (day 1, cycle 1).  A PET-CT must be performed at the run-in 2 visit in 
subjects that become MRD-positive during run-in 1.  Subjects that are MRD-positive at 
screening may qualify for treatment assignment to blinatumomab with historical PET-CT 
negative results as long as PET-CT was performed ≤ 6 weeks from day 1 cycle 1 
(first dose of blinatumomab) and subject has no clinical signs or symptoms suggestive of 
disease progression (eg, increase in LDH not otherwise explained) as described in 
Section 4.2.1 (Part 2 Inclusion Criteria).  Every attempt should be made to complete PET 
and CT within 3 days of each other. 
Pregnancy testing must be completed 72 hours prior to the first dose of blinatumomab.   
7.2.4 
Treatment 
During the treatment period visits and procedures will occur per the Schedule of 
Assessments (Table 4). 
Subjects should be monitored in a hospital for a minimum of 72 hours following initiation 
of blinatumomab treatment and 48 hours at each dose-step increase in blinatumomab 
(see Section 6.2.1.1).  On days of hospitalization, vital signs should be monitored 


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every 4 to 8 hours based on institutional standard of practice.  When subject is in the 
outpatient clinic, only obtain 1 baseline vital sign per visit. 
Mandatory premedication with dexamethasone is required before treatment start of 
blinatumomab and dose-step for the prevention of CRS.  Dexamethasone premedication 
will also be required before restarting blinatumomab after a dose interruption due to an 
adverse event or technical/logistical issue of > 4 hours (see Table 2). 
Cycle 1 of blinatumomab will be 12 weeks in duration which includes 8 weeks of 
continuous blinatumomab IV infusion followed by a 4-week treatment-free interval break.   
MRD status will be assessed during treatment (day 1 prior to initiation of treatment and 
days 15 and 43), at the end of the blinatumomab infusion (day 57), and 2 weeks after 
the end of blinatumomab infusion (day 71 [+3 days]) to evaluate disease status.  A 
PET-CT will be performed only if a subject remains MRD-positive (day 57 [cycle 1] of 
assessment) or has clinical signs and symptoms of disease progression.  
Subjects must complete all protocol-required procedures prior to the start of 
blinatumomab continuous IV infusion (cycle 1 day 1). 
7.2.5 
Safety Follow-up Visit 
All subjects assigned to treatment, including subjects who withdraw from treatment early, 
should complete a safety follow-up visit 30 days (+ 3 days) after the last dose of 
blinatumomab.  The procedures per Table 4 will be performed. 
7.2.6 
Long-term Follow-up 
Following the safety follow-up visit, there will be a long term follow-up period for clinical 
evaluation of disease status and survival.  Subjects will be followed via clinical visit every 
3 months (± 2 weeks) after their safety follow-up visit for a maximum of 1 year from the 
first dose of blinatumomab, or until subject death, whichever occurs first.  During the 
long-term follow-up, subjects will be followed for MRD assessment and by institutional 
standard of care disease evaluation (PET-CT or CT) until relapse at which time the 
subject will be followed for survival via telephone contact.   
Subjects will allow Amgen continued access to medical records so that information 
related to subjects’ health condition, including disease status and survival, may be 
obtained.   


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7.3 
Description of General Study Procedures 
The sections below provide a description of the individual study procedures for required 
timepoints. 
7.3.1 
Informed Consent 
All subjects or legally acceptable representative must sign and date the most current 
IRB/IEC approved informed consent form.  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. 
7.3.2 
Demographics 
Demographic data collection including sex, age, race, and ethnicity will be collected in 
order to study their possible association with subject safety and treatment effectiveness. 
7.3.3 
Medical History 
The investigator or designee will collect a complete medical and surgical history that 
started 3 years prior to screening through the time of signing of informed consent.  
Medical history will include information on the subject’s concurrent medical conditions.  
The current toxicity grade will be collected for each condition that has not resolved. 
In addition to the medical history above, all history related to the subject’s diagnosis of 
DLBCL must date back to the initial diagnosis and any subsequent relapse including 
date of relapse and secondary IPI will be recorded.  The following history related to the 
subject’s diagnosis of DLBCL may be collected: date of initial diagnosis, stage at 
diagnosis, cell or origin if available (immunohistochemistry pattern, gene expression 
profiling, other), BCL2 and -6 (by Fluorescent in-situ hybridization [FISH]: translocation, 
immunohistochemistry expression levels), c-myc (by FISH: translocation, 
immunohistochemistry expression levels).   
7.3.4 
Prior Therapies 
For prior therapies being taken for DLBCL, collect therapy name, indication, dose, unit, 
frequency, route, start date and stop date, as well as responses.   
For all other prior therapies such as radiotherapy, collect therapy name, indication, site, 
dose, unit, frequency, route, start date and stop date. 
For prior aHSCT, collect hematopoietic stem cell mobilization source, conditioning 
regimen, number of cells infused (CD34+/kg) on day 0, date of neutrophil engraftment 


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(first day that ANC > 0.5 x 109/L for 3 consecutive days), date of platelet engraftment 
(first day that platelets > 20 x 109/ L), complications.  
7.3.5 
Performance Status 
The performance status will be assessed at the time points indicated in the Schedule of 
Assessments (Table 4) using the ECOG performance status scale (Appendix F). 
7.3.6 
Physical Measurements 
Height in centimeters and weight in kilograms should be measured without shoes.  
Height will only be collected at screening.  
7.3.7 
Vital Signs 
Vital signs will be monitored throughout the duration of the study as indicated in the 
schedule of assessments (Table 4).  On days of hospitalization, vital signs will be 
monitored every 4 to 8 hours based on institutional standard of practice for a minimum of 
72 hours following initiation of blinatumomab treatment and 48 hours at each dose-step.  
When subject is in the outpatient clinic, only obtain 1 baseline vital sign per visit. 
The following measurements must be performed: systolic/diastolic blood pressure, heart 
rate, respiratory rate and temperature.  Subject must be in a supine position in a rested 
and calm state for at least 5 minutes before blood pressure assessments are conducted.  
If the subject is unable to be in the supine position, the subject should be in the most 
recumbent position possible.  The position selected for a subject should be the same 
throughout the study and documented on the vital signs CRF.  The temperature location 
selected for a subject should be the same throughout the study and documented on the 
vital signs CRF.  If abnormalities are found and they are considered an adverse event, 
record on the Event CRF. 
7.3.8 
Physical Exam 
Physical examination will be completed as per standard of care.  Physical examination 
findings at screening will include medical and surgical history.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event). 
7.3.9 
Neurological Examination 
A neurological examination will be performed as outlined in the Schedule of 
Assessments (Table 4).  Subjects will be specifically queried for neurological symptoms 
observed in the interval since the last 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 


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tone and trophic findings, coordination, sensory system, neuropsychological findings 
(eg, speech, cognition and emotion).  Neurological examination findings should be 
recorded on the appropriate CRF (eg, medical history, event). 
7.3.10 
Electrocardiogram 
Standard of care electrocardiogram (ECG) will be performed. 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 
the most recumbent position as possible.  
The ECG must include the following measurements: heart rate, QRS, QT, QTc, and PR 
intervals. 
The principal investigator or designated site physician 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.  
Findings should be recorded on the ECG CRF. 
7.3.11 
Clinical Tumor Assessment 
Clinical tumor assessments will be performed as indicated in the Schedule of 
Assessments (Table 4) and are based on changes in the size of previously abnormal 
lymph node groups or extranodal sites, or the appearance of new lesions suspected to 
represent lymphoma progression or relapse.  Findings will be recorded on the clinical 
tumor assessment CRF. 
7.3.12 
Radiographic Assessment 
PET-CT scans with whole body images from base of skull to mid-thigh will be conducted 
per the Schedule of Assessments (Table 4).  Examinations should be consistent across 
timepoints including: amount of tracer, location of injection, arm location, scan delay. 
The following data should be collected per center: standard procedures, height, weight, 
gender, administration dose, time between dose administration and imaging, blood 
glucose level, time between blood glucose level sampling and tracer injection. 
PET images should be converted to standardized uptake values maps to support 
comparison across timepoints and to standardize viewing conditions.  CT anatomical 
coverage includes neck, chest, abdomen, and pelvis. 
The PET-CT will be interpreted per Lugano Classification (see Appendix E) by the local 
institution and will be used to determine if a subject can proceed to treatment with 


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blinatumomab.  If PET and CT are acquired on the same day, it is strongly 
recommended that PET is performed prior to the CT with IV contrast.  If PET and CT are 
not acquired on the same day it is strongly recommended that PET is performed first 
followed by CT no later than 3 days apart. 
7.3.13 
Lumbar Puncture to Examine Cerebro Spinal Fluid 
A lumbar puncture will not be performed at screening.  In case there is a concern of 
DLBCL CNS involvement and the investigator determines that cerebro spinal fluid (CSF) 
analysis or Magnetic Resonance Imaging (MRI) needs to be performed in order to 
assess eligibility, results will need to be documented.  A lumbar puncture is 
recommended as outlined in the Schedule of Assessments (Table 4) during treatment 
period if subject has a neurologic event leading to interruption/discontinuation or seizure.  
CSF analysis will be performed by the local laboratory (see Table 6) and an aliquot will 
be shipped to Amgen.  Additional investigations of the CSF should be performed as 
clinically appropriate.  
7.3.14 
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 the subject is 
deceased, the date and reported cause of death should be obtained if available. 
7.4 
Laboratory Procedures 
All screening and on-study laboratory samples will be collected, processed and sent to 
the investigator local laboratory or central laboratory as applicable (Table 5).  Detailed 
instructions for sample collection, processing, and shipping are provided in the central 
laboratory manual and/or Amgen-provided training materials.  The date and time of 
sample collection will be recorded in the source documents at the site.  
Blood draws should not be done via central venous access.  Exception: if a permanent 
central line with more than one lumen is used, blood draws can be done via the lumen 
that is not used for drug administration.   
Table 5 outlines the specific analytes that will be assessed during the study at time 
points outlined in the Schedule of Assessments (Table 4). 


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Table 5.  Analyte Listing 
Local Laboratory 
 
Central Laboratory 
Chemistry 
Coagulation 
Hematology 
Other 
Neurological 
Safety 
Other 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatininea 
Uric acid 
Total bilirubin 
Direct 
bilirubin 
Alkaline 
phosphatase 
AST (SGOT) 
ALT (SGPT) 
Amylase 
Lipase 
PTT/INR 
PT 
Fibrinogen 
Red blood cells 
Hemoglobin 
Hematocrit 
Platelets 
White blood cells 
Differential 
• 
Neutrophils 
• 
Bands/stabs 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
Urine or serum 
pregnancy test 
C-reactive protein 
Immunoglobulins 
(IgG, IgA, IgM) 
Lumbar punctureb 
LDH 
HIV 
HBsAg 
HCVAb 
 
CSF cell 
count 
CSF 
differential 
CSF flow 
cytometry 
CSF protein 
CSF glucose 
Additional 
CSF viral 
studies as 
clinically 
indicated 
Pathology tumor 
block/slides for 
MRD assay 
Anti-blinatumomab 
antibodies 
Plasma for MRD 
testing 
Neurological 
safety sample for 
lumbar puncture 
(if applicable) 
ALT = alanine aminotransferase; AST = Aspartate aminotransferase; BSA = body surface area; 
BUN = blood urea nitrogen; CSF = cerebro spinal fluid; HBsAg = hepatitis B surface antigen; 
HCVAb = hepatitis C virus antibody; HIV = human immunodeficiency virus; Ig = immunoglobulin; 
INR = international normalized ratio MRD = minimal residual disease; LDH = Lactase dehydrogenase; 
PTT = partial thromboplastin time; PT = prothrombin time ratio; SGOT = serum glutamic oxaloacetic 
transaminase; SGPT = serum glutamic-pyruvic transaminase 
a Creatinine clearance will be calculated using the Cockcroft-Gault equation: 
(140 - age [years] x weight [kg] x 0.85 if female) / (72 x creatinine mg/dL),  
adjusted for BSA by 1.73 m2/BSA 
b Lumbar puncture only required if concerns of disease presence per investigator judgement and lumbar 
puncture at time of neurologic events leading to interruption/discontinuation and seizure 
7.4.1 
Pregnancy Tests 
Urine or serum pregnancy tests will be performed locally at each site on all females of 
child bearing potential (see Section 6.9) 72 hours from the start of run-in period and 
72 hours prior to the first dose of blinatumomab (day 1 of cycle 1).  If the pregnancy test 
is positive at either timepoint the subject should not be enrolled or assigned to treatment 
respectively. 


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7.4.2 
Minimum Residual Disease Testing  
MRD testing will be performed at the central laboratory. 
At screening, a lymph node biopsy FFPE tumor sample obtained at the initial diagnosis 
or at relapse will be collected for testing of disease clone(s) identification.  The relapse 
biopsy sample is preferred over the initial diagnosis sample.  Formalin-fixed 
paraffin-embedded block or slides (a minimum of 10 of each, 5 µm thickness) are 
acceptable for MRD testing.  Fine needle aspirates are not acceptable.   
In addition, samples of peripheral blood will be collected for MRD testing in plasma by 
NGS as previously described by (Kurtz et al, 2015; Roschewski et al, 2014).  The time 
points for MRD testing is described in Section 3.1, Study Design, and indicated in the 
Schedule of Assessments (Table 4).  The screening MRD test should be performed 
24 to 28 days before enrollment and should be shipped to central laboratory 
together with the slides of tumor tissue without any delay. 
Of note, an MRD test will be performed on cycle 1 day 1 before blinatumomab treatment.  
The last MRD test in the run-in period and the MRD test at cycle 1 day 1 are expected to 
be approximately 2 weeks apart and will provide information on the circulating tumor 
DNA level fluctuation over time. 
7.5 
Antibody Testing Procedures 
Blood sample(s) for antibody testing are to be collected at the timepoints listed in the 
Schedule of Assessments (Table 4) for the measurement of anti-blinatumomab binding 
antibodies.  Samples testing positive for binding antibodies will also be tested for 
neutralizing antibodies and may be further characterized for quantity/titer, isotype, affinity 
and presence of immune complexes.  Additional blood samples may be obtained to rule 
out anti-blinatumomab antibodies during the study.   
Subjects who test positive for binding antibodies and have clinical sequelae that are 
considered potentially related to an anti-blinatumomab antibody response may also be 
asked to return for additional follow-up testing. 
7.6 
Biomarker Development 
Biomarkers are objectively measured and evaluated indicators of normal biologic 
processes, pathogenic processes, or pharmacologic responses to a therapeutic 
intervention.  In oncology, there is particular interest in the molecular changes underlying 
the oncogenic processes that may identify cancer subtypes, stage of disease, assess 


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the amount of tumor growth, or predict disease progression, metastasis, and responses 
to investigational product or protocol required therapies. 
Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to blinatumomab to investigate and further understand 
the DLBCL. 
Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to blinatumomab using the blood and CSF samples 
collected as outlined in the Schedule of Assessments (Table 4).  Biomarker development 
may be pursued by the use of advanced biochemical analyses such as proteomic 
methods, ribonucleic acid transcript profiling and DNA sequencing.  Refer to the 
laboratory manual for detailed collection and handling procedures for all biomarker 
development samples. 
7.7 
Sample Storage and Destruction  
Any blood or tumor sample collected according to the Schedule of Assessments Table 4 
analyzed for any of the tests outlined in the protocol and for any tests necessary to 
minimize risks to study subjects.  This includes testing to ensure analytical methods 
produce reliable and valid data throughout the course of the study.  This can also 
include, but is not limited to, investigation of unexpected results, incurred sample 
reanalysis, and analyses for method transfer and comparability.  
All samples will be coded to de-identify the subjects prior to being shipped from the site 
for analysis or storage.  Samples will be tracked using a unique identifier that is assigned 
to the samples for the study.  Results are stored in a secure database to ensure 
confidentiality. 
If informed consent is provided by the subject, Amgen can perform additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
disease under study (DLBCL), the dose response and/or prediction of response to 
blinatumomab, characterize antibody response, and characterize aspects of the 
molecule (eg, mechanism of action/target, metabolites) or to learn how the minimal 
residual disease can be better measured.  Results from these analyses are to be 
documented and maintained, but are not reported as part of this study.  Samples can be 
retained for up to 20 years.   
Since the evaluations are not expected to benefit the subject directly or to alter the 
treatment course, the results of biomarker development, or other exploratory studies are 


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not placed in the subject’s medical record and are not to be made available to the 
subject, members of the family, the personal physician, or other third parties, except as 
specified in the informed consent. 
The subject retains the right to request that the sample material be destroyed by 
contacting the investigator.  Following the request from the subject, the investigator is to 
provide the sponsor with the required study and subject number so that any remaining 
sample types (eg, blood, tumor) samples and any other components from the cells can 
be located and destroyed.  Samples will be destroyed once all protocol-defined 
procedures are completed.  However, information collected from samples prior to the 
request for destruction, will be retained by Amgen. 
The sponsor is the exclusive owner of any data, discoveries, or derivative materials from 
the sample materials and is responsible for the destruction of the sample(s) at the 
request of the subject through the investigator, at the end of the storage period, or as 
appropriate (eg, the scientific rationale for experimentation with a certain sample type no 
longer justifies keeping the sample).  If a commercial product is developed from this 
research project, the sponsor owns the commercial product.  The subject has no 
commercial rights to such product and has no commercial rights to the data, information, 
discoveries, or derivative materials gained or produced from the sample.  
See Section 11.3 for subject confidentiality. 
8. 
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY 
8.1 
Subjects’ Decision to Withdraw 
Subjects have the right to withdraw from the study at any time and for any reason 
without prejudice to their future medical care by the physician or at the institution. 
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, device or other protocol-required therapies and must 
discuss with the subject the options for continuation of the Schedule of Assessments 
(Table 4) 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, 
disease-related events, and device related events, as applicable.  Subjects who have 
discontinued investigational product and/or protocol required therapies or procedures 


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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.  The investigator must document the level of follow-up that is agreed to 
by the subject.   
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, publically available 
data can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study. 
8.2 
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion 
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. 
Subjects may be eligible for continued treatment with Amgen investigational product(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 12.1. 
8.3 
Reasons for Removal From Run-in, Treatment, or Study 
8.3.1 
Reasons for Removal From Run-in  
Reasons for removal from the run-in include any of the following: 
• 
subject request  
• 
safety concern (eg, due to an adverse event [including disease progression], 
ineligibility determined, protocol deviation, non-compliance, requirement for 
alternative therapy, pregnancy) 
• 
decision by sponsor (other than subject request or safety concern) 
• 
death 
• 
lost to follow-up 
• 
other protocol-specified criteria as described in Section 4.2. 


