Clinical trial NCT03023878
Conditions: High-risk Diffuse Large B-Cell Lymphoma
Sponsor: Amgen
Start date: 2017-03-13; Completion date: 2019-10-28
Enrollment: 47 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A phase 2, multicenter, open-label, single arm clinical trial in adults with newly diagnosed aggressive high-risk DLBCL.

Detailed description:
The safety profile of blinatumomab after frontline rituximab (R)-chemotherapy, consisting of either R-CHOP (14 or 21) (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) or R-DA-EPOCH (rituximab and dose adjusted-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), or R-CHOEP (rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide), will be determined. The study will consist of a screening period of up to 14 days, a standard of care (SOC) R-chemotherapy run-in period of approximately 21 weeks, a 12 to 16 week blinatumomab treatment period, a 30-day safety follow-up visit, and a long-term follow-up period that begins after the safety follow-up visit is completed until 1 year from the first dose blinatumomab.

Arms: arm 1: Blinatumomab was administered as a continuous intravenous (IV) infusion. Cycle 1 was 12 weeks (84 days) in duration with step dosing of 9 µg/day for 7 days, 28 µg/day for 7 days, 112 µg/day for 6 weeks, followed by a 4-week treatment free time.

An optional 4-week Cycle 2 of blinatumomab was available for participants whose disease did not progress, with step dosing of 9 µg/day for 7 days, 28 µg/day for 7 days, and 112 µg/day for 14 days.

There was a safety follow-up for 30 days. And a long-term follow-up of up to 8 months for a maximum of 1 year from first dose of blinatumomab or until participant death.
Interventions: intervention 1: Blinatumomab intervention 2: Investigator's Choice Chemotherapy intervention 3: Dexamethasone
Intervention descriptions: intervention 1: Blinatumomab monotherapy was supplied in single-use sterile glass injection vials and administered as an IV infusion. intervention 2: During the run-in period participants received 6 cycles of standard of care rituximab-chemotherapy dosed per investigator's institution standard as follows:

* R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine,prednisone)
* R-DA-EPOCH (rituximab and dose adjusted-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) or
* R-CHOEP (rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide). intervention 3: Dexamethasone 20 mg IV: within 1 hour prior to start of treatment in each treatment cycle, and within 1 hour prior to dose-step (increase).

Protocol documents:
Prot_000.pdf: 
Product:  Blinatumomab
Protocol Number:  20150288
Date:  03 June 2018
Page 1 of 102
CONFIDENTIAL
Title:  A Phase 2 Open-label Study Investigating the Safety and Efficacy of 
Blinatumomab After Frontline R-Chemotherapy in Adult Subjects With Newly 
Diagnosed High-risk Diffuse Large B-Cell Lymphoma (DLBCL)
Amgen Protocol Number (Blinatumomab) 20150288
EudraCT number 2016-002190-35
Clinical Study Sponsor:
Amgen Inc
One Amgen Center Drive
Thousand Oaks, CA 91320, USA
Phone: +1-805-447-1000
Key Sponsor Contact(s):
 MD
Clinical Research Medical Director
One Amgen Center Drive
Thousand Oaks, CA 91320-1799
Telephone:
Email:
Global Clinical Trial Manager
240 Cambridge Science Park
Milton Road
Cambs, CB4 0WD
Telephone:
Email:
Date:
28 June 2016
Amendment 1
28 February 2017 (not submitted)
Amendment 2
11 May 2017
Amendment 3
03 June 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 or the local Key Sponsor contact.
NCT Number: NCT03023878 
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov


Product:  Blinatumomab
Protocol Number:  20150288
Date:  03 June 2018
Page 2 of 102
CONFIDENTIAL
Investigator’s Agreement
I have read the attached protocol entitled A Phase 2 Open-label Study Investigating the 
Safety and Efficacy of Blinatumomab After Frontline R-Chemotherapy in Adult Subjects
With Newly Diagnosed High-risk Diffuse Large B-Cell Lymphoma (DLBCL), dated
03 June 2018, and agree to abide by all provisions set forth therein.  
I agree to comply with the International Council for Harmonisation (ICH) Tripartite 
Guideline on Good Clinical Practice (GCP) 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:  20150288
Date:  03 June 2018
Page 3 of 102
CONFIDENTIAL
Protocol Synopsis
Title:  A Phase 2 Open-label Study Investigating the Safety and Efficacy of Blinatumomab After 
Frontline R-Chemotherapy in Adult Subjects With Newly Diagnosed High-risk Diffuse Large 
B-Cell Lymphoma (DLBCL)
Study Phase:  Phase 2
Indication:  High-risk Diffuse Large B-Cell Lymphoma (DLBCL)
Primary Objective:  To evaluate the safety of blinatumomab administered after frontline standard 
of care (SOC) rituximab (R)-chemotherapy in newly diagnosed subjects with high-risk DLBCL.
Secondary Objective(s):  

To estimate the efficacy of blinatumomab administered after frontline SOC 
R-chemotherapy in newly diagnosed subjects with high-risk DLBCL.

To characterize the pharmacokinetics (PK) of blinatumomab administered to subjects 
after frontline SOC R-chemotherapy in newly diagnosed subjects with high risk DLBCL.
Exploratory Objectives:

To evaluate minimal residual disease (MRD) from the frequency of detectable clonotypic 
immunoglobulin heavy chain (IgH) sequences by next generation sequencing (NGS) of 
cell-free circulating tumor DNA (CT-DNA) positivity among subjects at various time points 
before, during, and after SOC R-chemotherapy and blinatumomab treatment.

To evaluate the relationship of cell of origin (COO) determination, c-myc, and/or 
Bcl-2/Bcl-6 rearrangements to response after blinatumomab treatment.

To evaluate the immunopharmacodynamics of blinatumomab administered after SOC 
R-chemotherapy.

To determine the incidence of anti-blinatumomab antibody formation.
Hypotheses:  Blinatumomab, given after 6 cycles of frontline SOC R-chemotherapy to subjects 
with newly diagnosed, aggressive high-risk DLBCL, can safely be administered and will 
demonstrate a tumor response based on objective response rate (ORR) and complete response 
(CR) rate at completion of therapy, progression free survival (PFS) from first dose of 
blinatumomab, and overall survival (OS) from first dose of blinatumomab.
Primary Endpoint:

Overall incidence and severity of treatment-emergent adverse events occurring during 
the blinatumomab treatment period graded by investigators according to Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 and characterized as 
related or unrelated to study drug (blinatumomab)
Secondary Endpoint(s):  

ORR expressed as the proportion of subjects achieving CR and partial response (PR).  
Responses will be determined by central radiographic assessment using the Lugano 
Classification 

Duration of response 

CR rate 

OS from first dose of blinatumomab

PFS from first dose of blinatumomab 

Hematopoietic stem cell transplantation (HSCT) rate

Blinatumomab PK parameters


Product:  Blinatumomab
Protocol Number:  20150288
Date:  03 June 2018
Page 4 of 102
CONFIDENTIAL
Exploratory Endpoints:

MRD measured by the detection of clonotypic IgH sequences by NGS of cell-free 
CT-DNA positivity in plasma at various time points before, during, and after SOC 
R-chemotherapy and blinatumomab treatment

Response rates and duration according to COO designation or, c-myc and/or Bcl-2/Bcl-6 
rearrangement as determined from pretreatment specimens

Pharmacodynamics, including quantitative and qualitative lymphocyte subsets and 
cytokine levels in peripheral blood at various time points during blinatumomab treatment

Incidence of anti-blinatumomab antibodies in the study
Study Design:  This is a phase 2, multicenter, open-label, single arm clinical trial in adult 
subjects with newly diagnosed aggressive high-risk DLBCL.  The safety profile of blinatumomab 
after frontline SOC R-chemotherapy consisting of either R-CHOP (14 or 21) or R-DA-EPOCH or 
R-CHOEP will be determined. The study will consist of up to a 14-day screening period, a SOC 
R-chemotherapy run-in period of approximately 21 weeks, a 12 to 16 week blinatumomab 
treatment period, a 30-day safety follow-up visit, 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, or 
until subject death, whichever comes first.
Sample Size:  Approximately 38 subjects will be enrolled and 35 subjects are expected to be 
assigned to treatment with blinatumomab. 
Summary of Subject Eligibility Criteria:  The study will enroll subjects age ≥18 years with 
untreated and histologically proven high-risk DLBCL defined by International Prognostic Index 
(IPI) 3 to 5 and/or double-hit or higher or double protein expression. To be eligible subjects must 
have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, have adequate 
organ and bone marrow function and meet criteria per investigator’s institution to receive SOC 
R-chemotherapy (ie, R-CHOP or R-DA-EPOCH or R-CHOEP) of 6 cycles. Subjects must be 
enrolled on study prior to cycle 1 or cycle 2. Enrolled subjects will complete a run-in period 
consisting of  6-cycles of SOC R-chemotherapy. In order to be assigned to treatment with 
blinatumomab subjects must achieve CR, PR, or stable disease as determined by positron 
emission tomography/computed tomography (PET/CT) performed 3-weeks (± 3 days) after 
cycle 6 of SOC R-chemotherapy. 
For a full list of eligibility criteria, please refer to Section 4.1 and Section 4.2.
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 an intravenous 
(IV) infusion. Cycle 1 is 12 weeks (84 days) in duration. 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) followed by a 4 week
(+ 1 week) treatment free interval (day 57 to 84). In subjects without disease progression, a 
second cycle of blinatumomab (cycle 2) may be given at the discretion of the investigator. 
Cycle 2 of blinatumomab is 4 weeks (28 days) in duration, which includes 4 weeks of 
blinatumomab IV infusion (9µg/day x 7 days; 28 µg/day x 7 days; 112 µg/day x 14 days). Prior to 
initiation of blinatumomab and each dose-step escalation, dexamethasone is administered as 
described in Table 2. 
Non-investigational Product:
Non-Amgen Non-investigational Product Dosage and Administration: During the run-in 
period subjects will receive SOC R-chemotherapy dosed per investigator’s institution standard as 
follows (See Section 6.3): 

R-CHOP 14 or 21 (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) 
chemotherapy OR

R-DA-EPOCH (rituximab and dose adjusted-etoposide, prednisone, vincristine, 
cyclophosphamide, and doxorubicin) OR

R-CHOEP (rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone, and
etoposide)


Product:  Blinatumomab
Protocol Number:  20150288
Date:  03 June 2018
Page 5 of 102
CONFIDENTIAL
Subjects must complete a total of 6-cycles of SOC R-chemotherapy prior to treatment assignment 
with blinatumomab.  Subjects may be enrolled on study prior to either cycle 1 or cycle 2 of SOC 
R-chemotherapy. Subjects that are enrolled prior to cycle 1 will complete 6 cycles of SOC R-
chemotherapy during the run-in period, while subjects enrolled prior to cycle 2 of SOC 
R-chemotherapy will receive 1 cycle of SOC R-chemotherapy prior to enrollment and an 
additional 5 cycles of SOC R-chemotherapy during the run-in period (See Section 4.1.1).  All 
subjects on study must complete a total of 6 cycles of SOC R-chemotherapy prior to treatment 
assignment with blinatumomab.  Disease evaluation during the run-in period is per institutional 
SOC and must be recorded in the subject’s electronic case report form (eCRF).
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, Table 5, and Table 6): medical history and prior therapies, 
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, c-reactive protein, IgG, IgA 
and IgM, beta-2 microglobulin.  Urine will be collected for urinalysis. In females of childbearing 
potential, a urine or serum pregnancy test will be performed locally. Additional on-treatment 
pregnancy testing may be performed at the investigator’s discretion or as required by local laws 
and regulations. Central laboratory tests include:  blood for biomarker analysis, 
pharmacogenetics, anti-blinatumomab antibodies and blinatumomab PK. Formalin-fixed 
paraffin-embedded tumor tissue and the associated pathology reports will be collected and 
submitted to the central laboratory. Radiographic (PET/CT) scans will also be performed. 
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, Table 5, and Table 6).  
Statistical Considerations:  
The overall incidence (overall and by severity) of treatment-emergent adverse events during 
blinatumomab treatment will be summarized with exact binomial 2-sided 95% confidence 
intervals (CIs).  Subject incidence of all and treatment-related treatment-emergent adverse events
(including grade ≥3 adverse events, grade ≥ 4 adverse events, serious adverse events, fatal 
adverse events, adverse events of interest (eg, neurological adverse events), and adverse events 
requiring permanent discontinuation of study drug, and adverse events requiring interruption of 
study drug) after initiation of blinatumomab therapy through the 30-day safety follow-up visit will 
be summarized.
ORR, CR rate, and HSCT rate will also be summarized with point estimates accompanied by 
exact binomial 2-sided 95% CIs.  For duration of response and PFS (time to event endpoints), the 
Kaplan-Meier (KM) method  will be used. KM quartiles along with 2-sided 95% CIs, the number 
of subjects censored, and the number of events will be provided.  Subjects who are alive at the 
date that triggers the analysis will be censored at the date last known to be alive.  If the date last 
known to be alive is after the date that triggers the analysis, the subject will be censored at the 
analysis trigger date.
For a full description of statistical analysis methods, please refer to Section 10.
Sponsor: Amgen Inc
Data Element Standards 
Version(s)/Date(s): 
5: 20 March 2015


Product:  Blinatumomab
Protocol Number:  20150288
Date:  03 June 2018
Page 6 of 102
CONFIDENTIAL
Study Design and Treatment Schema


Product:  Blinatumomab
Protocol Number:  20150288
Date:  03 June 2018
Page 7 of 102
CONFIDENTIAL
DLBLC = Diffuse Large B-Cell Lymphoma; d = day; R = rituximab; IV = intravenous; EOS =  end of study; 
PET/CT = positron emission tomography/computed tomography; SOC = standard of care; 
IP = investigational product
a All subjects (whether enrolled prior to cycle 1 or prior to cycle 2) must complete 6 cycles of SOC 
R-chemotherapy. Subjects can be enrolled prior to cycle 1 of 6 cycles or prior to cycle 2 of  6 cycles of SOC 
R-chemotherapy (see Inclusion Criteria 105).
b In subjects receiving radiation to bulky disease, this will occur after cycle 6 SOC R-chemotherapy and 
PET/CT is completed:

Radiation will occur as soon as possible after the PET/CT post cycle 6 SOC R-chemotherapy.  

Blinatumomab treatment will start 2 to 3 weeks after radiation is completed and toxicity from the 
radiation has resolved to a safe level per investigator’s recommendation.

A PET/CT will not be obtained post radiation prior to proceeding to blinatumomab. 
c PET/CT must be performed 3 weeks (± 3 days) after cycle 6 SOC R-chemotherapy.
d PET/CT must be performed 3 weeks (+ 3 days) after the last blinatumomab dose of cycle 1, ie, day 78 of 
cycle 1.
e At the discretion of the investigator, a second cycle of blinatumomab may be administered to subjects who 
do not have progressive disease (PD). 
f PET/CT must be performed 3 weeks (± 3 days) after the last blinatumomab dose of cycle 2, ie, day 50 of 
cycle 2.
g Safety follow-up visit must be completed 30 days (± 3 days) after the last dose of blinatumomab.
h Subjects should be followed for 1 year from the first dose of blinatumomab
i If only cycle 1 of blinatumomab is given, long-term follow-up (LTFU) begins 3 months (3 weeks) after the 
last scan (C1D78), LTFU visit 1 occurs at 3 months post last scan (C1D78), LTFU visit 2 occurs at 6 months 
post last scan (C1D78) and LTFU visit 3 occurs at 9 months post last scan (C1D78) for a maximum of 1 year
from the first dose of blinatumomab, or until subject death, whichever occurs first.
j If cycle 2 is given, LTFU begins 3 months (3 weeks) after cycle 2 day 50, LTFU visit 1 occurs at 3 months 
post last scan (C2D50), LTFU visit 2 occurs at 6 months post last scan (C2D50), and LTFU visit 3 occurs at 
8 months from last scan (C2D50) for a maximum of 1 year from the first dose of blinatumomab or until 
subject death, whichever occurs first.


Product:  Blinatumomab
Protocol Number:  20150288
Date:  03 June 2018
Page 8 of 102
CONFIDENTIAL
Study Glossary
Abbreviation or 
Term
Definition/Explanation
ABC
activated B cell
ALL
acute lymphocytic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
CI
confidence interval
CNS
central nervous system
COO
cell of origin
CR
complete response
CRF 
case report form
CRS
cytokine release syndrome
CRu
unconfirmed complete response
CSF
cerebro spinal fluid
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CT-DNA
cell-free circulating tumor DNA 
CYP450
cytochrome P450
DFS
disease free survival
DHL
double-hit lymphomas
DILI
drug-induced liver injury
DLBCL
Diffuse Large B-Cell Lymphoma
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
End of Study for 
Individual Subject
defined as the last day that protocol-specified procedures are conducted 
for an individual subject (ie, the date the subject withdraws full consent 
from the study, completes the safety follow-up visit or long-term 
follow-up [whichever is later] or death).
End of Study (primary 
completion)
Primary Completion:  the time when the last subject is assessed or 
receives an intervention for the purposes of final collection of data for the 
primary analysis (ie, completion of the safety follow-up visit).
End of Study (end of 
trial)
the time when the last subject is assessed or receives an intervention for 
evaluation in the study (ie, completion of the long-term follow-up period).  


Product:  Blinatumomab
Protocol Number:  20150288
Date:  03 June 2018
Page 9 of 102
CONFIDENTIAL
Abbreviation or 
Term
Definition/Explanation
End of Treatment
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject
EOI
events of interest
ESMO
European Society for Medical Oncology
EU
European Union
FISH
Fluorescent in-situ hybridization
GCB
germinal center B
GCP
Good Clinical Practice
GI
gastrointestinal
Heart rate
number of cardiac cycles per unit of time
HLGT
high level group term
HSCT
hematopoietic stem cell transplantation
HR
hazard ratio
ICH
International Council for Harmonisation
Ig
Immunoglobulin
IgH
immunoglobulin heavy chain
INR
International normalization ratio
IP
investigational product
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
Interactive Voice 
Response system
(IVRS)
telecommunication technology that is linked to a central computer in real 
time as an interface to collect and process information.  
KM
Kaplan-Meier
LDH
lactate dehydrogenase
LTFU
long-term follow-up
MRD
minimal residual disease
MRI
magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
NF-kB
nuclear factor kappa B cells
NGS
next generation sequencing
NHL
Non-Hodgkin’s Lymphoma
ORR
objective response rate


Product:  Blinatumomab
Protocol Number:  20150288
Date:  03 June 2018
Page 10 of 102
CONFIDENTIAL
Abbreviation or 
Term
Definition/Explanation
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
Ph-
Philadelphia chromosome-negative
PK
pharmacokinetics or pharmacokinetic
PMBL
primary mediastinal B-cell lymphoma
PMR
partial metabolic response
PR
partial response
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
PT
prothrombin time
PTT/aPTT
partial thromboplastin time/activated partial thromboplastin time
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
R
rituximab
RUQ
right upper quadrant
SOC
standard of care
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
SUV
standardized uptake values
TBL
total bilirubin
ULN
upper limit of normal


Product:  Blinatumomab
Protocol Number:  20150288
Date:  03 June 2018
Page 11 of 102
CONFIDENTIAL
TABLE OF CONTENTS
Protocol Synopsis............................................................................................................3
Study Design and Treatment Schema .............................................................................6
Study Glossary................................................................................................................8
1.
OBJECTIVES .......................................................................................................17
1.1
Primary .....................................................................................................17
1.2
Secondary.................................................................................................17
1.3
Exploratory................................................................................................17
2.
BACKGROUND AND RATIONALE ......................................................................17
2.1
Disease.....................................................................................................17
2.2
Amgen Investigational Product Background..............................................20
2.3
Rationale...................................................................................................22
2.4
Clinical Hypotheses...................................................................................22
3.
EXPERIMENTAL PLAN........................................................................................22
3.1
Study Design.............................................................................................22
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 .........................................................27
4.2
Inclusion and Exclusion Criteria – Part 2...................................................29
4.2.1
Inclusion Criteria – Part 2 ..........................................................29
4.2.2
Exclusion Criteria – Part 2 .........................................................29
5.
SUBJECT ENROLLMENT....................................................................................29
5.1
Treatment Assignment ..............................................................................30
6.
TREATMENT PROCEDURES..............................................................................30
6.1
Classification of Product(s) and/or Medical Device(s)................................30
6.2
Investigational Product: Blinatumomab .....................................................30
6.2.1
Dosage, Administration, and Schedule......................................31
6.2.1.1
Inpatient Dosing ......................................................32
6.2.1.2
Outpatient Dosing ...................................................32


Product:  Blinatumomab
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6.2.2
Dosage Adjustments, Delays, Rules for Withholding or 
Restarting, Permanent Discontinuation .....................................33
6.2.2.1
Infusion Interruption due to 
Technical/Logistical Reasons..................................33
6.2.2.2
Infusion Interruption/Dose Modifications 
due to Adverse Events ............................................33
6.2.2.3
Permanent Discontinuation of 
Blinatumomab .........................................................36
6.2.3
Dose Limiting Toxicities.............................................................37
6.3
Non-Amgen Non-investigational Product: SOC R-chemotherapy..............38
6.4
Other Protocol-required Therapies ............................................................38
6.4.1
Dexamethasone Premedication.................................................38
6.5
Hepatotoxicity Stopping and Rechallenge Rules .......................................39
6.5.1
Criteria for Withholding and/or Permanent 
Discontinuation of Amgen Investigational Product and 
Other Protocol-required Therapies due to Potential 
Hepatotoxicity............................................................................39
6.5.2
Criteria for Rechallenge of Amgen Investigational 
Product and Other Protocol-required Therapies After 
Potential Hepatotoxicity.............................................................41
6.6
Concomitant Therapy................................................................................41
6.7
Other Treatment Procedures.....................................................................42
6.8
Medical Devices........................................................................................42
6.9
Product Complaints...................................................................................43
6.10
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period..................................................................................43
6.11
Contraceptive Requirements.....................................................................43
6.11.1
Female Subjects........................................................................43
6.11.2
Unacceptable Methods of Birth Control for Male and 
Female Subjects .......................................................................44
7.
STUDY PROCEDURES .......................................................................................44
7.1
Schedule of Assessments.........................................................................44
7.2
General Study Procedures ........................................................................53
7.2.1
Screening..................................................................................53
7.2.2
Re-screening.............................................................................53
7.2.3
Run-in Period: SOC R-Chemotherapy.......................................54
7.2.4
Treatment Period.......................................................................54
7.2.5
Safety Follow-up Visit................................................................55
7.2.6
Long-term Follow-up/End of Study ............................................55
7.3
Description of General Study Procedures .................................................56
7.3.1
Informed Consent......................................................................56
7.3.2
Demographics ...........................................................................56
7.3.3
Medical History..........................................................................57
7.3.4
Prior Therapies..........................................................................57


Product:  Blinatumomab
Protocol Number:  20150288
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7.3.5
Performance Status...................................................................57
7.3.6
Physical Measurements ............................................................57
7.3.7
Vital Signs .................................................................................57
7.3.8
Physical Exam...........................................................................58
7.3.9
Neurological Examination..........................................................58
7.3.10
Electrocardiogram .....................................................................58
7.3.11
Response Assessment..............................................................58
7.3.12
Radiographic Assessment.........................................................58
7.3.13
Lumbar Puncture to Examine Cerebrospinal Fluid.....................59
7.3.14
Bone Marrow Biopsy .................................................................59
7.4
Laboratory Procedures..............................................................................59
7.4.1
Pregnancy Tests .......................................................................61
7.4.2
Pharmacokinetics ......................................................................61
7.4.3
Serum Cytokines.......................................................................61
7.4.4
Lymphocyte Subsets .................................................................61
7.4.5
Cell-free Circulating Tumor DNA for IgH Sequencing 
for Minimal Residual Disease Assessment................................61
7.5
Antibody Testing Procedures ....................................................................61
7.6
Biomarker Development............................................................................62
7.7
Optional Pharmacogenetic Studies ...........................................................62
7.8
Sample Storage and Destruction...............................................................63
8.
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY..................64
8.1
Subjects’ Decision to Withdraw .................................................................64
8.2
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion......................................64
8.3
Reasons for Removal From Run-in, Treatment, or Study..........................65
8.3.1
Reasons for Removal From Run-in ...........................................65
8.3.2
Reasons for Removal From Treatment......................................65
8.3.3
Reasons for Removal From Study.............................................65
9.
SAFETY DATA COLLECTION, RECORDING, AND REPORTING.......................66
9.1
Definition of Safety Events ........................................................................66
9.1.1
Disease Related Events ............................................................66
9.1.2
Adverse Events .........................................................................66
9.1.3
Serious Adverse Events ............................................................67
9.2
Safety Event Reporting Procedures ..........................................................68
9.2.1
Reporting Procedures for Disease Related Events....................68
9.2.2
Adverse Events .........................................................................68
9.2.2.1
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria............................68
9.2.2.2
Reporting Procedures for Serious Adverse 
Events.....................................................................69


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9.2.2.3
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ...................71
9.2.2.4
Serious Adverse Events That are not to be 
Reported by the Sponsors to Regulatory 
Agencies in an Expedited Manner...........................71
9.2.3
Reporting of Delayed Time to HSCT for Subjects With 
Partial Response/Partial Metabolic Response 
(PR/PMR) at Baseline ...............................................................71
9.3
Pregnancy and Lactation Reporting ..........................................................71
10.
STATISTICAL CONSIDERATIONS......................................................................72
10.1
Study Endpoints, Analysis Sets, and Covariates .......................................72
10.1.1
Study Endpoints ........................................................................72
10.1.1.1
Primary Endpoint.....................................................72
10.1.1.2
Secondary Endpoints ..............................................72
10.1.1.3
Exploratory Endpoints .............................................73
10.1.2
Analysis Sets.............................................................................73
10.1.2.1
Full Analysis Set......................................................74
10.1.2.2
Target Dose Analysis Set........................................74
10.1.2.3
Responder Analysis Set..........................................74
10.1.2.4
Pharmacokinetic Analysis Set .................................74
10.1.2.5
Pharmacodynamic Analysis Set ..............................74
10.1.2.6
SOC R-chemotherapy Analysis Set.........................74
10.1.3
Subgroup Analysis.....................................................................74
10.1.4
Handling of Missing and Incomplete Data..................................75
10.2
Sample Size Considerations .....................................................................75
10.3
Planned Analyses .....................................................................................75
10.3.1
Data Review Team....................................................................75
10.3.2
Interim Analysis.........................................................................76
10.3.3
Primary Analysis........................................................................77
10.3.4
Final Analysis ............................................................................77
10.4
Planned Methods of Analysis ....................................................................77
10.4.1
General Considerations.............................................................77
10.4.2
Primary Safety Endpoint............................................................77
10.4.3
Secondary Efficacy Endpoints ...................................................77
10.4.4
Safety Endpoints .......................................................................78
10.4.4.1
Adverse Events.......................................................78
10.4.4.2
Disease Related Events..........................................78
10.4.4.3
Laboratory Test Results ..........................................78
10.4.4.4
Vital Signs...............................................................79
10.4.4.5
Electrocardiogram...................................................79
10.4.4.6
Antibody Formation .................................................79
10.4.4.7
Exposure to Investigational Product ........................79
10.4.4.8
Exposure to SOC R-Chemotherapy ........................79


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10.4.4.9
Exposure to Concomitant Medication ......................80
11.
REGULATORY OBLIGATIONS............................................................................80
11.1
Informed Consent......................................................................................80
11.2
Institutional Review Board/Independent Ethics Committee........................81
11.3
Subject Confidentiality...............................................................................81
11.4
Investigator Signatory Obligations.............................................................82
12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS..................................................82
12.1
Protocol Amendments and Study Termination ..........................................82
12.2
Study Documentation and Archive ............................................................83
12.3
Study Monitoring and Data Collection .......................................................83
12.4
Investigator Responsibilities for Data Collection........................................85
12.5
Language..................................................................................................85
12.6
Publication Policy......................................................................................85
12.7
Compensation...........................................................................................86
13.
REFERENCES.....................................................................................................87
14.
APPENDICES ......................................................................................................90
List of Tables
Table 1.  Infusion Interruptions and Dose Modifications.................................................33
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 – Screening and Run-In ........................................45
Table 5.  Schedule of Assessments – Cycle 1 (Blinatumomab).....................................48
Table 6.  Schedule of Assessments – Cycle 2 (Blinatumomab).....................................51
Table 7.  Analyte Listing ................................................................................................60
Table 8.  Stopping Boundary With Batch Size of 7 Subjects, Posterior 
Probability of 90% and DLT Limit of 25%................................................76
Table 9.  Operating Characteristics With Batch Size of 7 Subjects ................................76
List of Appendices
Appendix A.  Additional Safety Assessment Information................................................91
Appendix B.  Sample Serious Adverse Event Report Form or eSerious Event 
Contingency Form ..................................................................................93
Appendix C.  Pregnancy and Lactation Notification Worksheets....................................96
Appendix D.  International Prognostic Index for Diffuse Large B-cell 
Lymphoma..............................................................................................98
Appendix E.  Eastern Cooperative Oncology Group Performance Status......................99


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Appendix F.  Response Assessment per the Lugano Classification.............................100
Appendix G.  Disease Related Events.........................................................................101
Appendix H.  Clinically Relevant Neurologic Events by High Level Group 
Term (HLGT) ........................................................................................102


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1.
OBJECTIVES
1.1
Primary

To evaluate the safety of blinatumomab administered after frontline standard of 
care (SOC) rituximab (R)-chemotherapy in newly diagnosed subjects with 
high-risk Diffuse Large B-cell Lymphoma (DLBCL).
1.2
Secondary

To estimate the efficacy of blinatumomab administered after frontline SOC 
R-chemotherapy in newly diagnosed subjects with high-risk DLBCL.

To characterize the pharmacokinetics (PK) of blinatumomab administered to 
subjects after frontline SOC R-chemotherapy in newly diagnosed subjects with 
high risk DLBCL.
1.3
Exploratory

To evaluate minimal residual disease (MRD) from the frequency of detectable 
clonotypic immunoglobulin H (IgH) sequences by next generation sequencing 
(NGS) of cell-free circulating tumor DNA (CT-DNA) positivity among subjects at 
various time points before, during and after SOC R-chemotherapy and 
blinatumomab treatment

To evaluate the relationship of cell of origin (COO) determination, c-myc and/or 
Bcl-2/Bcl-6 rearrangements to response after blinatumomab treatment

To evaluate the immunopharmacodynamics of blinatumomab administered after 
SOC R-chemotherapy

To determine the incidence of anti-blinatumomab antibody formation
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 0.3/100.000/year (35 to 39 years) to 26.6/100.000/year (80 to 84 years) 
(Tilly and Dreyling, 2009).
DLBCL is biologically and clinically heterogeneous, with subgroups defined by 
morphology, immune-phenotype, genetic alterations, and transcriptional patterns. 
Immuno-phenotyping is an essential diagnostic procedure which allows DLBCL to be 
identified and to be further divided into germinal center B type (GCB) and non-GCB type 
(Hans et al, 2004). GCB/non-GCB stratification by the Hans algorithm was derived 
primarily from patients treated in the pre-rituximab era and its prognostic value with 


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immune-chemotherapy as opposed to cyclophosphamide, doxorubicin, vincristine, and 
prednisone (CHOP) has been shown not to predict outcome (Nyman et al, 2007).  
Alternatively, prognostic differentiation by COO can be achieved with gene expression 
profiling (GEP) (Rosenwald et al, 2002), subdividing DLBCL’s into 3 types: GCB (50% 
DLBCL), activated B-cell (ABC) (40% of DLBCL) and Primary Mediastinal B-cell 
Lymphoma (PMBL) (10% of DLBCL) (Scott et al, 2014). This prognostic stratification 
between GCB and ABC subtypes remains valid in patients receiving 
immune-chemotherapy (Lenz et al, 2008). Further studies using this methodology in 
large cohorts of subjects are needed to determine if the COO is an independent 
prognostic indicator, which would make it a useful tool for directing prospective clinical 
trials.  
All three subtypes of DLBCL have distinct genetic aberrations.  GCB DLBCL is 
associated with markers of germinal center such as CD10 and Bcl-6 gene 
(Pasqualucci et al, 2003) whereas the ABC subtype has constitutive activation of nuclear 
factor kappa B cells (NF-kB) target genes.  Both the GCB and ABC subtypes express
Bcl-2, in the GCB subtype this expression is associated with a t(14;18) translocation and 
in the ABC subtype it reflects NF-kB activation (Alizadeh et al, 2000).  The distinct 
genetic aberrations reflect that these subtypes are derived from different stages of B-cell 
differentiation and therefore a standard therapy for both subtypes may not be the best 
approach for treatment.  This has been shown to be the case when standard 
immune-chemotherapy with R-CHOP resulted in an inferior outcome in the ABC subtype 
compared to the GBC subtype (Lenz et al, 2008). 
Additional poor prognostic genetic abnormalities in DLBCL include myc rearrangement 
in approximately 10% of patients associated with poor outcome following standard 
therapy with R-CHOP (Savage et al, 2009), and myc rearrangement with Bcl-2 (orBcl-6) 
translocation (known as double-hit lymphomas (DHL)) associated with dismal clinical 
outcome following R-CHOP (Green et al, 2012). These DHL’s progress rapidly and are 
refractory to therapy.  Double protein expression of myc and Bcl-2 (activated by 
mechanisms such as NF-kB activation) in the absence of rearrangements have also 
demonstrated a very poor outcome following R-CHOP therapy (Hu et al, 2013).  Dose 
intensification with R-DA-EPOCH (dose-adjusted etoposide, prednisone, vincristine, 
cyclophosphamide and doxorubicin plus rituximab) has promising results in a 
phase 2 trial but very few DHL were in this study (Dunleavy, 2014). Novel alternative 
therapies are needed to improve the prognosis of these aggressive DLBCLs. 


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To tailor therapy to the aggressiveness of DLBCLs, the International Prognostic Index 
(IPI) has been developed as a model for predicting outcomes based on clinical factors 
(The International NHL prognostic factors project, 1993; see Appendix D).  The IPI is 
widely used for stratification and analysis of clinical trials. The IPI is predictive of 
outcomes in the rituximab era (Ziepert et al, 2010).  
Overall, DLBCLs are aggressive but potentially curable malignancies. Cure rate is 
particularly high in patients with limited disease with a 5-year progression free survival 
(PFS) ranging from 80-85%. However, the prognosis for patients with advanced disease 
is substantially worse with a 5-year PFS of approximately 50% (Martelli et al, 2013).  
DLBCL patients are a very heterogeneous group both clinically and molecularly. Thus, 
PFS varies widely in response to treatment when rituximab is combined with present 
chemotherapy regimens (Dunleavy, 2015).
The choice of first line treatment for patients with DLBCL is based on the individual 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 to 1) and young patients with high risk (≤60 years, aaIPI=2 to 3; Martelli et al,
2013). R-CHOP given every 14 or 21 days is the cornerstone of first-line therapy for 
DLBCL (NCCN and ESMO guidelines), particularly for elderly patients and younger 
patients with low risk features. Younger patients with low risk features may also be 
treated with R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, 
and prednisone) without radiotherapy or R-CHOP21 with radiotherapy for bulky disease.  
Young patients with high risk represent the greatest current challenge in the front-line 
treatment of DLBCL. Around 30% of these patients are refractory to front-line R-CHOP. 
Several options in addition to R-CHOP are being considered, including enrollment in 
clinical trials or use of high dose chemotherapy with autologous hematopoietic stem cell 
transplantation (HSCT). Autologous HSCT is currently only recommended in eligible 
patients with DLBCL who did not achieve complete response (CR) after first line 
chemotherapy or in patients with chemo-sensitive relapse and results of this type of 
therapy remain poor today with only 20% disease free survival (DFS) (Robinson et al,
2016).  An alternative therapy to R-CHOP that has been used to treat newly diagnosed 
patients with poor prognosis high risk disease is R-DA-EPOCH, but PFS at 5 years 
continues to remain low in patients with IPI 4 and 5 at only 67%  and 47%, respectively 
(Wilson et al, 2008).


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Despite the improvements observed since the introduction of rituximab into front-line 
treatments, relapse continues to be observed in 10 to 20% of patients with low IPI and 
30 to 50% of patients with high IPI (Martelli et al, 2013).  Various salvage regimens are 
currently used in relapsed/refractory DLBCL. 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 autologous HSCT. Outcomes were particularly poor for patients that had 
received prior rituximab or had relapsed within one year of diagnosis. (Gisselbrecht et al,
2010). Allogeneic HSCT is considered for a select group of patients with relapsed 
DLBCL (Friedberg, 2011). However, this treatment is associated with a high 
treatment-related mortality rate (up to ~25%) (Lazarus et al, 2010). Since salvage 
therapy after relapse results in poor responses and high treatment related toxicities, 
novel new agents need to be introduced into the upfront therapy setting to help improve 
PFS and overall survival (OS). 
2.2
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.
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 acute lymphocytic leukemia (ALL) and NHL, 
including DLBCL. 
Study MT103-104 evaluated the efficacy of blinatumomab in subjects with 
relapsed/refractory B-cell NHL.  In this phase 1 study, subjects with relapsed/refractory 
NHL where treated with a target blinatumomab dose of 60µg/m2. In the subset of 
subjects with DLBCL (n=11), 2 achieved a partial response (PR) and 4 achieved 
CR/unconfirmed complete response (CRu) (objective response rate [ORR] was 55%).


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Neurologic events were the dose limiting toxicity, but were reversible in all cases upon 
interruption of the infusion (Goebeler et al, 2016).  As of the most recent analysis, 2 of 
the DLBCL subjects with CR/CRu had ongoing responses beyond 600 days. Of the 
other two, one subject underwent allogeneic HSCT and was censored and the other 
relapsed approximately 7 months after therapy. 
A subsequent open-label phase 2 blinatumomab study (MT-103-208) in 
relapsed/refractory DLBCL included 25 subjects. Twenty three subjects received 
stepwise dosing (9/28/112 µg/day) and 2 subjects received a flat dose of 112 µg/day. At 
baseline, the median number of prior regimens was 3 (range 1 to 7) and all subjects had 
received prior rituximab. Seven (28%) had relapsed after prior allogenic HSCT. This 
study demonstrated that stepwise dosing, with weekly dose escalation of blinatumomab,
was tolerable and associated with anti-tumor activity with an ORR after 1 cycle of 
blinatumomab of 43% for evaluable subjects, including CR in 19%. The most common 
adverse events were tremor, pyrexia and fatigue. Grade 3 neurologic adverse events 
were reported in 22% of subjects (no grade 4 or 5) but were generally reversible with
treatment interruption (Viardot et al, 2016).
The single agent clinical response seen in relapsed or refractory DLBCL subjects 
suggests blinatumomab may be a novel agent to add to frontline therapy to improve the 
low PFS/OS that occurs in high risk newly diagnosed subjects with present day 
therapies.  
Blinatumomab (BLINCYTO) is approved in multiple regions for the treatment of 
Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor acute 
lymphoblastic leukemia (ALL). Additionally, confirmation of clinical benefit is a condition 
of approval in multiple countries.  
Refer to the specific section of the Investigator’s Brochure for additional information 
related to the physical, chemical, and pharmaceutical properties and formulation(s).
No formal drug interaction studies have been performed on blinatumomab.  Results from 
an in vitro test in human hepatocytes suggest that blinatumomab did not affect CYP450 
enzyme activities.  Initiation of blinatumomab treatment causes transient release of 
cytokines during the first days of treatment that may suppress CYP450 enzymes up to 
30% for a week.  Subjects who are receiving medicinal products that are CYP450 and 
transporter substrates with a narrow therapeutic index should be monitored for adverse 


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effects (eg, warfarin) or drug concentrations (eg, cyclosporine) during this time.  The 
dose of the concomitant medicinal product should be adjusted as needed.
2.3
Rationale
The current study in newly diagnosed DLBCL subjects will provide an opportunity to 
further define blinatumomab’s safety and efficacy profile. DLBCLs are aggressive but 
potentially a curable malignancy in subjects with limited disease, with a 5-year PFS 
ranging from 80-85%. 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.   
This study focuses on an unmet medical need in subjects with high risk, newly 
diagnosed DLBCL to improve their PFS.  This study proposes that adding blinatumomab 
to frontline SOC R-chemotherapy can be administered with a favorable safety profile and 
will improve subject outcomes.  
2.4
Clinical Hypotheses
Blinatumomab, given after 6 cycles of frontline SOC R-chemotherapy to subjects with 
newly diagnosed, aggressive high-risk DLBCL, can safely be administered and will 
demonstrate a tumor response based on ORR, CR rate at completion of therapy, OS 
from first dose of blinatumomab, and PFS from first dose of blinatumomab.
3.
EXPERIMENTAL PLAN
3.1
Study Design
This is a phase 2, multicenter, open-label, single arm clinical trial in adult subjects with 
newly diagnosed aggressive high-risk DLBCL.  The safety profile of blinatumomab after 
frontline SOC R-chemotherapy consisting of either R-CHOP (every 14 or 21 days) or 
R-DA-EPOCH or R-CHOEP will be determined. The study will consist of a screening 
period (up to 14-days), a SOC R-chemotherapy run-in period of approximately 
21 weeks, a 12 to 16 week blinatumomab treatment period, a 30-day safety follow-up, 
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, or until subject death, whichever comes 
first.
Screening Period
The screening period consists of up to 14 days prior to enrollment.  During this time 
period medical history, laboratory and radiographic assessments are obtained to 
determine eligibility for study enrollment.  Positron emission tomography/computed 


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tomography (PET/CT) and CT scans used for enrollment must have occurred within 
21 days prior to enrollment if starting prior to cycle 1 or within 21 days of starting cycle 1 
if enrollment is prior to cycle 2 (new scans are not required when enrollment is prior to 
cycle 2).  In order to be eligible for enrollment in the study subjects must have 
histologically proven high-risk DLBCL (defined as either IPI 3 to 5 and/or double-hit or 
higher or double protein expression) and must meet criteria per the investigator’s 
institution to receive SOC R-chemotherapy (ie, R-CHOP 14 or 21 or R-DA-EPOCH or 
R-CHOEP) for 6 cycles during the study run-in period.  
Run-in Period
The run-in period consists of enrollment on study (run-in visit 1) and SOC
R-chemotherapy followed by an assessment of disease status (run-in visit 2).
Subjects must be enrolled into the run-in period either prior to the start of cycle 1 or 
cycle 2 of SOC R-chemotherapy. Enrollment prior to cycle 2 is allowed so that results of 
molecular assessments that may not be known at the time of diagnosis (ie, prior to 
cycle 1) can be obtained as these results may potentially upgrade the subject’s tumor to 
high-risk and thus meet enrollment eligibility criteria (see Section 4.1.1, inclusion 
criterion 105).     
Subjects that are enrolled prior to cycle 1 will complete 6 cycles of SOC R-chemotherapy 
during the run-in period, while subjects enrolled prior to cycle 2 of SOC R-chemotherapy 
will receive 1 cycle of SOC R-chemotherapy prior to enrollment and an additional
5 cycles of SOC R-chemotherapy during the run-in period. All subjects on study must 
complete a total of 6 cycles of SOC R-chemotherapy prior to treatment assignment with 
blinatumomab.  Disease evaluation during the run-in period is per institutional standard 
of care and must be recorded in the subject’s electronic case report form (eCRF).
At the end of the 6 cycles of SOC R-chemotherapy, disease status will be assessed by a 
PET/CT (run-in visit 2). The PET/CT will be obtained 3 weeks after completion of cycle 6 
(± 3 days).  In order to be eligible for treatment assignment to blinatumomab, subjects 
must demonstrate either CR, PR or have stable disease based on Lugano Classification
(Cheson et al, 2014) (see Appendix F). Subjects with progressive disease (PD) are not 
eligible for treatment with blinatumomab and will end the study. 
After the post SOC cycle 6 PET/CT (run-in visit 2) subjects that require radiation to bulky 
disease per investigator judgement must complete radiation therapy as soon as possible
(see Section 6.7 Other Treatment Procedures). Treatment with blinatumomab will be 
delayed until 2 to 3 weeks after radiation therapy is completed to allow for resolution of


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toxicity from the radiation to a safe level per the investigator’s judgement.  A PET/CT is 
not required after the radiation therapy to proceed to the treatment period. 
Treatment Period
Subjects that complete the run-in period successfully will be assigned to treatment with 
blinatumomab. During the treatment period, subjects will receive 1 to 2 cycles of 
blinatumomab.  Blinatumomab will be administered as an intravenous (IV) infusion.  
Cycle 1 will be 8 weeks in duration followed by a 4-week treatment-free interval break
(+ 1 week if results of PET/CT are delayed to determine eligibility for cycle 2). Cycle 2 
should start immediately after the treatment-free period.  Cycle 2 will be 4 weeks in 
duration and given at the discretion of the investigator if the subject does not have PD. 
Each cycle of blinatumomab will be dosed at 9 µg/day for 7 days, followed by 28 µg/day 
for 7 days and 112 µg/day for the remainder of that treatment cycle (42 days for cycle 1, 
14 days for cycle 2). PET/CT will be performed 3 weeks after cycle 1 of blinatumomab 
(D78 ± 3 days) to evaluate disease status. Subjects with PD by PET/CT after cycle 1 of 
blinatumomab will not be eligible to receive cycle 2 of blinatumomab.  In subjects that 
receive cycle 2 of blinatumomab a final disease assessment by PET/CT will occur 
3 weeks after the last dose of blinatumomab (D50 ± 3 days of cycle 2). 
Safety Follow-up Period
Thirty days (+ 3 days) after the last dose of blinatumomab, subjects will complete a 
safety follow-up visit for assessment of disease related events, adverse events and 
serious adverse events.  This visit will occur 30 days (+ 3 days) after last dose of
blinatumomab either:

after cycle 1 of blinatumomab if cycle 2 is not given, or

after the last dose of blinatumomab in cycle 2.
Long-Term Follow-up Period
A long-term follow up period to assess disease and clinical status follows the safety 
follow-up period.  The frequency of long-term follow-up (LTFU) visits is every 3 months 
(3 weeks).