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8.3.2 
Reasons for Removal From Treatment 
Reasons for removal from protocol-required investigational product(s) or procedural 
assessments include any of the following: 
• 
subject request   
• 
safety concern (eg, due to an adverse event, ineligibility determined, protocol 
deviation, non-compliance, requirement for alternative therapy, pregnancy) 
• 
death 
• 
lost to follow-up 
• 
decision by sponsor (other than subject request, safety concern, lost to follow-up) 
• 
disease progression  
• 
other protocol-specified criteria as described in Section 6.2.1.3 
8.3.3 
Reasons for Removal From Study 
Reasons for removal of a subject from the study are: 
• 
decision by sponsor  
• 
withdrawal of consent from study 
• 
death 
• 
lost to follow-up 
9. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
9.1 
Definition of Safety Events 
9.1.1 
Disease-related Events 
Disease-related events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease as summarized in Table 6 below. 
Table 6.  Disease-related Events by System Organ Class 
System Organ Class 
Term 
Blood and lymphatic system disorders 
lymphadenopathy 
General disorders and administration site 
conditions 
disease progression  
Investigations 
weight decreased 
Skin and subcutaneous tissue disorders 
night sweats   


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Disease-related events that do not qualify as adverse events or serious adverse events:  
• 
An event which is part of the normal course of disease under study (eg, disease 
progression in oncology or hospitalization due to disease progression) is to be 
reported as a Disease-related event.  
• 
Death due to the disease under study is to be recorded on the Event CRF.  
Disease-related events that would qualify as an adverse event or serious adverse event: 
• 
An event based on the underlying disease that is worse than expected as assessed 
by the investigator for the subject’s condition or if the investigator believes there is a 
causal relationship between the investigational product(s)/study 
treatment/protocol-required therapies and disease worsening, this must be reported 
as an adverse event or serious adverse event. 
9.1.2 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.   
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study, 
is not considered an adverse event.   
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Event CRF. 
For situations when an adverse event or serious adverse event is due to DLBCL, 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, DLBCL).  
Note:  The term “disease progression” should not be used to describe the 
disease-related event or adverse event.   
An adverse device effect is any adverse event related to the use of a medical device.  
Adverse device effects include adverse events resulting from insufficient or inadequate 


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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. 
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
legally acceptable representative requests to withdraw from protocol-required therapies 
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study. 
9.1.3 
Serious Adverse Events 
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a Disease-Related Event as 
defined in Section 9.1.1): 
• 
fatal 
• 
life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
congenital anomaly/birth defect 
• 
other medically important serious event 
A disease-related event as listed in Table 6 is to be reported as a serious adverse 
event if: 
• 
the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, or 
• 
if the investigator believes a causal relationship exists between the investigational 
medicinal product(s)/protocol-required therapies and the event,  
• 
and the event meets at least 1 of the serious criteria. 
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).   
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, liver injury, or events that 
necessitate an emergency room visit, outpatient surgery, or urgent intervention. 


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9.2 
Safety Event Reporting Procedures 
9.2.1 
Reporting Procedures for Disease-related Events 
The investigator is responsible for ensuring that all Disease-Related Events observed by 
the investigator or reported by the subject that occur after the first dose of blinatumomab 
through the safety follow-up visit are recorded on the Event CRF as a Disease-Related 
Event. 
Disease-Related Events assessed by the investigator to be more severe than expected 
and/or related to the investigational medicinal product(s)/study 
treatment/protocol-required therapies, and determined to be serious, must be recorded 
on the Event CRF as Serious Adverse Events. 
Additionally, the investigator is required to report a fatal Disease-Related Event on the 
Event CRF as a Disease-Related Event. 
9.2.2 
Adverse Events 
9.2.2.1 
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of blinatumomab 
through the safety follow-up visit are reported using the Event CRF. 
The investigator must assign the following adverse event attributes: 
•
adverse event diagnosis or syndrome(s), if known (if not known, signs or symptoms)
•
dates of onset and resolution (if resolved)
•
severity (and/or toxicity per protocol)
•
assessment of relatedness to investigational product(s), medical device(s) or other
protocol-required therapies
•
action taken.
The adverse event grading scale used will be the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0.  The grading scale used in this study is described 
in Appendix A.   
The investigator must assess whether the adverse event is possibly related to the 
investigational product(s), and/or other protocol-required therapies.  This relationship is 
indicated by a “yes” or “no” response to the question:  Is there a reasonable possibility 
that the event may have been caused by the investigational product(s), and/or other 
protocol-required therapies?  


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The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a clinically 
significant change from the subject’s baseline values.  All grade 3 and grade 4 laboratory 
values should be recorded as adverse events.  In addition, if signs or symptoms are 
associated with the laboratory abnormality, the signs/symptoms and the laboratory 
abnormality should all be recorded as adverse events.  The laboratory abnormality and 
any signs/symptoms should be graded according to their own CTCAE criteria.  
The investigator is expected to follow reported adverse events until stabilization or 
reversibility.  
9.2.2.2 
Reporting Procedures for 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 after signing of the informed 
consent  through 30 days after the last dose of investigational product are recorded in 
the subject’s medical record and are submitted to Amgen.  Additionally 
blinatumomab-related serious adverse events that occur after the safety follow-up visit 
through the end of the long-term follow-up will be reported. 
All serious adverse events must be submitted to Amgen within 24 hours following the 
investigator’s knowledge of the event via the Event CRF. 
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event Contingency Report Form within 24 hours of the investigator’s 
knowledge of the event.  See Appendix B for a sample of the Serious Adverse Event 
Worksheet /electronic Serious Adverse Event Contingency Report Form.  For EDC 
studies where the first notification of a Serious Adverse Event is reported to Amgen via 
the eSerious Adverse Event Contingency Report Form, the data must be entered into 
the EDC system when the system is again available. 
The investigator must assess whether the serious adverse event is possibly related to 
investigational product, medical device, and/or other protocol-required therapies.  This 
relationship is indicated by a “yes” or “no” response to the question: Is there a 
reasonable possibility that the event may have been caused by the investigational 
product, medical device, and/or other protocol-required therapies?  Relatedness means 
that there are facts or reasons to support a relationship between investigational product 
and the event. 


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The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility.  
New information relating to a previously reported serious adverse event must be 
submitted to Amgen.  All new information for serious adverse events must be sent to 
Amgen within 24 hours following knowledge 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 Event CRF. 
If a subject is permanently withdrawn from protocol-required therapies because of a 
serious adverse event, this information must be submitted to Amgen. 
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local regulatory requirements and procedures. 
9.2.2.3 
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period 
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  In some countries (eg, European Union [EU] 
member states), investigators are required to report serious adverse events that they 
become aware of after end of study.  If serious adverse events are reported, the 
investigator is to report them to Amgen within 24 hours following the investigator’s 
knowledge 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 for the purposes of expedited 
reporting. 


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9.2.2.4 
Serious Adverse Events That are not to be Reported by the 
Sponsors to Regulatory Agencies in an Expedited Manner  
Events which are morbidities associated in general with lymphoma and lymphoma 
therapy do not require expedited reporting: 
• 
Planned hospitalization 
Expected disease related serious adverse events are not subjected to report individually 
in an expedited manner by Amgen unless it meets the criteria listed in Section 9.1.3.  A 
local Safety Review Committee will be used to monitor the benefit/risk of such events.  
9.3 
Pregnancy and Lactation Reporting 
If a female subject becomes pregnant, or a male subject fathers a child, while the 
subject is taking blinatumomab report the pregnancy to Amgen Global Patient Safety as 
specified below. 
In addition to reporting any pregnancies occurring during the study, investigators should 
report pregnancies that occur 48 hours after the last dose of blinatumomab.  
The pregnancy should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of the event of a pregnancy.  Report a pregnancy on the 
Pregnancy Notification Worksheet (Appendix C).  Amgen Global Patient Safety will 
follow-up with the investigator regarding additional information that may be requested.  
If a female subject becomes pregnant during the study, the investigator should attempt 
to obtain information regarding the birth outcome and health of the infant.   
If the outcome of the pregnancy meets a criterion for immediate classification as a 
Serious Adverse Event (eg, female subject experiences a spontaneous abortion, 
stillbirth, or neonatal death or there is a fetal or neonatal congenital anomaly) the 
investigator will report the event as a Serious Adverse Event. 
If a female breastfeeds while taking protocol-required therapies report the lactation case 
to Amgen as specified below.  
Any lactation case should be reported to Amgen Global Patient Safety within 24 hours of 
the investigator’s knowledge of event.  Report a lactation case on the Lactation 
Notification Worksheet (Appendix C).  Amgen Global Patient Safety will follow-up with 
the investigator regarding additional information that may be requested. 


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If a male subject's female partner becomes pregnant, the investigator should discuss 
obtaining information regarding the birth outcome and health of the infant from the 
pregnant partner. 
10. 
STATISTICAL CONSIDERATIONS  
10.1 
Study Endpoints, Analysis Sets, and Covariates 
10.1.1 
Study Endpoints 
10.1.1.1 
Primary Endpoint 
MRD-negative rate at the end of cycle 1 of blinatumomab 
10.1.1.2 
Secondary Endpoint(s) 
• 
PFS  
• 
Duration of MRD-negative status 
• 
OS 
• 
Incidence, grade and severity of treatment emergent adverse events  
10.1.1.3 
Exploratory Endpoint(s) 
• 
Anti-blinatumomab antibody formation 
• 
MRD-negative rate calculated at each timepoint measured following blinatumomab 
treatment 
• 
Incidence of alloHSCT (number of subjects with alloHSCT), including the 
methodology and clinical outcomes 
• 
Relationship between pre-specified co-variates with MRD-negative status and clinical 
outcomes 
• 
Summary of MRD characteristics prior to treatment with blinatumomab: 
− 
The percentage of MRD positivity in PET-CT negative subjects post aHSCT 
− 
Rate and timing of MRD-negative to MRD-positive change during the 24-month 
run-in period   
10.1.2 
Analysis Sets 
10.1.2.1 
Full Analysis Set  
The full analysis set will include all subjects who received blinatumomab.  Subjects who 
were treated beyond the required sample size of 30 subjects will be included in this 
analysis set.  The full analysis set will be used for the final analysis. 
10.1.2.2 
Primary Analysis Set 
The primary analysis set will include the first 30 subjects who received blinatumomab.  
The primary analysis set will be used for the primary analysis.  


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10.1.2.3 
Target Dose Analysis Set  
The target dose analysis set will include all subjects from the full analysis set who 
completed at least 7 days of infusion on the highest intended dose.  In addition, all 
subjects who discontinue treatment with blinatumomab due to disease progression 
during cycle 1 will also be included in the target analysis set.  The target dose analysis 
set will be used as sensitivity analysis set for the final analysis.  
10.1.2.4 
Pre-treatment Analysis Set 
The pre-treatment analysis set will include all subjects that enroll in the study.  
10.1.2.5 
DLT Analysis Set 
A subject needs to meet 1 of the following criteria to be DLT evaluable: 
• 
The subject experiences a DLT in the DLT evaluation period; OR 
• 
The subject is removed from treatment for an adverse event/toxicity; OR 
• 
The subject is removed from treatment for reasons other than an adverse 
event/toxicity, ie, disease progression, and the subject has received at least 7 days 
of the target blinatumomab dose; OR 
• 
The subject does not experience a DLT and completes DLT evaluation period. 
10.1.3 
Covariates and Subgroups 
The relationship of clinical and baseline covariates to endpoints will be explored.  
Categories for the covariates will be defined in the Statistical Analysis Plan.  Baseline 
covariates include: 
• 
Age 
• 
Sex 
• 
Race 
• 
Stage at diagnosis 
• 
IPI, aaIPI, at diagnosis and secondary IPI, secondary aaIPI at relapse 
• 
Cell of origin (if available locally) 
• 
Double and triple hit (if available locally) 
• 
Refractory to frontline treatment 
• 
Relapse within 1 year of diagnosis 
• 
High-risk first complete remission  
• 
MRD-positive at enrollment/MRD-positive within 6 months from 
enrollment/MRD-positive any time later during run-in.   


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10.1.4 
Handling of Missing and Incomplete Data 
Subjects missing post-baseline MRD assessments will be considered not to have 
achieved MRD-negative status. 
10.2 
Sample Size Considerations 
This is a single-arm estimation study.  It is assumed that an MRD-negative rate of 10% 
could be observed by chance in this study.  Therefore, if the assumed rate of MRD 
negativity is at least 30%, then the sample size for this study (N = 30) is sufficient to 
demonstrate that, with 95% confidence, the rate of achieving MRD negativity is greater 
than 10%.  This would also be sufficient to demonstrate evidence of clinical activity.  
A table showing the CI for different assumed rates of MRD negativity with a sample size 
of N = 30 is presented below: 
Assumed rate of MRD 
negativity, n (%) 
Lower 95% Confidence Limit 
(%) 
Upper 95% Confidence Limit 
(%) 
8 (26.7) 
12.3 
45.9 
9 (30) 
14.7 
49.4 
11 (36.7) 
19.9 
56.1 
12 (40) 
22.7 
59.4 
14 (46.7) 
28.3 
65.7 
The study will enroll approximately 90 subjects to achieve the desired sample size of 
30 subjects who are MRD-positive at the time of enrollment or during the run-in period.  
As part of the run-in period subjects will be followed by clinic visits at 3, 5, 7, 9 and 
12 months and thereafter every 3 months up to 24 months for monitoring of MRD status, 
it is therefore expected that there could be more than 30 subjects who at some point 
become MRD-positive before the study ends.  Any subject who becomes MRD-positive 
after the 30 subjects required are treated will still be eligible for treatment with 
blinatumomab, therefore the final sample size may be higher than 30 subjects. 
10.3 
Planned Analyses 
10.3.1 
Interim Analyses 
Amgen will conduct evaluations of the ongoing DLT rate to assess if the threshold for 
early trial termination as defined in Section 6.2.2 has been reached.  The stopping rules 
use a Bayesian approach to terminate the study if the posterior probability that the DLT 
rate is greater than 25% is > 90%.  The stopping boundaries assume a prior distribution 
of (0.50, 1.50) are presented in Table 7 and the operating characteristics with 
pre-specified batch size of 10 new subjects per batch are presented in Table 8.  The 


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evaluations could occur more frequently if necessary to address emerging safety 
concerns.  The operating characteristics in Table 8 provide the probability of stopping 
the trial early for given hypothetical true DLT rates, whereas the stopping criteria in 
Table 7 are based on situations where the empirical evidence would result in a posterior 
probability of ≥ 90% that the true DLT rate is ≥ 25%. 
Table 7.  Stopping Boundary With Posterior Probability of 90% and DLT Limit of 
25% 
Number of DLT evaluable subjects 
(inclusive) 
Stop study if observing these many DLTs 
10 
≥ 5 
20 
≥ 8 
30 
Study completes 
DLT = dose limiting toxicity 
Table 8.  Operating Characteristics With Batch Size of 10 Subjects 
True DLT rate 
Probability of stopping 
Average sample size 
0.20 
5% 
30 
0.25 
14% 
28 
0.30 
27% 
26 
0.35 
44% 
24 
0.40 
62% 
21 
DLT = dose limiting toxicity 
10.3.2 
Data Review Team 
A DRT will review safety data periodically.  A DRT is a group, internal to Amgen but 
external to the relevant blinatumomab product team, that reviews accumulating data 
from the ongoing clinical trial to ensure no avoidable increased risk for harm to subjects.  
Continuous toxicity monitoring for early termination of the trial will be performed.  
Adverse events and DLTs (as defined in Section 6.2.2) observed in all subjects will be 
evaluated every 10th subject or every 6 months, whichever occurs earlier.  The DRT 
includes a clinician, a safety physician, and a biostatistician.  Membership, procedures, 
and meeting timing will be described in detail in the study DRT charter. 
10.3.3 
Primary Analysis 
The objective of the primary analysis is to estimate the primary endpoint, MRD-negative 
rate at the end of cycle 1 of blinatumomab.  All subjects in the treatment period are 
considered MRD positive, regardless whether the cycle 1 day 1 MRD test results are 


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positive or negative because these subjects have been tested MRD positive in the run-in 
period.  The primary analysis will be triggered when the first 30 enrolled subjects have 
had the opportunity to complete cycle 1 of blinatumomab treatment.  Any subjects 
treated beyond the required sample size of 30 subjects will not be part of the primary 
analysis.  The safety and tolerability of blinatumomab will also be assessed at the time of 
the primary analysis. 
At the time of the primary analysis the following will be obtained using the pre-treatment 
analysis set:  estimates of the rate and timing of conversion from MRD-negative to MRD 
positive, and exploratory endpoints of MRD status by the NGS MRD test in PET-CT 
negative subjects. 
10.3.4 
Final Analysis 
The main objective of the final analysis is to provide estimates of the secondary and 
exploratory endpoints.  The final analysis will also include updated estimates for the 
endpoints assessed at the primary analysis (MRD-negative rate and MRD prior to 
blinatumomab treatment).  The updated estimates will include all subjects enrolled in the 
study who received at least one dose of blinatumomab.  This would include any subjects 
treated after the expected sample size of 30 subjects. 
A sensitivity analysis will be performed on the time to event endpoints in relation to 
MRD-negative versus no MRD-negative. 
The other exploratory endpoints will also be assessed at the point of the final analysis. 
The final analysis will be conducted when the subjects in the Primary Analysis Set have 
had an opportunity to complete the long-term follow-up visit 1 year from the first dose of 
blinatumomab. 
The final analysis will also assess the potential long-term effect of blinatumomab on 
safety. 
10.4 
Planned Methods of Analysis  
10.4.1 
General Considerations 
Continuous variables will be summarized by the non-missing sample size (n), mean, 
standard deviation, median, first and third quartiles, minimum, and maximum. 
Categorical variables will be summarized by the n and percentage in each category. 
Time to event endpoints will be summarized with Kaplan-Meier (KM) curves, KM 
proportions at selected time points, KM quartiles (when estimable), the number  of 
subjects with events, the number of subjects censored, and the pattern of censoring. 


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Point estimates for efficacy endpoints will be accompanied by 2-sided 95% CI including 
estimates of KM quartiles (Brookmeyer and Crowley, 1982), KM proportions (Kalbfleisch 
and Prentice, 1980), and binomial proportions (Clopper and Pearson, 1934). 
No adjustments for multiplicity are planned for the analyses of the efficacy endpoints. 
10.4.2 
Primary Efficacy Endpoint 
MRD-negative rate at the end of cycle 1 of blinatumomab.  MRD is defined as negative 
when the tumor clone sequence in plasma is below the assay’s limit of detection (to be 
determined in the assay validation). 
MRD-negative rate is calculated as the number of subjects with MRD-negative status 
after treatment with blinatumomab divided by the total number of subjects in the 
respective analysis set. 
Exact binomial 95% CI will be used to analyze MRD-negative rate. 
10.4.3 
Secondary Efficacy Endpoint(s) 
PFS is calculated as the time from the date of first dose of blinatumomab until the date 
of diagnosis of relapse of lymphoma (by PET-CT, CT, clinical assessment or relapse 
biopsy, whichever is the preferred method), or date of death, whichever is the earliest.  
Subjects alive who did not have progression or new anti-tumor treatment (excluding any 
stem cell transplantation) will be censored at last date of tumor assessment. 
The duration of MRD-negative status will be assessed only in subjects who achieve 
MRD-negative status after blinatumomab treatment.  Duration of MRD-negative status 
will be defined from the time when a negative MRD result is first established until 
documented MRD-positive reoccurrence, or disease progression (or, death due to any 
cause).  Subjects without any of these events at the time of the analysis will be censored 
at their last disease assessment date. 
Overall survival will be defined from the first dose of blinatumomab treatment until death 
due to any cause.  Subjects still alive at the time of the analysis will be censored at date 
last known to be alive. 
PFS, duration of MRD-negative status and OS will be summarised with KM analyses. 
10.4.4 
Safety Endpoints 
10.4.4.1 
Adverse Events 
The Medical Dictionary for Regulatory Activities will be used to code all adverse events 
to a system organ class and a preferred term.  Adverse events of interest (EOI) 


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categories will be based on search strategies defined by Medical Coding.  All adverse 
event tables will be summarized by treatment group.  Treatment-emergent adverse 
events are events with an onset after the administration of the first dose of 
blinatumomab treatment. 
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, serious adverse events, adverse events leading to withdrawal of 
protocol-specified therapy, and fatal adverse events. 
Subject incidence of all treatment-emergent adverse events, serious adverse events, 
adverse events leading to withdrawal of blinatumomab, and fatal adverse events will be 
tabulated by system organ class and preferred term in descending order of frequency; 
similar summaries will be repeated for EOIs.  Time to onset and duration of selected 
EOIs (infection and neurologic events) may also be summarized. 
Any serious adverse event that occurs from enrolment through the day before the first 
dose of blinatumomab (during the run-in period) will be documented and summarised.  
This applies to all subjects who have been enrolled onto the study, regardless of 
whether they achieve the MRD-positive status required to start treatment with 
blinatumomab. 
A summary of blinatumomab treatment-emergent adverse events will be tabulated by 
system organ class, preferred term, and worst grade. 
10.4.4.2 
Disease Related Events 
Subject incidence of disease related events and fatal disease related events in the 
blinatumomab treatment period (through the safety follow-up visit) will be tabulated by 
system organ class and preferred term. 
10.4.4.3 
Laboratory Test Results 
Shift tables between the worst post-baseline and baseline grades for selected laboratory 
parameters will be provided.  The analyses of selected safety laboratory parameters 
including immunoglobulins, platelets, and liver parameters will include summary 
statistics over time. 
10.4.4.4 
Vital Signs 
The number and percentage of subjects with abnormal changes in systolic blood 
pressure, diastolic blood pressure and heart rate will be summarized. 