If only cycle 1 of blinatumomab is given, long-term follow-up begins 3 months 
(3 weeks) after the last scan (C1D78), LTFU visit 1 occurs at 3 months post 
last scan (C1D78), LTFU visit 2 occurs at 6 months post last scan (C1D78) and 
LTFU visit 3 occurs at 9 months post last scan (C1D78) for a maximum of 1 year 
from the first dose of blinatumomab, or until subject death, whichever occurs first.


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
If cycle 2 is given, long-term follow-up begins 3 months (± 3 weeks) after cycle 2 
day 50, LTFU visit 1 occurs at 3 months post last scan (C2D50), LTFU visit 2 
occurs at 6 months post last scan (C2D50), and LTFU visit 3 occurs at 8 months 
from last scan (C2D50) for a maximum of 1 year from the first dose of 
blinatumomab or until subject death, whichever occurs first.  
Subjects will be followed via clinic visit every 3 months (± 3 weeks) by institutional SOC
disease evaluation.  
The following procedures and tests will be performed at long-term follow-up visits until 
completion of the period 1 year from the first dose of blinatumomab:

Clinical Evaluation of Disease Status

Summaries of radiographic reports used for surveillance or detection of relapse 
(per institutional SOC disease evaluation)

Pathology reports relevant to relapse determination (per institutional SOC 
disease evaluation)

Recording of anti-lymphoma concomitant medication

Recording of serious adverse events possibly related to blinatumomab

Lactate dehydrogenase (LDH)

Plasma for CT-DNA assessment of clonotypic IgH sequences for MRD analysis
The overall study design is described by a study schema at the end of the protocol 
synopsis.
The study endpoints are defined in Section 10.1.1.
3.2
Number of Sites
Approximately 37 sites in North America 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
considered for closure to further participation in the trial.    
3.3
Number of Subjects
Participants in this clinical investigation shall be referred to as “subjects”.
Approximately 38 subjects will be enrolled in the study. It is expected that approximately 
7% of subjects in the run-in period will drop-out of the study (ie,  due to PD, subject 
request, requirement for alternative therapy). Amgen may choose to alter the sample 
size of subjects enrolled in the run-in period in order to ensure that approximately 
35 subjects are 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 the treatment period with blinatumomab 
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 be approximately 18 months 
(20 months for subjects receiving radiation to bulky disease). This includes a 14-day 
screening period, approximately a 21 week run-in period, a 12 to 16 week treatment 
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 time when the last subject is assessed or receives an 
intervention for the purposes of final collection of data for the primary analysis
(ie, completion of the safety follow-up visit).
End of Trial:  the time when the last subject is assessed or receives an intervention for 
evaluation in the study (ie, completion of the long-term follow-up period). 
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).  This log may be completed and updated via an Interactive Voice Response 
system (IVRS). 
Part 1 eligibility criteria will be evaluated during screening. Part 2 eligibility criteria will be 
evaluated at the completion of the run-in period in subjects that successfully meet Part 1 
eligibility criteria (see Section 5. Subject Enrollment). 
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).  


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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
102
Age ≥18 at time of informed consent
103
Subject must have untreated and histologically proven high-risk DLBCL defined 
by at least one of the following:

IPI 3 to 5 (see Appendix D)

Double-hit or higher or double protein expression
104
Eastern Cooperative Oncology Group (ECOG) performance status ≤2
105
Subject meets the criteria per investigator’s institution to receive SOC 
R-chemotherapy (ie, R-CHOP [14 or 21] or R-DA-EPOCH or R-CHOEP) of 
6 cycles. Subjects may be enrolled on study prior to cycle 1 or cycle 2 of SOC 
R-chemotherapy
106
Adequate organ and bone marrow function determined within 14 days prior to 
enrollment defined as follows:
Hematological:

Absolute neutrophil count (ANC) ≥1.0 x 109/L

Platelet count  ≥75 x 109/L

Hemoglobin 8g/dL
Renal:

Creatinine clearance ≥50 mL/min Cockcroft-Gault equation
Hepatic:

Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) < 3X 
upper limit of normal (ULN)

Total bilirubin < 2X ULN (unless Gilbert’s Disease or if liver involvement with 
lymphoma)
4.1.2
Exclusion Criteria – Part 1
201
Clinically relevant central nervous system (CNS) pathology requiring treatment 
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
Subject has active infection requiring systemic therapy
205
Prior anti-CD19 therapies


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206
Known 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)
207
History of other malignancy 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 malignancy without 
evidence of disease

Adequately treated cervical carcinoma in situ without evidence of disease

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
208
Subject has known hypersensitivity to immunoglobulins or any of the products or 
components to be administered during dosing.
209
Subject likely to not 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. 
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
Females 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
Females of childbearing potential unwilling to use an effective method of
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 (eg, SOC R-chemotherapy) given during the 
study.


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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
107
Subject must have completed 6 cycles of SOC R-chemotherapy and achieved 
CR, PR or stable disease by PET/CT performed 3 weeks (± 3 days) after cycle 6 
of SOC R-chemotherapy. 
Note: Subjects with PD are not eligible for treatment with blinatumomab and will 
end the study.
4.2.2
Exclusion Criteria – Part 2
214
Any clinically significant change in the Part 1 eligibility criteria during the run-in 
period
215
Subject has a clinically significant laboratory abnormality during run-in period 
which in the opinion of the investigator poses a safety risk, will prevent the 
subject from completing the study, or will interfere with the interpretation of the 
study results 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 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 date
when the subject signs the IRB/IEC approved main study informed consent form) 
receives a unique subject identification number before any study-related 
activities/procedures are performed.  The subject identification number will be assigned
by IVRS. This number will be used to identify the subject throughout the clinical study 


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and must be used on all study documentation related to that subject.  Subjects not 
meeting Part 1 eligibility criteria are permitted to re-screen one additional time after 
failing the first screening.
The subject identification number must remain constant throughout the entire clinical 
study; it must not be changed after initial assignment, including if a subject is 
rescreened. 
5.1
Treatment Assignment
Subjects who meet Part 2 eligibility criteria will be assigned to open-label 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) and/or Medical Device(s)
The Amgen investigational product used in this study is: blinatumomab.
The non-Amgen non-investigational product used in this study is: SOC R-chemotherapy:

R-CHOP given every 14 or 21 days (rituximab and cyclophosphamide, 
doxorubicin, vincristine, prednisone) chemotherapy OR

R-DA-EPOCH (rituximab and dose adjusted-etoposide, prednisone, vincristine, 
cyclophosphamide, and doxorubicin) OR

R-CHOEP (rituximab and cyclophosphamide, doxorubicin, vincristine,
prednisone, and etoposide)
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: Blinatumomab
Blinatumomab will be manufactured and packaged by Amgen and distributed using 
Amgen clinical study drug distribution procedures.
Blinatumomab will be supplied as 4 mL single-use glass injection vials as a sterile, 
preservative-free, white to off-white, lyophilized powder for reconstitution and 
administration by IV infusion. Each vial contains a target of 38.5 μg blinatumomab with 
additional excipients and buffers including citric acid monohydrate, trehalose dihydrate, 
lysine hydrochloride and polysorbate 80, pH 7.


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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 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 6.8.
Medical Devices.
6.2.1
Dosage, Administration, and Schedule
Blinatumomab is administered as an 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) (+ 1 week 
if results of PET/CT are delayed to determine eligibility for cycle 2) treatment-free 
interval.  
For cycle 1, the initial dose of blinatumomab will be 9 μg/day for the first 7 days of 
treatment (to mitigate for potential cytokine release syndrome [CRS] and CNS events 
associated with introduction to blinatumomab). 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 on day 15 continuing until completion of therapy (day 56).
In subjects without disease progression, a second cycle of blinatumomab (cycle 2) may 
be given at the discretion of the investigator. Cycle 2 of blinatumomab treatment is 
4 weeks (28 days) in duration, which includes 4 weeks of blinatumomab IV infusion.  
Dosing will be 9 µg/day x 7 days, followed by dose-steps to 28 µg/day x 7 days and 
112 µg/day x 14 days.
Prior to initiation of blinatumomab and each dose-step escalation, dexamethasone is 
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.  


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A dose of up to 10% higher than the intended dose may not require specific intervention. 
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.  
Routine supportive and symptomatic care according to standard medical practice is 
recommended.  Once the subject is stabilized and no clinically relevant safety findings 
due to blinatumomab are observed, resumption of blinatumomab at a correct dose can 
be considered after consultation with the Amgen medical monitor.
If the overdose results in an adverse event, the subject should be followed carefully until 
all signs of toxicity are resolved and the adverse event(s) should be recorded/reported.
The dose, start and stop date/time, and lot number of blinatumomab is to be recorded on 
each subject’s CRF.
6.2.1.1
Inpatient Dosing
Subjects should be monitored in a hospital for a minimum of 72 hours following initiation 
of therapy or a 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.  After a subject 
meets the minimum criteria for inpatient administration and monitoring as described 
above, and if subject is deemed stable by the investigator, continuation of blinatumomab 
infusion may continue as an outpatient. 
6.2.1.2
Outpatient Dosing
In the outpatient setting, the subject will either return to the study site for changes of 
infusion bag or 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 care provider 
will be trained and will receive written instructions for storage of the IV bags.  For the 
ambulatory home care provider study-specific requirements and recording source 
documentation must be completed before any study related tasks are started.  A 
comprehensive list of at home 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 ambulatory home care 
services visit worksheet and forwarded to the investigator.  Any unexpected or unusual 
events as well as deviations will be communicated promptly to the investigator.  The 


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ambulatory home care professionals provide 24 hour emergency on call service.  In 
addition, the subject will visit the study site for the examinations according to the 
schedule of assessments (Table 5 and Table 6). 
6.2.2
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation
6.2.2.1
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, re-start 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 re-start.  Administration of dexamethasone premedication prior to 
resumption of blinatumomab infusion after a treatment interruption of more than 4 hours 
is described in Table 2.
6.2.2.2
Infusion Interruption/Dose Modifications due to Adverse Events
Table 1.  Infusion Interruptions and Dose Modifications
Toxicity
Grade
Instructions for Treatment Interruption and Re-start
Cytokine 
Release 
Syndrome
3

Interrupt blinatumomab until 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 g/day resume at 28 g/day
o
If event occurred at 9 or 28 g/day resume at 9 g/day

Escalate up 1 dose level after 7 days if toxicity does not 
recur.  Increase dose stepwise at 7-day intervals to target 
dose of 112 g/day if toxicity does not recur

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 g/day without 
prior dose-step escalation
4

Permanently discontinue blinatumomab
Page 1 of 3
Footnotes defined on last page on the table.


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Table 1.  Infusion Interruptions and Dose Modifications
Toxicity
Grade
Instructions for Treatment Interruption and Re-start
Neurologic 
Events
3

Interrupt blinatumomab until 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 g/day resume at 28 g/day
o
If event occurred at 28 g/day resume at 9 g/day

Escalate up 1 dose level after 7 days if toxicity does not 
recur.  Increase dose stepwise at 7-day intervals to target 
dose of 112 g/day if toxicity does not recur

Permanently discontinue if:
o
Initial grade 3 neurologic event occurred at 9 g/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
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
Elevated liver 
enzymes

Interrupt blinatumomab, (refer to Table 2) if any one of the 
following occurs:
o
TBL > 3x ULN at any time
o
ALP > 8x ULN at any time
o
AST or ALT > 8x ULN at any time
o
AST or ALT > 5x ULN but < 8x ULN for 2 weeks
o
AST or ALT > 3x ULN with clinical signs or symptoms 
that are consistent with hepatitis (eg, RUQ abdominal 
pain/tenderness, fever, nausea, vomiting, jaundice)
Page 2 of 3
Footnotes defined on last page of the table.


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Table 1.  Infusion Interruptions and Dose Modifications
Toxicity
Grade
Instructions for Treatment Interruption and Re-start
Elevated liver 
enzymes
(Continued)

Permanently discontinue blinatumomab if:
o
TBL > 2x ULN OR INR > 1.5x ULN (for subjects not 
on anticoagulant therapy)
AND
o
AST or ALT > 3x ULN (when baseline was < ULN)
AND
o
No other cause for the combination of the above 
laboratory abnormalities is immediately apparent
Refer to Section 6.5 for additional details
Other clinically 
relevant 
adverse events
3

Interrupt blinatumomab until grade 1 (refer to Table 2) 
for dexamethasone dosing before restarting 
blinatumomab)

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 g/day resume at 28 g/day
o
If event occurred at 9 or 28 g/day resume at 
9 g/day

Escalate up 1 dose level after 7 days if toxicity does not 
recur.  Increase dose stepwise at 7-day intervals to target 
dose of 112 g/day if toxicity does not recur

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 

Grade 3 event reoccurs at a dose of 9 µg/day without 
prior dose-step escalation
4

Permanently discontinue blinatumomab
Page 3 of 3
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CRS 
= Cytokine Release Syndrome; INR = international normalized ratio; MRI = Magnetic Resonance Imaging; 
TBL = total bilirubin; ULN = upper limit of normal; RUQ = right upper quadrant.
a Obtain head MRI and perform cerebrospinal fluid (CSF) analysis, if there are no contraindications
To restart blinatumomab after an interruption requiring dose modification 
(Table 1), if the restart of continuous IV infusion of blinatumomab is 9 g/day 
follow the Schedule of Assessments (Table 5) for week 1 (if restart continuous IV 
infusion of blinatumomab is 28 g/day follow Schedule of Assessments [Table 5] 
for week 2) and continue to follow through week 36.  The total days of 
blinatumomab for cycle 1 will not exceed 56 days (ie, the total days a patient 
receives 112 g/day will be decreased if an interruption in continuous IV infusion 
of blinatumomab occurs).  Following dose escalation to 112 g/day and 


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completion of the required assessments (week 3, days 15 to 17 [Table 5]), return 
to the Schedule of Assessments at the next opportunity (eg, if dose interrupted at 
day 9, restart occurs from 9 g/day [day 10], with dose escalations at day 17 
[28 g/day] and day 24 [112 g/day]. Required assessments for 112 g/day dose 
escalation continue until day 26, and assessments can return to the Schedule of 
Assessments by day 29). The Schedule of Assessments on day 50 will occur the 
first day of the last week of continuous IV infusion of blinatumomab to be given.  
The treatment free period begins on day 57 and will continue to be 4 weeks in 
length with assessments obtained the first day of weeks 1 and 4 of the treatment 
free period as per the Schedule of Assessments (Table 5).
6.2.2.3
Permanent Discontinuation of Blinatumomab
Blinatumomab will be permanently discontinued for:

Disease progression

Subject or investigator not compliant with the study protocol

Administration of relevant non-permitted concomitant medication(s)

CRS (meeting the criteria below)

Initial grade 3 CRS does not improve to grade 1 within 7 days

Grade 3 CRS that reoccurs at the lower dose level within 7 days of 
re-initiation

Grade 3 CRS reoccurs at a dose of 9 g/day without prior dose-step
escalation

Grade 4 CRS

Neurologic Events (meeting the criteria below)

Initial grade 3 neurological event occurred at 9 g/day

Initial grade 3 neurological event does not improve to grade 1 within 7 days

Grade 3 neurological event that reoccurs at the lower dose level within 7 days
of reinitiation

Reoccurs at a dose of 9 g/day

Grade 4 neurological event

A second seizure occurs with re-start of blinatumomab (refer to 
Section 6.2.2.2)

Elevated Liver Enzymes (meeting the criteria below)

Total bilirubin (TBL) > 2x ULN OR International Normalized Ratio 
(INR) > 1.5x ULN (for subjects not on anticoagulant therapy)
AND

AST or ALT > 3x ULN (when baseline was < ULN)


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AND

No other cause for the combination of the above laboratory abnormalities is 
immediately apparent

Other Clinically Relevant Adverse Events (meeting the criteria below)

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 g/day without prior dose-step
escalation

Grade 4 clinically relevant adverse event

An infusion interruption of more than 14 days due to an adverse event related 
to blinatumomab (with the exception of a delay in restart due to logistical 
difficulties, in which case the restart may be postponed for an additional 
7 days). 
Subjects who permanently discontinue study treatment due to adverse event should 
continue with other study procedures, including response assessment, as appropriate.
6.2.3
Dose Limiting Toxicities
The dose limiting toxicity (DLT) evaluation period will be the entire duration of cycle 1 of 
blinatumomab treatment. If cycle 2 is given, the DLT evaluation period also includes the 
entire duration of cycle 2 infusion.  Subjects who are removed from study treatment for 
reasons other than an adverse event/toxicity, ie, disease progression, will be considered 
DLT evaluable if they have received at least 7 days of the target blinatumomab dose.  
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 (eg, death not due to disease progression)

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)

Grade ≥3 neurologic events that do not improve to grade ≤1 within 7 days with 
treatment interruption and routine medical management

Grade ≥3 cytokine release syndrome that do not improve to grade ≤1 within 7 
days with treatment interruption and routine medical management
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 10.3.2).


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6.3
Non-Amgen Non-investigational Product: SOC R-chemotherapy
During the run-in period subjects will receive SOC R-chemotherapy, dosed per 
investigator’s institution SOC, as listed below.

R-CHOP 14 or 21 (Feugier et al, 2005) or

R-DA-EPOCH (Wilson et al, 2008) or

R-CHOEP (Gang et al, 2012)
Subjects must complete 6 cycles of SOC R-chemotherapy prior to treatment assignment 
with blinatumomab. Subjects may be enrolled on study either prior to cycle 1 or prior to 
cycle 2 of SOC R-chemotherapy. Subjects that are enrolled prior to cycle 1 will 
complete 6 cycles of SOC R-chemotherapy during the run-in period, while subjects 
enrolled prior to cycle 2 of SOC R-chemotherapy will receive 1 cycle of SOC 
R-chemotherapy prior to enrollment and 5 cycles of SOC R-chemotherapy during the 
run-in period (See Section 3.1). 
SOC R-chemotherapy is commercially available and will not be provided or reimbursed 
by Amgen (except if required by local regulation).  The investigator will be responsible 
for obtaining supplies and for providing the subject (male and female) with contraceptive 
and breastfeeding (female only) requirements for SOC R-chemotherapy given during the 
study.  The SOC R-chemotherapy treatments with rituximab, in particular, have longer 
contraceptive requirements than blinatumomab. 
The SOC R-chemotherapy regimen, dose, route of administration, start and stop 
date/time of each cycle of SOC R-chemotherapy is to be recorded on each subject’s 
CRF.
6.4
Other Protocol-required Therapies
All other protocol-required therapies that are commercially available, including 
dexamethasone, are not provided or reimbursed by Amgen (except if required by local 
regulation).  The investigator will be responsible for obtaining supplies.
Additional details regarding these protocol-required therapies are provided in the IPIM.
6.4.1
Dexamethasone Premedication
Mandatory premedication with dexamethasone is required before each treatment cycle 
and dose-step for the prevention of CRS 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.


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Table 2. Dexamethasone Pre-dose Treatment and for Events
Treatment Phase
Target Subjects:
Dexamethasone Dose
Pre-dose Dexamethasone 
Prior to Each 
Blinatumomab Treatment
Cycle and Before Each 
Dose-Step Increase
All subjects 
Dexamethasone 20 mg IV: within 
1 hour prior to start of treatment in
each 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 re-start 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
per 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.  The 
dose should then be reduced 
step-wise over 4 days.
CRS = cytokine release syndrome; IV = intravenous
6.5
Hepatotoxicity Stopping and Rechallenge Rules
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
ALT, total bilirubin and/or 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.
6.5.1
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 (total bilirubin, INR and transaminases) has 
not been identified. 


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Important alternative causes for elevated AST/ALT and/or total bilirubin values include, 
but are not limited to:

Hepatobiliary tract disease

Viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, cytomegalovirus, 
Herpes Simplex Virus, Varicella, toxoplasmosis, and Parvovirus)

Right sided heart failure, hypotension or any cause of hypoxia to the liver causing 
ischemia.

Exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal and 
dietary supplements, plants and mushrooms

Heritable disorders causing impaired glucuronidation (eg, Gilbert’s Syndrome,
Crigler-Najjar syndrome) and drugs that inhibit bilirubin glucuronidation (eg, 
indinavir, atazanavir)

Alpha-one antitrypsin deficiency

Alcoholic hepatitis

Autoimmune hepatitis

Wilson’s disease and hemochromatosis

Nonalcoholic Fatty Liver Disease including Steatohepatitis

Non-hepatic causes (eg, rhabdomylosis, hemolysis)

Cytokine storm
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 total bilirubin is discovered and the laboratory abnormalities 
resolve to normal or baseline (Section 6.5.2).


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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
Total bilirubin
> 3x ULN at any time
> 2x ULN
OR
INR
--
> 1.5x ULN (for subjects not on 
anticoagulation therapy)
OR
AND
AST/ALT
> 8x ULN at any time
> 5x ULN but < 8x ULN for ≥ 2 weeks
> 5x ULN but < 8x ULN and unable to 
adhere to enhanced monitoring 
schedule
> 3x ULN with clinical signs or 
symptoms that are consistent with 
hepatitis (such as right upper 
quadrant pain/tenderness, fever, 
nausea, vomiting, jaundice).
In the presence of no important 
alternative causes for elevated 
AST/ALT and/or total bilirubin
values
> 3x ULN (when baseline was
< ULN)
No other cause for the combination 
of the above laboratory 
abnormalities is immediately 
apparent
OR
ALP
> 8x ULN at any time
--
AST = Aspartate aminotransferase; ALT = alanine aminotransferase; ALP = alkaline phosphatase; 
INR = international normalized ratio; ULN = upper limit of normal 
6.5.2
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.
6.6
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 6.10.
During the run-in period intrathecal or IV methotrexate for CNS prophylaxis per 
investigators’ institutional SOC is permitted.


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Concomitant therapies are to be collected from enrollment through the safety follow-up 
period.
For concomitant therapies being taken for DLBCL and that assist in the evaluation of 
efficacy or safety endpoints, collect therapy name, indication, dose, unit, frequency, 
route, start date and stop date. 
For all other concomitant therapies, collect therapy name, indication, dose, unit, 
frequency, route, start date and stop date.  
6.7
Other Treatment Procedures
During the run-in period after completion of 6-cycles of SOC R-chemotherapy, subjects 
may receive radiotherapy to previous bulky sites of disease per investigators’
institutional standard of care. Radiotherapy to bulky disease must occur as soon as 
possible after PET/CT post cycle 6 of SOC R-chemotherapy. Blinatumomab treatment 
will start 2 to 3 weeks after radiotherapy is completed and toxicity from the radiation has 
resolved to a safe level per investigator’s recommendation.  
6.8
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.
Infusion pumps, IV bags, tubing, and other medical devices (eg, syringes, sterile 
needles, alcohol prep pads) that are commercially available should be procured by the 
trial site.  Infusion pumps and tubing may be available in limited quantities for provision
by Amgen (where provision is required by local regulation).
The Investigator overseeing the conduct of the study at each respective institution will be 
responsible for obtaining these supplies.  


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6.9
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.
6.10
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period
The following treatments and/or procedures are excluded during the Run-in Period:

Any other immunosuppressive therapies (except for transient use of 
corticosteroids)

Any other investigational agent
The following treatments and/or procedures are excluded during the Treatment Period:

Any anti-tumor 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

Chronic systemic (> 7 days) high-dose corticosteroid therapy (dexamethasone 
>24 mg/day or equivalent)
6.11
Contraceptive Requirements
6.11.1
Female Subjects 
Female subjects of childbearing potential must agree to practice true sexual abstinence 
(refrain from heterosexual intercourse) or use an effective method of contraception 
during treatment and for an additional 48 hours after the last dose of blinatumomab.  


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Acceptable methods of effective contraception include: 

Hormonal (Combined estrogen and progestogen or progesterone-only hormonal 
contraception given via oral, intravaginal, transdermal, injectable, or implantable 
route)

Intrauterine device; Intrauterine hormonal-releasing system

Bilateral tubal occlusion/ligation

Vasectomized partner (provided that partner is the sole sexual partner of the 
female participant who is of childbearing potential and that the vasectomized 
partner has received medical assessment of the surgical success)

Two barrier methods (one by each partner) and the female partner must use 
spermicide (if spermicide is commercially available) with the barrier method. The 
male must use a condom (latex or other synthetic material) and the female may 
select either a diaphragm, cervical cap or contraceptive sponge. A female 
condom is not an option because there is a risk of tearing when both partners 
use a condom

The reliability of true sexual abstinence must be evaluated by the investigator 
and be the preferred and usual lifestyle of the subject
Females not of childbearing potential are defined as: Any female who has had a 
hysterectomy, OR bilateral salpingectomy, OR bilateral oophorectomy, OR is
post-menopausal. Post-menopausal women are:

Age > 55 years with cessation of menses for 12 or more months 

Age < 55 years but no spontaneous menses for at least 2 years

Age < 55 years and spontaneous menses within the past 1 year, but currently 
amenorrheic (eg, spontaneous or secondary to hysterectomy), AND with 
follicle-stimulating hormone levels > 40 IU/L, or postmenopausal estradiol levels 
< 5 ng/dL, or according to the definition of "postmenopausal range" for the 
laboratory involved.
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.  
6.11.2
Unacceptable Methods of Birth Control for Male and 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 amenorrhoea method.
7.
STUDY PROCEDURES
7.1
Schedule of Assessments 
For Schedule of Assessments refer to Table 4, Table 5, and Table 6. 


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Table 4.  Schedule of Assessments – Screening and Run-In
Screeninga
Run-In 
SOC R-Chemotherapy (6 cycles)b
Up to 14 days
Visit 1c
Visit 2
-7 days
General Assessments
Informed consent
X
Eligibility Determination
X
X
Enrollment
X
Demographics
X
Medical history & prior therapies
X
Vital signs
X
X
Height
X
X
Weight
X
X
BSA
X
X
ECOG PS
X
X
Concomitant medications
X
X
Neurological Exam
X
X
Physical exam 
X
X
Clinical Tumor assessment
X
X
Adverse Events
Continuously from enrollment
Disease Related Events
Neurological Adverse Events
Serious Adverse Event
Continuously from Informed Consent
SOC R-Chemotherapy
X
Page 1 of 2
Footnotes defined on the last page of the table.


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Table 4.  Schedule of Assessments – Screening and Run-In
Screeninga
Run-In
Up to 14 days
SOC R-Chemotherapy (6 cycles)b
Visit 1c
Visit 2
-7 days
Staging/Response
PET/CTd
Xe
Xf
Local Labs /Tests
ECG
X
Chemistry
X
X
Hematology
X
X
Coagulation
X
LDH
X
Beta-2 microglobulin
X
Creatinine clearanceg
X
X
Pregnancy testingh
X
X
CRP
X
Bone marrow biopsyi/ Lumbar puncturei
X
X
Central Labs
Pathology tumor Blockj
X
CT-DNA IgH
X
Pharmacogenetics (optional)k
X
Page 2 of 2
BSA = body surface area; CRP = C-reactive protein; CT = computed tomography; CT-DNA IgH = cell-free circulating tumor DNA immunoglobulin H; 
ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; LDH = lactate dehydrogenase; CSF = cerebrospinal fluid; 
PET = positron emission tomography; SOC = standard of care.
a Screening assessments and tests should be completed within 14 days prior to enrollment, before the subject starts SOC R-chemotherapy cycle 1.  Subjects enrolling 
prior to cycle 2, refer to Section 7.2 for screening requirements.
b SOC R-chemotherapy per investigator’s institution SOC (R-CHOP [14 or 21 days] or R-DA-EPOCH or R-CHOEP).  Subjects must complete 6 cycles of SOC 
R-chemotherapy prior to treatment assignment with blinatumomab.
c Subjects may be enrolled (visit 1) on study prior to either cycle 1 or cycle 2 of SOC R-chemotherapy.  Subjects that are enrolled prior to cycle 1 will complete 6 cycles 
of SOC R-chemotherapy during the run-in period, while subjects enrolled prior to cycle 2 of SOC R-chemotherapy will receive 1 cycle of 
SOC R-chemotherapy prior to enrollment and an additional 5 cycles of SOC R-chemotherapy during the run-in period. (see Section 6.3 and Section 4.1.1).
d Every attempt should be made to complete PET and CT within 3 days of each other if not obtained as a combined study.
e At diagnosis PET/CT should be within 21 days of starting cycle 1 SOC R-chemotherapy.  If combined PET/CT is obtained at diagnosis, additional separate CT scans 
(neck, chest, abdomen, and pelvis) with IV contrast are strongly recommended to be obtained for staging evaluation.
f During the run-in period the baseline PET/CT should be performed 3 weeks (3 days) after completion of 6 cycles SOC R-chemotherapy (run-in visit 2).
g Creatinine clearance is calculated by the Cockcroft Gault equation.
h Pregnancy test must be performed within 72 hours from run-in visit 1 and within 72 hours prior to the first dose of blinatumomab given on cycle 1 day 1.


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I Bone marrow biopsy evaluation should be performed if occult bone marrow involvement is suspected with an ambiguous or negative PET/CT and/or lumbar puncture 
is required if there are concerns of disease presence per investigator judgement.
j Pathology tumor block assessments include Cell of Origin (COO), c-myc and Bcl rearrangement, primers for minimal residual disease (MRD).
k Only obtain if subject signs consent (optional).


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Table 5.  Schedule of Assessments – Cycle 1 (Blinatumomab)
Treatment, Cycle 1a
Treatment 
free
(d57-d84)
Follow-up
Dose (µg/d)
9
28
112
Visit
1
2
3
Week
1
2
3
4
5
6
7
8
9-12
SFUPj
LTFUk
Day
1b
Pre
1 
(+6h)
2
3
8
Pre
8 
(+6h)
9
10
15 Pre
15 
(+6h)
16
17
22i
29i
36i
43i
50i
57i
78i
General assessments
Vital Signsn
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Proceed to SFUP and LTFU schedule, unless subject proceeding to Cycle 2 
blinatumomab schedulem
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BSA
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological exam
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
Clinical tumor assessmento
X
X
X
X
X
ECOG PS
X
Anti-lymphoma therapies
X
X
X
AE / DRE / Neurological AE
Continuously from enrollment
Serious AEl
Continuously from Informed Consent
Staging response
PET/CT scanh
X
Local Labs/Tests 
Chemistry
X
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
X
CRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
LDH
X
X
X
X
X
Beta-2 microglobulin
X
X
Immunoglobulins (IgG, IgM, 
IgA)
X
X
Bone marrow biopsyc
X
Lumbar puncturec,d
X
Creatinine clearancee
X
Page 1 of 2
Footnotes defined on the last page of the table.


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Table 5.  Schedule of Assessments – Cycle 1 (Blinatumomab)
Treatment, Cycle 1a
Treatment 
free
(d57-d84)
Follow-up
Dose (µg/d)
9
28
112
Visit
1
2
3
Week
1
2
3
4
5
6
7
8
9-12
SFUPj
LTFUk
Day
1b
Pre
1 
(+6h)
2
3
8
Pre
8 
(+6h)
9
10
15 Pre
15 
(+6h)
16
17
22i
29i
36i
43i
50i
57i
78i
Central labs
Cytokinesf
X
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subsetsf
X
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokineticsg
X
X
X
X
CT DNA IgH 
X
X
X
X
X
X
X
X
Anti-Blinatumomab 
antibodies
X
X
Page 2 of 2
AE = adverse event; BSA = body surface area; CRP = C-reactive protein; CSF = cerebrospinal fluid; CT = computed tomography; CT-DNA IgH = cell-free circulating 
tumor DNA immunoglobulin H; DRE = Disease Related Event; ECOG PS = Eastern Cooperative Oncology Group performance status ECG = electrocardiogram;
Ig = immunoglobulin; IV = intravenous; LDH = lactate dehydrogenase; LTFU = Long-Term Follow-Up; PET = positron emission tomography; PK = pharmacokinetics; 
SFUP = Safety Follow-Up.
a Blinatumomab will be administered by continuous IV infusion. Cycle 1 is 8 weeks in duration. Dosing 9 µg/day x 7 days (day 1 - day 7); 28 µg/day x 7 days 
(day 8 - day 14); 112 µg/day x 42 days (day 15 – day 56) followed by a 4 week treatment free interval (day 57 – day 84).
b Obtain day 1 laboratory analytes prior to starting blinatumomab IV infusion.
c Bone marrow evaluation should be performed if occult bone marrow involvement is suspected with an ambiguous or negative PET/CT and/or lumbar puncture 
required if concerns of disease presence per investigator judgement prior to proceeding to cycle 2 (obtain C1D78 ± 3 days).  Refer to Section 7.3.13 and 
Section 7.3.14.
d Lumbar puncture for CSF blinatumomab PK if seizure or grade ≥3 neurotoxicity and subject is stable to obtain the CSF.  Refer to Section 7.3.13.
e Creatinine clearance is calculated by the Cockcroft-Gault equation.
f Blood samples for cytokine measurement and lymphocyte subsets will be taken on D1 (at baseline prior to dosing with blinatumomab), D1 (6 h), D2, D3, D8 (prior to 
dose increase), D8 (6 h), D9, D10, D15 (prior to dose increase), D15 (6 h), D16, D17 and day 57.
g Blood samples for blinatumomab PK measurements will be taken on D1 at baseline (pre-dose), D2 at least 24 hours after blinatumomab was started and on D9 and 
D16 at least 24 hours after blinatumomab dose was increased.
h If the PET/CT is not combined every attempt should be made to complete PET and CT within 3 days of each other.  PET/CT should occur ± 3 days from the 
scheduled visit date.
i Samples scheduled for collection on D22, D29, D36, D43, D50, D57, and D78 have a sampling window of +2 days in order to try to coordinate with blinatumomab bag 
changes.
j Safety follow-up (SFUP) visit to be completed 30 days (+ 3 days) after the last dose of blinatumomab.
k If only cycle 1 of blinatumomab is given, long-term follow-up (LTFU) begins 3 months (± 3 weeks) after the last scan (C1D78), LTFU visit 1 occurs at 3 months post 
last scan (C1D78), LTFU visit 2 occurs at 6 months post last scan (C1D78) and LTFU visit 3 occurs at 9 months post last scan (C1D78) for a maximum of 1 year from 
the first dose of blinatumomab, or until subject death, whichever occurs first.
l During the long-term follow-up only serious adverse events related to blinatumomab will be collected.


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m In subjects without disease progression, a second cycle of blinatumomab (cycle 2) may be given at the discretion of the investigator. If proceeding to Cycle 2 
proceed to Table 6 for Schedule of Assessments for cycle 2.
n On days of hospitalization, obtain vital sign monitoring every 4 to 8 hours per institution SOC.  When subject is in the outpatient clinic, only obtain 1 baseline 
vital sign per visit.
o Clinical tumor assessment includes clinical evaluation of disease status, summaries of radiographic reports used for surveillance or detection of relapse (per 
institutional SOC disease evaluation) and pathology reports relevant to relapse determination (per institutional SOC disease evaluation.


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Table 6.  Schedule of Assessments – Cycle 2 (Blinatumomab)
Treatment, Cycle 2a
EOT
Follow-up
Dose (µg/d)
9
28
112
Visit
1
2
3
Week
1
2
3
4
SFUP j
LTFUk
Cycle 2 Day
1b
Pre
1 
(+6h)
2
3
8
Pre
8
(+6h)
9
10
15
Pre
15
(+6h)
16
17
22i
29
50
General Assessments
Proceed to SFUP and LTFU schedule
Vital Signsm
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
BSA
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Neurological exam
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
Clinical tumor assessmentn
X
X
X
X
ECOG PS
X
Anti-lymphoma therapies
X
X
X
AE / DRE / Neurological AE
Continuously from enrollment
Serious AEl
Continuously from Informed Consent
Staging Response
PET/CT scanh
X
Local Labs/tests
Chemistry
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
CRP
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
LDH
X
X
X
X
Beta-2 microglobulin
X
Bone marrow biopsyc
X
Lumbar puncturec,d
X
Creatinine clearancee
X
Immunoglobulins (IgG, IgM, 
IgA)
X
X
Page 1 of 2
Footnotes defined on the last page of the table.


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Table 6.  Schedule of Assessments – Cycle 2 (Blinatumomab)
Treatment, Cycle 2a
EOT
Follow-up
Dose (µg/d)
9
28
112
Visit
1
2
3
Week
1
2
3
4
SFUPj
LTFUk
Cycle 2 Day
1b
Pre
1
(±6h)
2
3
8
Pre
8
(+6h)
9
10
15
Pre
15
(+6h)
16
17
22i
29
50
Central labs
Cytokinesf
X
X
X
X
X
X
X
X
X
X
X
X
Lymphocyte subsetsf
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokineticsg
X
X
X
X
CT DNA IgH 
X
X
X
X
X
Anti-Blinatumomab 
antibodies
X
Page 2 of 2
BSA = body surface area; ECOG PS = Eastern Cooperative Oncology Group performance status; AE = adverse event; DRE = Disease Related Event;
ECG = electrocardiogram; LDH: lactate dehydrogenase; CSF = cerebrospinal fluid; CRP = C-reactive protein; CT-DNA IgH = cell-free circulating tumor DNA 
immunoglobulin H; PET = positron emission tomography; CT = computed tomography; Ig = immunoglobulin; EOT = End of Treatment; LTFU = Long-Term Follow-Up; 
SFUP = Safety Follow-Up.
a Blinatumomab will be administered by continuous IV infusion. Cycle 2 is 4 weeks in duration. Dosing 9 µg/day x 7 days (day 1 – day 7); 28 µg/day x 7 days
(day 8 - day 14); 112 µg/day x 14 days (day 15 – day 28).
b Obtain day 1 laboratory analytes prior to starting blinatumomab IV infusion.
c Bone marrow evaluation should be performed if occult bone marrow involvement is suspected with an ambiguous or negative PET/CT and/or lumbar puncture 
required if concerns of disease presence per investigator judgement.
d Lumbar puncture for CSF blinatumomab PK if seizure or grade ≥3 neurotoxicity and subject is stable to obtain the CSF.
e Creatinine clearance is calculated by the Cockcroft-Gault equation.
f Blood samples for cytokine measurement and lymphocyte subsets will be taken on D1 (prior to dosing with blinatumomab), D1 (6 h), D2, D3, D8 (prior to dose 
increase), D8 (6 h), D9, D10, D15 (prior to dose increase), D15 (6 h), D16, and D17. 
g Blood samples for blinatumomab PK measurements will be taken on D1 at baseline (pre-dose), D2 at least 24 hours after blinatumomab was started and on D9 and 
D16 at least 24 hours after blinatumomab dose was increased.
h If the PET/CT is not combined every attempt should be made to complete PET and CT within 3 days of each other.  PET/CT should occur ± 3 days from the 
scheduled visit date.
i Samples scheduled for collection on D22 have a sampling window of +2 days.  
j Safety follow-up (SFUP) visit to be completed 30 days (+ 3 days) after the last dose of blinatumomab.
k Long-term follow-up begins 3 months (± 3 weeks) after cycle 2 D50, LTFU visit 1 occurs at 3 months post last scan (C2D50), LTFU visit 2 occurs at 6 months post last 
scan (C2D50), and LTFU visit 3 occurs at 8 months from last scan (C2D50) for a maximum of 1 year from the first dose of blinatumomab or until subject death, 
whichever occurs first.
l During the long-term follow-up only serious adverse events related to blinatumomab will be collected.
m On days of hospitalization, obtain vital sign monitoring every 4 to 8 hours per institution SOC.  When subject is in the outpatient clinic, only obtain 1 baseline 
vital sign per visit.
n Clinical tumor assessment includes clinical evaluation of disease status, summaries of radiographic reports used for surveillance or detection of relapse (per 
institutional SOC disease evaluation) and pathology reports relevant to relapse determination (per institutional SOC disease evaluation.


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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, Table 5, and Table 6).  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, Table 5, and Table 6).  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, IVRS, IPIM, and study manuals 
for detailed collection and handling procedures.  
7.2.1
Screening
The screening period is up to 14 days, with the exception of the PET/CT and CT scans, 
which must be within 21 days of the start of cycle 1 SOC R-chemotherapy.  In addition, 
subjects enrolled prior to cycle 2 SOC R-chemotherapy will use the same scans 
(PET/CT and CT) obtained prior to cycle 1 at diagnosis as their enrollment scans.  If 
combined PET/CT is obtained at diagnosis, additional separate CT scans (neck, chest, 
abdomen, and pelvis) with IV contrast are strongly recommended to be obtained for 
staging evaluation.  Every attempt should be made to complete the PET and CT within 
3 days of each other. 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 in IVRS 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 
14-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 in the Run-in period.
7.2.2
Re-screening
Subjects who are unable to complete or meet Part 1 eligibility criteria on initial screening 
will be permitted to re-screen once.  Re-screen subjects must first be registered as 
screen failed in IVRS and subsequently registered as re-screened.  Subjects will retain 


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the same subject identification number assigned at the original screening.  Once the 
subject is registered as re-screened, a new 14 day screening window will begin.  If the 
rescreening period is ≤30 days, the subject needs to only repeat the test that caused 
them to fail at the initial screening period. If the re-screening period begins more than 
30 days after the original signing of the informed consent form, informed consent must 
be repeated. Rescreening labs studies should be repeated, however, PET/CT does not 
need to be repeated.  
7.2.3
Run-in Period: SOC R-Chemotherapy
Once a subject has met the Part 1 eligibility criteria evaluated during screening, the 
subject will enter the SOC R-chemotherapy run-in period.  During the run-in period, Part 
2 eligibility criteria will be evaluated at run-in visit 2. If the subject does not meet the Part 
2 eligibility criteria they will end the study.
SOC R-chemotherapy will be per investigator’s institution standard of care (R-CHOP
[every 14 or 21 days] or R-DA-EPOCH or R-CHOEP; See Section 6.3). Subjects may 
complete up to 1 cycle of SOC R-chemotherapy prior to enrollment in the study but all 
subjects must receive a total of 6-cycles of SOC R-chemotherapy to be eligible to 
proceed to blinatumomab (See Section 4.2.1). Disease evaluation during the run-in 
period is per institutional standard of care and must be recorded in the subjects eCRF.  
A PET/CT must be performed 3 weeks (± 3 days) after completion of cycle 6 SOC 
R-chemotherapy (run-in visit 2). If required per investigator’s judgement, radiotherapy to 
bulky disease must occur as soon as possible after PET/CT post cycle 6 of SOC 
R-chemotherapy. If radiotherapy is given, treatment with blinatumomab will start 2 to 
3 weeks after radiotherapy is completed and toxicity from the radiation has resolved to a 
safe level per investigator’s judgement (See Section 6.7).  
All other procedures during run-in visit 2 (see Schedule of Assessments, Table 4) must 
be completed within 7 days from the first dose of blinatumomab (day 1,cycle 1) in order 
to confirm part 2 eligibility and treatment assignment.  Pregnancy testing must be 
completed within the 72 hours prior to the first dose of blinatumomab.  
7.2.4
Treatment Period
Visits and procedures will occur per the Schedule of Assessments (Table 5 and Table 6)
during the treatment period. 


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Subjects should be monitored in a hospital for a minimum of 72 hours following initiation 
of blinatumomab treatment or a dose-step increase in blinatumomab (see Section 6.2.1
Dosage, Administration, and Schedule).  
Mandatory premedication with dexamethasone is required before each treatment cycle
of blinatumomab and dose-step for the prevention of CRS 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 of > 4 hours (see Table 2).
Cycle 1 of blinatumomab will be 8 weeks in duration followed by a 4-week (+ 1 week if 
results of PET/CT are delayed to determine eligibility for cycle 2) treatment-free interval 
break. In subjects without disease progression, a second cycle of blinatumomab 
(cycle 2) may be given at the discretion of the investigator. Cycle 2 of blinatumomab will 
be 4-weeks in duration.
Prior to IV infusion of blinatumomab (day 1), subjects must complete all 
protocol-required procedures.
For the visits on D22, D29, D36, D43, D50, D57 and D78 there is a visit window of 
± 2 days.
PET/CT will be performed 3 weeks (3 days) after the last dose of blinatumomab to 
evaluate disease status (eg, D78 ± 3 days for cycle 1). Subjects with PD by PET/CT 
after cycle 1 of blinatumomab will not be eligible to receive cycle 2 of blinatumomab.  A 
final PET/CT will be performed 3 weeks (3 days) after the last dose of blinatumomab in 
subjects that receive cycle 2 of blinatumomab (D50 ± 3 days).
7.2.5
Safety Follow-up Visit
All subjects, 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 5 and Table 6 will be performed.
7.2.6
Long-term Follow-up/End of Study
There will be a long-term follow-up portion of the study for clinical evaluation of disease 
status and OS.  The long-term follow-up (LTFU) period to assess disease status occurs:

If only cycle 1 of blinatumomab is given, long-term follow-up begins 3 months 
(3 weeks) after the last scan (C1D78), LTFU visit 1 occurs at 3 months post 
last scan (C1D78), LTFU visit 2 occurs at 6 months post last scan (C1D78) 
and LTFU visit 3 occurs at 9 months post last scan (C1D78) for a maximum of 
1 year from the first dose of blinatumomab, or until subject death, whichever 
occurs first.


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
If cycle 2 is given, long-term follow-up begins 3 months (± 3 weeks) after 
cycle 2 day 50, LTFU visit 1 occurs at 3 months post last scan (C2D50), LTFU 
visit 2 occurs at 6 months post last scan (C2D50), and LTFU visit 3 occurs at 
8 months from last scan (C2D50) for a maximum of 1 year from the first dose 
of blinatumomab or until subject death, whichever occurs first.
Subjects will be followed via clinical visit or telephone contact.  
The following procedures and tests will be performed at long-term follow-up visits until 
completion of the period 1 year from the first dose of blinatumomab:

Clinical Evaluation of Disease Status

Summaries of radiographic reports used for surveillance or detection of relapse 
(per institutional SOC disease evaluation)

Pathology reports relevant to relapse determination (per institutional SOC 
disease evaluation)

Recording of anti-lymphoma concomitant medication

Recording of serious adverse events possibly related to blinatumomab

LDH

Plasma for CT-DNA assessment of clonotypic IgH sequences for MRD analysis
During the long-term follow-up, use of anti-lymphoma therapies will be collected and 
serious adverse events related to blinatumomab will be reported. For other procedures 
refer to Table 5 and Table 6. 
Subjects will allow Amgen continued access to medical records so that information 
related to subjects’ health condition, including disease status and OS, may be obtained.  
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 must sign and date the most current IRB/IEC approved informed consent 
form. Confirmation that the informed consent form has been signed should occur before 
any study specific procedures are performed. All subjects who are enrolled and receive 
protocol-specified therapy should be re-consented 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.