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10.4.4.5 
Electrocardiogram 
The 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 QTc 
effect.  Since these evaluations may not necessarily be performed under the rigorous 
conditions expected to lead to meaningful evaluation of QTc data; summaries and 
statistical analyses of ECG measurements are not planned, and these data would not be 
expected to be useful for meta-analysis with data from other trials. 
10.4.4.6 
Antibody Formation 
The incidence and percentage of subjects who develop anti-blinatumomab antibodies 
(binding and if positive, neutralizing) at any time may be tabulated. 
10.4.4.7 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to blinatumomab for 
subjects in the Full Analysis Set.  The number of days on IP and the proportion of 
subjects receiving each dose level will be summarized.  In addition, the duration of 
therapy, the relative treatment duration, the cumulative dose, and the percent of 
intended 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.  
10.4.4.8 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving concomitant medications from 
enrolment through the day before the first dose of blinatumomab (run-in period) and from 
day 1 through safety follow-up will be summarized by preferred term as coded by the 
World Health Organization Drug dictionary by Full Analysis Sets.  In addition, the 
number and proportion of subjects receiving anticancer therapies during long term 
follow-up will be summarized by World Health Organization Drug dictionary preferred 
term in the Full Analysis Set. 
11. 
REGULATORY OBLIGATIONS 
11.1 
Informed Consent 
An initial sample informed consent form is provided for the investigator to prepare the 
informed consent document to be used at his or her site.  Updates to the template are to 
be communicated formally in writing from the Amgen Clinical Manager to the 
investigator.  The written informed consent form is to be prepared in the language(s) of 
the potential patient population. 


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Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject or legally acceptable representative 
after adequate explanation of the aims, methods, anticipated benefits, and potential 
hazards of the study and before any protocol-specific screening procedures or any 
investigational product(s) is/are administered.  A legally acceptable representative is 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. 
The investigator is also responsible for asking the subject if the subject has a primary 
care physician and if the subject agrees to have his/her primary care physician informed 
of the subject’s participation in the clinical study.  If the subject agrees to such 
notification, the investigator is to inform the subject’s primary care physician of the 
subject’s participation in the clinical study.  If the subject does not have a primary care 
physician and the investigator will be acting in that capacity, the investigator is to 
document such in the subject’s medical record.   
The acquisition of informed consent and the subject’s agreement or refusal of his/her 
notification of the primary care physician is to be documented in the subject’s medical 
records, and the informed consent form  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.  The original signed informed consent form is to be 
retained in accordance with institutional policy, and a copy of the signed consent form is 
to be provided to the subject or legally acceptable 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 
informed consent form to the subject and must allow for questions.  Thereafter, both the 
subject and the witness must sign the informed consent form to attest that informed 
consent was freely given and understood.   
11.2 
Institutional Review Board/Independent Ethics Committee 
A copy of the protocol, proposed informed consent form, other written subject 
information, and any proposed advertising material must be submitted to the IRB/IEC for 
written approval.  A copy of the written approval of the protocol and informed consent 
form must be received by Amgen before recruitment of subjects into the study and 
shipment of Amgen investigational product. 


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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 is to notify the IRB/IEC of deviations from the protocol or 
serious adverse events occurring at the site and other adverse event reports received 
from Amgen, in accordance with local procedures. 
The investigator is responsible for 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. 
11.3 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained for 
documents submitted to Amgen.   
• 
Subjects are to be identified by a unique subject identification number.   
• 
Where permitted, date of birth is to be documented and formatted in accordance with 
local laws and regulations.   
• 
On the CRF demographics page, in addition to the unique subject identification 
number, include the age at time of enrollment.   
• 
For Serious Adverse Events 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 date of birth (in accordance with local laws and 
regulations). 
• 
Documents that are not submitted to Amgen (eg, signed informed consent forms) are 
to be kept in confidence by the investigator, except as described below. 
In compliance with governmental/International Conference on Harmonisation Good 
Clinical Practice (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. 


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11.4 
Investigator Signatory Obligations 
Each clinical study report is to be signed by the investigator or, in the case of 
multi-center 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 
11.5 
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 ICH GCP Guidelines, and 
• 
applicable laws and regulations. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments and Study Termination 
Amgen may amend the protocol at any time.  After Amgen amends the protocol, the 
Investigator is to return the signed Investigator’s Signature page confirming agreement 
to continue participation in the study according to the amendment.  The IRB/IEC must be 
informed of all amendments and give approval.  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. 
Amgen reserves the right to terminate the study at any time.  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 investigational product(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 investigational product(s) and by what mechanism, after 
termination of the study and before the product(s) is/are available commercially. 


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12.2 
Study Documentation and Archive 
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 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. 
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, informed consent forms, 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. 
• 
Non-investigational product(s), and/or medical device(s) or combination product(s) 
documentation, as applicable. 
In addition, all original source documents supporting entries in the CRFs must be 
maintained and be readily available. 
Retention of study documents will be governed by the Clinical Trial Agreement. 
12.3 
Study Monitoring and Data Collection 
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. 
The clinical monitor is responsible for verifying the CRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research.  The 


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Clinical Monitor is to have access to subject medical records and other study-related 
records needed to verify the entries on the CRFs. 
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. 
In accordance with ICH GCP and the sponsor’s audit plans, this study may be selected 
for audit by representatives from Amgen’s Global R&D 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. 
Data capture for this study is planned to be electronic: 
• 
All source documentation supporting entries into the CRFs must be maintained and 
readily available. 
• 
Updates to CRFs will be automatically documented through the software’s “audit 
trail”. 
• 
To ensure the quality of clinical data across all subjects and sites, a clinical data 
management review is performed on subject data received at Amgen.  During this 
review, subject data are checked for consistency, omissions, and any apparent 
discrepancies.  In addition, the data are reviewed for adherence to the protocol and 
GCP.  To resolve any questions arising from the clinical data management review 
process, data queries are created in the EDC system database for site resolution 
and subsequently closed by the EDC system or by an Amgen reviewer. 
• 
The investigator signs only the Investigator Verification Form for this EDC study or 
the investigator applies an electronic signature in the EDC system if the study is set 
up to accept an electronic signature.  This signature indicates that investigator 
inspected or reviewed the data on the CRF, the data queries, and agrees with the 
content. 
Amgen (or designee) will perform self-evident corrections to obvious data errors in the 
clinical trial database.  Self-evident corrections will be documented in the CRF Standard 
Instructions and the CRF Specific Instructions, both of these will be available through the 
EDC system.  Examples of obvious data errors that may be corrected by Amgen (or 
designee) include deletion of obvious duplicate data (ie, the same results sent twice with 
the same date with different visit, [eg, week 4 and early termination]) and updating a 
specific response if the confirming datum is provided in the “other, specify” field (eg, for 
race, reason for ending study). 


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12.4 
Investigator Responsibilities for Data Collection 
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subjects not receiving protocol-required therapies) as 
stipulated in the protocol for each subject in the study.  For subjects who withdraw prior 
to completion of all protocol-required visits and are unable or unwilling to continue the 
Schedule of Assessments (Table 4), the investigator can search publically 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.   
12.5 
Language 
CRFs must be completed in English.  TRADENAMES® (if used) for concomitant 
medications may be entered in the local language.  All written information and other 
material to be used by subjects and investigative staff must use vocabulary and 
language that are clearly understood.   
12.6 
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 International Committee of Medical Journal Editors Recommendations for the 
Conduct of Reporting, Editing, and Publications of Scholarly Work in Medical Journals, 
which states: 
• 
Authorship credit should 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 should meet conditions 1, 
2, 3 and 4. 
• 
When a large, multicenter group has conducted the work, the group should identify 
the individuals who accept direct responsibility for the manuscript.  These individuals 
should fully meet the criteria for authorship defined above. 


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• 
Acquisition of funding, collection of data, or general supervision of the research 
group, alone, does not justify authorship. 
• 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
• 
Each author should 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. 
12.7 
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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13. 
REFERENCES 
Avivi I, Zilberlicht A, Dann EJ, et al. Strikingly high false positivity of surveillance 
FDG-PET/CT scanning among patients with diffuse large cell lymphoma in the rituximab 
era. Am J Hematol. 2013;88:400-405. 
Bader P, Kreyenberg H, Henze GH, et al. Prognostic value of minimal residual disease 
quantification before allogeneic stem-cell transplantation in relapsed childhood acute 
lympho-blastic leukemia: the ALL-REZ BFM Study Group. J.Clin.Oncol. 
2009;27:377-384. 
Bassan R, Spinelli O, Oldani E, et al.  Improved risk classification for risk-specific 
therapy based on the molecular study of MRD in adult ALL. Blood. 2009;113:4153-4162. 
Bhatt VR, Vose JM.  Hematopoietic stem cell transplantation for non-Hodgkin 
lymphoma. Hematol Oncol Clin North Am.  2014;28(6):1073-1095. 
Borowitz MJ, Devidas M, Hunger SP, et al.  Clinical significance of minimal residual 
disease in childhood acute lymphoblastic leukemia and its relationship to other 
prognostic factors: a Children's Oncology Group study.  Blood.  2008;111:5477-5485. 
Brookmeyer R, Crowley J.  A Confidence Interval for the Median Survival Time. 
Biometrics. 1982;38:29-41. 
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;107:1116-1123.  
Cheah CY, Hofman MS, Dickinson M, et al.  Limited role for surveillance PET-CT 
scanning in patients with diffuse large B-cell lymphoma in complete metabolic remission 
following primary therapy.  Br J Cancer. 2013;109:312-317. 
Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. United 
Kingdom National Cancer Research, I. Recommendations for initial evaluation, staging, 
and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification.  J Clin Oncol.  2014;32:3059-3068.  
Clopper CJ and Pearson ES.  The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial.  Biometrika.  1934;26:404-413. 
Conter V, Bartram CR, Valsecchi MG, et al.  Molecular response to treatment redefines 
all prognostic factors in children and adolescents with B-cell precursor acute 
lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study.  
2010.  Blood.  115:3206–3214. 
Crump M, Kuruvilla J, Couban S, et al.  Randomized comparison of gemcitabine, 
dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin 
chemotherapy before autologous stem-cell transplantation for relapsed and refractory 
aggressive lymphomas: NCIC-CTG LY.12.  J Clin Oncol.  2014;32:3490-3496. 
Dreier T, Baeuerle PA, Fichtner I, et al.  T cell co-stimulus-independent and very 
efficacious inhibition of tumor growth in mice bearing subcutaneous or leukemic human 
B cell lymphoma xenografts by a CD19-/CD3- bispecific single-chain antibody construct. 
J Immunol.  2003;170:4397-4402. 
ESMO guidelines for Non-Hodgkin’s Lymphoma. www.esmo.org/Guidelines  
Fisher SG and Fisher RI.  The Epidemiology of Non-Hodgkin's Lymphoma. Oncogene. 
2004;23:6524-534.  


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Friedberg W.  Relapsed/refractory diffuse large B-cell lymphoma.  Hematology Am Soc 
Hematol Educ Program.  2011;10:498-505. 
Ghielmini M, Vitolo U, Kimby E, et al.  Panel Members of the 1st, ECCoML. ESMO 
Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large 
B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia 
(CLL).  Ann Oncol.  2013;24:561-576. 
Gisselbrecht C, Glass B, Mounier N, et al.  Salvage Regimens With Autologous 
Transplantation for Relapsed Large B-Cell Lymphoma in the Rituximab Era.  J Clin 
Oncol.  2010;28:4184-4190. 
Gökbuget N, Kneba R, Raff T, et al.  German Multicenter Study Group for Adult Acute 
Lymphoblastic Leukemia. Adult patients with acute lymphoblastic leukemia and 
molecular failure display a poor prognosis and are candidates for stem cell 
transplantation and targeted therapies.  Blood.  2012;120:1868–1876. 
Green TM, Young KH, Visco C, et al.  Immunohistochemical double-hit score is a strong 
predictor of outcome in patients with diffuse large B-cell lymphoma treated with rituximab 
plus cyclophosphamide, doxorubicin, vincristine, and prednisone.  J Clin Oncol.  2012; 
30:3460-3467. 
Hartge P and Wang SS.  Overview of the etiology and epidemiology of lymphoma. 
Non-Hodgkin’s Lymphomas. Lippincott, Philadelphia, 2004;711-727. 
Hicks L K, Bering H, Carson KR, et al.  The ASH Choosing Wisely(R) campaign: five 
hematologic tests and treatments to question.  Hematology Am Soc Hematol Educ 
Program.  2013,9-14. 
Huntington S, Svoboda J, Doshi JA.  Cost-effectiveness analysis of routine surveillance 
imaging of patients with diffuse large B-cell lymphoma in first remission.   
J Clin Oncol.  2015;33:1467-1474.  
Jahr S, Hentze H, Englisch S, et al.  DNA fragments in the blood plasma of cancer 
patients: quantitations and evidence for their origin from apoptotic and necrotic cells. 
Cancer Res.  2001;61:1659-1665. 
Kalbfleisch J D, Prentice R L.  The Statistical Analysis of Failure Time Data.  New York: 
John Wiley & Sons; 1980. 
Kurtz DM, Green MR, Bratman SV, et al.  Noninvasive monitoring of diffuse large B-cell 
lymphoma by immunoglobulin high-throughput sequencing.  Blood.  
2015;125:3679-3687 
Lazarus HM, Zhang MJ, Carreras J, et al.  A comparison of HLA-identical sibling 
allogeneic versus autologous transplantation for diffuse large B cell lymphoma: a report 
from the CIBMTR.  Biol Blood Marrow Transplant.  2010;16:35-45. 
Leon S A., Shapiro B, Sklaroff, DM, and Yaros MJ.  Free DNA in the serum of cancer 
patients and the effect of therapy.  Cancer Res.  1977;37:646-650. 
Martelli M, Ferreri AJ, Agostinelli C, Di Rocco A,  Pfreundschuh M, Pileri SA.  Diffuse 
Large B-cell Lymphoma.  Crit Rev Oncol Hematol.  2013;87:146-171. 
National Comprehensive Cancer Network (NCCN) Practice Guidelines in Oncology®: 
Non-Hodgkin’s Lymphomas version 1 2016. 
https://www.nccn.org/professionals/physician_gls/f_guidelines.asp 


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Raff T, Gökbuget N, Lüschen S, et al.  Molecular relapse in adult standard-risk ALL 
patients detected by prospective MRD monitoring during and after maintenance 
treatment: Data from the GMALL 06/99 and 07/03 trials.  Blood.  2007;109: 910-915. 
Robinson SP, Boumendil A, Finel H, et al.  Autologous stem cell transplantation for 
relapsed/refractory diffuse large B-cell lymphoma: efficacy in the rituximab era and 
comparison to first allogeneic transplants. A report from the EBMT Lymphoma Working 
Party.  Bone Marrow Transplant.  2016;51:365–371 
Roschewski M, Dunleavy K, Pittaluga S, et al.  Monitoring of circulating tumor DNA as 
minimal residual disease in diffuse large B-cell lymphoma.  Blood.  2014;124:139-139. 
Sauter CS, Matasar MJ, Meikle J, et al.  Prognostic value of FDG-PET prior to 
autologous stem cell transplantation for relapsed and refractory diffuse large B-cell 
lymphoma.  Blood.  2015;125:2579-2581. 
Savage KJ, Johnson NA, Ben-Neriah S, et al. MYC gene rearrangements are associated 
with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP 
chemotherapy.  Blood.  2009;114:3533-3537 
Schlereth B, Quadt C, Dreier T, et al.  T-cell activation and B-cell depletion in 
chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody 
construct.  Cancer Immunol Immunother.  2006;55:503-514. 
Swerdlow SH, Campo E, Harris NL, et al.  WHO Classification of Tumors of 
Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France:  The International Agency 
for Research on Cancer; 2008. 
Thompson CA, Ghesquieres H, Maurer MJ, et al.  Utility of routine post-therapy 
surveillance imaging in diffuse large B-cell lymphoma.  J Clin Oncol. 2014;32:3506-3512. 
Tilly H, Gomes da Silva M, Vitolo U, et al.  Diffuse Large B-Cell Lymphoma: ESMO 
Clinical Practice Guidelines. Ann Oncol. 2015;26 (suppl 5):116-125. 
Tilly H, Dreyling M. Diffuse Large B-cell Non-Hodgkin's Lymphoma: ESMO Clinical 
Recommendations for Diagnosis, Treatment and Follow-up.  Ann. Oncol.  
2009;20:(Supp 4): iv110-iv112. 
van der Velden, V, Cazzaniga G, Schrauder A et al.  Analysis of minimal residual 
disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time 
quantitative PCR data.  Leukemia.  2007;21:604-611. 
van Imhoff GW, McMillan A, Matasar MJ, et al.  Ofatumumab Versus Rituximab Salvage 
Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The 
ORCHARRD Study (OMB110928).  56th Annual Meeting of the American Society of 
Hematology. 2014;124:630 


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14. 
APPENDICES 


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Appendix A.  Additional Safety Assessment Information 
Adverse Event Grading Scale 
Refer to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 for adverse event grading and information.  The CTCAE scale is 
available at the following location:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
Drug-induced Liver Injury Reporting & Additional Assessments  
Reporting 
To facilitate appropriate monitoring for signals of Drug Induced Liver Injury (DILI), cases 
of concurrent AST or ALT and total bilirubin and/or international normalized ratio (INR) 
elevation according to the criteria specified in Section 6.4 require the following: 
• 
The event is to be reported to Amgen as a serious adverse event within 24 hours of 
discovery or notification of the event (ie, before additional etiologic investigations 
have been concluded) 
• 
The appropriate care report form (CRF) (eg, Event 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 serious adverse 
events if they meet the criteria for a serious adverse event defined in Section 9.1.3. 
Additional Clinical Assessments and Observation 
All subjects in whom investigational product(s) or protocol-required therapies is/are 
withheld (either permanently or conditionally) due to potential DILI as specified in 
Table 3. or who experience AST or ALT elevations > 3 x 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 (total and direct), and INR within 24 hours  
• 
In cases of TBL > 2 x ULN or INR > 1.5, retesting of liver tests, bilirubin (total and 
direct), and INR is to be performed every 24 hours until laboratory abnormalities 
improve 


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Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(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 (CBC) with differential to assess for eosinophilia 
− 
Serum total immunoglobulin IgG, Anti-nuclear antibody, Anti Smooth Muscle 
Antibody, and Liver Kidney Microsomal antibody 1 to assess for autoimmune 
hepatitis 
− 
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 
− 
CPK, haptoglobin, LDH, and peripheral blood smear 
− 
Appropriate liver imaging if clinically indicated 
• 
Appropriate blood sampling for pharmacokinetic analysis if this has not already been 
collected  
• 
Hepatology consult (liver biopsy may be considered in consultation with an 
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 investigational product(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. 