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Additionally demographic data may be used to study the impact on biomarkers variability 
and PK of the protocol required therapies.
7.3.3
Medical History
The investigator or designee will collect a complete medical and surgical history that 
started 5 years prior to screening through the time of signing of informed consent.  
Medical history will include information on the subject’s concurrent medical conditions.  
In addition to the medical history above, all history related to the subject’s diagnosis of 
DLBCL (eg, IPI at diagnosis, stage at diagnosis, COO at diagnosis if available
[immunohistochemistry pattern, GEP, other], Bcl-2/Bcl-6 [Fluorescent in-situ 
hybridization [FISH]: translocation, immunohistochemistry expression levels], myc [FISH: 
translocation, immunohistochemistry expression levels]) must date back to the initial 
diagnosis (before the start of cycle 1) and any response duration must be recorded.  The 
current toxicity grade will be collected for each condition that has not resolved.
7.3.4
Prior Therapies
For prior therapies being taken for DLBCL, if enrollment is just prior to cycle 2, collect: 
therapy name, indication, dose, unit, frequency, route, start date and stop date. 
For all other prior therapies for all malignancies (DLBCL excluded) collect: therapy
name, indication, dose, unit, frequency, route, start date and stop date.  
7.3.5
Performance Status
The performance status will be assessed at the time points indicated in the Schedule of 
Assessments (Table 5 and Table 6) using the ECOG performance status scale (see
Appendix E).
7.3.6
Physical Measurements
Height in centimeters and weight in kilograms should be measured without shoes.
7.3.7
Vital Signs
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, 


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record on the Event CRF.  Refer to Schedule of Assessments (Table 4, Table 5, 
Table 6) for frequency and days to record vital signs in eCRF.
7.3.8
Physical Exam
Physical examination will be conducted as per standard of care.  Physical examination 
findings should be recorded on the appropriate CRF (eg, medical history, event).
7.3.9
Neurological Examination
A neurological examination, performed by the investigator, will be done as outlined in the 
Schedule of Assessments (Table 4, Table 5, and Table 6).  Subjects will be specifically 
queried for neurological symptoms observed in the interval since the last extended 
neurological examination. Abnormalities of the following should be recorded: level of 
consciousness, orientation, vision, cranial nerves and brain stem functions, pyramidal 
and extra pyramidal motor system, reflexes, muscle tone and trophic findings, 
coordination, sensory system, neuropsychological findings (eg, speech, cognition and 
emotion). Neurological examination findings should be recorded on the appropriate CRF 
(eg, medical history, event).  See Appendix H for clinically relevant neurologic adverse 
events.
7.3.10
Electrocardiogram
Standard of care 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
Response Assessment
The Lugano Classification will be used to assess treatment response by central review 
as described in Appendix F. 
7.3.12
Radiographic Assessment
PET-whole body images from base of skull to mid-thigh. Examinations should be 
consistent across timepoints and include the following information: amount of tracer, 
location of injection, arm location, scan delay.


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The following data should be collected per site: 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 (SUV) 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 by the local institution and will 
be used to determine if a subject can proceed to treatment with blinatumomab.  Central 
review of all PET/CT’s will also be done and compared to the local readings but will not 
be used to determine if a subject can proceed to treatment.
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.
Every attempt should be made to complete the PET and CT scan within 3 days of each 
other.
If PET/CT is combined than a separate CT (neck, chest, abdomen, and pelvis) with IV 
contrast will be strongly recommended for staging evaluation at diagnosis because it is a 
more detailed CT than the PET/CT.
7.3.13
Lumbar Puncture to Examine Cerebrospinal Fluid
A lumbar puncture will be performed at screening if there is a concern of CNS lymphoma 
involvement, as outlined in the Schedule of Assessments (Table 4) or during treatment 
period if subject has a seizure.  CSF, cell count, glucose, and protein will be measured 
at the local laboratory as part of the examination. Additional investigations of the CSF 
should be performed as clinically appropriate, such as at local lab CD19, or cultures and 
at central lab blinatumomab PK. 
7.3.14
Bone Marrow Biopsy
Bone marrow evaluation should be performed if occult bone marrow involvement is 
suspected with an ambiguous or negative PET-CT as outlined in the Schedule of 
Assessments (Table 4, Table 5, and Table 6).
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 7). Detailed 
instructions for sample collection, processing, and shipping are provided in the central 


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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 7 outlines the specific analytes that will be assessed during the study at time 
points outlined in the Schedule of Assessments (Table 4, Table 5, and Table 6).
Table 7.  Analyte Listing
Local Laboratory
Central Laboratory
Chemistry
Coagulation
Hematology
Other
Other
Sodium
Potassium
Chloride
Bicarbonate
Total protein
Albumin
Calcium
Magnesium
Phosphorus
Glucose
BUN or Urea
Creatininea
Uric acid
Alkaline
phosphatase
LDH
AST (SGOT)
ALT (SGPT)
Amylase
Lipase
Total bilirubin
Direct bilirubin
PT/INR
PTT
Fibrinogen
Red blood cells
Hemoglobin
Hematocrit
Platelets
White blood cells
ANC
Differential

Bands/stabs

Eosinophils

Basophils

Lymphocytes

Monocytes
Urine or serum 
pregnancy test
C-reactive protein
IgG, IgA, IgM
Beta-2 microglobulin
Bone marrow biopsyb
Lumbar punctureb
Anti- blinatumomab 
antibodies
Pharmacokinetics
Cytokines
Lymphocyte subsets
Pathology tumor 
block (COO, c-myc 
and 
Bcl rearrangements; 
primers for MRD)
Plasma for CT-DNA
IgH
Optional 
Pharmacogenetics
AST = Aspartate aminotransferase; ALT = alanine aminotransferase; LDH = Lactase dehydrogenase; 
PTT = partial thromboplastin time; INR = international normalization ratio; PT = prothrombin time; 
ANC = absolute neutrophil count; Ig = immunoglobulin; CT-DNA IgH = cell-free circulating tumor DNA IgH; 
COO = cell of origin; MRD = minimal residual disease
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 Bone marrow evaluation should be performed if occult bone marrow involvement is suspected with an 
ambiguous or negative PET/CT per investigator judgement. Lumbar puncture required if concerns of 
disease presence per investigator judgement or during treatment period if subject has a seizure (refer to 
Section 7.3.13 and Section 7.3.14)


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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 6.11.1) within 72 hours from run-in visit 1 and within 
the 72 hours prior to the first dose of blinatumomab (day 1, cycle 1).  If the pregnancy 
test is positive at either timepoint the subject should not be enrolled or assigned to 
treatment respectively.  
7.4.2
Pharmacokinetics
Blood samples for blinatumomab PK will be taken as outlined in the Schedule of 
Assessments (Table 5 and Table 6). Samples will be collected for determination of 
steady state drug concentrations (Css) and clearance.
7.4.3
Serum Cytokines
To monitor activation of immune effector cells, blood samples for measurement of 
peripheral blood cytokine levels will be taken and the following cytokines will be 
assessed: interleukin 2 (IL-2), IL-6, IL-10, tumor necrosis factor alphaTNFand 
interferon gamma (IFN. Blood samples will be collected as per the Schedule of 
Assessments (Table 5 and Table 6). 
7.4.4
Lymphocyte Subsets
Changes in lymphocytes (B-cell and T-cell populations) and leukocyte populations 
(leukocytes, lymphocytes, monocytes, and granulocytes) will be monitored in peripheral 
blood. Blood samples will be collected as outlined in the Schedule of Assessments
(Table 5 and Table 6). The frequent sample collection during the treatment period will 
help to better understand the mechanism of action of the T-cell response.
7.4.5
Cell-free Circulating Tumor DNA for IgH Sequencing for Minimal 
Residual Disease Assessment
Samples of peripheral blood will be collected at timepoints indicated in the Schedule of 
Assessments (Table 4, Table 5, and Table 6). Plasma will be separated by 
centrifugation and frozen in aliquots. At the initial time point, a cell pellet will also be 
obtained and frozen for genomic DNA isolation in subjects that provide additional 
consent (see Section 7.7 Optional Pharmacogenetic Studies). Frozen plasma and cell 
pellets will be shipped to a central laboratory for high throughput sequencing.   
7.5
Antibody Testing Procedures
Blood sample(s) for antibody testing will be collected at the timepoints listed in the 
Schedule of Assessments (Table 5 and Table 6) for the measurement of 
anti-blinatumomab antibodies. Samples testing positive for binding antibodies may be 


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further characterized for quantity/titer, isotype, affinity, in-vitro neutralizing activity 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 
the amount of tumor growth, or predict disease progression, metastasis, and responses 
to investigational product(s) or protocol required therapies.  
Amgen may attempt to develop test(s) designed to identify subjects most likely to 
respond positively or negatively to blinatumomab using the blood, CSF, and bone 
marrow samples collected as outlined in the Schedule of Assessments (Table 4, 
Table 5, and Table 6).  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
Optional Pharmacogenetic Studies
If the subject consents to the optional pharmacogenetic portion of this study, DNA 
analyses may be performed.  These optional pharmacogenetic analyses focus on 
inherited genetic variations to evaluate their possible correlation to the disease and/or 
responsiveness to the therapies used in this study.  Genomic DNA will be isolated from 
non-malignant as well as tumor tissue in order to determine if genetic polymorphisms in 
the tumor sample are tumor-associated or germline mutations.  At present there is no 
plan to perform targeted analysis of non-tumor associated genes in order to identify 
predictors of efficacy, toxicity, or to understand drug metabolism. No additional samples 
are collected for this part of the study. The baseline sample for CT-DNA will be used to 
obtain a cell pellet for genomic DNA isolation (see Section 7.4.5).


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7.8
Sample Storage and Destruction 
Any blood (eg, biomarker, PK) or tumor sample collected according to the Schedule of 
Assessments (Table 4, Table 5, and Table 6) can be 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 and associated results will be coded 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 do 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).  Results from this analysis are 
to be documented and maintained, but are not necessarily 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 
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 
samples (eg, blood, tumor) 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 


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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 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, Table 5, and Table 6) and 
collection of data, including endpoints, adverse events, disease related events, and 
device related events, as applicable.  The investigator must document the change to the 
Schedule of Assessments (Table 4, Table 5, and Table 6) and the level of follow-up that 
is agreed to by the subject (eg, in person, by telephone/mail, through family/friends, in 
correspondence/communication with other physicians, from review of the medical 
records).  
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.   


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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, ineligibility determined, protocol 
deviation, non-compliance (eg, procedural or dosing as defined in Section 6.2.2), 
requirement for alternative therapy, pregnancy)

decision by sponsor (other than subject request or safety concern)

death

lost to follow-up

other protocol-specified criteria (per Section 4.2.1 and 4.2.2)

disease progression
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

protocol specified criteria as described in Section 6.2.2.3
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

protocol specified criteria (see Section 4.2.1 and 4.2.2)


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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.  Please refer to Appendix G for expected 
disease related events by system organ class. Such events do not meet the definition of 
an adverse event unless assessed to be more severe than expected for the subject’s 
condition. 
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.  


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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 
instructions for use, adverse events resulting from any malfunction of the device, or 
adverse events resulting from user 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 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 inpatient 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 Appendix G 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.


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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, DILI (see Appendix A for 
drug-induced liver injury reporting criteria), or events that necessitate an emergency 
room visit, outpatient surgery, or urgent intervention.
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 enrollment 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 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.  
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 enrollment 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), device, or other 
protocol-required therapies, and

Action taken.


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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 blinatumomab, and/or other protocol-required 
therapies?  
The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of blinatumomab, protocol-required 
therapies, device(s) and/or procedure [including any screening procedures]).  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 a study activity (eg, 
administration of blinatumomab,  protocol-required therapies, device(s)), and/or 
procedure”?
The investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a 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 a laboratory 
abnormality, the signs/symptoms and the laboratory abnormality should 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 day of the dosing interval 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.  


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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 
blinatumomab, 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 blinatumomab, and/or other protocol-required therapies?
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.
Amgen will report serious adverse events and/or suspected unexpected serious adverse 
reactions as required to regulatory authorities, investigators/institutions, and IRBs/IECs 
in compliance with all reporting requirements according to local regulations and good 
clinical practice (GCP).
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.


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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.
9.2.2.4
Serious Adverse Events That are not to be Reported by the 
Sponsors to Regulatory Agencies in an Expedited Manner 
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. 
9.2.3
Reporting of Delayed Time to HSCT for Subjects With Partial 
Response/Partial Metabolic Response (PR/PMR) at Baseline
The investigator is responsible for reporting delays to HSCT in subjects that meet the 
following criteria:

PR/PMR at baseline per Lugano classification and 

Do not proceed to HSCT within 30 days of the first response assessment
These events will be recorded in the CRF and must be submitted to Amgen within 
24 hours following the investigator’s knowledge of the event.  Refer to eCRF completion 
guidelines for specific reporting directions.
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.


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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 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.  
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. 
In addition to reporting a lactation case during the study, investigators should report 
lactation cases that occur 48 hours after the last dose of protocol-required therapies.
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.
10.
STATISTICAL CONSIDERATIONS
10.1
Study Endpoints, Analysis Sets, and Covariates
10.1.1
Study Endpoints
10.1.1.1
Primary Endpoint
Overall incidence and severity of treatment-emergent adverse events occurring during 
the blinatumomab treatment period graded by investigators according to CTCAE version 
4.0 and characterized as related or unrelated to study drug (blinatumomab).
10.1.1.2
Secondary Endpoints

ORR expressed as the proportion of subjects achieving CR and PR.  Responses 
will be determined by central radiographic assessment using the Lugano 
classification

Duration of response is calculated only for responders. For subjects who had CR
or PR on the PET/CT scan at the end of the run-in period, response will be 


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measured from the start of blinatumomab treatment.  For subjects who had 
stable disease at the end of the run-in period, the duration will be calculated from 
documentation of the first assessment of either PR or CR on blinatumomab.  
Response duration will be calculated until the start of new anti-tumor treatment 
(excluding any stem cell transplantation), progression of disease, or death, 
whichever is the earliest event.    A subject who did not have new anti-tumor 
treatment (excluding any stem cell transplantation), progression of disease, or 
death will be censored at the last tumor assessment date.  If the last disease 
assessment date is after the date that triggers the analysis, the subject will be 
censored at the analysis trigger date.

CR rate using the Lugano classification

OS is calculated as the time from the date of first blinatumomab infusion until 
death due to any cause. Subjects who are alive at the date that triggers the 
analysis will be censored at the date last known to be alive. If the date last 
known to be alive is after the date that triggers the analysis, the subject will be 
censored at the analysis trigger date.  Kaplan-Meier (KM) estimate of OS at 
1 year will be provided.

PFS is calculated as the time from the date of first blinatumomab infusion until 
the date of diagnosis of progression of DLBCL, the start date of new anti-tumor 
treatment (excluding any stem cell transplantation) or date of death, whichever is 
the earliest. Subjects who are alive and did not have progression or new 
anti-tumor treatment (excluding any stem cell transplantation) will be censored at 
the last date of tumor assessment. If the last disease assessment date is after 
the date that triggers the analysis, the subject will be censored at the analysis 
trigger date.  KM estimate of PFS at 1 year will be provided.

HSCT rate is the incidence of HSCT (number of subjects with HSCT/number of 
subjects who received blinatumomab).

Blinatumomab PK parameters
10.1.1.3
Exploratory Endpoints

MRD measured by the detection of clonotypic IgH sequences by NGS of cell-free 
CT-DNA positivity in plasma collected at various time points before, during, and 
after SOC R-chemotherapy and blinatumomab treatment 

Response rates and duration according to COO designation or, c-myc and/or 
Bcl-2/Bcl-6 rearrangement as determined from pretreatment specimens

Pharmacodynamics, including quantitative and qualitative lymphocyte subsets
and cytokine levels in peripheral blood at various time points during 
blinatumomab treatment    

Anti-blinatumomab antibodies at various timepoints during blinatumomab 
treatment
10.1.2
Analysis Sets
The primary analysis of safety and efficacy will be performed on the full analysis set 
which will include all subjects who received at least 1 dose of blinatumomab. Sensitivity 
analyses of efficacy will be performed on the target dose analysis set.  


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10.1.2.1
Full Analysis Set
The Full Analysis Set includes all subjects who received at least one dose of 
blinatumomab.
10.1.2.2
Target Dose Analysis Set
The Target Dose Analysis Set includes all subjects in the full analysis set that have at 
least one tumor assessment unless terminating the study early due to disease 
progression.
10.1.2.3
Responder Analysis Set
Includes all subjects in the full analysis set that achieve objective response (CR or PR as 
per the Lugano classification, Appendix F) on the PET/CT scan. 
10.1.2.4
Pharmacokinetic Analysis Set
All subjects who received any infusion of blinatumomab will be included in the 
pharmacokinetic analysis set. These subjects will be evaluated for pharmacokinetics 
unless significant protocol deviations affect the data analysis or if key dosing, dosing 
interruption, or sampling information is missing.
10.1.2.5
Pharmacodynamic Analysis Set
The pharmacodynamics analysis set includes all subjects who received at least 1 dose 
of blinatumomab and have at least 1 pharmacodynamic sample collected.
10.1.2.6
SOC R-chemotherapy Analysis Set
The SOC R-chemotherapy analysis set includes all subjects who received at least one 
dose of SOC R-chemotherapy.  SOC R-chemotherapy analysis set is used for safety
analyses of SOC R-chemotherapy–emergent events.
10.1.3
Subgroup Analysis
The relationship of baseline covariates to endpoints will be explored if appropriate. 
Categories for the covariates will be defined in the Statistical Analysis Plan.  Baseline 
covariates include:

Age

Sex

Race

Stage at diagnosis

IPI, R-IPI, aaIPI, NCCN-IPI at diagnosis

Bulky disease

Extranodal


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
COO: GCB, ABC, non-GCB 

Bcl-2/Bcl-6 rearrangement/expression status

Myc rearrangement/expression status
10.1.4
Handling of Missing and Incomplete Data 
In general, missing data will be treated as missing, unless otherwise specified.  For the 
ORR and CR rate, subjects with missing response will be considered as non-responders
in the analyses.  
10.2
Sample Size Considerations
This is a single arm estimation trial.  The number of subjects enrolled in the run-in period 
will be approximately 38 (See Section 3.3).  If 38 subjects complete 6 cycles of SOC 
R-chemotherapy, it is expected that 15% will need radiation prior to receiving 
blinatumomab. Among the remaining 85% of subjects, 93% are expected to have a best 
overall response of CR/PR/stable disease and will receive blinatumomab.  Thus it is 
anticipated that 35 subjects will receive blinatumomab during the treatment period.
With 35 subjects, the width of the 95% exact confidence interval (Clopper and Pearson, 
1934) for the estimate of the percentage of subjects with a particular adverse event of 
interest and/or severity can be calculated. The table shows the 95% confidence interval
for some example adverse event incidences. 
Estimated 95% Confidence Interval for Example Adverse Event Incidences
Number of Subjects 
Reporting Events
Estimate (%)
95% Confidence Interval 
0/35
0
(0.0, 10.0)
2/35
5.7
(0.7, 19.2)
5/35
14.3
(4.8, 30.3)
9/35
25.7
(12.5, 43.3)
12/35
34.3
(19.1, 52.2)
14/35
40.0
(23.9, 57.9)
19/35
54.3
(36.6, 71.2)
10.3
Planned Analyses
10.3.1
Data Review Team
A Data Review Team (DRT) will review safety data on an ongoing basis, following 
treatment of every 7th subject with blinatumomab or every 3 months, whichever occurs 
sooner.  A DRT is a group, internal to Amgen but external to the relevant blinatumomab 


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product team, that reviews accumulating data from the ongoing clinical trial to ensure no 
avoidable increased risk for harm to subjects.  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.
10.3.2
Interim Analysis
Amgen will conduct evaluations of the ongoing DLT rate to assess if the threshold for 
early trial termination as defined in Section 6.2.3 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 8 and the operating characteristics with 
pre-specified batch size are presented in Table 9.  The evaluations could occur more 
frequently if necessary to address emerging safety concerns.  The operating 
characteristics in Table 9 provide the probability of stopping the trial early for given 
hypothetical true DLT rates, whereas the stopping criteria in Table 8 are based on 
situations where the empirical evidence would result in a posterior probability of 90% 
that the true DLT rate is 25%.
Table 8.  Stopping Boundary With Batch Size of 7 Subjects, Posterior Probability 
of 90% and DLT Limit of 25%
Number of DLT Evaluable Subjects 
(inclusive)
Stop Study if Observing this Number of 
DLTs
7
4
14
6
21
9
28
11
35
Study Completes
Table 9.  Operating Characteristics With Batch Size of 7 Subjects
DLT Rate
Probability of Stopping
Average Sample Size
0.20
7%
34
0.25
17%
32
0.30
33%
29
0.35
52%
25
0.40
71%
20


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10.3.3
Primary Analysis
The primary analysis will occur when the last subject who received blinatumomab has 
had the opportunity to complete the safety follow-up visit. The primary safety endpoint, 
secondary efficacy endpoints, other safety data as outlined in Section 10.4.4, and the 
exploratory endpoints will be analyzed.  The purpose is estimation. 
10.3.4
Final Analysis
The final analysis will occur when the last subject assigned to treatment with 
blinatumomab has had the opportunity to complete the long-term follow-up period 
(ie, 1 year from the first dose of blinatumomab).  Duration of response, PFS from first 
dose of blinatumomab, OS from first dose of blinatumomab and HSCT rate will be 
analyzed.  Additional safety data (eg, serious adverse events) will also be summarized. 
The purpose is estimation.
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 hazard ratios, Kaplan-Meier (KM) 
curves, KM proportions at select time points, KM quartiles (when estimable), the number 
of subjects with events, the number of subjects censored, and the pattern of censoring.  
Point estimates for efficacy endpoints will be accompanied by 2-sided 95% confidence 
intervals including estimates of KM quartiles (Brookmeyer and Crowley, 1982), KM 
proportions (Kalbfleisch and Prentice, 1980), and binomial proportions 
(Clopper and Pearson, 1934).
10.4.2
Primary Safety Endpoint
Overall incidence and severity of treatment-emergent adverse events occurring during 
the blinatumomab treatment period (through the safety follow-up visit) will be 
summarized with exact binomial 95% confidence intervals.  The safety summary 
described in Section 10.4.4  will also be performed.  Confidence intervals will not be 
calculated for adverse events by system organ classes and preferred terms.
10.4.3
Secondary Efficacy Endpoints
To estimate the efficacy of blinatumomab, ORR, CR rate and HSCT rate will be 
summarized with exact binomial 95% confidence intervals. PFS, OS, and duration of 
response will be summarized with KM analyses.   