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Appendix B.  Sample eSerious Event Contingency Form 
 


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Appendix C.  Pregnancy and Lactation Notification Worksheets 
 


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Appendix D.  International Prognostic Index for Diffuse Large B-cell Lymphoma  
IPI 
aaIPI 
Risk group 
IPI Factors 
Risk group 
IPI Factors 
Low 
0 or 1 
Low 
0 
Low Intermediate 
2 
Low Intermediate 
1 
High Intermediate 
3 
High Intermediate 
2 
High 
4 or 5 
High 
3 
IPI Factors 
Older than 60 years of age (not used for aaIPI) 
Disease stage III/IV 
Lactate dehydrogenase level elevated 
ECOG performance score ≥ 2 
Extranodal disease > 1 site (not used for aa-IPI) 
IPI = International Prognostic Index; aaIPI = age-adjusted IPI; ECOG = Eastern Cooperative Oncology 
Group 


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Appendix E.  Response Assessment per the Lugano Classification  
5-point scale 
1, no uptake above background;  
2, uptake ≤ mediastinum;  
3, uptake > mediastinum but ≤ liver;  
4, uptake moderately > liver;  
5, uptake markedly higher than liver and/or new lesions;  
X, new areas of uptake unlikely to be related to lymphoma. 
Response 
Complete 
Response 
Partial Response 
Stable Disease 
Progressive 
Disease 
PET-CT 
Response 
Complete 
Metabolic 
Response 
Partial Metabolic 
Response 
No Metabolic 
Response 
Progressive 
Metabolic Disease 
Target 
Masses 
Score 1, 2, or 3 
with or without a 
residual mass 
Score 4 or 5  
reduced uptake 
compared with 
baseline  
residual mass(es) 
of any size 
Score 4 or 5  
no significant 
change in FDG 
uptake from 
baseline  
Score 4 or 5 with an 
increase in intensity 
of uptake from 
baseline and/or new 
FDG-avid foci 
consistent with 
lymphoma  
New 
Lesions 
None 
None 
None 
New FDG-avid foci 
consistent with 
lymphoma rather 
than another 
etiology  
Bone 
Marrow 
No FDG-avid focal 
lesions 
Residual uptake 
higher than 
uptake in normal 
marrow but 
reduced 
compared with 
baseline  
No change from 
baseline 
New or recurrent 
FDG-avid foci 
FDG = fluorodeoxyglucose; PET-CT = positron emission tomography and computed tomography 


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Appendix F.  Eastern Cooperative Oncology Group Performance Status 
Grade 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
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 house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours 
3 
Capable of only limited self-care; confined to a bed or chair more than 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair 
5 
Dead 
 


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Amendment 3 
Protocol Title:  A Phase 2 Open-Label Study to Determine the Effect of 
Blinatumomab on Minimal Residual Disease in Subjects With High-risk Diffuse 
Large B-cell Lymphoma Post-autologous Hematopoietic Stem-cell Transplantation 
 
Amgen Protocol Number (Blinatumomab) 20150291 
EudraCT Number:  2016-003255-30 
NCT Number: 03298412 
 
Amendment Date: 
18 July 2018 
 
Rationale: 
This is Amendment 3 for Blinatumomab Study 20150291. 
This protocol is being amended to: 
• 
Increase the screening window to 28 days. 
• 
Clarify when pathology tumor block/slides should be collected and MRD tests should 
be performed during screening. 
• 
Clarify that the MRD plasma sample needs to be drawn after the post aHSCT 
PET-CT scan. 
• 
Clarify that subjects will be excluded from receiving blinatumomab if there is 
evidence of CNS involvement with DLBCL at disease evaluation prior to starting 
blinatumomab. 
• 
Clarify that grade 4 hematologic toxicity and grade 4 laboratory abnormalities lasting 
≥ 7 days exclude lymphopenia.  This lymphopenia is reported to last for 6 months or 
as long as a year after therapy completion (Chiappella et al, 2017; Coffier, 2007; 
Plosker and Figgitt, 2003).  Lymphopenia is also a known adverse event with 
blinatumomab that does resolve after the therapy is completed.  Lymphopenia is not 
an immediately life-threatening threatening event, is treated well with supportive 
care, and reverses after completion of R-chemotherapy and blinatumomab infusion. 
• 
Clarify when vital signs will be obtained for hospitalized subjects versus subjects in 
the outpatient clinic. 
• 
Make administrative and editorial updates. 


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Description of Changes: 
Section:  Global 
Change:  Make administrative updates and correct minor editorial errors throughout the 
protocol. 
Section:  Header 
Replace: 
Date:  24 August 2017 
With: 
Date:  18 July 2018 
Section:  Title Page 
Add: 
NCT Number: 03298412 
Section:  Title Page 
Replace: 
, MD 
Medical Director, Clinical Development 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA  
Telephone: 
 
Email: 
 
 
Global Clinical Trial Manager 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA  
Telephone: 
 
Email: 
 
With: 
 
Senior Medical Scientist, Clinical Research 
AMGEN Research (Munich) GmbH 
Staffelseestr. 2, 81477 München, Germany 
Telephone: 
 
Email:
 
Global Clinical Trial Manager 
AMGEN Research (Munich) GmbH 
Staffelseestr. 2, 81477 München, Germany 
Telephone:
 
Email:


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Section:  Title Page 
Add: 
Date: 
26 January 2017 
Amendment 1: 
23 May 2017 
Amendment 2: 
24 August 2017 
Amendment 3: 
18 July 2018 
Section:  Investigator’s Agreement 
Paragraph 1 
Replace: 
I have read the attached protocol entitled A Phase 2 Open-Label Study to Determine the 
Effect of Blinatumomab on Minimal Residual Disease in Subjects With High-risk Diffuse 
Large B-cell Lymphoma Post-autologous Hematopoietic Stem-cell Transplantation, 
dated 24 August 2017, and agree to abide by all provisions set forth therein.   
With: 
I have read the attached protocol entitled A Phase 2 Open-Label Study to Determine the 
Effect of Blinatumomab on Minimal Residual Disease in Subjects With High-risk Diffuse 
Large B-cell Lymphoma Post-autologous Hematopoietic Stem-cell Transplantation, 
dated 18 July 2018, and agree to abide by all provisions set forth therein.   
Section:  Protocol Synopsis 
Study Design:  Paragraph 1 
Replace: 
The study will consist of up to a 21-day screening period, a run-in period of up to 
24 months, a 12-week treatment period (8 weeks of blinatumomab treatment followed by 
a 4-week treatment free period), a 30-day safety follow-up visit after the last dose of 
blinatumomab, and a long-term follow-up period that begins after the safety follow-up 
visit is completed until 1 year from the first dose of blinatumomab. 
With: 
The study will consist of up to a 28-day screening period, a run-in period of up to 
24 months, a 12-week treatment period (8 weeks of blinatumomab treatment followed by 
a 4-week treatment free period), a 30-day safety follow-up visit after the last dose of 
blinatumomab, and a long-term follow-up period that begins after the safety follow-up 
visit is completed until 1 year from the first dose of blinatumomab. 
Section:  Protocol Synopsis 
Summary of Subject Eligibility Criteria, Paragraph 1 
Replace: 
Finally, subjects must have an MRD plasma sample collected ≤ 3 weeks from the post 
aHSCT PET-CT scan.   
With: 
Finally, subjects must have an MRD plasma sample collected ≤ 3 weeks after the post 
aHSCT PET-CT scan. 


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Section:  Study Design and Treatment Schema, page 6 
Replace: 
 
 
Day 1 
Cycle 1 
Blinatumomab 
Cycle 1: 8 weeks of IV 
infusion (9 µg/d x 7d; 
28 µg/d x 7d; 
112 µg/d x 42d) followed 
by 4 week treatment-free 
interval  
Screening (Up to 21 days) 
Enrollment (n = 90) 
Safety Follow-up 
Run-in Period
a 
Treatment Period  
Long-term Follow-upd 
MRD Monitoring up 
to 24 months  
Treatment Assignment n = 30 
Run-in 2: 
Treatment 
Assignment  
(-7 days) 
Run-in 1 
(MRD 
Monitoring) 
MRD-positive/ 
PET-CT negative 
(at any time after 
enrollment)
b 
Day 71 
30 d after the 
last dose of IP 
EOS 
MRD Monitoringc 


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With: 
 
Day 1 
Cycle 1 
Blinatumomab 
Cycle 1: 8 weeks of IV 
infusion (9 µg/d x 7d; 
28 µg/d x 7d; 
112 µg/d x 42d) followed 
by 4 week treatment-free 
interval  
Screening (Up to 28 days) 
Enrollment (n = 90) 
Safety Follow-up 
Run-in Period
a 
Treatment Period  
Long-term Follow-upd 
MRD Monitoring up 
to 24 months  
Treatment Assignment n = 30 
Run-in 2: 
Treatment 
Assignment  
(-7 days) 
Run-in 1 
(MRD 
Monitoring) 
MRD-positive/ 
PET-CT negative 
(at any time after 
enrollment)
b 
Day 71 
30 d after the 
last dose of IP 
EOS 
MRD Monitoringc 


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Section:  3.1 Study Design 
Bullet 1 
Replace: 
• 
Screening period (up to 21 days) 
With: 
• 
Screening period (up to 28 days) 
Section:  3.5.1 Study Duration for Subjects 
Bullet 1 
Replace: 
The total study duration for an individual subject will vary from approximately 
1 to 3 years.  This includes a 21-day screening period, a run-in period of up to 
24-months, a 12 week treatment period (8 weeks of treatment with blinatumomab 
followed by a 4-week treatment free period), a 30-day safety follow-up and a long term 
follow-up period that begins after the safety follow-up period until 1-year from the first 
dose of blinatumomab. 
With: 
The total study duration for an individual subject will vary from approximately 
1 to 3 years.  This includes a 28-day screening period, a run-in period of up to 
24-months, a 12-week treatment period (8 weeks of treatment with blinatumomab 
followed by a 4-week treatment free period), a 30-day safety follow-up and a long term 
follow-up period that begins after the safety follow-up period until 1-year from the first 
dose of blinatumomab. 
Section:  4.1.1 Inclusion Criteria – Part 1 
Criteria 108 
Replace: 
MRD plasma sample collected ≤ 3 weeks from post aHSCT PET-CT scan 
With: 
MRD plasma sample collected ≤ 3 weeks after the post aHSCT PET-CT scan 
Section:  4.1.2 Exclusion Criteria – Part 1 
Criteria 202 
Replace: 
Evidence of CNS involvement with DLBCL 
With: 
Evidence of CNS involvement with DLBCL at disease evaluation obtained prior to 
starting blinatumomab 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 7 of 20 
CONFIDENTIAL 
 
 
Section:  4.2.1 Inclusion Criteria – Part 2 
Criteria 113 
Replace: 
PET-CT negative (defined by Deauville criteria ≤ 3) at run-in 2 performed ≤ 3 weeks from 
MRD-positive assessment at run-in 1.  Historical PET-CT are allowed if performed 
≤ 6 weeks from day 1 (first dose of blinatumomab) and subject has no clinical signs or 
symptoms suggestive of disease progression (eg, increase in lactate dehydrogenase 
[LDH] not otherwise explained) 
With: 
PET-CT negative (defined by Deauville criteria ≤ 3) at run-in 2 performed ≤ 3 weeks from 
MRD test result available to the site at run-in 1.  Historical PET-CT are allowed if 
performed ≤ 6 weeks from day 1 (first dose of blinatumomab) and subject has no clinical 
signs or symptoms suggestive of disease progression (eg, increase in lactate 
dehydrogenase [LDH] not otherwise explained) 
Section:  4.2.1 Inclusion Criteria – Part 2 
Criteria 114 
Replace: 
Adequate organ function determined ≤ 2 week prior to treatment assignment with 
blinatumomab as follows: 
With: 
Adequate organ function determined ≤ 7 days prior to treatment assignment with 
blinatumomab as follows: 
Section:  6.2.2 Study Stopping Rules 
Bullets 3 and 4 
Replace: 
• 
grade 4 hematologic toxicity lasting ≥ 7 days 
• 
grade 4 laboratory abnormalities lasting ≥ 7 days 
With: 
• 
grade 4 hematologic toxicity lasting ≥ 7 days (excluding lymphopenia) 
• 
grade 4 laboratory abnormalities lasting ≥ 7 days (excluding lymphopenia) 
 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 8 of 20 
CONFIDENTIAL 
 
 
Section:  7.1 Schedule of Assessments, Table 4.  Schedule of Assessments 
Replace: 
Study Period 
Screen 
Run-ina 
Treatment 
Follow-up 
 
 
Run-in 1a Run-in 2 
Blinatumomab Cycle 1h 
Treatment 
Free 
interval 
Safety 
Long-term/
EOS 
Cycle Day (d) 
-21d 
to  
-14d 
Up to 
21 d 
MRD 
monitor 
Treatment 
Assign 
 (-7 d) 
1 
2 3 8 9 
10 
15 
16 
17 
22 
29 
36 
43 
50 
57 
71 
30 d after 
last dose 
of IPi 
Q3 
monthsj 
Cycle Week 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 to 12 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part 1 eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part 2 eligibility 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Assignment 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history & Prior 
therapies 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsb 
 
X 
 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG PS 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Concomitant 
medications 
 
 
←       Continuous from enrollment     → 
 
Anti-lymphoma 
therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurological Exam 
 
X 
 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam  
 
X 
 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical tumor 
assessment 
 
X 
 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Adverse Events 
 
 
 
 
←       Continuous from first dose of blinatumomab       → 
 
Disease Related 
Events 
 
 
 
 
←       Continuous from first dose of blinatumomab       → 
 
Page 1 of 3 
Footnotes defined on the last of this table 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 9 of 20 
CONFIDENTIAL 
 
 
Study Period 
Screen 
Run-ina 
Treatment 
Follow-up 
 
 
Run-in 1a Run-in 2 
Blinatumomab Cycle 1h 
Treatment 
Free 
interval 
Safety 
Long-term/
EOS 
Cycle Day (d) 
-21d 
to  
-14d 
Up to 
21 d 
MRD 
monitor 
Treatment 
Assign 
 (-7 d) 
1 2 3 8 9 10 
15 
16 
17 
22 
29 
36 
43 
50 
57 
71 
30 d after 
last dose 
of IPi 
Q3 
monthsj 
Cycle Week 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 to 12 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological AE 
 
 
 
 
←       Continuous from first dose of blinatumomab        → 
 
Serious AE 
←       Continuous from Informed Consent    → 
X j 
Local Labs/Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serology 
(HBsAg and HCVAb) 
and HIV testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry  
 
X 
 
X 
 
X X X X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Hematology  
 
X 
 
X 
 
X X X X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Coagulation  
 
 
 
X 
 
X  
X X 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
LDH 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Creatinine clearance c 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing d 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoglobulins (IgG, 
IgM, IgA) 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
CRP 
 
X 
 
 
X X  
X X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Lumbar puncture 
 
 
 
 
Only if  neurological event leading to interruption/discontinuation 
of IP or seizure e 
 
 
 
 
Neurological safety 
blood 
 
 
 
 
Only if  neurological event leading to interruption/discontinuation 
of IP or seizure 
 
 
 
 
Central Labs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-blinatumomab 
antibodies  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pathology tumor 
block/slides l 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
MRD testing  
X 
 
X 
 
X  
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Xm 
 
Xf 
Page 2 of 3 
Footnotes defined on the last of this table 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 10 of 20 
CONFIDENTIAL 
 
 
Study Period 
Screen 
Run-ina 
Treatment 
Follow-up 
 
 
Run-in 1a Run-in 2 
Blinatumomab Cycle 1h 
Treatment 
Free 
interval 
Safety 
Long-term/
EOS 
Cycle Day (d) 
-21d 
to  
-14d 
Up to 
21 d 
MRD 
monitor 
Treatment 
Assign 
(-7 d) 
1 2 3 8 9 10 
15 
16 
17 
22 
29 
36 
43 
50 
57 
71 
30 d 
after last 
dose of 
IPi 
Q3 
monthsj 
Cycle Week 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 to 12 
 
 
Radiographic  
Assessments 
PET-CT g 
 
 
 
X g 
 
 
 
 
 
 
 
 
 
X g 
 
X g 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinatumomab h 
 
 
 
 
← IV infusion → 
 
 
 
 
Page 3 of 3 
AE = adverse event; IV = intravenous; CT = computed tomography; CRP = C-reactive protein; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology 
Group performance status; HBsAg = hepatitis B surface antigen; HCVAb = hepatitis C virus antibody; HIV = human immunodeficiency virus; Ig = immunoglobulin; 
IP = investigational product; LDH = lactate dehydrogenase; MRD = minimal residual disease; PET = positron emission tomography; Q3 = every 3 months; EOS = end 
of study 
a Run-in period is up to 24 months in duration.  During the run-in 1 period enrolled subjects that are MRD-negative/PET-CT negative will be followed at 3, 5, 7, 
9 months and thereafter every 3 months (± 1 week) up to 24 months for MRD testing.  At enrollment or during the run-in 1 subjects that are MRD-positive will 
complete Run-in 2 assessments to determine part 2 eligibility and treatment assignment. 
b Vitals signs will be monitored every 4 to 8 hours based on institutional standard of practice for a minimum of 72 hours following initiation of blinatumomab treatment 
and 48 hours at each dose-step. 
c Creatinine clearance is calculated by the Cockcroft-Gault equation 
d Pregnancy test must be performed within 72 hours from the start of run-in period and 72 hours prior to the first dose of blinatumomab (day [D] 1, cycle 1).  
e Lumbar puncture only required during treatment period if subject has a neurologic event leading to interruption/discontinuation or at seizure.  
f During the long term follow-up period an optional sample for MRD testing will be obtained at the time of suspicion of relapse and relapse. 
g  PET-CT must be performed at run-in 2 in subjects that are MRD positive during run-in 1.  Subjects that are MRD-positive at screening may qualify for treatment 
assignment with historical PET-CT negative results as long as PET-CT was performed ≤ 6 weeks from  day 1 cycle 1 (first dose of blinatumomab) and subject has no 
clinical signs or symptoms  suggestive of disease progression (eg, increase in LDH not otherwise explained).  Every attempt should be made to complete PET and 
CT within 3 days of each other, particularly during blinatumomab treatment. PET-CT at day 71 (+ 3 days) will only be performed if subject remains MRD+ at 
cycle 1 day 57 or has clinical signs and symptoms of disease progression.  During the long-term follow-up period a PET-CT or CT will be obtained at time of relapse 
and as per institutional standards for surveillance. 
h Blinatumomab will be administered by continuous IV infusion.  Cycle 1 is 12 weeks (84 days) in duration and includes 8 weeks (56 days) of blinatumomab IV infusion 
followed by a 4-week (28-day) treatment-free interval (day 57 to 84).  Cycle 1 dosing is 9 µg/day x 7 days (days 1 to 7); 28 µg/day x 7 days (days 8 to 14); 112 µg/day 
x 42 days (15 to 56).  Subjects should be monitored in a hospital for a minimum of 72 hours following initiation of blinatumomab treatment and 48 hours at each 
dose-step of blinatumomab (see Section 6.2.1.1). 
i Safety follow-up visit to be completed 30 days (+ 3 days) after the last dose of blinatumomab   


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 11 of 20 
CONFIDENTIAL 
 
 
j Long-term follow-up begins after the safety follow-up visit and visits will occur every 3 months (± 2 weeks) for a maximum of 1 year from the first dose of 
blinatumomab, or until relapse at which time the subject will be followed for survival via telephone contact. 
k During the long-term follow-up only serious adverse events related to blinatumomab will be collected 
l Relapsed and/or diagnostic pathology tumor block/slides must be shipped for determination of malignant clone sequence at the time of enrollment.  During the 
long-term follow up an optional pathology tumor block/slides will be obtained at the time of relapse. 
m Visit must be completed within + 3 days of day 71 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 12 of 20 
CONFIDENTIAL 
 
 
With: 
Study Period 
Screen 
Run-ina 
Treatment 
Follow-up 
 
 
Run-in 1a Run-in 2 
Blinatumomab Cycle 1h 
Treatment 
Free 
interval 
Safety 
Long-term/
EOS 
Cycle Day (d) 
-28 d to  
-24 dn,o  
Up to 
28 d 
MRD 
monitor 
Treatment 
Assign      
(-7 d) 
1 
2 3 8 9 
10 
15 
16 
17 
22 
29 
36 
43 
50 
57 
71 
30 d after 
last dose 
of IPi 
Q3 
monthsj 
Cycle Week 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 to 12 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part 1 eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Part 2 eligibility 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment Assignment 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history & Prior 
therapies 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsb 
 
X 
 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG PS 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Concomitant 
medications 
 
 
←       Continuous from enrollment     → 
 
Anti-lymphoma 
therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurological Exam 
 
X 
 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Physical exam  
 
X 
 
X 
X X X X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical tumor 
assessment 
 
X 
 
X 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Adverse Events 
 
 
 
 
←       Continuous from first dose of blinatumomab       → 
 
Disease Related 
Events 
 
 
 
 
←       Continuous from first dose of blinatumomab       → 
 
Page 1 of 3 
Footnotes defined on the last of this table 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 13 of 20 
CONFIDENTIAL 
 
 
Study Period 
Screen 
Run-ina 
Treatment 
Follow-up 
 
 
Run-in 1a Run-in 2 
Blinatumomab Cycle 1h 
Treatment 
Free interval 
Safety 
Long-term/
EOS 
Cycle Day (d) 
-28 d to  
-24 dn,o  
Up to 
28 d 
MRD 
monitor 
Treatment 
Assign    
(-7 d) 
1 2 3 8 9 10 
15 
16 
17 
22 
29 
36 
43 
50 
57 
71 
30 d 
after 
last 
dose 
of IPi 
Q3 
monthsj 
Cycle Week 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 to 12 
 
 
General Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological AE 
 
 
 
 
←       Continuous from first dose of blinatumomab        → 
 
Serious AE 
←       Continuous from Informed Consent    → 
X j 
Local Labs/Tests 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serology 
(HBsAg and HCVAb) 
and HIV testing 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry  
 
X 
 
X 
 
X X X X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Hematology  
 
X 
 
X 
 
X X X X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Coagulation  
 
 
 
X 
 
X  
X X 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
LDH 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xm 
 
X 
Creatinine clearance c 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing d 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Immunoglobulins (IgG, 
IgM, IgA) 
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
X 
CRP 
 
X 
 
 
X X  
X X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
Lumbar puncture 
 
 
 
 
Only if  neurological event leading to interruption/discontinuation 
of IP or seizure e 
 
 
 
 
Neurological safety 
blood 
 
 
 
 
Only if  neurological event leading to interruption/discontinuation 
of IP or seizure 
 
 
 
 
Central Labs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Anti-blinatumomab 
antibodies  
 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pathology tumor 
block/slides l 
Xo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
MRD testing  
Xp 
 
X 
 
X  
 
 
 
 
X 
 
 
 
 
 
X 
 
X 
Xm  
 
Xf 
Page 2 of 3 
Footnotes defined on the last of this table 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 14 of 20 
CONFIDENTIAL 
 
 
Study Period 
Screen 
Run-ina 
Treatment 
Follow-up 
 
 
Run-in 1a Run-in 2 
Blinatumomab Cycle 1h 
Treatment 
Free 
interval 
Safety 
Long-term/
EOS 
Cycle Day (d) 
-28 d to  
-24 dn,o  
Up to 
28 d 
MRD 
monitor 
Treatment 
Assign    
(-7 d) 
1 2 3 8 9 10 
15 
16 
17 
22 
29 
36 
43 
50 
57 
71 
30 d 
after last 
dose of 
IPi 
Q3 
monthsj 
Cycle Week 
 
 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 to 12 
 
 
Radiographic  
Assessments 
PET-CT g 
 
 
 
X g 
 
 
 
 
 
 
 
 
 
X g 
 
X g 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blinatumomab h 
 
 
 
 
← IV infusion → 
 
 
 
 
Page 3 of 3 
AE = adverse event; IV = intravenous; CT = computed tomography; CRP = C-reactive protein; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology 
Group performance status; HBsAg = hepatitis B surface antigen; HCVAb = hepatitis C virus antibody; HIV = human immunodeficiency virus; Ig = immunoglobulin; 
IP = investigational product; LDH = lactate dehydrogenase; MRD = minimal residual disease; PET = positron emission tomography; Q3 = every 3 months; EOS = end 
of study 
a Run-in period is up to 24 months in duration.  During the run-in 1 period enrolled subjects that are MRD-negative/PET-CT negative will be followed at 3, 5, 7, 
9 months and thereafter every 3 months (± 1 week) up to 24 months for MRD testing.  At enrollment or during the run-in 1 subjects that are MRD-positive will 
complete Run-in 2 assessments to determine part 2 eligibility and treatment assignment. 
b On days of hospitalization, obtain vital sign monitoring every 4 to 8 hours based on institutional standard of practice.  When subject is in the outpatient clinic, 
only obtain 1 baseline vital sign per visit. 
c Creatinine clearance is calculated by the Cockcroft-Gault equation 
d Pregnancy test must be performed within 72 hours from the start of run-in period and 72 hours prior to the first dose of blinatumomab (day [D] 1, cycle 1).  
e Lumbar puncture only required during treatment period if subject has a neurologic event leading to interruption/discontinuation or at seizure.  
f During the long term follow-up period an optional sample for MRD testing will be obtained at the time of suspicion of relapse and relapse. 
g  PET-CT must be performed at run-in 2 in subjects that are MRD positive during run-in 1.  Subjects that are MRD-positive at screening may qualify for treatment 
assignment with historical PET-CT negative results as long as PET-CT was performed ≤ 6 weeks from  day 1 cycle 1 (first dose of blinatumomab) and subject has no 
clinical signs or symptoms  suggestive of disease progression (eg, increase in LDH not otherwise explained).  Every attempt should be made to complete PET and 
CT within 3 days of each other, particularly during blinatumomab treatment. PET-CT at day 71 (+ 3 days) will only be performed if subject remains MRD+ at cycle 1 
day 57 or has clinical signs and symptoms of disease progression.  During the long-term follow-up period a PET-CT or CT will be obtained at time of relapse and as 
per institutional standards for surveillance. 
h Blinatumomab will be administered by continuous IV infusion.  Cycle 1 is 12 weeks (84 days) in duration and includes 8 weeks (56 days) of blinatumomab IV infusion 
followed by a 4-week (28-day) treatment-free interval (day 57 to 84).  Cycle 1 dosing is 9 µg/day x 7 days (days 1 to 7); 28 µg/day x 7 days (days 8 to 14); 112 µg/day 
x 42 days (15 to 56).  Subjects should be monitored in a hospital for a minimum of 72 hours following initiation of blinatumomab treatment and 48 hours at each 
dose-step of blinatumomab (see Section 6.2.1.1). 
i Safety follow-up visit to be completed 30 days (+ 3 days) after the last dose of blinatumomab   


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 15 of 20 
CONFIDENTIAL 
 
 
j Long-term follow-up begins after the safety follow-up visit and visits will occur every 3 months (± 2 weeks) for a maximum of 1 year from the first dose of 
blinatumomab, or until relapse at which time the subject will be followed for survival via telephone contact. 
k During the long-term follow-up only serious adverse events related to blinatumomab will be collected 
l Relapsed and/or diagnostic pathology tumor block/slides must be shipped for determination of malignant clone sequence at the time of enrollment.  During the 
long-term follow up an optional pathology tumor block/slides will be obtained at the time of relapse. 
m Visit must be completed within + 3 days of day 71. 
n The screen tests should be completed within the indicated window (ie, 28 to 24 days before enrollment), but the subject won’t be considered a screen fail 
if these tests are completed outside of this window. 
o An exception to the maximum 28-day screening period may be allowed at certain sites/countries with prior approval from Amgen to ensure sufficient time 
to obtain pathology tumor block/slides prior to enrollment.  However, all other screening procedures must be completed within the 28-day screening 
period. 
p The screening MRD test should be performed 28 to 24 days before enrollment and should be shipped to central laboratory together with the slides of 
tumor tissue without any delay.


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 16 of 20 
CONFIDENTIAL 
 
 
Section:  7.2.1 Screening/Enrollment 
Replace: 
The screening period is up to 21 days.  Screening procedures are to be completed 
during the screening period at time points designated in the Schedule of Assessments 
(Table 4). 
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy or any disallowed therapy.  After signing the written 
informed consent form, the site will register the subject and screen the subject for part 1 
eligibility criteria.   
If a subject has not met all part 1 eligibility criteria at the end of the 21-day window, the 
subject will be registered as a screen fail (see Section 7.2.2).  Screen fail subjects may 
be eligible for re-screening once.  Subjects satisfying part 1 eligibility requirements will 
be enrolled. 
With: 
The screening period is up to 28 days.  Screening procedures are to be completed 
during the screening period at time points designated in the Schedule of Assessments 
(Table 4). 
Note:  An exception to the maximum 28-day screening period may be allowed at 
certain sites/countries with prior approval from Amgen to ensure sufficient time to 
obtain pathology tumor block/slides prior to enrollment.  However, all other 
screening procedures must be completed within the 28-day screening period.   
Informed consent must be obtained before completing any screening procedure or 
discontinuation of standard therapy or any disallowed therapy.  After signing the written 
informed consent form, the site will register the subject and screen the subject for part 1 
eligibility criteria.   
If a subject has not met all part 1 eligibility criteria at the end of the 28-day window, the 
subject will be registered as a screen fail (see Section 7.2.2).  Screen fail subjects may 
be eligible for re-screening once.  Subjects satisfying part 1 eligibility requirements will 
be enrolled. 
Section:  7.2.2 Rescreening 
Replace: 
Subjects who are unable to complete or meet Part 1 eligibility criteria on initial screening 
will be permitted to rescreen once.  Rescreen subjects must first be registered as screen 
failed and subsequently registered as rescreened.  Subjects will retain the same subject 
identification number assigned at the original screening.  Once the subject is registered 
as rescreened, a new 21-day screening window will begin.  If the rescreening period 
begins more than 30 days after the original signing of the informed consent form, 
informed consent must be repeated. 
With: 
Subjects who are unable to complete or meet Part 1 eligibility criteria on initial screening 
will be permitted to rescreen once.  Rescreen subjects must first be registered as screen 
failed and subsequently registered as rescreened.  Subjects will retain the same subject 
identification number assigned at the original screening.  Once the subject is registered 
as rescreened, a new 28-day screening window will begin.  If the rescreening period 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 17 of 20 
CONFIDENTIAL 
 
 
begins more than 30 days after the original signing of the informed consent form, 
informed consent must be repeated. 
Section:  7.2.4 Treatment 
Paragraph 2 
Replace: 
Subjects should be monitored in a hospital for a minimum of 72 hours following initiation 
of blinatumomab treatment and 48 hours at each dose-step increase in blinatumomab 
(see Section 6.2.1.1) and vital signs monitored every 4 to 8 hours based on institutional 
standard of practice.  
With: 
Subjects should be monitored in a hospital for a minimum of 72 hours following initiation 
of blinatumomab treatment and 48 hours at each dose-step increase in blinatumomab 
(see Section 6.2.1.1).  On days of hospitalization, vital signs should be monitored 
every 4 to 8 hours based on institutional standard of practice.  When subject is in the 
outpatient clinic, only obtain 1 baseline vital sign per visit. 
Section:  7.3.7 Vital Signs 
Paragraph 1 
Replace: 
Vital signs will be monitored throughout the duration of the study as indicated in the 
schedule of assessments (Table 4).  Vitals signs will be monitored every 4 to 8 hours 
based on institutional standard of practice for a minimum of 72 hours following initiation 
of blinatumomab treatment and 48 hours at each dose-step. 
With: 
Vital signs will be monitored throughout the duration of the study as indicated in the 
schedule of assessments (Table 4).  On days of hospitalization, vital signs will be 
monitored every 4 to 8 hours based on institutional standard of practice for a minimum of 
72 hours following initiation of blinatumomab treatment and 48 hours at each dose-step.  
When subject is in the outpatient clinic, only obtain 1 baseline vital sign per visit. 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 18 of 20 
CONFIDENTIAL 
 
 
Section:  7.4 Laboratory Procedures 
Table 5.  Analyte Listing 
Replace: 
Local Laboratory 
 
Central 
Laboratory 
Chemistry 
Coagulation 
Hematology 
Other 
Neurological 
Safety 
Other 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatininea 
Uric acid 
Total bilirubin 
Direct 
bilirubin 
Alkaline 
phosphatase 
AST (SGOT) 
ALT (SGPT) 
Amylase 
Lipase 
PTT/INR 
PT 
Fibrinogen 
Red blood cells 
Hemoglobin 
Hematocrit 
Platelets 
White blood cells 
Differential 
• 
Neutrophils 
• 
Bands/stabs 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
Urine or serum 
pregnancy test 
C-reactive protein 
Immunoglobulins 
(IgG, IgA, IgM) 
Lumbar punctureb 
LDH 
HIV 
HBsAg 
HCVAb 
 
CSF cell 
count 
CSF 
differential 
CSF flow 
cytometry 
CSF protein 
CSF glucose 
Additional 
CSF viral 
studies as 
clinically 
indicated 
Pathology tumor 
block/slides for 
MRD assay 
Anti-blinatumoma
b antibodies 
Plasma for MRD 
testing 
Serum sample for 
neurological 
safety 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 19 of 20 
CONFIDENTIAL 
 
 
With: 
Local Laboratory 
 
Central 
Laboratory 
Chemistry 
Coagulation 
Hematology 
Other 
Neurological 
Safety 
Other 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Total protein 
Albumin 
Calcium 
Magnesium 
Phosphorus 
Glucose 
BUN or Urea 
Creatininea 
Uric acid 
Total bilirubin 
Direct 
bilirubin 
Alkaline 
phosphatase 
AST (SGOT) 
ALT (SGPT) 
Amylase 
Lipase 
PTT/INR 
PT 
Fibrinogen 
Red blood cells 
Hemoglobin 
Hematocrit 
Platelets 
White blood cells 
Differential 
• 
Neutrophils 
• 
Bands/stabs 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
Urine or serum 
pregnancy test 
C-reactive protein 
Immunoglobulins 
(IgG, IgA, IgM) 
Lumbar punctureb 
LDH 
HIV 
HBsAg 
HCVAb 
 
CSF cell 
count 
CSF 
differential 
CSF flow 
cytometry 
CSF protein 
CSF glucose 
Additional 
CSF viral 
studies as 
clinically 
indicated 
Pathology tumor 
block/slides for 
MRD assay 
Anti-blinatumoma
b antibodies 
Plasma for MRD 
testing 
Neurological 
safety sample 
for lumbar 
puncture (if 
applicable) 
Section:  7.4.2 Minimum Residual Disease Testing 
Paragraph 3 
Add: 
In addition, samples of peripheral blood will be collected for MRD testing in plasma by 
NGS as previously described by (Kurtz et al, 2015; Roschewski et al, 2014).  The time 
points for MRD testing is described in Section 3.1, Study Design, and indicated in the 
Schedule of Assessments (Table 4).  The screening MRD test should be performed 
24 to 28 days before enrollment and should be shipped to central laboratory 
together with the slides of tumor tissue without any delay. 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  18 July 2018 
Page 20 of 20 
CONFIDENTIAL 
 
 
References 
Chiappella A, Martelli M, Angelucci E, et al.  Rituximab-dose-dense chemotherapy with 
or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk 
diffuse large B-cell lymphoma (DLCL04):  final results of a multicentre, open-label, 
randomised, controlled, phase 3 study.  Lancet Oncol.  2017;18:1076–1088. 
Coffier B.  Rituximab therapy in malignant lymphoma.  Oncogene.  2007;26:3603-3613. 
Plosker GL, Figgitt DP.  Rituximab: a review of its use in non-Hodgkin's lymphoma and 
chronic lymphocytic leukaemia.  Drugs.  2003;63(8):803-843. 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  24 August 2017 
Page 1 of 8 
CONFIDENTIAL 
 
 
Amendment 2 
Protocol Title:  A Phase 2 Open-Label Study to Determine the Effect of 
Blinatumomab on Minimal Residual Disease in Subjects With High-risk Diffuse 
Large B-cell Lymphoma Post-autologous Hematopoietic Stem-cell Transplantation 
 
Amgen Protocol Number (blinatumomab) 20150291 
EudraCT Number:  2016-003255-30 
 
Amendment Date: 
24 August 2017 
 
Rationale: 
This is Amendment 2 for Blinatumomab Study 20150291. 
This protocol is being amended to: 
• 
include stopping rules for disease progression. 
• 
add hepatitis serology and human immunodeficiency virus testing.  
• 
add benefit/risk assessment language. 
• 
make administrative and editorial updates. 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  23 May 2017 
Page 1 of 11 
Amendment 1 
Protocol Title:  A Phase 2 Open-Label Study to Determine the Effect of 
Blinatumomab on Minimal Residual Disease in Subjects With High-risk Diffuse 
Large B-cell Lymphoma Post-autologous Hematopoietic Stem-cell Transplantation 
 