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10.4.4
Safety Endpoints
10.4.4.1
Adverse Events
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code all 
adverse events 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 
protocol-specified therapy. They include blinatumomab treatment-emergent adverse 
events and SOC R-chemotherapy treatment-emergent adverse events. Blinatumomab 
and SOC R-chemotherapy treatment-emergent adverse events will be summarized 
separately.  Safety analysis for SOC R-chemotherapy treatment-emergent adverse 
events will be detailed in the Statistical Analysis Plan.  Adverse events of interest (EOI) 
categories for blinatumomab will be based on search strategies defined by Medical 
Coding.   
The subject incidence of adverse events will be summarized for blinatumomab 
treatment-emergent adverse events, serious adverse events, adverse events leading to 
withdrawal of protocol-specified therapy, and fatal adverse events.  For the 
blinatumomab incidences, 95% confidence intervals will be calculated. 
Subject incidence of blinatumomab treatment-emergent adverse events, serious adverse 
events, adverse events leading to withdrawal of investigational product, 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 for blinatumomab. Time to onset and 
duration of selected EOIs (infection and neurologic events) may also be summarized.
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.  Plots or other summaries overtime will be presented for 
selected laboratory parameters including immunoglobulin, platelets, and liver 


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parameters. These analyses will only be done for the blinatumomab treatment period 
(through the safety follow-up visit).
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. These analyses 
will only be done for the blinatumomab treatment period (through the safety follow-up 
visit).
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 will be tabulated.
10.4.4.7
Exposure to Investigational Product
Descriptive statistics will be produced to describe the exposure to blinatumomab . The 
number of cycles will be summarized with an additional breakdown of the number of 
cycles completed and discontinued.  In addition, the duration of therapy, the cumulative 
dose, and the percent of intended dose will be summarized by cycle and overall.  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 SOC R-Chemotherapy
Descriptive statistics will be produced to describe the exposure to SOC R-chemotherapy 
from enrollment through the end of the run-in period . The number of cycles will be 
summarized with an additional breakdown of the number of cycles completed and 
discontinued.  In addition, the duration of therapy, the cumulative dose, and the percent 
of intended dose will be summarized by cycle and overall.  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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10.4.4.9
Exposure to Concomitant Medication
The number and proportion of subjects receiving concomitant medications will be 
summarized by preferred term as coded by the World Health Organization Drug 
(WHODRUG) dictionary. The summary will be provided by day 1 of SOC 
R-chemotherapy until the day before the first dose of blinatumomab and day 1 of 
blinatumomab until safety follow-up respectively. In addition, the number and proportion 
of subjects receiving anti-cancer therapies during long-term follow-up will be 
summarized by WHODRUG preferred term.
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 Global Clinical Trial Manager to the 
investigator.  The written informed consent form is to be prepared in the language(s) of 
the potential patient population.
Before a subject’s participation in the clinical study, the investigator is responsible for 
obtaining written informed consent from the subject 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.  
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 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.


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If a potential subject is illiterate or visually impaired 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.
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/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 


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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.
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
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.
In this study, the IVRS captures the following data point and this is considered source 
data: subject identification number.
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, Return of Investigational Product 
for Destruction Form(s), Final Investigational Product Reconciliation Statement,
as applicable.

Non-investigational product(s) and or medical device(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.


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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
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 Research & Development Compliance 
and Audit function (or designees).  Inspection of site facilities (eg, pharmacy, 
protocol-required therapy storage areas, laboratories) and review of study-related 
records will occur to evaluate the study conduct and compliance with the protocol, ICH 
GCP, and applicable regulatory requirements.
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 the 
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 (SEC) to obvious data errors 
in the clinical trial database.  SECs will be documented in the CRF instructions available 
in 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 


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specific response if the confirming datum is provided in the “other,specify” field (eg, for 
race, reason for ending study).
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, Table 5, and Table 6), 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 (ICMJE) 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.


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
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.

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.
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Cheson B, Fisher R, Barrington S, et al.  Recommendations for Initial Evaluation, 
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Clopper CJ and Pearson ES. The Use of Confidence or Fiducial Limits Illustrated in the 
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Dreier T, Baeuerle PA, Fichtner I, et al. T cell co-stimulus-independent and very
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Dunleavy K. Double-hit lymphomas: current paradigms and novel treatment approaches.
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Dunleavy K. Aggressive B cell Lymphoma: Optimal Therapy for MYC-positive, 
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Feugier P, Van Hoof A, Sebban C, et al, Long-term results of the R-CHOP study in the 
treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe 
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Fisher SG, and Fisher RI. "The Epidemiology of Non-Hodgkin's Lymphoma." Oncogene.
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Friedberg W. Relapsed/refractory diffuse large B-cell lymphoma. Hematology Am Soc 
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Gisselbrecht C, Glass B, Mounier N, et al. Salvage Regimens With Autologous 
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Goebeler ME, Knop S, Viardot A, et al. Bispecific T-Cell Engager (BiTE) Antibody 
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Hans CP, Weisenburger DD, Greiner TC, et al. Confirmation of the molecular 
classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue 
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Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/BCL2 protein coexpression contributes to 
the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and 
demonstrates high-risk gene expression signatures: a report from The International 
DLBCL Rituximab-CHOP Consortium Program Blood. 2013;121:4021-31.
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Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical 
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York: John Wiley & Sons; 1980
Lazarus HM, Zhang MJ, Carreras J, et al. A comparison of HLA-identical sibling 
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Engl J Med. 1993;329:987-94
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immunohistochemically defined germinal center phenotype in diffuse large B-cell 
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lymphoma: the role of Bcl-6. Leuk Lymphoma. 2003; 44 (Suppl 3):S5-S12.
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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 
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survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med.
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with a poor prognosis in diffuse large B-cell lymphoma patients treated with R-CHOP 
chemotherapy. Blood. 2009;114:3533-3537
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chimpanzees treated with a bispecific anti-CD19/anti-CD3 single-chain antibody
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Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumors of 
Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: The International Agency 
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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 aspartate aminotransferase  (AST) or alanine aminotransferase (ALT) and 
total bilirubin and/or international normalization ratio (INR) elevation according to the 
criteria specified in Section 6.5 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 case 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 >3x upper limit of normal (ULN) or 
2-fold increases above baseline values for subjects with elevated values before drug are 
to undergo a period of “close observation” until abnormalities return to normal or to the 
subject’s baseline levels.  
Assessments that are to be performed during this period include: 

Repeat AST, ALT, alkaline phosphatase (ALP), bilirubin (total and direct), and 
INR within 24 hours 

In cases of total bilirubin > 2x 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


Product:  Blinatumomab
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Date:  03 June 2018
Page 92 of 102
CONFIDENTIAL
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 total bilirubin.  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 (ANA), Anti Smooth Muscle 
Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to assess for autoimmune 
hepatitis

Serum acetaminophen (paracetamol) levels

A more detailed history of: 

Prior and/or concurrent diseases or illness

Exposure to environmental and/or industrial chemical agents 

Symptoms (if applicable) including right upper quadrant pain, 
hypersensitivity-type reactions, fatigue, nausea, vomiting and fever

Prior and/or concurrent use of alcohol, recreational drugs and special diets

Concomitant use of medications (including non-prescription medicines and 
herbal and dietary supplements), plants, and mushrooms

Viral serologies

CPK, haptoglobin, lactase dehydrogenase (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, total bilirubin, 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.


Product:  Blinatumomab
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Date:  03 June 2018
Page 93 of 102
CONFIDENTIAL
Appendix B.  Sample Serious Adverse Event Report Form or eSerious Event 
Contingency Form


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Date:  03 June 2018
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CONFIDENTIAL


Product:  Blinatumomab
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Date:  03 June 2018
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CONFIDENTIAL


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CONFIDENTIAL
Appendix C.  Pregnancy and Lactation Notification Worksheets


Product:  Blinatumomab
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Date:  03 June 2018
Page 97 of 102
CONFIDENTIAL


Product:  Blinatumomab
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Date:  03 June 2018
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CONFIDENTIAL
Appendix D.  International Prognostic Index for Diffuse Large B-cell Lymphoma
(Ann Arbor Staging)
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 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


Product:  Blinatumomab
Protocol Number:  20150288
Date:  03 June 2018
Page 99 of 102
CONFIDENTIAL
Appendix E. 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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Date:  03 June 2018
Page 100 of 102
CONFIDENTIAL
Appendix F.  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
Source:  Cheson et al, 2014


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CONFIDENTIAL
Appendix G.  Disease Related Events
System Organ Class
Term
Blood and lymphatic system 
disorders
lymphadenopathy
General disorders and 
administration site conditions
disease progression
fatigue  
Investigations
weight increased
Skin and subcutaneous tissue 
disorders
night sweats


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Date:  03 June 2018
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CONFIDENTIAL
Appendix H.  Clinically Relevant Neurologic Events by High Level Group Term
(HLGT)

Cranial nerve disorders (excluding neoplasms)

Demyelinating disorders

Encephalopathies

Mental impairment disorders

Movement disorders (including parkinsonism)

Neurological disorders NEC

Seizures (including subtypes)

Cognitive and attention disorders and disturbances

Communication disorders and disturbances


Product:  Blinatumomab 
Protocol Number:  20150288 
Date:  03 June 2018 
Page 1 of 4 
CONFIDENTIAL 
 
 
Amendment 3 
Protocol Title:  A Phase 2 Open-label Study Investigating the Safety and Efficacy 
of Blinatumomab After Frontline R-Chemotherapy in Adult Subjects With Newly 
Diagnosed High-risk Diffuse Large B-Cell Lymphoma (DLBCL) 
 
Amgen Protocol Number (Blinatumomab) 20150288 
EudraCT Number 2016‐002190‐35 
 
Amendment Date: 
03 June 2018 
 
Rationale: 
This is Amendment 3 for Blinatumomab Study 20150288.  The primary changes to the 
protocol are to clarify that grade 4 hematologic toxicity and grade 4 laboratory 
abnormalities lasting ≥ 7 days exclude lymphopenia.  Grade 4 lymphopenia is known to 
occur from Rituximab (R)-chemotherapy used in the treatment of lymphoma.  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. 
In addition, the following changes were made: 
 
Clarify that subjects will be excluded from receiving blinatumomab if there is 
evidence of CNS involvement with DLBCL at evaluation prior to starting 
blinatumomab 
 
Clarify when vital signs will be obtained for hospitalized subjects versus subjects in 
the outpatient clinic. 
 
Clarify what assessments in the Schedule of Assessments should be obtained after 
restart of continuous IV infusion of blinatumomab after interruption requiring dose 
modification 
 
Administration, typographical, and formatting changes were made throughout the 
protocol. 


Product:  Blinatumomab 
Protocol Number:  20150288 
Date:  03 June 2018 
Page 2 of 4 
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:  20150288 
Date:  03 June 2018 
Page 3 of 4 
CONFIDENTIAL 
 
 
Description of Changes: 
Section:  Global 
Change:  Updated document date from 11 May 2017 to 03 June 2018. 
Section:  Global 
Change:  Editorial changes (including typographical, grammatical, and formatting) have 
been made throughout the document. 
Section:  Title Page 
Add: 
Amendment 3 
03 June 2018 
Section:  4.1.2 Exclusion Criteria – Part 1, Criterion 202 
Add: 
202 
Evidence of CNS involvement with DLBCL at disease evaluation obtained 
prior to starting blinatumomab 
Section:  6.2.2.2 Infusion Interruption/Dose Modifications due to Adverse Events, 
Paragraph 1 
Add: 
To restart blinatumomab after an interruption requiring dose modification 
(Table 1), if the restart of continuous IV infusion of blinatumomab is 9 g/day 
follow the Schedule of Assessments (Table 5) for week 1 (if restart continuous IV 
infusion of blinatumomab is 28 g/day follow Schedule of Assessments [Table 5] 
for week 2) and continue to follow through week 36.  The total days of 
blinatumomab for cycle 1 will not exceed 56 days (ie, the total days a patient 
receives 112 g/day will be decreased if an interruption in continuous IV infusion 
of blinatumomab occurs).  Following dose escalation to 112 g/day and 
completion of the required assessments (week 3, days 15 to 17 [Table 5]), return 
to the Schedule of Assessments at the next opportunity (eg, if dose interrupted at 
day 9, restart occurs from 9 g/day [day 10], with dose escalations at day 17 
[28 g/day] and day 24 [112 g/day].  Required assessments for 112 g/day dose 
escalation continue until day 26, and assessments can return to the Schedule of 
Assessments by day 29).  The Schedule of Assessments on day 50 will occur the 
first day of the last week of continuous IV infusion of blinatumomab to be given.  


Product:  Blinatumomab 
Protocol Number:  20150288 
Date:  03 June 2018 
Page 4 of 4 
CONFIDENTIAL 
 
 
The treatment free period begins on day 57 and will continue to be 4 weeks in 
length with assessments obtained the first day of weeks 1 and 4 of the treatment 
free period as per the Schedule of Assessments (Table 5). 
Section:  6.2.3 Dose Limiting Toxicities, Paragraph 1, Bullets 3 and 4 
Add: 
 
Grade 4 hematologic toxicity lasting ≥ 7 days (excluding lymphopenia) 
 
Grade 4 laboratory abnormalities lasting ≥ 7 days (excluding lymphopenia) 
Section:  7.1 Schedule of Assessments, Table 5, Footnote n 
Replace: 
Vital sign monitoring every 4 to 8 hours dependent upon institution SOC. 
With: 
On days of hospitalization, obtain vital sign monitoring every 4 to 8 hours per 
institution SOC.  When subject is in the outpatient clinic, only obtain 1 baseline 
vital sign per visit. 
Section:  7.1 Schedule of Assessments, Table 6, Footnote m 
Replace: 
Vital sign monitoring every 4 to 8 hours dependent upon institution SOC. 
With: 
On days of hospitalization, obtain vital sign monitoring every 4 to 8 hours per 
institution SOC.  When subject is in the outpatient clinic, only obtain 1 baseline 
vital sign per visit. 
Section:  7.3.7 Vital Signs, Paragraph 1 
Add: 
Refer to Schedule of Assessments (Table 4, Table 5, Table 6) for frequency and 
days to record vital signs in eCRF. 


Product:  Blinatumomab 
Protocol Number:  20150288 
Date:  11 May 2017 
Page 1 of 66 
Amendment 2 
Protocol Title:  A Phase 2 Open-label Study Investigating the Safety and Efficacy 
of Blinatumomab After Frontline R-Chemotherapy in Adult Subjects With Newly 
Diagnosed High-risk Diffuse Large B-Cell Lymphoma (DLBCL) 
 
Amgen Protocol Number 20150288 
EudraCT number 2016‐002190‐35 
 
Amendment 1 Date: 
Amendment 2 Date: 
28 February 2017 (not submitted) 
11 May 2017 
Rationale: 
Since Amendment 1 of this protocol was never submitted to any regulatory agency, 
Protocol Amendment 2 reflects changes that were made to the original protocol in both 
Protocol Amendment 1 and Protocol Amendment 2.   
The primary rationale for Protocol Amendment 1 was to align the Study 20150288 
protocol to changes made in the other DLBCL protocols (Studies 20150292 and 
20140286) with respect to safety assessments and dose interruptions and stopping 
criteria. 
Protocol Amendment 2 includes the Protocol Amendment 1 changes along with the 
inclusion of changes to address feedback received from health authorities specifically for 
Study 20150288.  The following areas are addressed: 
- 
Sample size has been reduced to support consideration of the study as a pilot 
study.  The estimated 95% confidence intervals for adverse event incidences has 
been adjusted to align with the reduced sample size. 
- 
Clarification of run-in period treatment and the evaluation of tumor response 
timing and frequency is done at the discretion of the investigator according to 
their institutional standard of care and must be recorded in the subject’s eCRF.  
Clarification that subjects with progressive disease are not eligible for treatment 
with blinatumomab. 
- 
Due to pancreatitis label warning for blinatumomab, amylase has been added to 
the laboratory analyte listing and both will be collected at screening and 
periodically throughout the study. 
CONFIDENTIAL 
 
 


Product:  Blinatumomab 
Protocol Number:  20150288 
Date:  11 May 2017 
Page 2 of 66 
- 
The schedule of assessments has been updated to provide clarity for procedures 
during the screening and run-in phase and to provide clear guidance for cycle 1 
and cycle 2 periods.  A footnote has been added to the schedule of assessments 
for cycle 1 and cycle 2 to indicate that vital sign monitoring will be done every 
4 to 8 hours dependent upon institutional standard of care. 
- 
To ensure consistency and clarity, the text in Section 6.2.2.2 of the protocol has 
been replaced with a toxicity management table and the permanent 
discontinuation criteria in Section 6.2.2.3 have been revised to ensure 
consistency and clarity. 
- 
Section 9.2.2.1 has been revised to include the requirement that all grade 
3-4 laboratory abnormalities be recorded as adverse events.  Additionally, the 
protocol language has been modified to state that if signs or symptoms are 
associated with a laboratory abnormality that both the signs/symptoms and the 
laboratory abnormality will be recorded as adverse events. 
- 
The list of disease-related events included in Appendix G has been revised such 
that only AEs that are directly related to the underlying disease (ie, progressive 
disease) are excluded from AE recording and reporting. 
- 
The protocol has been revised to include a data review team (DRT) that will 
review safety data on an ongoing basis, following treatment of every 7th subject 
with blinatumomab or every 3 months, whichever occurs sooner. 
- 
Continuous toxicity monitoring for early termination of the study has been added 
including stopping rules and inclusion of a listing of criteria for dose limiting 
toxicities (DLTs).  A maximum DLT rate of 25% will trigger early stopping.  The 
evaluation period for DLTs will include both cycle 1 and cycle 2 of infusions of 
blinatumomab. 
- 
A requirement for investigator reporting of delayed time to HSCT for subjects with 
partial response or partial metabolic response at baseline has been included. 
- 
The assessment of blinatumomab pharmacokinetics was changed from an 
exploratory objective and endpoint to a secondary objective and endpoint.  
Subsequent sections were revised accordingly.  Blinatumomab pharmacokinetics 
are important to assess in this new patient population.  This study is conducted in 
newly diagnosed patients as opposed to relapsed patients heavily pretreated with 
chemotherapy (that were studied in previous blinatumomab trials) and may have 
CONFIDENTIAL 
 
 


Product:  Blinatumomab 
Protocol Number:  20150288 
Date:  11 May 2017 
Page 3 of 66 
a different pharmacokinetic profile and so this was felt to be important as a 
secondary objective and endpoint as opposed to an exploratory endpoint. 
- 
The assessment of overall survival has been added in the clinical hypothesis and 
as a secondary endpoint.  The Final Analysis section (Section 10.3.4 was 
updated accordingly.  This endpoint was not initially included because of 
accidental deletion during protocol writing.  It is now added back into the protocol 
as the endpoint is felt important to evaluate. 
- 
The timing for PET/CT scans in the study design and in the schedule of 
assessments, was changed from 14 days to 21 days prior to enrollment in the 
study.  This is to prevent subjects from being exposed to extra radiation if their 
scans were obtained in an acceptable time frame to assess disease and 21 days 
was felt to be an acceptable duration.  This will also allow for time to obtain 
histology after the diagnostic scans. 
CONFIDENTIAL 
 
 


Product:  Blinatumomab 
Protocol Number:  20150288 
Date:  28 February 2017 
Page 1 of 63 
Amendment 1 
Protocol Title:  A Phase 2 Open-label Study Investigating the Safety and Efficacy 
of Blinatumomab After Frontline R-Chemotherapy in Adult Subjects With Newly 
Diagnosed High-risk Diffuse Large B-Cell Lymphoma (DLBCL) 
 
Amgen Protocol Number 20150288 
EudraCT number 2016‐002190‐35 
 
Amendment Date: 
28 February 2017 
Rationale: 
One of the major reasons is to align to the changes made to the other DLBCL 
protocols 20150292/20140286 in regards to safety assessment and dose 
interruptions/stopping, which were done due to feedback from health authorities.  The 
protocol is also being amended to make administrative and editorial changes. 
CONFIDENTIAL 
 
 

SAP_001.pdf: 
Product:  Blinatumomab
Statistical Analysis Plan:  20150288
Date: 12 September 2018
Page 1
STATISTICAL ANALYSIS PLAN
A Phase 2 Open-label Study Investigating the Safety and Efficacy of 
Blinatumomab After Frontline R-Chemotherapy in Adult Subjects With Newly 
Diagnosed High-risk Diffuse Large B-Cell Lymphoma (DLBCL)
Protocol Number:
20150288
Version:
Version 3.0
Date:
12 September 2018
Authors:
NCT number: NCT03023878
This NCT number has been applied to the document
for purposes of posting on clinicaltrials.gov


Product:  Blinatumomab
Statistical Analysis Plan:  20150288
Date: 12 September 2018
Page 2
Table of Contents
Table of Abbreviations.....................................................................................................5
1.
Introduction.............................................................................................................7
2.
Objectives...............................................................................................................7
2.1
Primary .......................................................................................................7
2.2
Secondary...................................................................................................7
2.3
Exploratory..................................................................................................7
3.
Study Overview ......................................................................................................7
3.1
Study Design...............................................................................................7
3.2
Sample Size..............................................................................................10
4.
Study Endpoints and Covariates...........................................................................11
4.1
Study Endpoints........................................................................................11
4.1.1
Primary Endpoint.......................................................................11
4.1.2
Secondary Endpoints ................................................................11
4.1.3
Exploratory Endpoints ...............................................................12
5.
Hypotheses and/or Estimations ............................................................................12
6.
Definitions.............................................................................................................12
6.1
General Definitions....................................................................................12
6.2
Safety Endpoints.......................................................................................16
6.3
Efficacy Endpoints.....................................................................................17
7.
Analysis Sets........................................................................................................18
7.1
Full Analysis Set........................................................................................18
7.2
Target Dose Analysis Set..........................................................................18
7.3
Responder Analysis Set............................................................................18
7.4
Pharmacokinetic Analysis Set ...................................................................18
7.5
Pharmacodynamic Analysis Set................................................................19
7.6
SOC R-chemotherapy Analysis Set...........................................................19
7.7
Subgroup Analyses...................................................................................19
8.
Interim Analysis and Early Stopping Guidelines....................................................19
8.1
Data Review Team....................................................................................19
8.2
Interim Analysis.........................................................................................19
9.
Data Screening and Acceptance...........................................................................22
9.1
General Principles.....................................................................................22
9.2
Data Handling and Electronic Transfer of Data..........................................22
9.3
Handling of Missing and Incomplete Data .................................................22
9.4
Detection of Bias.......................................................................................22
9.5
Outliers .....................................................................................................22
9.6
Distributional Characteristics.....................................................................23


Product:  Blinatumomab
Statistical Analysis Plan:  20150288
Date: 12 September 2018
Page 3
9.7
Validation of Statistical Analyses...............................................................23
10.
Statistical Methods of Analysis..............................................................................23
10.1
General Principles.....................................................................................23
10.2
Subject Accountability ...............................................................................23
10.3
Important Protocol Deviations ...................................................................24
10.4
Demographic and Baseline Characteristics...............................................24
10.5
Efficacy Analyses......................................................................................25
10.5.1
Analysis of Primary Endpoint(s).................................................25
10.5.2
Analysis of Secondary Efficacy Endpoint(s)...............................25
10.5.3
Analyses of Exploratory Endpoints ............................................27
10.5.4
Analyses of Patient Reported Outcomes and Other 
Health Related Quality of Life Endpoints ...................................27
10.5.5
Health Economic Analyses........................................................27
10.6
Safety Analyses ........................................................................................27
10.6.1
Adverse Events and Disease Related Events............................27
10.6.2
Laboratory Test Results.............................................................28
10.6.3
Vital Signs .................................................................................29
10.6.4
Electrocardiogram (ECG) ..........................................................29
10.6.5
Antibody Formation ...................................................................29
10.6.6
Exposure to Investigational Product ..........................................30
10.6.7
Exposure to SOC R-chemotherapy ...........................................30
10.6.8
Exposure to Concomitant Medication ........................................30
10.7
Pharmacokinetic or Pharmacokinetic/Pharmacodynamic 
Analysis ....................................................................................................30
10.7.1
Pharmacokinetic Analysis..........................................................30
10.7.2
Pharmacodynamic Analysis.......................................................31
10.7.3
Exposure Response Analysis....................................................31
11.
Changes From Protocol-specified Analyses..........................................................31
12.
Literature Citations / References...........................................................................32
13.
Prioritization of Analyses.......................................................................................33
14.
Data Not Covered by This Plan.............................................................................33
15.
Appendices...........................................................................................................34
List of Tables
Table 1.  Estimated 95% Confidence Interval for Example Adverse Event 
Incidences ..............................................................................................11
Table 2.  Stopping Boundary With Batch Size of 7 Subjects, Posterior 
Probability of 90% and DLT Limit of 25%................................................20
Table 3.  Operating Characteristics With Batch Size of 7 Subjects, Posterior 
Probability of 90% and DLT Limit of 25%................................................21