Amgen Protocol Number (blinatumomab) 20150291 
EudraCT Number:  2016-003255-30 
 
Amendment Date: 
23 May 2017 
 
Rationale: 
This is Amendment 1 for Blinatumomab Study 20150291. 
This protocol is being amended to: 
• 
Include stopping rules for excessive toxicity, define DLT evaluable subjects, and add 
interim analyses to review DLT rate 
• 
Clarify timing and purpose of MRD tests that occur before treatment and on cycle 1 
day 1 
• 
Remove language related to sensitivity analysis performed on the MRD-negative rate 
at the end of cycle 1 of blinatumomab 
• 
Make administrative and editorial updates (this includes an update to the Schedule of 
Assessments table to re-add 2 PET assessments that were mistakenly deleted 
during publication of original protocol) 
CONFIDENTIAL 
 
 

SAP_001.pdf: 
Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  29 May 2019 
Page 1 of 43 
CONFIDENTIAL  
 
 
Statistical Analysis Plan 
 
Protocol Title: 
A Phase 2 Open-Label Study to Determine the 
Effect of Blinatumomab on Minimal Residual 
Disease in Subjects With High-risk Diffuse Large 
B-cell Lymphoma Post-autologous Hematopoietic 
Stem-cell Transplantation 
Short Protocol Title: 
CAPILANO 
Protocol Number: 
20150291 
NCT Number: 
03298412 
Authors: 
 ; 
    
Sponsor: 
Amgen Inc 
One Amgen Center Drive 
Thousand Oaks, CA 91320, USA 
Phone: +1-805-447-1000 
SAP Date: 
Document Version 
Date 
Original (v[2.0]) 
29 May 2019 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  29 May 2019 
Page 2 of 43 
CONFIDENTIAL  
 
 
Version Number 
Date 
(DDMMMYYYY) 
Summary of Changes,  
including rationale for changes 
Original (v1.0) 
08DEC2017 
 
[Amendment 1 (v2.0)] 
29May2019 
1. SAP is updated as per protocol 
amendment 3 by using SMART 
Template version. 
2. Section 3 Study Design and 
Treatment Schema 
The screening period is up to 21 days. 
Screening procedures are to be 
completed during the screening 
period at time points designated in the 
Schedule of Assessments, 
Revised per protocol amendment 3 as 
follows: 
The screening period is up to 28 days. 
Screening procedures are to be 
completed during the screening 
period at time points designated in the 
Schedule of Assessments 
3. Section 6 Definitions for Triple Hit 
added. 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  29 May 2019 
Page 3 of 43 
CONFIDENTIAL  
 
 
Table of Contents 
1. 
Introduction ............................................................................................................. 8 
2. 
Objectives, Endpoints and Hypotheses ................................................................... 8 
2.1 
Objectives and Endpoints ............................................................................ 8 
2.2 
Hypotheses and/or Estimations ................................................................... 9 
3. 
Study Overview .................................................................................................... 10 
3.1 
Study Design ............................................................................................. 10 
3.2 
Sample Size .............................................................................................. 12 
3.3 
Adaptive Design ........................................................................................ 13 
4. 
Covariates and Subgroups ................................................................................... 13 
4.1 
Planned Covariates ................................................................................... 13 
4.2 
Subgroups ................................................................................................. 14 
5. 
Definitions ............................................................................................................. 14 
6. 
Analysis Sets ........................................................................................................ 18 
6.1 
Full Analysis Set........................................................................................ 18 
6.2 
Primary Analysis Set ................................................................................. 18 
6.3 
Target Dose Analysis Set .......................................................................... 18 
6.4 
Pre-treatment Analysis Set ........................................................................ 18 
6.5 
Dose Limiting Toxicity (DLT) Analysis Set ................................................. 18 
6.6 
Safety Analysis Set ................................................................................... 19 
7. 
Planned Analyses ................................................................................................. 19 
7.1 
Interim Analysis and Early Stopping Guidelines ........................................ 19 
7.2 
Data Review Team .................................................................................... 19 
7.3 
Primary Analysis ....................................................................................... 20 
7.4 
Final Analysis ............................................................................................ 20 
8. 
Data Screening and Acceptance ........................................................................... 21 
8.1 
General Principles ..................................................................................... 21 
8.2 
Data Handling and Electronic Transfer of Data ......................................... 21 
8.3 
Handling of Missing and Incomplete Data ................................................. 21 
8.4 
Detection of Bias ....................................................................................... 21 
8.5 
Outliers ..................................................................................................... 21 
8.6 
Distributional Characteristics ..................................................................... 21 
8.7 
Validation of Statistical Analyses ............................................................... 22 
9. 
Statistical Methods of Analysis.............................................................................. 22 
9.1 
General Considerations ............................................................................. 22 
9.2 
Subject Accountability ............................................................................... 22 
9.3 
Important Protocol Deviations ................................................................... 22 


Product:  Blinatumomab 
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Page 4 of 43 
CONFIDENTIAL  
 
 
9.4 
Demographic and Baseline Characteristics ............................................... 23 
9.5 
Efficacy Analyses ...................................................................................... 24 
9.5.1 
Analyses of Primary Efficacy Endpoint(s) .................................. 25 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s).............................. 26 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) ............................. 26 
9.6 
Safety Analyses ........................................................................................ 27 
9.6.1 
Analyses of Primary Safety Endpoint(s) ..................................... 27 
9.6.2 
Adverse Events  ........................................................................ 28 
9.6.3 
Laboratory Test Results ............................................................ 29 
9.6.4 
Vital Signs ................................................................................. 30 
9.6.5 
Physical Measurements ............................................................ 30 
9.6.6 
Electrocardiogram ..................................................................... 30 
9.6.7 
Antibody Formation ................................................................... 30 
9.6.8 
Exposure to Investigational Product .......................................... 30 
9.6.9 
Exposure to Other Protocol-required Therapy ........................... 31 
9.6.10 
Exposure to Concomitant Medication ........................................ 31 
9.7 
Other Analyses ......................................................................................... 31 
9.7.1 
Analyses of Pharmacokinetic or 
Pharmacokinetic/Pharmacodynamic Endpoints ......................... 31 
9.7.2 
Analyses of Clinical Outcome Assessments .............................. 31 
9.7.3 
Analyses of Health Economic Endpoints ................................... 31 
9.7.4 
Analyses of Biomarker Endpoints .............................................. 31 
10. 
Changes From Protocol-specified Analyses.......................................................... 31 
11. 
Literature Citations / References ........................................................................... 32 
12. 
Prioritization of Analyses....................................................................................... 33 
13. 
Data Not Covered by This Plan............................................................................. 33 
14. 
Appendices ........................................................................................................... 34 
Appendix A. Reference Values/Toxcity Grades .................................................... 35 
Appendix B.  Handling of Dates, Incomplete Dates and Missing Dates ................. 37 
Appendix C.  Code Fragments .............................................................................. 39 
Appendix D. International Prognostic Index for Diffuse Large B-cell 
Lymphoma ................................................................................................ 40 
Appendix E.  Clinical Outcome Assessment Forms/Instruments ........................... 41 
Appendix F.  Health Economic Forms/Instruments ............................................... 42 
Appendix G.  Details of PK or PK/PD Methods for Modeling ................................. 43 
 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  29 May 2019 
Page 5 of 43 
CONFIDENTIAL  
 
 
List of Tables 
Table 3-1.  Confidence Intervals for Different Observed Rates of MRD 
Negativity With a Sample Size of 30 ....................................................... 13 
Table 7-1.  Stopping Boundary With Posterior Probability of 90% and DLT 
Limit of 25% ............................................................................................ 19 
Table 7-2.  Operating Characteristics With Batch Size of 10 Subjects ........................... 19 
Table 9-1.  Primary Efficacy Endpoint Summary Table .................................................. 24 
Table 9-2.  Secondary Efficacy Endpoint Summary Table ............................................. 24 
Table 9-3.  Exploratory Efficacy Endpoint Summary Table ............................................ 25 
Table 9-4.  Safety Endpoint Summary Table ................................................................. 27 
Table 14-1.  Grading of Selected Laboratory Parameters .............................................. 35 
Table 14-2.  Notable Abnormalities of Vital Signs .......................................................... 36 
Table 14-3.  Imputation Rules for Partial or Missing Start Dates .................................... 37 
 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  29 May 2019 
Page 6 of 43 
CONFIDENTIAL  
 
 
List of Abbreviations and Definition of Terms 
 
Abbreviation or Term 
Definition/Explanation 
ABC 
activated B cell  
AE 
adverse event 
aHSCT 
autologous hematopoietic stem cell transplantation 
alloHSCT 
allogeneic hematopoietic stem cell transplantation 
ALT  
alanine aminotransferase  
AST  
aspartate aminotransferase  
CDM  
Clinical Data Management  
CI  
confidence interval  
CNS  
central nervous system  
CR 
complete response 
CSR  
Clinical Study Report  
CT 
computer tomography 
CTCAE  
Common Terminology Criteria for Adverse Events  
DLBCL 
diffuse large B-cell lymphoma 
DLT  
dose limiting toxicity  
DRE  
disease-related events  
DRT 
data review team 
eCRF 
electronic case report form 
ECG  
electrocardiogram  
ECOG  
Eastern Cooperative Oncology Group  
EOI  
Events of interest  
GCB  
germinal center B  
GI 
Gastrointestinal  
GSO-DM  
Global Study Operations-Data Management  
Ig  
Immunoglobulin  
IP 
investigational product  


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  29 May 2019 
Page 7 of 43 
CONFIDENTIAL  
 
 
Abbreviation or Term 
Definition/Explanation 
IPD 
important protocol deviation 
IPI/aaIPI 
international prognostic index/age-adjusted international prognostic 
index 
IV 
intravenous 
KM  
Kaplan-Meier  
LDH  
lactate dehydrogenase  
MedDRA  
Medical Dictionary for Regulatory Activities  
MRD 
minimal residual disease 
ND 
not done 
NGS 
next generation sequencing 
OS 
overall survival 
PET-CT 
positron emission tomography - computed tomography 
PFS 
progression free survival 
QTc interval  
QT interval corrected for heart rate using accepted methodology  
SAP  
statistical analysis plan 
SAS  
statistical analysis software  
TFLSD 
table figure listing shell document 
 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  29 May 2019 
Page 8 of 43 
CONFIDENTIAL  
 
 
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 3 for study 20150291, 
Blinatumomab dated 18 July 2018. The scope of this plan includes the primary analysis 
and the final analysis that are planned and will be executed by the Amgen Global 
Biostatistical Science department unless otherwise specified. 
2. 
Objectives, Endpoints and Hypotheses 
2.1 
Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary 
• 
To determine minimal residual 
disease 
(MRD) 
negative 
rate 
following blinatumomab treatment 
in high-risk Diffuse Large B-cell 
Lymphoma (DLBCL) subjects who 
are MRD-positive post-autologous 
hematopoietic 
stem 
cell 
transplantation (aHSCT). 
• 
MRD negativity in cycle 1 of 
blinatumomab, defined as the best 
MRD response on day 57 or 
day71(+3 days) via MRD testing 
Secondary 
• 
To 
describe 
the 
efficacy 
of 
blinatumomab 
in 
relation 
to 
progression-free survival (PFS), 
duration of MRD-negative status, 
and overall survival (OS) 
• 
PFS  
• 
Duration of MRD negative status 
• 
OS 
• 
To 
evaluate 
the 
safety 
and 
tolerability of blinatumomab 
• 
Incidence, grade and severity of 
treatment 
emergent 
adverse 
events (AE) 
Exploratory 
• 
To describe the incidence of anti-
blinatumomab antibody 
• 
Incidence of anti-blinatumomab 
antibody formation 
• 
To describe the MRD-negative 
rate 
over 
time 
following 
blinatumomab treatment 
• 
MRD negative rate calculated at 
each 
time 
point 
measured 
following blinatumomab treatment 
• 
To describe rate, features and 
outcomes 
of 
allogeneic 
hematopoietic 
stem 
cell 
transplantation 
(alloHSCT) 
following 
treatment 
with 
blinatumomab 
• 
Incidence of alloHSCT (rate and 
number 
of 
subjects 
with 
alloHSCT) and the feature and 
clinical outcomes 
Page 1 of 2 
 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  29 May 2019 
Page 9 of 43 
CONFIDENTIAL  
 
 
Objectives 
Endpoints 
Exploratory (Continued) 
• 
To 
describe 
the 
relationship 
between clinical and baseline 
parameters 
and 
response 
to 
blinatumomab treatment 
• 
Relationship 
between 
pre-specified 
co-variates 
with 
MRD negative status and clinical 
outcomes 
• 
To describe MRD status relative to 
clinical relapse 
• 
Relationship 
between 
MRD 
negative 
status 
and 
clinical 
relapse 
• 
To describe MRD status prior to 
treatment with blinatumomab in 
positron 
emission 
tomography 
(PET)-computed tomography (CT) 
negative high-risk DLBCL subjects 
following aHSCT: 
− To describe MRD-positive status 
post aHSCT 
− To describe the rate and timing 
of 
MRD-negative 
to 
MRD-
positive change at screening 
and during the run-in period 
• 
Summary of MRD characteristics 
prior 
to 
treatment 
with 
blinatumomab: 
- 
The percentage of MRD positivity 
in PET-CT negative subjects post 
aHSCT 
- 
Rate and timing of MRD negative 
to MRD positive change during the 
24-month run-in period   
 
Page 2 of 2 
 
2.2 
Hypotheses and/or Estimations 
The study will estimate the MRD-negative response rate after treatment with 
blinatumomab in subjects with high-risk DLBCL who are MRD-positive following aHSCT. 
The clinical hypothesis is that the MRD negative response rate will be greater than 
10%  Achieving an MRD negative response rate of 30% would be of scientific and 
clinical interest.  
No formal statistical hypothesis will be tested. The study will estimate the MRD negative 
rate and also calculate its 95% exact binomial confidence interval.   


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  29 May 2019 
Page 10 of 43 
CONFIDENTIAL  
 
 
3. 
Study Overview 
3.1 
Study Design 
This is a phase 2, multicenter, open-label, single arm estimation study in adult subjects 
with high-risk DLBCL that are PET-CT negative post aHSCT. The study will consist of 
the following periods: 
− 
Screening period (up to 28 days) 
− 
Run-in period of up to 24 months to evaluate MRD status and assess eligibility 
for treatment assignment 
− 
Treatment period of 12 weeks (which includes 8 weeks of treatment with 
blinatumomab followed by a 4-week treatment-free period) 
− 
Safety follow-up visit 30 days after the last dose of blinatumomab 
− 
Long-term follow-up period that begins after the safety follow-up visit is 
completed until 1 year from the first dose of blinatumomab. 
The study will enroll approximately 90 subjects in the study with relapsed/refractory, 
biopsy-proven, high-risk DLBCL who are PET-CT negative at 90 days (± 30 days) post 
aHSCT (see Section 4.1 Part 1 Inclusion and Exclusion criteria of the protocol 
amendment 3 dated 18 July 2018).  
During the run-in period, subjects will be followed by clinic visits at 3, 5, 7, and 9 months, 
and thereafter every 3 months (± 1 week) up to 24 months for monitoring of MRD status 
in plasma by next generation sequencing (NGS)-based assay. Subjects who remain 
MRD-negative by the end of the 24-month run-in period will end the study. It is expected 
that approximately 30 subjects will be MRD-positive either at screening or become 
MRD-positive during the 24-month run-in period. 
The number of subjects enrolled may be altered in order to ensure that approximately 
30 subjects are assigned to treatment with blinatumomab. Enrollment may be stopped 
once approximately 30 subjects have been assigned to treatment with blinatumomab. 
Subjects, who are MRD-positive at enrollment or become MRD-positive during the run-in 
period, and who meet all other part 2 eligibility criteria (see Section 4.2 Part 2 Inclusion 
and Exclusion criteria of the protocol amendment 3 dated 18 July 2018), will be assigned 
to treatment with blinatumomab. 
Blinatumomab will be administered as a continuous intravenous (IV) infusion. Cycle 1 
will be 12 weeks (84 days) in duration, which includes 8 weeks (56 days) of 
blinatumomab IV infusion followed by a 4-week (28 days) treatment-free interval. 


Product:  Blinatumomab 
Protocol Number:  20150291 
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Page 11 of 43 
CONFIDENTIAL  
 
 
Blinatumomab will be dosed at 9 μg/day for 7 days, followed by 28 μg/day for 7 days and 
112 μg/day for 42 days. 
MRD status will be assessed at cycle 1 day 1 prior to blinatumomab infusion, on 
cycle 1 days 15 and 43, the end of the blinatumomab infusion (day 57) and 2 weeks 
after the end of the blinatumomab infusion (day 71 + 3 days) to evaluate disease status. 
A PET-CT will be performed only if a subject remains MRD-positive (day 57 of cycle 1 
assessment) after blinatumomab or has clinical signs and symptoms of disease 
progression. 
A safety follow-up visit will occur 30 days (+ 3 days) after the last dose of blinatumomab 
for assessment of disease-related events, adverse events, and serious adverse events. 
A long-term follow-up period to assess disease status and OS begins at completion of 
the safety follow-up visit and continues for 1 year from the first dose of blinatumomab. 
Subjects will be followed via clinic visit every 3 months (± 2 weeks) for MRD assessment 
and by institutional standard of care disease evaluation (PET-CT or CT) until relapse at 
which time the subject will be followed for survival via telephone contact.  
A Data Review Team (DRT) will monitor the study for safety on a regular basis. 
The overall study design is described by a study schema below. 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  29 May 2019 
Page 12 of 43 
CONFIDENTIAL  
 
 
Study Design and Treatment Schema 
 
EOS = end of study; IP = investigational product;; MRD = minimal residual disease; PET-CT = positron 
emission tomography/computed tomography 
a Run-in period is up to 24 months in duration.  During the run-in period, enrolled subjects that are MRD 
negative/PET-CT negative will be followed at 3, 5, 7 and 9 months and thereafter every 3 months up to 
24 months for monitoring of MRD status by next generation sequencing.  
b At any time after enrollment and during the run-in period subjects who turn MRD positive/ PET-CT negative 
and that meet all other part 2 eligibility will be assigned to treatment with blinatumomab.  Subjects that do 
not display MRD positivity at the end of the 24-month run-in period will end the study. 
c MRD status will be assessed at cycle 1 day 1 prior to blinatumomab infusion, on cycle 1 days 15 and 43, 
the end of the blinatumomab infusion (day 57), and 2 weeks after the end of the blinatumomab infusion 
(day 71 + 3 days). 
d Long-term follow-up period will be 1 year from the first dose of blinatumomab.  Subjects will be followed via 
clinic visit every 3 months (± 2 weeks) until relapse and from this point onwards via telephone contact for 
overall survival. 
3.2 
Sample Size 
This is a single-arm estimation study. It is anticipated that an MRD negative rate of 10% 
could be observed by chance in this study. Therefore, if the observed rate of MRD 
negativity is at least 30%, then the sample size for this study (N = 30) is sufficient to 
demonstrate that, with 95% confidence, the rate of achieving MRD negativity is greater 
than 10%.  This would also be sufficient to demonstrate evidence of clinical activity.  
A table showing the exact binomial confidence intervals for different observed rates of 
MRD negativity with a sample size of N = 30 is presented below: 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  29 May 2019 
Page 13 of 43 
CONFIDENTIAL  
 
 
Table 3-1.  Confidence Intervals for Different Observed Rates of MRD Negativity 
With a Sample Size of 30 
Observed rate of MRD 
negativity, n (%) 
Lower 95% Confidence Limit 
(%) 
Upper 95% Confidence Limit 
(%) 
8 (26.7) 
12.3 
45.9 
9 (30.0) 
14.7 
49.4 
11 (36.7) 
19.9 
56.1 
12 (40.0) 
22.7 
59.4 
14 (46.7) 
28.3 
65.7 
The study will enroll approximately 90 subjects to achieve the desired sample size of 
30 subjects who are MRD positive at the time of enrollment or during the run-in period.  
As part of the run-in period, subjects will be followed by clinic visits at 3, 5, 7, 9 and 
12 months and thereafter every 3 months up to 24 months for monitoring of MRD status, 
thus it could be more than 30 subjects who at some point become MRD positive before 
the study ends.  Any subject who becomes MRD positive after the first 30 subjects with 
treatment of blinatumomab will still be eligible for treatment and included in Full Analysis 
Set. Therefore the final sample size may be higher than 30 subjects. 
3.3 
Adaptive Design 
Not Applicable 
4. 
Covariates and Subgroups 
4.1 
Planned Covariates 
The relationship of clinical and baseline covariates to endpoints will be explored, if 
appropriate. Clinical and baseline covariates include: 
• 
Age at enrollment (<65, 65-74, 75-84, ≥85 years) 
• 
Sex (Male vs. Female) 
• 
Race (categories will depend on the data) 
• 
Stage at diagnosis (I, II, III, IV.  Categories maybe combined depending on the data) 
• 
International prognosis index (IPI) at diagnosis and secondary IPI at relapse (Low 
(0-1), Low – intermediate (2), High – intermediate (3), High (4-5)) 
• 
Age-adjusted IPI (aaIPI) at diagnosis and secondary aaIPI at relapse (Low (0), 
Low - intermediate (1), High – intermediate (2), High (3)) 
• 
Cell of origin (if available locally) (GCB, Non-GCB/ABC) 
• 
Double hit (Yes, No, Not Done) 


Product:  Blinatumomab 
Protocol Number:  20150291 
Date:  29 May 2019 
Page 14 of 43 
CONFIDENTIAL  
 
 
• 
Triple hit (if available locally) (Yes, No) 
• 
Refractory to frontline treatment (Yes, No) 
• 
Relapse within 1 year of diagnosis (Yes, No) 
• 
High-risk first complete remission (Yes, No) 
• 
MRD-positive at enrollment/MRD-positive within 6 months from 
enrollment/MRD-positive any time later during run-in.   
4.2 
Subgroups 
Analysis of primary and secondary endpoints in the subgroups defined by the above 
baseline covariates will be explored, if appropriate, depending on the sample size.   
5. 
Definitions 
Age-adjusted international prognostic index (aaIPI) 
aaIPI score will be derived by assigning one point to each of the risk factors:  disease 
stage III/IV, elevated LDH level and ECOG score ≥ 2 (please refer to Appendix D of the 
protocol).  
Age at enrollment 
Subject age at enrollment will be collected in years in the clinical database.  
Baseline  
Unless otherwise specified the baseline value for parameters/assessments scheduled to 
be performed on the same day as the first administration of blinatumomab, is the last 
value measured before the first administration of blinatumomab on that day. For 
parameters/assessments not scheduled to be performed (or scheduled but not 
performed) on the same day as the first administration of blinatumomab, the baseline 
value is the value measured closest to the day of first administration of blinatumomab.  
Cumulative dose of investigational product (blinatumomab) 
The cumulative dose in μg is defined as the following with summation over infusions: 
∑ (duration of infusion [days] for each dose received x dose received [µg]). Cumulative 
dose will be calculated within blinatumomab cycle 1. 
Death date 
For subjects who die during the study, the death date will be recorded on the event, end 
of study and/or survival status eCRF. The earliest death date will be used for analysis if 
the dates are inconsistent among these CRF pages. For deaths collected after a subject 
has ended study (eg, through public records), the death date will be recorded on the 
long-term follow-up. 


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Duration of blinatumomab treatment 
For each infusion episode within cycle 1, the duration of exposure to blinatumomab 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 infusion. The duration will be the sum of the individual infusion 
durations within cycle 1. The duration will be rounded to the nearest day.  
Duration of MRD-negative status 
The duration of MRD-negative status will be assessed only in subjects who achieve 
MRD-negative status after blinatumomab treatment. Subjects missing post-baseline 
MRD assessments will be considered not to have achieved MRD negative status. 
Duration of MRD-negative status will be defined from the time when a negative MRD 
result is first established until documented MRD-positive reoccurrence, or disease 
progression (or, death due to any cause). Subjects without any of these events at the 
time of the analysis will be censored at their last disease assessment date. 
End of Treatment 
End of Treatment is defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject. 
End of follow-up  
End of Follow-up is defined as when the last subject completes the last protocol-
specified assessment in the study. 
End of study  
For a subject: End of study for a subject is defined as the last day that protocol-specified 
procedures are conducted for an individual subject. 
For the study as a whole: The end of trial is defined as the date when the last subject is 
assessed or receives an intervention for evaluation in the study (ie, last subject last 
visit), following any additional parts in the study (eg, long-term follow-up), as applicable. 
The primary completion date: The primary completion date is defined as the date when 
the last subject is assessed or receives an intervention for the final collection of data for 
the primary endpoint, for the purposes of conducting the primary analysis, whether the 
study concluded as planned in the protocol or was terminated early. 


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High-risk first complete remission 
High-risk first complete remission is defined as subjects who an interim PET-CT positive 
or less than complete remission to frontline chemotherapy AND achieved complete 
remission to platinum-containing salvage) 
as collected on the Prior Anti-Cancer Therapies for Current Malignancies eCRF page. 
International prognostic index (IPI) 
International prognostic index (IPI) at diagnosis will be collected on the ‘IPI at diagnosis’ 
field on the DLBCL Disease History (Staging and Risk Initial) eCRF page.  Secondary 
IPI at relapse will be collected on the ‘IPI prior to S1’ field on the DLBCL Disease History 
(Staging and Risk Prior S1) eCRF page. 
Minimum residual disease (MRD) 
Minimum residual disease (MRD) is defined as negative when the tumor clone sequence 
in plasma is below the assay limit of detection (to be determined in the assay validation).   
Positive MRD status will be defined as plasma levels above the assay limit of detection.  
All subjects in the treatment period are considered MRD positive, regardless whether the 
Cycle 1 Day 1 MRD test results are positive or negative because these subjects have 
been tested MRD positive in the run-in period.  
Overall survival (OS) 
Overall survival will be defined from the first dose of blinatumomab treatment until death 
due to any cause. Subjects still alive at the time of the analysis will be censored at date 
last known to be alive. 
Percent of intended dose of blinatumomab 
For cycle 1, the percent of intended dose of blinatumomab will be the cumulative dose 
divided by the planned cumulative dose.  The planned cumulative dose for cycle 1 will 
be (9 µg x 7 days) + (28 µg x 7 days) + (112 µg x 42 days) = 4963 µg.  
Progression free survival (PFS) 
Progression free survival (PFS) is calculated as the time from the date of first dose of 
blinatumomab until the date of diagnosis of relapse of lymphoma (by PET-CT, CT, 
clinical assessment or relapse biopsy, whichever is the preferred method), or date of 
death, whichever is the earliest.  Subjects alive who did not have progression will be 
censored at last date of tumor assessment. 


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Refractory to frontline treatment 
Refractory to frontline treatment is defined as failure to achieve complete response as 
the best response after completion of frontline chemotherapy, as collected on the Prior 
Anti-Cancer Therapies for Current Malignancies eCRF page. 
Relapse within 1 year of diagnosis 
A subject will be classified as relapsed within 1 year of diagnosis if the difference 
between the earliest date of relapse captured on the History of Relapses eCRF page 
and date of diagnosis on DLBCL Medical History eCRF page is less than 1 year. 
Date of first relapse – Date of diagnosis + 1 < 365.25 
Stage at diagnosis 
As collected on the ‘Ann-Arbor’ field on the DLBCL Disease History (Staging and Risk 
Initial) eCRF page. 
Study day 1 
Study day 1 is defined as the first day that protocol-specified investigational products are 
administered to the subject. 
Study day 
Pre study day 1: study day= (date – date of Study Day 1)  
On and after study day 1: study day= (date - date of Study Day 1) + 1 
Treatment-emergent adverse event (TEAE)  
Adverse events (AEs) starting on or after first dose of protocol-specified therapy as 
determined by the flag indicating if the adverse event started prior to the first dose on the 
Adverse Events Summary CRF and up to and including 30 days after the end of 
protocol-specified therapy. This reporting window also applies to treatment-emergent 
serious adverse events (SAEs). 
Treatment-emergent disease-related event 
Events categorized as Disease-related Events (DREs) starting on or after first dose of 
blinatumomab as determined by the flag indicating if the event started prior to the first 
dose on the Events CRF and up to and including 30 days after the end of blinatumomab. 
Disease Related Events 
Subject incidence of disease related events and fatal disease related events in the 
blinatumomab treatment period (through the safety follow-up visit) will be tabulated by 


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system organ class and preferred term. Refer Protocol section 9.1.1 for more details on 
disease related events by their system organ class. 
Triple hit 
Triple hit is defined as the positive rearrangement of c-MYC, BCL2 and BCL6 as 
collected on the ‘Disease-Specific Features on the DLBCL Disease History (COO)’ 
eCRF page. 
6. 
Analysis Sets 
This study will define the following analysis sets for the purpose of statistical analysis: 
Full Analysis set, Primary analysis Set, Target Dose Analysis Set, Pre-treatment 
Analysis Set and Dose Limiting Toxicity (DLT) Analysis Set. 
6.1 
Full Analysis Set 
The full analysis set will include all subjects who received blinatumomab. Subjects who 
were treated beyond the required sample size of 30 subjects will be included in this 
analysis set. The full analysis set will be used for the final analysis.  
6.2 
 Primary Analysis Set 
The primary analysis set will include the first 30 enrolled subjects who received at least 
1 dose of blinatumomab. The primary analysis set will be used for the primary analysis.  
6.3 
Target Dose Analysis Set 
The target dose analysis set will include all subjects from the full analysis set who 
completed at least 7 days of infusion on the highest intended dose.  In addition, all 
subjects who discontinue treatment with blinatumomab due to disease progression 
during cycle 1 will also be included in the target analysis set.  The target dose analysis 
set will be used as sensitivity analysis set for the final analysis. 
6.4 
Pre-treatment Analysis Set 
The pre-treatment analysis set will include all subjects that enroll in the study. 
6.5 
Dose Limiting Toxicity (DLT) Analysis Set 
The DLT Analysis Set includes all subjects who are DLT evaluable. A subject needs to 
meet one of the following criteria to be DLT evaluable: 
1. The subject experiences a DLT in the DLT evaluation period, OR 
2. The subject is removed from treatment for an adverse event/toxicity; OR 


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3. The subject is removed from treatment for reasons other than an adverse 
event/toxicity, i.e., disease progression, and the subject has received at least 
7 days of the target blinatumomab dose; OR 
4. The subject does not experience a DLT and completes DLT evaluation period 
The DLT evaluation period will be the entire duration of cycle 1 blinatumomab treatment. 
6.6 
Safety Analysis Set 
Safety endpoints will be analyzed at the Primary Analysis using the Primary Analysis Set 
and at Final Analysis using the  Full Analysis Set. 
7. 
Planned Analyses 
The following subsections define the planned analyses for this study. 
7.1 
Interim Analysis and Early Stopping Guidelines 
Amgen will conduct evaluations of the ongoing DLT rate to assess if the threshold for 
early trial termination as defined in section 6.2.2 of protocol amendment 3 dated 
July 18, 2018 has been reached. The stopping rules will use a Bayesian approach to 
terminate the study if the posterior probability that the true DLT rate is greater than 25% 
is > 90%. 
Table 7-1.  Stopping Boundary With Posterior Probability of 90% and DLT Limit of 
25% 
Number of DLT evaluable subjects 
Stop study if observing these many DLTs 
10 
≥ 5 
20 
≥ 8 
30 
Study completes 
Table 7-2.  Operating Characteristics With Batch Size of 10 Subjects 
True DLT rate 
Probability of stopping 
Average sample size 
0.20 
5% 
30 
0.25 
14% 
28 
0.30 
27% 
26 
0.35 
44% 
24 
0.40 
62% 
21 
7.2 
Data Review Team 
A Data Review Team (DRT) will review safety data periodically.   A DRT is a group, 
internal to Amgen but external to the relevant blinatumomab product team, that reviews 


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accumulating data from the ongoing clinical trial to ensure no avoidable increased risk 
for harm to subjects. Continuous toxicity monitoring for early termination of the trial will 
be performed with the early stopping boundary defined in Table 7-1. Adverse events and 
DLTs (as defined in protocol Section 6.2.2) observed in all subjects will be evaluated 
every 10th subject or every 6 months, whichever occurs earlier. The DRT includes a 
clinician, a safety physician, and a biostatistician.  Membership, procedures, and 
meeting timing will be described in detail in the study DRT charter. 
7.3 
Primary Analysis 
The objective of the primary analysis is to estimate the primary endpoint, MRD-negative 
rate at the end of cycle 1 of blinatumomab. The primary analysis will be triggered when 
the first 30 enrolled subjects have had the opportunity to complete cycle 1 of 
blinatumomab treatment. Any subjects treated beyond the required sample size of 
30 subjects will not be part of the primary analysis. 
At the time of the primary analysis, the primary endpoint (MRD-negative rate at end of 
cycle 1 of blinatumomab) will be analyzed using the Primary Analysis Set.  The safety 
and tolerability of blinatumomab, pre-treatment estimates of the rate and timing of 
conversion from MRD-negative to MRD-positive, and MRD status by the NGS MRD test 
in PET-CT negative subjects will also be assessed. 
The primary analysis is will be based on a clean and locked database. 
7.4 
Final Analysis 
The main objective of the final analysis is to provide estimates of the secondary and 
exploratory endpoints. The final analysis will also include updated estimates for the 
endpoints assessed at the primary analysis (MRD-negative rate and MRD prior to 
blinatumomab treatment). The updated estimates will include all subjects enrolled in the 
study who received at least one dose of blinatumomab. This would include any subjects 
treated after the expected sample size of 30 subjects. 
The final analysis will be conducted when the subjects in the Primary Analysis Set have 
had an opportunity to complete the long-term follow-up visit 1 year from the first dose of 
blinatumomab. The final analysis will also assess the potential long-term effect of  
blinatumomab on safety.  This will include any subjects treated after the expected 
sample size of 30 subjects. 
For the final analysis, the secondary and exploratory endpoints will be assessed as well 
as updating the estimates for the endpoints assessed at the primary analysis 


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(MRD-negative rate and MRD prior to blinatumomab treatment).  The Full Analysis Set 
will be used for the final analysis, which includes any subjects treated after the expected 
sample size of 30 subjects. Sensitivity analysis will be performed on Target Dose 
Analysis set.  
The final analysis is will be based on a clean and locked database. 
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 database will be subjected to edit checks outlined in the data validation 
specifications plan by Amgen Clinical Data Management (CDM) department. Any 
outstanding data issues will be communicated to CDM for resolution before the database 
is locked. 
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. 
8.3 
Handling of Missing and Incomplete Data 
Rule for handling missing data related to endpoints are described in the endpoint 
definitions (section 6) or in the description of analyses (section 10). The handling of 
incomplete and partial dates for adverse events and concomitant medications are 
described in Appendix B. 
8.4 
Detection of Bias 
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. 
8.6 
Distributional Characteristics 
Not Applicable 


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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 9.4 or 
later. 
9. 
Statistical Methods of Analysis 
9.1 
General Considerations 
Continuous variables will be summarized by the non-missing sample size (n), mean, 
standard deviation, median, first and third quartiles, minimum, and maximum. 
Categorical variables will be summarized by the n and percentage in each category. 
Point estimates for binomial proportions (eg., the primary efficacy endpoint) will be 
accompanied by 2-sided exact binomial 95% confidence intervals 
(Clopper and Pearson, 1934).Time to event endpoints will be summarized with 
Kaplan-Meier (KM) curves, KM proportions at selected time points, KM quartiles (when 
estimable), the number of subjects with events, the number of subjects censored, and 
the pattern of censoring. Point estimates of KM quartiles 
(Brookmeyer and Crowley, 1982) and KM proportions (Kalbfleisch and Prentice, 1980) 
will be accompanied by 2-sided 95% confidence intervals. 
9.2 
Subject Accountability 
The disposition of all enrolled subjects will be tabulated. Number of subjects screened, 
enrolled, received blinatumomab along with the reasons for discontinuing blinatumomab 
and discontinuing study will be summarized. The number of subjects who completed and 
discontinued from the run-in period, and their reasons for discontinuation will also be 
summarized. 
Key study dates for the first and last subject enrolled, first and last subject’s 
blinatumomab start date, last subject’s blinatumomab end date and last subject’s end of 
study date 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 


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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. 
9.4 
Demographic and Baseline Characteristics 
The following demographic and baseline disease characteristics will be summarized 
using descriptive statistics for the Pre-Treatment Analysis Set and the Primary/Full 
Analysis Set. 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:  
• 
Age at enrollment (summary statistics and age categories <65, 65-74, 75-84, 
≥ 85 years) 
• 
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Pacific Islander, White, Other) 
• 
Geographical region (North America, Europe, rest of world) 
• 
Disease Stage (Ann-Arbor-Staging) at diagnosis (I, IE, II, IIE, II bulky, III, IV) 
• 
International prognosis index(IPI) at diagnosis and secondary IPI at relapse (Low 
(0-1), Low – intermediate (2), High – intermediate (3), High (4-5)) 
• 
Age-adjusted IPI (aaIPI) at diagnosis and secondary aaIPI at relapse (Low (0), 
Low - intermediate (1), High – intermediate (2), High (3)) 
• 
Extranodal disease: (Yes, No) 
• 
Cell of Origin Determination (GCB, Non-GCB, ABC, Not done) 
• 
Bcl-2 rearrangement (Positive, Negative, Indeterminate) 
• 
Bcl-6 rearrangement (Positive, Negative, Indeterminate) 
• 
C-myc rearrangement (Positive, Negative, Indeterminate) 
• 
Bcl-2 overexpression (Positive, Negative, Indeterminate) 
• 
Bcl-6 overexpression (Positive, Negative, Indeterminate) 
• 
C-myc overexpression (Positive, Negative, Indeterminate) 
• 
Double-hit (Yes, No, Not Done)  
• 
Double protein expression (Yes, No, Not Done)  
• 
Triple-hit (Yes, No)  
• 
Refractory to frontline treatment (Yes, No) 
• 
Relapse within 1 year of diagnosis (Yes, No) 
• 
High-risk first complete remission (Yes, No) 


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9.5 
Efficacy Analyses 
Table 9-1.  Primary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method  
Sensitivity Analysis 
Proportion of subjects 
who achieve MRD 
response (MRD 
negativity) after cycle 1 
of blinatumomab. MRD 
negativity is determined 
as the best MRD 
response on day 57 or 
day 71(+3 days)  via 
MRD testing. 
 