Product:  Blinatumomab
Statistical Analysis Plan:  20150288
Date: 12 September 2018
Page 4
Table 4.  Stopping Boundaries for All Numbers of DLT Evaluable Subjects 
With Posterior Probability of 90% and DLT Limit of 25%.........................21
Table 5.  Distribution of Score and Risk Categories for Different Prognostic 
Indices....................................................................................................25
Table 6.  Secondary Efficacy Endpoint Summary Table ................................................26
Table 7.  Imputation Rules for Partial or Missing Start Dates.........................................35
Table 8.  Grading of Selected Laboratory Parameters...................................................37
Table 9.  Notable Abnormalities of Vital Signs ...............................................................38
List of Appendices
Appendix A.  Handling of Dates, Incomplete Dates and Missing Dates..........................35
Appendix B.  Reference Values/Toxicity Grades ...........................................................37
Appendix C.  Response Assessment Per the Lugano Classification..............................39
Appendix D.  International Prognostic Index for Diffuse Large B-cell 
Lymphoma..............................................................................................40


Product:  Blinatumomab
Statistical Analysis Plan:  20150288
Date: 12 September 2018
Page 5
Table of Abbreviations
Abbreviation or 
Term
Definition/Explanation
ABC
activated B cell
ALT
alanine aminotransferase
AST
aspartate aminotransferase
COO
cell of origin
CI
confidence interval
CNS
central nervous system
CR
complete response
CRF 
case report form
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
EOI
Events of interest
GCB
germinal center B
GI
Gastrointestinal
HSCT
hematopoietic stem cell transplantation
Ig
Immunoglobulin
IPI/aaIPI
International prognostic index/age-adjusted international prognostic 
index
IV
Intravenous
Interactive Voice 
Response system 
(IVRS)
telecommunication technology that is linked to a central computer in real 
time as an interface to collect and process information.  
KM
Kaplan-Meier
LDH
lactate dehydrogenase
MRD
minimal residual disease
NCCN
National Comprehensive Cancer Network
NGS
next generation sequencing
ORR
objective response rate


Product:  Blinatumomab
Statistical Analysis Plan:  20150288
Date: 12 September 2018
Page 6
Abbreviation or 
Term
Definition/Explanation
OS
overall survival
PD
progressive disease
PET
positron emission tomography
PFS
progression-free survival
PR
partial response
SD
Stable Disease
SOC
standard of care
SUV
standardized uptake values
ULN
upper limit of normal


Product:  Blinatumomab
Statistical Analysis Plan:  20150288
Date: 12 September 2018
Page 7
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 the 
blinatumomab study 20150288, dated 3 June 2018.  The scope of this plan includes the 
primary analysis and the final analysis that are planned and will be executed by the 
Global Biostatistical Science department unless otherwise specified. PK/PD analyses 
will be provided by Clinial Pharmacology, Modeling and Simulation (CPMS) group and 
clinical biomarker group in Department of Medical Sciences.
2.
Objectives
2.1
Primary
To evaluate the safety of blinatumomab administered after frontline standard of care 
(SOC) rituximab (R)-chemotherapy in newly diagnosed subjects with high-risk Diffuse 
Large B-cell Lymphoma (DLBCL).
2.2
Secondary

To estimate the efficacy of blinatumomab administered after frontline SOC
R-chemotherapy in newly diagnosed subjects with high-risk DLBCL.  

To characterize the pharmacokinetic (PK) parameters of blinatumomab 
administered to subjects after frontline chemotherapy with high-risk 
DLBCL.
2.3
Exploratory

To evaluate minimal residual disease (MRD) from the frequency of detectable 
clonotypic immunoglobulin H (IgH) sequences by next-generation sequencing (NGS) 
of cell-free circulating tumor DNA (CT-DNA) positivity among subjects at various time 
points before, during and after standard of care (SOC) R-chemotherapy and 
blinatumomab treatment

To evaluate the relationship of cell of origin (COO) determination, c-myc and/or 

Bcl-2/Bcl-6 rearrangements to response after blinatumomab treatment

To evaluate the immunopharmacodynamics of blinatumomab administered after 
SOC R-chemotherapy

To determine the incidence of anti-blinatumomab antibody formation during 
blinatumomab treatment
3.
Study Overview
3.1
Study Design
This is a phase 2, multicenter, open-label, single arm clinical trial in adult subjects with 
newly diagnosed aggressive high-risk DLBCL.  The safety profile of blinatumomab after 
frontline SOC R-chemotherapy consisting of either R-CHOP (every 14 or 21 days) or
R-DA-EPOCH or R-CHOEP will be determined. The study will consist of a screening 


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period (up to 14-days), a SOC R-chemotherapy run-in period of approximately 
21 weeks, a 12 to 16 week blinatumomab treatment period, a 30-day safety follow-up, 
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, or until subject death, whichever 
comes first.
Screening Period
The screening period consists of up to 14 days prior to enrollment, with the exception 
of the PET/CT and CT scans, which must be within 21 days of the start of cycle 1 
SOC R-chemotherapy. During this time period medical history, laboratory and 
radiographic assessments are obtained to determine eligibility for study enrollment.
Positron emission tomography/computed tomography (PET/CT) and CT scans 
used for enrollment must have occurred within 21 days prior to enrollment if 
starting prior to cycle 1 or within 21 days of starting cycle 1 if enrollment is prior 
to cycle 2 (new scans are not required when enrollment is prior to cycle 2). In order 
to be eligible for enrollment in the study subjects must have histologically proven 
high-risk DLBCL (defined as either IPI 3 to 5 and/or double-hit or higher or double 
protein expression) and must meet criteria per the investigator’s institution to receive 
SOC R-chemotherapy (ie, R-CHOP 14 or 21 or R-DA-EPOCH or R-CHOEP) for 6 cycles 
during the study run-in period. 
Run-in Period
The run-in period consists of enrollment on study (run-in visit 1) and 
SOC-R-chemotherapy followed by an assessment of disease status (run in visit 2).
Subjects must be enrolled into the run-in period either prior to the start of cycle 1 or 
cycle 2 of SOC R-chemotherapy. Enrollment prior to cycle 2 is allowed so that results of 
molecular assessments that may not be known at the time of diagnosis (ie, prior to 
cycle 1) can be obtained as these results may potentially upgrade the subject’s tumor to 
high-risk and thus meet enrollment eligibility criteria (Section 4.1.1, inclusion 
criterion 103 of the protocol). 
Subjects who are enrolled prior to cycle 1 will complete 6 cycles of SOC 
R-chemotherapy during the run-in period, while subjects enrolled prior to cycle 2 of SOC
R-chemotherapy will receive 1 cycle of SOC R-chemotherapy prior to enrollment and 
additional 5 cycles of SOC R-chemotherapy during the run-in period. All subjects on 


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study must complete a total of 6-cycles of SOC R-chemotherapy prior to treatment 
assignment with blinatumomab.   
At the end of the 6 cycles of SOC R-chemotherapy, disease status will be assessed by a 
PET/CT(run-in visit 2). The PET/CT will be obtained 3 weeks (± 3 days) after completion 
of cycle 6.  In order to be eligible for treatment assignment to blinatumomab, subjects 
must demonstrate either CR, PR or have stable disease based on the Lugano 
Classification (Chelson 2014) (see Appendix C). Subjects with progressive disease 
(PD) are not eligible for treatment with blinatumomab and will end the study.   
After the post SOC cycle 6 PET/CT (run-in visit 2) subjects who require radiation to bulky 
disease per investigator judgement must complete radiation therapy as soon as possible 
(Section 6.7 Other Treatment Procedures of the protocol). Treatment with 
blinatumomab will be delayed until 2 to 3 weeks after radiation therapy is completed to 
allow for resolution of toxicity from the radiation to a safe level per the investigator’s 
judgement.  A PET/CT is not required after the radiation therapy to proceed to the 
treatment period. 
Treatment Period
Subjects who complete the run-in period successfully will be assigned to treatment with 
blinatumomab. During the treatment period, subjects will receive 1 to 2 cycles of 
blinatumomab.  Blinatumomab will be administered as an intravenous (IV) infusion.  
Cycle 1 will be 8 weeks in duration followed by a 4-week treatment-free interval break 
(+1 week if results of PET/CT are delayed to determine eligibility for cycle 2).  
Cycle 2 will be 4-weeks in duration and given at the discretion of the investigator if the 
subject does not have PD. Each cycle of blinatumomab will be dosed at 9 µg/day for 
7 days, followed by 28 µg/day for 7 days and 112 µg/day for the remainder of that 
treatment cycle (42 days for cycle 1, 14 days for cycle 2). PET/CT will be performed 
3 weeks after cycle 1 of blinatumomab (D78 ± 3 days) to evaluate disease status. 
Subjects with PD by PET/CT after cycle 1 of blinatumomab will not be eligible to receive 
cycle 2 of blinatumomab.  In subjects who receive cycle 2 of blinatumomab a final 
disease assessment by PET/CT will occur 3 weeks after the last dose of blinatumomab 
(D50 ± 3 days of cycle 2). 
Safety Follow-Up Period
Thirty days (+ 3 days) after the last dose of blinatumomab, subjects will complete a 
safety follow-up visit for assessment of disease related events, adverse events and 


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serious adverse events. This visit will occur 30 days (+ 3 days) after last dose of 
blinatumomab either:

after cycle 1 of blinatumomab if cycle 2 is not given, or

after the last dose of blinatumomab in cycle 2.
Long-Term Follow-Up Period
A long-term follow up period to assess disease and clinical status follows the safety 
follow up period.  The frequency of long-term follow-up visits is every 3 months 
(± 3 weeks).

If only cycle 1 of blinatumomab is given, long-term follow-up begins 3 months 
(± 3 weeks) after the last scan (C1D78), LTFU visit 1 occurs at 3 months post 
last scan (C1D78), LTFU visit 2 occurs at 6 months post last scan (C1D78) and 
LTFU visit 3 occurs at 9 months post last scan (C1D78) for a maximum of 
1 year from the first dose of blinatumomab, or until subject death, whichever 
occurs first.

If cycle 2 is given, long-term follow-up begins 3 months (± 3 weeks) after 
cycle 2 day 50, LTFU visit 1 occurs at 3 months post last scan (C2D50), LTFU 
visit 2 occurs at 6 months post last scan (C2D50), and LTFU visit 3 occurs at 
8 months from last scan (C2D50) for a maximum of 1 year from the first dose of 
blinatumomab or until subject death, whichever occurs first.
Subjects will be followed via clinic visit every 3 months (± 3 weeks) by institutional SOC 
disease evaluation.
3.2
Sample Size
This is a single arm estimation trial.  The number of subjects enrolled in the run-in 
period will be approximately 38. If 38 subjects complete 6 cycles of SOC 
R-chemotherapy, it is expected that 15% will need radiation prior to receiving 
blinatumomab. Among the remaining 85% of subjects, 93% are expected to have 
a best overall response of CR/PR/stable disease and will receive blinatumomab.  
Thus it is anticipated that 35 subjects will receive blinatumomab during the 
treatment period.
With 35 subjects, the width of the 95% exact confidence interval (Clopper and 
Pearson, 1934) for the estimate of the percentage of subjects with a particular 
adverse event of interest and/or severity can be calculated. The table shows the 
95% confidence interval for some example adverse event incidences. 


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Table 1.  Estimated 95% Confidence Interval for Example Adverse Event 
Incidences
Number of Subjects 
Reporting Events
Estimate (%)
95% Confidence Interval 
0/35
0
(0.0, 10.0)
2/35
5.7
(0.7, 19.2)
5/35
14.3
(4.8, 30.3)
9/35
25.7
(12.5, 43.3)
12/35
34.3
(19.1, 52.2)
14/35
40.0
(23.9, 57.9)
19/35
54.3
(36.6, 71.2)
4.
Study Endpoints and Covariates
4.1
Study Endpoints
4.1.1
Primary Endpoint
Overall incidence and severity of treatment-emergent adverse events occurring 
during the blinatumomab treatment period graded by investigators according to 
CTCAE version 4.0 and characterized as related or unrelated to study drug 
(blinatumomab).
4.1.2
Secondary Endpoints

ORR during cycle 1 expressed as the proportion of subjects achieving CR and PR. 
Responses will be determined by central radiographic assessment using the Lugano 
classification. Summary of ORR during blinatumomab treatment will also be 
provided.

Duration of response is calculated only for responders during cycle 1 of 
blinatumomab treatment. For subjects who had CR or PR on the PET/CT scan at 
the end of the run-in period, response will be measured from the start of 
blinatumomab treatment. For subjects who had stable disease at the end of the 
run-in period, the duration will be calculated from documentation of the first 
assessment of either PR or CR on blinatumomab. Response duration will be
calculated until the start of new anti-tumor treatment (excluding any stem cell
transplantation), progression of disease, or death, whichever is the earliest event. A 
subject who did not have new anti-tumor treatment (excluding any stem cell
transplantation), progression of disease, or death will be censored at the last tumor
assessment date. If the last disease assessment date is after the date that triggers
the analysis, the subject will be censored at last tumor assessment date before the 
analysis trigger date.

CR rate during cycle 1 and during blinatumomab treatment using the Lugano 
classification


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
PFS from first dose of blinatumomab is calculated as the time from the date of first 
blinatumomab infusion until the date of diagnosis of progression of DLBCL, the start 
date of new anti-tumor treatment (excluding any stem cell transplantation) or date of 
death, whichever is the earliest. The date of diagnosis is defined as the date 
when the subject took the PET/CT scan. Subjects who are alive and did not have
progression or new anti-tumor treatment (excluding any stem cell transplantation) will
be censored at the last date of tumor assessment. If the last disease assessment
date is after the date that triggers the analysis, the subject will be censored at last 
tumor assessment date before the analysis trigger date. PFS at 1 year is the KM 
estimate of PFS at 1 year. KM estimate of PFS at 1 year will be provided.

Overall Survival (OS): OS is calculated as the time from the date of first 
blinatumomab infusion until death due to any cause. Subjects who are alive at the 
date that triggers the analysis will be censored at the date last known to be alive.
KM estimate of OS at 1 year will be provided.

HSCT rate is the incidence of HSCT (number of subjects with HSCT/number of
subjects who received blinatumomab).

Blinatumomab PK parameters (eg, steady state concentrations)
4.1.3
Exploratory Endpoints

Minimal residual disease (MRD)

Response rates and duration according to COO designation or c-myc and/or Bcl-2/6
rearrangement as determined from pre-treatment specimens

Pharmacodynamics, including quantitative and qualitative lymphocyte subsets 
and cytokine levels in peripheral blood at various time points during 
blinatumomab treatment

Anti-blinatumomab antibodies at various timepoints during blinatumomab 
treatment
5.
Hypotheses and/or Estimations
For the primary and secondary objectives, analyses will be descriptive and include 
estimations; no formal hypotheses will be tested. Overall incidence and severity of 
treatment-emergent adverse events occurring during the blinatumomab treatment period
(through the safety follow-up visit) will be summarized with exact binomial 
95% confidence intervals. 
6.
Definitions
6.1
General Definitions
Age at Screening
Subject age at screening will be collected in years in the clinical database.


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Baseline
Baseline for assessing response (ORR and CR rate) is defined as the value obtained in 
the PET/CT scan at run-in Visit 2 ( 3 weeks (± 3 days) after completion of 6 cycles SOC 
R-chemotherapy) prior to the start of blinatumomab. 
For laboratory and vital signs measurements, baseline is defined as the value measured 
on day 1 of the first cycle of blinatumomab therapy.  The protocol specifies that 
procedures and labs on day 1 should be completed before the initiation of blinatumomab 
which will be the assumption in the analysis unless the time of the assessment is 
recorded.  If a day 1 value is not available, the most recent value before the day of the 
start of blinatumomab may be used.
Body Surface Area (BSA)
Subject’s BSA will be derived in m2 in the clinical database. The formula for BSA 
calculation is given as
BSA = Weight 0.425 (in kg) * Height 0.725 (in cm) * 0.007184
Height will be measured at screening and run-in visit 2. For BSA at screening, the 
screening height will be used for derivation. For BSA calculation at other visits, the 
height at run-in visit 2 will be used. 
Complete Cycle
A complete cycle is defined as undergoing ≥90% of a planned cycle’s duration (in 
days).
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 a cycle and across all cycles. 
Cumulative dose of SOC R-chemotherapy
Provided sites enter the dose of a given chemotherapy drug in the same units within and 
across subjects, the cumulative dose will be calculated. The cumulative dose will be the 
total dose of a given chemotherapy drug within a chemotherapy regimen. Cumulative 
dose will be calculated within a cycle and across all cycles.


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Death date
Death date for each subject is defined as the date collected on the Event page where 
the reason for ending the study is equal to Death or the date entered into the Subject 
Status Date on the Survival Status CRF where the reason is equal to Dead. For 
subjects who die during the study, the death date will be recorded on the event, end of 
study and/or survival status CRF. The earliest date will be used 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.
Derivation of Study Day
Day 1 is defined as the first day of investigational product, which is the first day of 
the first cycle of blinatumomab infusion after successful completion of the run-in 
period.
On and after study day 1: study day= (date - date of Study Day 1) + 1
Duration of blinatumomab treatment
For each infusion episode within a cycle, 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. For each cycle, the duration will be the sum of the 
individual infusion durations within that cycle. For the entire study, the duration will be 
the sum of the durations across cycles. The duration will be rounded to the nearest day. 
Duration of SOC R-chemotherapy treatment
Because many of the drugs within SOC R-Chemotherapy are given only over the course 
of the first few days of a 2 to 3 week chemotherapy cycle, the duration of chemotherapy 
will not be as informative as the duration of blinatumomab. Therefore, the number of 
chemotherapy cycles will be emphasized in descriptive analyses as opposed to the 
duration of chemotherapy. If duration of a chemotherapy drug is calculated, it will be 
defined as the time from the first start date of the drug to the last stop date of a drug. 
The duration of a chemotherapy regimen will be measured from the earliest start date 
among the drugs within the regimen to the latest stop date among the drugs within a 
regimen.


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End of blinatumomab/SOC-R chemotherapy administration date
For both blinatumomab and SOC-R chemotherapy, the end of protocol-specified therapy 
date is the last dose date of blinatumomab or SOC-R chemotherapy reported on the End 
of Investigational Product Administration CRF for blinatumomab and the End of 
Non-Investigational Product Administration CRF for SOC-R chemotherapy.
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 (ie, the date the subject withdraws 
full consent from the study, completes the safety follow-up visit or long-term follow-up 
[whichever is later] or death). The date will be recorded on the End of Study CRF page.
Primary completion: The primary completion date is defined as the date when the last 
subject is assessed or receives an intervention for the purposes of final collection of data 
for the primary analysis (ie, completion of the safety follow-up visit).
End of Trial:  The end of trial is defined as the time when the last subject is assessed or 
receives an intervention for evaluation in the study (ie, completion of the long-term 
follow-up period).
Final Analysis
The final analysis will occur when the last subject who received blinatumomab has had 
the opportunity to complete the long-term follow-up period (ie,1 year from the first dose 
of blinatumomab).
Long-term follow-up 
The long-term follow up period begins after the end of the safety follow up visit and 
continues for a maximum of 1 year from the first dose of blinatumomab or until subject 
death or withdrawal, whichever occurs first.
Percent of intended dose of blinatumomab
For a given cycle, the percent of intended dose of blinatumomab will be the cumulative 
dose in that cycle divided by the planned cumulative dose for that cycle. For the first 
cycle, the planned cumulative dose will be (9 μg x 7 days) + (28 μg x 7 days) + (112 μg x 
42 days) = 4963 μg. For the second cycle, the planned cumulative dose will be (9 μg x 
7 days) + (28 μg x 7 days) + (112 μg x 14 days) = 1827 μg. For the entire study, the 
percent of intended dose of blinatumomab will be the sum of the cumulative doses 


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across cycles divided by the sum of the planned cumulative doses across the cycles 
started.
Percent of intended dose of SOC R-chemotherapy
Given that there are variations in how sites define a SOC R-chemotherapy regimen, it 
may not be possible to define a planned dose for all drugs within a regimen. In which 
case, the percent of intended dose will not be calculated for that drug. If a planned dose 
can be identified for certain drugs within a regimen, then the percent of intended dose 
may be calculated as follows. For a given cycle, the percent of intended dose will be the 
cumulative dose of a given drug within a regimen divided by the planned amount of that 
drug for that cycle. For the entire study, the percent of intended dose will be the 
cumulative dose of a given drug over all cycles divided by the planned amount of that 
drug over all cycles.
Primary Analysis
The primary analysis will occur when the last subject who received blinatumomab has 
had the opportunity to complete the safety follow-up visit.
Study enrollment date
Study enrollment day is the date when the subject is enrolled in the study for SOC 
R-chemotherapyafter successfully completing the 14-day screening period. Subjects 
must be enrolled into the run-in period either prior to the start of cycle 1 or cycle 2 of 
SOC R-chemotherapy.
6.2
Safety Endpoints
Disease related events
Disease Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease.  Please refer to Appendix G of the 
protocol for expected disease related events by system organ class. Such events do not 
meet the definition of an adverse event unless assessed to be more severe than 
expected for the subject’s condition. 
Treatment emergent adverse events (TEAEs)
SOC-R chemotherapy treatment emergent adverse event
Events categorized as Adverse Events (AEs) starting on or after the first dose of SOC-R 
chemotherapy as determined by the flag indicating if the adverse event started prior to 
study procedure/activity on the Events CRF and the date of the first dose of SOC-R 


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chemotherapy and up to the first dose of blinatumomab or the end of study for subjects 
who do not subsequently receive blinatumomab.
Blinatumomab treatment-emergent adverse event
Events categorized as Adverse Events (AEs) starting on or after the first dose of 
blinatumomab as determined by the flag indicating if the adverse event started prior to 
the first dose on the Events CRF and up to and including 30 days after the end of 
blinatumomab (Safety Follow-up Visit).
These reporting windows also apply to treatment emergent serious adverse events 
(SAEs)
In case the start time or the exact start date of the AE is not available and it is thus 
unclear whether an AE started after the start of the first blinatumomab infusion or before 
30 days after the end of the last infusion, the AE will be included in the analysis as a 
TEAE. 
Treatment-emergent disease-related event
Events categorized as Disease-related Events (DREs) starting on or after the 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
(Safety Follow-up Visit).
6.3
Efficacy Endpoints
Complete Response (CR)
A score of 1, 2 or 3 with or without a residual mass in the target masses, along with no 
FDG avid focal lesions in the bone marrow (per the Lugano Classification).
Lugano Classification
The Lugano classification is a scale to grade response of DBLCL to treatment based on 
a PET/CT scan.  See Appendix C.
Minimal residual disease (MRD)
Presence of MRD measured by the detection of clonotypic IgH sequences by NGS of 
cell-free CT-DNA positivity in plasma.  
Partial Response (PR)
A score of 4 or 5 with reduced FDG uptake compared with baseline and residual 
mass(es) of any size in the target masses and residual FDG uptake in bone marrow is 