The MRD-negative rate at the end 
of cycle 1 of blinatumomab is 
calculated as the number of 
subjects with MRD-negative status 
after treatment with blinatumomab 
divided by the total number of 
subjects in the Primary Analysis Set 
for Primary Analysis.  Exact 
binomial 95% CI will be 
summarized. The Full Analysis Set 
will be used at final analysis..  
A sensitivity analysis will be 
performed using the Target 
Dose Analysis Set for the 
final analysis. 
Table 9-2.  Secondary Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method  
Sensitivity Analysis 
PFS 
Kaplan-Meier (KM) analyses (KM 
plot and KM estimates) on the Full 
Analysis Set. 
A sensitivity analysis will be 
performed using the Target 
Dose Analysis Set for the 
final analysis 
Duration of 
MRD-negative status  
Kaplan-Meier (KM) analyses (KM 
plot and KM estimates) on the Full 
Analysis Set. 
 
A sensitivity analysis will be 
performed using the Target 
Dose Analysis Set for the 
final analysis 
OS  
Kaplan-Meier (KM) analyses (KM 
plot and KM estimates) on the Full 
Analysis Set. 
 
A sensitivity analysis will be 
performed using the Target 
Dose Analysis Set for the 
final analysis. 
Secondary efficacy endpoints will be assessed only at final analysis. 


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Table 9-3.  Exploratory Efficacy Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis 
Method  
Sensitivity Analysis 
MRD-negative rate 
The MRD-negative rate will be 
summarized at each time point 
measured following blinatumomab 
treatment using both Primary and 
Full Analysis Sets. 
A sensitivity analysis will be 
performed using the Target 
Dose Analysis Set for the 
final analysis 
Incidence of alloHSCT 
Incidence of alloHSCT (number of 
subjects with alloHSCT), including 
the methodology (Intensity of 
Conditioning Regimen and Donor 
Type) and clinical outcomes 
(Maximum grade of aGVHD) will be 
summarized using Full Analysis 
Set. 
A sensitivity analysis will be 
performed using the Target 
Dose Analysis Set for the 
final analysis 
To describe the 
relationship between 
clinical outcomes and 
baseline covariates  and 
response to 
blinatumomab treatment 
MRD negative rates in subgroups 
specified in section 4.2 will be 
presented using Primary and Full 
Analysis Sets 
A sensitivity analysis will be 
performed using the Target 
Dose Analysis Set for the 
final analysis  
To describe MRD status 
relative to clinical relapse 
KM analysis of PFS and OS 
stratified by MRD response status 
after cycle 1 (landmark analysis on 
Day 75) will be performed in both 
Primary and Full Analysis Sets  
A sensitivity analysis will be 
performed using the Target 
Dose Analysis Set for the 
final analysis 
The percentage of  MRD 
positivity in PET-CT 
negative subjects post 
aHSCT 
Summary of subject who had 
PET-CT negative status post 
aHSCT and become MRD positivity 
status during run in period will be 
presented with pretreatment 
analysis set. 
A sensitivity analysis will be 
performed using the Target 
Dose Analysis Set for the 
final analysis 
Rate and timing of MRD 
negative to MRD positive 
change during the 
24-month run-in period   
 
Summary of MRD Status in 
different time points will be 
presented during run in period with 
pretreatment analysis set. 
A sensitivity analysis will be 
performed using the Target 
Dose Analysis Set for the 
final analysis 
Exploratory efficacy endpoints will be analyzed at primary analysis by using primary analysis set and 
pretreatment analysis set, and at final analysis using the Full analysis set.  
9.5.1 
Analyses of Primary Efficacy Endpoint(s) 
The MRD-negative rate at the end of cycle 1 of blinatumomab is calculated as the 
number of subjects with MRD-negative status after treatment with blinatumomab divided 
by the total number of subjects in Primary Analysis Set for Primary Analysis.  Exact 
binomial 95% CI will be summarized as well. 


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MRD-negative rate will also be analyzed in Full Analysis Set for final analysis. A 
sensitivity analysis will be performed using the Target Dose Analysis Set for the final 
analysis 
9.5.2 
Analyses of Secondary Efficacy Endpoint(s) 
The secondary endpoints PFS, duration of MRD-negative status and OS will be 
summarized with Kaplan-Meier (KM) analyses on the Full Analysis Set for final analysis. 
A sensitivity analysis will be performed on the Target Dose Analysis Set for final 
analysis. 
9.5.3 
Analyses of Exploratory Efficacy Endpoint(s) 
The following exploratory efficacy endpoints will be analyzed using Primary Analysis Set 
at primary analysis and Full Analysis Sets at the time of final analysis.  
• 
The MRD-negative rate will be summarized at each timepoint measured 
following blinatumomab treatment 
• 
Incidence of alloHSCT (number of subjects with alloHSCT), including the 
methodology (Intensity of Conditioning Regimen and Donor Type) and clinical 
outcomes (Maximum grade of aGVHD) will be summarised.  
• 
Relationship between pre-specified covariates mentioned in the section 4.1 with 
MRD negative status and clinical outcomes (PFS, OS) will be explored. Subject 
incidence of MRD negative status, and KM estimates for the clinical outcomes 
will be summarized for different pre-specified covariates as the data permits 
• 
Clinical outcomes (PFS, OS) will be analyzed by MRD status.  A landmark 
analysis will be performed using day 75 (end of cycle 1) as the landmark time 
point. Subjects will be defined as MRD negative or positive based on their MRD 
status as of at day 75.  Only subjects who are still being followed up for PFS or 
OS at day 75 will be included in the analysis. The KM summaries will be 
performed by MRD status for clinical outcomes (PFS, OS) from day 75. 
The following MRD characteristics prior to treatment with blinatumomab will be 
summarized using the Pre-Treatment Analysis Set: 
• 
MRD status at screening by the NGS test in PET-CT negative subjects post 
aHSCT will be summarized. 
• 
Estimates of the rate and timing of MRD-negative to MRD-positive change 
during the 24-month run-in period will also be summarized.  The run-in period 
will be divided into becoming MRD-positive at enrollment, MRD-positive within 
6 months from enrollment and MRD-positive any time later during run-in. 


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9.6 
Safety Analyses 
9.6.1 
Analyses of Primary Safety Endpoint(s) 
Table 9-4.  Safety Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method 
(Specify Analysis Set if FAS is Not Used) 
Sensitivity Analysis 
Adverse  Event  
The subject incidence of adverse events will 
be summarized for all treatment-emergent 
adverse events, serious adverse events, 
adverse events leading to withdrawal of 
protocol-specified therapy, and fatal 
adverse events. Primary Analysis Set at the 
time of Primary Analysis, and Final Analysis 
Set at the time of Final Analysis will be used 
for this analysis  
Not applicable 
Disease Related 
Events 
Subject incidence of disease related events 
and fatal disease related events in the 
blinatumomab treatment period (through the 
safety follow-up visit) will be tabulated by 
system organ class and preferred term. 
Primary analysis set will be used for this 
analysis and Final Analysis Set at the time 
of Final Analysis will be used for this 
analysis  
Not applicable 
Laboratory Test 
Results 
Shift tables between the worst post-baseline 
and baseline grades for selected laboratory 
parameters will be provided. The analyses 
of selected safety laboratory parameters 
including immunoglobulins, platelets, and 
liver parameters will include summary 
statistics over time. Primary Analysis Set at 
the time of Primary Analysis, and Final 
Analysis Set at the time of Final Analysis will 
be used for this analysis  
Not applicable 
Vital Signs 
The number and percentage of subjects 
with abnormal changes in systolic blood 
pressure, diastolic blood pressure and heart 
rate will be summarized. Primary Analysis 
Set at the time of Primary Analysis, and 
Final Analysis Set at the time of Final 
Analysis will be used for this analysis  
Not applicable 
Electrocardiogram 
summaries and statistical analyses of ECG 
measurements are not planned 
Not applicable 
Page 1 of 2 


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Table 9-4.  Safety Endpoint Summary Table 
Endpoint 
Primary Summary and Analysis Method 
(Specify Analysis Set if FAS is Not Used) 
Sensitivity Analysis 
Antibody 
Formation 
The incidence and percentage of subjects 
who develop anti-blinatumomab antibodies 
(binding and if positive, neutralizing) at any 
time may be tabulated. Primary Analysis Set 
at the time of Primary Analysis, and Final 
Analysis Set at the time of Final Analysis 
will be used for this analysis  
Not applicable 
Exposure to 
Investigational 
Product 
Descriptive statistics will be produced to 
describe the exposure to blinatumomab 
for subjects in the Primary Analysis Set 
at the time of Primary Analysis, and 
Final Analysis Set at the time of Final 
Analysis will be used for this analysis  
Not applicable 
Exposure to 
Concomitant 
Medication 
Summarized by preferred term as 
coded by the World Health Organization 
Drug dictionary by Primary Analysis Set 
at the time of Primary Analysis, and 
Final Analysis Set at the time of Final 
Analysis will be used for this analysis  
Not applicable 
Page 2 of 2 
9.6.2 
Adverse Events  
The Medical Dictionary for Regulatory Activities (MedDRA) version 21.1 or later will be 
used to code all events categorized as adverse events (AEs), disease-related events 
(DREs) to a system organ class and a preferred term.  Treatment-emergent adverse 
events are events with an onset after the administration of the first dose of 
blinatumomab treatment through 30 days after the end of blinatumomab treatment.  
Adverse events of interest (EOI) categories will be based on search strategies defined 
by Medical Coding. 
The subject incidence of adverse events will be summarized for all treatment-emergent 
adverse events, serious adverse events, adverse events leading to withdrawal of 
protocol-specified therapy, and fatal adverse events.  
Subject incidence of all treatment-emergent adverse events, serious adverse events, 
adverse events leading to withdrawal of blinatumomab, leading to interruption of IP and 
fatal adverse events will be tabulated by system organ class and preferred term in 
descending order of frequency; similar summaries will be repeated for EOIs. Time to 


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onset and duration of selected EOIs (infection, neurologic events, and CRS) may also be 
summarized.  
Any serious adverse event that occurs from enrolment through the day before the first 
dose of blinatumomab (during the run-in period) will be documented and summarized. 
This applies to all subjects who have been enrolled onto the study, regardless of 
whether they achieve the MRD-positive status required to start treatment with 
blinatumomab. 
A summary of blinatumomab treatment-emergent adverse events will be tabulated by 
system organ class, preferred term, and worst grade. 
9.6.3 
Laboratory Test Results 
Summary statistics over scheduled visits for actual values, changes from baseline of 
laboratory parameters listed below will be presented. In addition, shift tables will be 
summarized with toxicity grades using CTCAE by worst on-study increase and decrease 
values between study baseline and any visit up to the end of the study. The schedule of 
assessments is pre-specified in Table 4 of protocol amendment 3 dated July 18, 2018. 
1. Corrected Calcium  
2. Magnesium  
3. Total bilirubin  
4. Direct bilirubin  
5. Alkaline phosphatase  
6. AST (SGOT)  
7. ALT (SGPT)  
8. Hemoglobin  
9. Platelets  
10. Neutrophils  
11. Lymphocytes  
12. LDH  
13. Amylase  
14. Lipase 
15. Immunoglobulins (IgG, IgA, IgM), 
16. Creatinine increased. 


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9.6.4 
Vital Signs 
Vital signs (systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate 
and temperature) will be summarized at pre-specified times during treatment and at the 
safety follow-up (30 days after treatment).  Changes from baseline and percent change 
will also be calculated.  Additionally, summaries of the subject incidence with notable 
abnormalities defined in Appendix A, Table 14-2 in Full Analysis Set will be presented. 
9.6.5 
Physical Measurements 
Weight will be summarized at pre-specified times during treatment and at the safety 
follow-up (30 days after treatment).  Changes from baseline and percent change will also 
be calculated.  Additionally, summaries of the subject incidence with notable 
abnormalities defined in Appendix A, Table 14-2. in Full Analysis Set will be presented. 
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 
The incidence and percentage of subjects who develop anti-blinatumomab antibodies 
(binding and if positive, neutralizing) will be summarized and listed at each time point 
collected in Full Analysis Set. ,  
9.6.8 
Exposure to Investigational Product 
Descriptive statistics will be produced to describe the exposure to blinatumomab for 
subjects in the Full Analysis Set. The number of days on IP and the proportion of 
subjects receiving each dose level will be summarized. In addition, the duration of 
therapy, the relative treatment duration, the cumulative dose, and the percent of 
intended 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. 


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9.6.9 
Exposure to Other Protocol-required Therapy 
Descriptive statistics will be produced to describe the required pre-medication 
(dexamethasone) exposure in the pre-treatment analysis set.” 
9.6.10 
Exposure to Concomitant Medication 
The number and proportion of subjects receiving concomitant medications from 
enrolment through the day before the first dose of blinatumomab (run-in period) and from 
day 1 through safety follow-up will be summarized by preferred term as coded by the 
World Health Organization Drug dictionary in the Full Analysis Set. In addition, the 
number and proportion of subjects receiving anticancer therapies during long term 
follow-up will be summarized by World Health Organization Drug dictionary preferred 
term in the Full Analysis Set. 
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 
Not Applicable  
9.7.3 
Analyses of Health Economic Endpoints 
Not Applicable  
9.7.4 
Analyses of Biomarker Endpoints 
Exploratory analyses may be performed on the MRD data. If the analyses will be 
performed then a separate biomarker supplemental analysis plan will be generated. 
10. 
Changes From Protocol-specified Analyses 
There are no changes to the protocol-specified analyses. 


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11. 
Literature Citations / References 
Brookmeyer, R. and Crowley, J. A Confidence Interval for the Median Survival Time. 
Biometrics. 1982; 38:29-41.  
Clopper CJ and Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial, Biometrika. 1934;26:404-413.  
Kalbfleisch, J. D. and Prentice, R. L. The Statistical Analysis of Failure Time Data. New 
York: John Wiley & Sons; 1980. 


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12. 
Prioritization of Analyses 
Not Applicable  
13. 
Data Not Covered by This Plan 
Not Applicable 


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14. 
Appendices 


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Appendix A. Reference Values/Toxcity Grades 
Safety Laboratory Data 
Treatment emergent laboratory abnormalities are defined as those which occur between 
the start of the first infusion of blinatumomab and the end of the treatment period.  
Safety laboratory values below a distinct limit (eg, detection limit, documented as 
“< [limit]”) will be substituted by half of the limit and values above a distinct limit 
(documented as “> [limit]”) will be substituted by the limit itself for all analyses.  
Grading (based on CTCAE version 4.03 or above) will be assigned to each laboratory 
result as detailed in Table 14-1.  . Depending on the toxicity definition, the same result 
may be assigned to two gradings for deviations towards higher or lower values. In case 
no lower limit of normal is provided for the absolute lymphocyte, neutrophils or leukocyte 
counts, it will not be differentiated between grade 1 and grade 0 results for these 
parameters. Values not meeting any of the criteria will be assigned a grade 0. 
Table 14-1.  Grading of Selected Laboratory Parameters 
Laboratory 
Parameter 
[Unit] 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Lymphocytes 
[G/L] 
0.8 -  < LLN 
0.5 - < 0.8 
0.2 - < 0.5 
< 0.2 
Neutrophils  
[G/L] 
1.5 - < LLN 
1.0 - < 1.5 
0.5 - < 1.0 
< 0.5 
Leukocytes [G/L] 
3.0 - < LLN 
2.0 - < 3.0 
1.0 - < 2.0 
< 1.0 
Platelets [G/L] 
75 - < LLN 
50 - < 75 
25 - < 50 
< 25 
Hemoglobin 
[g/L]* 
100 - < LLN  
80 - < 100 
65 - < 80 
< 65 
Albumin [g/L] 
30 - < LLN 
20 - < 30 
< 20 
not defined 
AST* 
> ULN – 3*ULN 
> 3*ULN – 5*ULN 
> 5*ULN – 20*ULN 
> 20*ULN 
ALT * 
> ULN – 3*ULN 
> 3*ULN – 5*ULN 
> 5*ULN – 20*ULN 
> 20*ULN 
GGT  
> ULN – 2.5*ULN 
>2.5*ULN – 5*ULN 
> 5*ULN – 20*ULN 
> 20*ULN 
Bilirubin 
> ULN – 1.5*ULN 
>1.5*ULN – 3*ULN 
> 3*ULN – 10*ULN 
> 10*ULN 
Fibrinogen^ 
%change of BL 
<25%  or 
0.75*LLN - < LLN 
25%- <50% of BL 
  or  
< 75*LLN – 0.5*LLN 
50% -  <75% of BL  
or 
< 0.5* LLN – 0.25*LLN 
>= 75% of 
BL or 
< 50mg/dL 
or < 
0.25*LLN 
Page 1 of 2 
Footnotes defined on the next page of the table 


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Table 14-1.  Grading of Selected Laboratory Parameters 
Laboratory 
Parameter 
[Unit] 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Corrected 
Calcium 
[mmol/L]* 
2.0 - < LLN 
1.75 - < 2.0 
1.5 - < 1.75 
< 1.5 
Potassium 
[mmol/L]* 
not defined 
3.0 - < LLN 
2.5 - < 3.0 
< 2.5 
Lipase 
> ULN – 1.5*ULN 
> 1.5*ULN – 2.0*ULN 
> 2.0*ULN – 5.0*ULN 
> 5.0*ULN 
Amylase  
> ULN – 1.5*ULN 
> 1.5*ULN – 2.0*ULN 
> 2.0*ULN – 5.0*ULN 
> 5.0*ULN 
Page 2 of 2 
BL: baseline value, LLN: Lower limit of normal, ULN: Upper limit of normal 
*: Clinical criteria from CTC AE 4.0 grading were not considered in order to assign grades 
^: In case of conflicting criteria the higher grade will be assigned, % change only used when baseline is 
<LLN  
For more details refer The Common Terminology Criteria for Adverse Events 
(CTCAE), version 4.03 which is available at the following location:  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf  
Notable values for vital signs are defined according to the following table 
Table 14-2.  Notable Abnormalities of Vital Signs 
Vital Signs 
 
Notable Abnormalities 
Pulse rate (bpm) 
 
>120 
<50  
Blood pressure (mmHg) 
Systolic 
≥160 
≤90 
 
Diastolic 
≥105 
≤50  
Weight (kg) 
 
change from baseline ≥10% (in both directions) 
Body temperature (°C) 
 
> 39 


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Appendix B.  Handling of Dates, Incomplete Dates and Missing Dates 
The following data will be imputed using the following algorithm:  
• 
Adverse Events  
• 
Concomitant Medications 
Table 14-3.  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. 
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). 


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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. 


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Appendix C.  Code Fragments 


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Appendix D. International Prognostic Index for Diffuse Large B-cell Lymphoma 
IPI 
aaIPI 
Risk group 
IPI Factors 
Risk group 
aaIPI Factors 
Low 
0 or 1 
Low 
0 
Low Intermediate 
2 
Low Intermediate 
1 
High Intermediate 
3 
High Intermediate 
2 
High 
4 or 5 
High 
3 
IPI Factors 
Older than 60 years of age (not used for aa-IPI) 
Disease stage III/IV 
Lactate dehydrogenase level elevated 
ECOG performance score ≥ 2 
Extranodal disease > 1 site (not used for aa-IPI) 
IPI = International Prognostic Index;  aaIPI =  age-adjusted IPI; ECOG = Eastern Cooperative Oncology 
Group, 


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Appendix E.  Clinical Outcome Assessment Forms/Instruments 
Not Applicable  


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Appendix F.  Health Economic Forms/Instruments 
Not Applicable 


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Appendix G.  Details of PK or PK/PD Methods for Modeling 
Not Applicable