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higher than FDG uptake in normal marrow but reduced compared with baseline (per the 
Lugano classification).
Progressive Disease (PD)
A score of 4 or 5 with an increase in intensity of uptake from baseline and/or new 
FDG-avid foci consistent with lymphoma in the target masses along with new or 
recurrent FDG-avid foci in the bone marrow (per the Lugano classification).
Responders
Subjects who achieve objective response (CR or PR as per the Lugano classification) on 
the PET/CT scan.
Stable Disease (SD)
A score of 4 or 5 ,with no significant change in FDG uptake from baseline in the target 
masses and no change from baseline in FDG update in the bone marrow (per the 
Lugano classification).
7.
Analysis Sets
The primary analysis of safety and efficacy will be performed on the full analysis set. 
Sensitivity analyses of efficacy will be performed on the target dose analysis set.
7.1
Full Analysis Set
The Full Analysis Set includes all subjects who received at least one dose of 
blinatumomab.  Full Analysis Set is used for safety analyses of blinatumomab emergent 
events.
7.2
Target Dose Analysis Set
The Target Dose Analysis Set includes all subjects in the full analysis set that have at 
least one tumor assessment in the treatment phase unless terminating the study early 
due to disease progression.
7.3
Responder Analysis Set 
The Responder Analysis Set includes all subjects in the full analysis set that 
achieve objective response (CR or PR as per the Lugano classification) on the 
PET/CT scan during cycle 1 of blinatumomab administration.
7.4
Pharmacokinetic Analysis Set
All subjects who received any infusion of blinatumomab and had at least one PK sample 
collected will be included in the Pharmacokinetic Analysis Set. These subjects will be 


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evaluated for pharmacokinetics unless significant protocol deviations affect the data 
analysis or if key dosing, dosing interruption, or sampling information is missing.
7.5
Pharmacodynamic Analysis Set
The pharmacodynamic analysis set includes all subjects who received at least 1 dose of 
blinatumomab and have at least 1 pharmacodynamic sample collected.
7.6
SOC R-chemotherapy Analysis Set
The SOC R-chemotherapy analysis set includes all subjects who received at least one 
dose  of SOC R-chemotherapy. SOC R-chemotherapy Analysis Set is used for safety 
analyses of SOC R-chemotherapy emergent events.
7.7
Subgroup Analyses
Subgroup analyses for primary and key secondary endpoint may be performed, if 
appropriate, depending on the sample size, on the following categories:

Age: < 65, ≥65 , and ≥75 years old

Sex: male vs. female

Race: white vs. others

Geographic region: North America vs. Europe 

ECOG 0-1 vs 2 at screening
8.
Interim Analysis and Early Stopping Guidelines
8.1
Data Review Team
A Data Review Team (DRT) will review safety data, including dose limiting toxicity 
(DLT), on an ongoing basis, following treatment of every 7th evaluable subject with 
blinatumomab or every 3 months, whichever occurs sooner.  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. If a safety issue is identified, the DRT may 
review the efficacy data to evaluate the benefit to risk profile. 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.
8.2
Interim Analysis
Amgen will conduct evaluations of the ongoing DLT rate to assess if the threshold 
for early trial termination has been reached. For definition of DLT, refer to study 
protocol. For definition of DLT, refer to study protocol.


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The DLT evaluation period will be the entire duration of cycle 1 of blinatumomab 
treatment. If cycle 2 is given, the DLT evaluation period also includes the entire 
duration of cycle 2 infusion.
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
3. 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
4. The subject does not experience a DLT and completes the DLT evaluation 
period
The stopping rules use a Bayesian approach (Thall, Simon and Estey, 1995) to 
terminate the study if the posterior probability that the DLT rate is greater than 
25% is > 90%. The stopping boundaries assume a prior beta distribution 
of (0.50, 1.50). With pre-specified batch size of 7, the stopping boundaries are 
presented in Table 2 and the operating characteristics in Table 3 provide the 
probability of stopping the trial early for given hypothetical true DLT rates. The 
evaluations could occur more frequently if necessary to address emerging safety 
concerns. In case the actual number of DLT evaluable subjects deviates from 
what is planned in Table 2, the stopping boundaries for each possible number of 
DLT evaluable subjects is presented in Table 4
Table 2.  Stopping Boundary With Batch Size of 7 Subjects, Posterior Probability 
of 90% and DLT Limit of 25%
Number of DLT evaluable subjects 
Stop study if observing these many DLTs
7
> = 4
14
> = 6
21
> = 9
28
> = 11
35
Study completes


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Table 3.  Operating Characteristics With Batch Size of 7 Subjects, Posterior 
Probability of 90% and DLT Limit of 25%
DLT Rate
Probability of Stopping
Average Sample Size
0.20
7%
34
0.25
17%
32
0.30
33%
29
0.35
52%
25
0.40
71%
20
Table 4.  Stopping Boundaries for All Numbers of DLT Evaluable Subjects With 
Posterior Probability of 90% and DLT Limit of 25%
Number of DLT evaluable subjects 
(inclusive)
Stop study if observing these many 
DLTs
7-8
> = 4
9-11
> = 5
12-14
> = 6
15-17
> = 7
18-20
> = 8
21-23
> = 9
24-27
> = 10
28-30
> = 11
31-33
> = 12
34
> = 13
35
Study completes


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9.
Data Screening and Acceptance
9.1
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.
9.2
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.  
An Analysis Dataset for PK Concentrations (ADPC) will be provided to the appropriate 
Clinical Pharmacology Modeling and Simulation (CPMS) representative from Global 
Biostatistical Sciences.
9.3
Handling of Missing and Incomplete Data
In general, missing data will be treated as missing, unless otherwise specified.  For the 
ORR and CR rate, subjects with missing response will be considered as non-responders
in the primary analyses.  
9.4
Detection of Bias 
The sources of possible bias will be summarized and considered while interpreting the 
study results. Sources of bias to be considered may include protocol violations or 
informative censoring.
9.5
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. No statistical test for outliers will be 
performed. 
PK plasma concentration data will be evaluated for outliers by visual inspection, and 
decisions to re-assay individual samples will be made in accordance with standard 
pharmacokinetic evaluation practice.


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9.6
Distributional Characteristics
Due to the single-arm study, the summaries of analyses results are descriptive in nature.
Thus there are no distributional assumptions for analysis methods that need to be 
assessed.
9.7
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.
10.
Statistical Methods of Analysis
10.1
General Principles
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 number and percentage in each category. Point 
estimates for binomial proportions (eg, the primary safety endpoint and secondary 
efficacy endpoints) will be accompanied by 2-sided 95% confidence intervals (Clopper 
and Pearson, 1934). Time to event endpoints will be summarized with hazard ratios, 
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.
Additional exploratory analyses will be performed to adjust for the baseline covariates as 
deemed appropriate.
10.2
Subject Accountability
The number and percent of subjects who were screened, were enrolled in the run-in 
period prior to cycle 1, prior to cycle 2 and combined,completed the run-in period,
received at least one dose of blinatumomab, completed the blinatumomab treatment 
period, completed the long-term follow-up period, completed the study, prematurely 
withdrew from the run-in period, prematurely withdrew from the blinatumomab treatment 


Product:  Blinatumomab
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Page 24
period, and prematurely withdrew from the study will be tabulated and summarized.  
The reasons for premature withdrawal will also be tabulated and summarized.
The number and percent of subjects enrolled will be tabulated by study site.  Key study 
dates for the first subject enrolled, 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.
10.3
Important Protocol Deviations
Important Protocol Deviations (IPDs) categories are defined by the study team before 
the first subject’s visit and updated during the IPD reviews throughout the study prior to 
database lock.  These definitions of IPD categories, sub-category codes, and 
descriptions will be used during the course of the study. Eligibility deviations are defined 
in the protocol.
10.4
Demographic and Baseline Characteristics
The following demographic and baseline disease characteristics will be summarized 
using descriptive statistics. If multiple races have been reported for a subject, the 
subject will be categorized as multiple races as well as by combination of races.  

Age: < 65, ≥65 and ≥75 years old

Sex (Male, Female)

Race (White, Non-White)

Stage at diagnosis (I, IE, II, IIE, II bulky, III, IV)

IPI, aaIPI, R-IPI, NCCN-IPI at diagnosis 


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For each index, subjects will be summarized by each possible score as well as risk 
categories. The following table gives the description of the values and risk 
categories for the different prognostic indices.
Table 5.  Distribution of Score and Risk Categories for Different Prognostic 
Indices
Prognostic Index
Scores
Risk categories
IPI
3, 4 ,5
High-intermediate (3), High(4,5)
aaIPI
2, 3
High-intermediate (2), High (3)
NCCN-IPI
4, 5, ≥ 6
High-intermediate (4, 5), High (≥6)
R-IPI
3, 4, 5
Poor (3, 4, 5)

Bulky disease (Yes, No)

Radiation (Yes, No)

Extranodal (Yes, No)

Double-hit (Yes, No, Not Done)

Double protein expression (Yes, No, Not Done)

COO (GCB, ABC, non-GCB , Not Done)

Bcl-2 rearrangement (Positive, Negative, Not done)

Bcl-2 expression status (Positive, Negative, Not done)

Bcl-6 rearrangement (Positive, Negative, Not done)

Bcl-6 expression status (Positive, Negative, Not done)

Myc rearrangement (Positive, Negative, Not done)

Myc expression status (Positive, Negative, Not done)
10.5
Efficacy Analyses 
Primary efficacy analyses will be performed on the full analysis set, sensitivity analysis 
will be performed on the target dose analysis set. 
10.5.1
Analysis of Primary Endpoint(s)
The primary endpoint is a safety endpoint based on overall incidence and severity of 
TEAE(s) in the blinatumomab treatment period; please refer to section 10.6 for further 
details on this endpoint. 
10.5.2
Analysis of Secondary Efficacy Endpoint(s)
Three of the secondary endpoints are based on incidence (ORR, CR rate and HSCT).  
For each outcome, incidence will be estimated as described in Section 6.3, along with an 
exact binomial 2-sided 95% confidence interval (Clopper and Pearson, 1934). ORR 


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during cycle 1 of blinatumomab treatment and during whole blinatumomab 
treatment, CR rate during cycle 1 of blinatumomab treatment and during whole 
blinatumomab treatment will be summarized by response during the run-in period 
before administration of blinatumomab. HSCT rate will be summarized for the 
long-term follow-up period. Summary of reason for delayed HSCT will be 
provided in subjects that meet the following criteria:

PR/PMR at baseline per Lugano classification and

Do not proceed to HSCT within 30 days of the first response assessment
The remaining three secondary endpoints (duration of response, overall survival and 
progression free survival (PFS)) are time-to-event endpoints; details of the calculations 
and censoring criteria are provided in section 4.1.  The Kaplan-Meier (K-M) method will 
be used to summarize these endpoints. K-M quartiles along with 2-sided 95% CIs, the 
number of subjects censored and the number of subjects with events will be provided.  
Duration of response, OS and PFS will be calculated both for the primary and final 
analyses. Duration of response will be summarized by patient status (CR, PR or 
SD) after 6 cycles of SOC R-chemotherapy during the run-in period if sample size 
allows.
A summary of secondary efficacy endpoints is given in Table 6.
Table 6.  Secondary Efficacy Endpoint Summary Table
Endpoint
Primary Summary and 
Analysis Method
Sensitivity Analysis
ORR during cycle 1 of 
blinatumomab and 
during whole
blinatumomab 
treatment

Incidence – Proportion of 
FAS subjects achieving 
CR and PR (by Lugano 
classification) during 
cycle 1 of blinatumomab 
treatment and during 
whole blinatumomab 
treatment

Incidence – Proportion of Target 
dose analysis set subjects 
achieving CR and PR (by 
Lugano classification) during 
cycle 1 of blinatumomab 
treatment and during whole 
blinatumomab treatment
CR Rate during 
cycle 1 of 
blinatumomab and 
during whole 
blinatumomab 
treatment

Incidence – Proportion of 
FAS subjects achieving 
CR during cycle 1 of 
blinatumomab treatment 
and during whole 
blinatumomab 
treatment

Incidence – Proportion of Target 
dose analysis set subjects 
achieving CR during cycle 1 of 
blinatumomab treatment and 
during whole blinatumomab 
treatment
Page 1 of 2


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Table 6.  Secondary Efficacy Endpoint Summary Table
Endpoint
Primary Summary and 
Analysis Method
Sensitivity Analysis
HSCT rate

Incidence – Proportion of 
FAS subjects with HSCT 
by end of the long-term 
follow-up period

Incidence – Proportion of Target 
dose analysis set subjects with 
HSCT by end of the long-term 
follow-up period
Duration of response

Responder Analysis 
Set.  KM methodology 
will be utilized.
PFS

FAS subjects.  KM 
methodology will be 
utilized.

Target dose analysis set
subjects.  KM methodology will 
be utilized.
OS

FAS subjects. KM 
methodology will be 
utilized.

Target dose analysis set 
subjects. KM methodology will 
be utilized.
Page 2 of 2
10.5.3
Analyses of Exploratory Endpoints 

Analysis of pharmacokinetic includes but is not limited to blinatumomab 
steady state concentration (Css) in peripheral blood at various time points 
during blinatumomab treatment as per protocol schedule of assessments.

The pharmadynamic parameters will be analyzed by the Clinical Biomarker and 
Diagnostics group in a Contributing Scientific Report, detailed analyses 
method will be described within.
10.5.4
Analyses of Patient Reported Outcomes and Other Health Related 
Quality of Life Endpoints
Not Applicable
10.5.5
Health Economic Analyses 
Not Applicable
10.6
Safety Analyses
10.6.1
Adverse Events and Disease Related Events
The primary endpoint is based on the overall incidence and severity of 
treatment-emergent adverse events occurring during the blinatumomab treatment period 
(through the safety follow-up visit, 30 days (+3 days) after last dose) graded according to 
Common Toxicology Criteria for Adverse Events (CTCAE, version 4.0) and 
characterized as related or unrelated to blinatumomab. 
The Medical Dictionary for Regulatory Activities (MedDRA) version 19.1 or later will be 
used to code all events categorized as adverse events (AEs) or disease-related events 


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(DREs) to a system organ class and a preferred term.  Please refer to section 6.2 for the 
definition of TEAE.  
Blinatumomab and SOC R-chemotherapy treatment-emergent adverse events will be 
summarized separately.  The subject incidence of adverse events will be summarized for 
blinatumomab treatment-emergent adverse events, serious adverse events, adverse 
events leading to interruption or withdrawal and interruption of protocol-specified 
therapy, and fatal adverse events. Similar summaries will be repeated for EOIs. Time to 
onset and duration of selected EOIs (infection and neurologic events) may also be 
summarized. Duration of EOIs will be the sum of duration of all events. If there is an 
overlap, duration will be calculated only once. For the blinatumomab incidences, exact 
binomial 2-sided 95% confidence intervals will be calculated. 
Subject incidence of SOC and blinatumomab treatment-emergent AEs, serious AEs, 
grade ≥3 adverse events, grade ≥4 adverse events, AEs leading to withdrawal and 
interruption of investigational product, and fatal AEs will be tabulated by system organ 
class and preferred term in descending order of frequency.  
Summaries of treatment-emergent and serious adverse events will be tabulated by 
system organ class, preferred term, and grade in descending order of frequency.
Subgroup analyses (if there is a medical or regulatory rationale) will be presented by 
system organ class and preferred term in descending order of frequency. All races (if 
appropriate) with less than 5% of the total enrolled subjects will be pooled together for 
summary purposes. 
Subject incidence of DREs will be summarized for blinatumomab treatment-emergent 
DREs and fatal DREs during the blinatumomab treatment period (through the safety 
follow-up visit, 30 days (+ 3 days) after last dose).
10.6.2
Laboratory Test Results
Shift tables between the worst post-baseline and baseline grades for selected laboratory 
parameters will be provided.  (Grades will be based on the Common Terminology 
Criteria for Adverse Events). Plots or other summaries over time will be presented for 
selected laboratory parameters including immunoglobulin, platelets, and liver 
parameters. These analyses will only be done for the blinatumomab treatment period 
(through the safety follow-up visit, 30 days (+ 3 days) after last dose).
Summary statistics over scheduled visits for actual values, changes from study baseline 
of selected laboratory parameters below will be presented for subjects in Full Analysis 


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Set. In addition, shift tables will be summarized with toxicity grades using CTCAE by 
worst increase and decrease between study baseline and any visit up to the end of the 
study for selected laboratory parameters mentioned below.
1.
Corrected Calcium
2.
Magnesium
3.
Phosphorus
4.
Potassium
5.
Total bilirubin
6.
Direct bilirubin
7.
AST (SGOT)
8.
ALT (SGPT)
9.
Hemoglobin
10.
Platelets
11.
Neutrophils
12.
Lymphocytes
13.
Immunoglobulins (IgG, IgA, IgM)
10.6.3
Vital Signs
The number and percentage of subjects with abnormal changes (defined in Appendix B, 
Table 9) in systolic blood pressure, diastolic blood pressure and heart rate will be 
summarized. These analyses will only be done for the blinatumomab treatment period
(through the safety follow-up visit).
10.6.4
Electrocardiogram (ECG)
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. 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.
10.6.5
Antibody Formation 
The incidence and percentage of subjects who develop anti-blinatumomab antibodies 
(binding and if positive, neutralizing) at any time will be tabulated.


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10.6.6
Exposure to Investigational Product
Descriptive statistics will be produced to describe the exposure to blinatumomab . The 
number of cycles started will be summarized with an additional breakdown of the 
number of cycles completed and discontinued.  In addition, the duration of therapy, the 
cumulative dose, and the percent of intended dose will be summarized by cycle and 
overall.  The number and percent of subjects with dose modifications (eg, dose changes, 
dose interruptions) and reason for modification will be summarized. 
10.6.7
Exposure to SOC R-chemotherapy
Descriptive statistics will be produced to describe the exposure to SOC R-chemotherapy 
from enrollment through the end of the run-in period . The number of cycles will be 
summarized with an additional breakdown of the number of cycles completed and 
discontinued.  
10.6.8
Exposure to Concomitant Medication 
The number and proportion of subjects receiving concomitant medications will be 
summarized by preferred term as coded by the World Health Organization Drug 
(WHODRUG) dictionary. The summary will be provided by day 1 of SOC 
R-chemotherapy until the day before the first dose of blinatumomab and day 1 of 
blinatumomab until safety follow-up respectively. In addition, the number and proportion 
of subjects receiving anti-cancer therapies during long-term follow-up will be 
summarized by WHODRUG preferred term.
10.7
Pharmacokinetic or Pharmacokinetic/Pharmacodynamic Analysis 
10.7.1
Pharmacokinetic Analysis
Blinatumomab serum concentration will be quantified in subjects who received 
blinatumomab during cycle 1 of the treatment in phase 2 of the study. 
Summary statistics, including mean and standard deviation, will be computed for 
blinatumomab concentration data and grouped by dose.  Individual concentration-time 
data will be tabulated.  
Pharmacokinetic data of blinatumomab may be subject to population PK analysis as 
needed. If the analyses will be performed, a supplemental population PK  analysis plan 
will be generated. Data from multiple studies may be used and nonlinear mixed effects 
modeling will be used for the analysis. Effect of covariates on PK parameters will 
be assessed. These may include, age, body weight, body surface area, renal 
function, liver function, and sex. Other covariates may be analyzed if necessary. 


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Results of population PK analysis will not be included in the CSR and will be 
reported separately.
10.7.2
Pharmacodynamic Analysis
Pharmacodynamic data will be analyzed by the Clinical Biomarker and 
Diagnostics group in a separate Contribution Scientist Report.
10.7.3
Exposure Response Analysis
PK data of blinatumomab and selected efficacy and safety endpoints may be 
subjected to exploratory exposure-efficacy and exposure-safety analyses as 
needed.  Individual blinatumomab exposure at time of interest will be estimated 
with the population PK model and will be used for the exposure-response (E-R) 
analysis. 
Exposure-response relationships for selected efficacy and safety endpoints may 
be assessed as appropriate. The result of exposure response analysis will not be 
reported in the CSR and will be reported separately.
11.
Changes From Protocol-specified Analyses
There are no changes to the protocol-specified analyses.  


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12.
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
Thall, P. F., Simon, R. M. and Estey, E. H. Bayesian sequential monitoring designs for 
single-arm clinical trials with multiple outcomes. Statistics in Medicine. 1995; 14(4):357-
379


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13.
Prioritization of Analyses
Not Applicable.
14.
Data Not Covered by This Plan
Not Applicable.


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15.
Appendices


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Appendix A.  Handling of Dates, Incomplete Dates and Missing Dates
The following data will be imputed using the following algorithm: 

Adverse Events

Concomitant Medications
Table 7.  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 B.  Reference Values/Toxicity 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 CTC AE version 4.03 or above) will be assigned to each laboratory 
result as detailed in Table 8 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 8.  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
Page 1 of 2
Footnotes are defined on last page of the table


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Table 8.  Grading of Selected Laboratory Parameters
Laboratory 
Parameter 
[Unit]
Grade 1
Grade 2
Grade 3
Grade 4
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
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
Notable values for vital signs are defined according to the following table
Table 9.  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 C.  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


Product:  Blinatumomab
Statistical Analysis Plan:  20150288
Date: 12 September 2018
Page 40
Appendix D.  International Prognostic Index for Diffuse Large B-cell Lymphoma
Risk group
IPI 
aaIPI
NCCN-IPI
R-IPI
Low
0 or 1
0
0 or 1
0 (good)
Low Intermediate
2
1
2 or 3
1 or 2 (intermediate)
High Intermediate
3
2
4 or 5
High
4 or 5
3
≥ 6
3, 4, or 5 (poor)
IPI Factors
NCCN-IPI
R_IPI
Older than 60 years of age 
(not used for aa-IPI)
Age > 40 to 
< = 60
         > 60 to < = 75
          > 75 
1
2
3
Age > 60 yrs
Disease stage III/IV
Ann Arbor 
stage III-IV
1
Ann Arbor stage > = 3
Lactate dehydrogenase level 
elevated
LDH normalized
> 1 to < =3
> 3
1
2
Raised LDH
ECOG performance score 
≥ 2
ECOG > = 3
Extranodal disease > 1 site 
(not used for aa-IPI)
In bone marrow, 
CNS, liver/GI tract, or 
lung
1
Extranodal disease 
> = 2 sites
IPI = International Prognostic Index;  aaIPI =  age-adjusted IPI; ECOG = Eastern Cooperative Oncology 
Group, NCCN-IPI = National Comprehensive Cancer Network IPI. R-IPI = Revised IPI