Clinical trial NCT02961881
Conditions: Non-Hodgkin's Lymphoma
Sponsor: Amgen
Start date: 2017-09-18; Completion date: 2021-09-02
Enrollment: 35 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective:

• To evaluate the safety and tolerability of subcutaneous (SC) blinatumomab dose administrations

Secondary Objectives:

* To determine pharmacokinetics (PK) with continuous intravenous (cIV) and SC administrations
* To estimate the maximum tolerated dose (MTD) tested for blinatumomab administered subcutaneously
* To determine the incidence of anti-blinatumomab antibody formation following SC administration
* To evaluate efficacy response following treatment with SC blinatumomab administration

Exploratory Objective:

* To determine the pharmacodynamics (PD) time profiles for B-and T-lymphocytes as well as cytokine profiles during SC administration
* To evaluate efficacy response following treatment with SC blinatumomab administration using Lugano criteria if positron emission tomography-computed tomography (PET/CT) is used for evaluation

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: blinatumomab
Intervention descriptions: intervention 1: Blinatumomab used as both continuous IV infusion and subcutaneous injection

Protocol documents:
Prot_000.pdf: 
Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
Page 1 of 113
CONFIDENTIAL
Title:  A Phase 1b Open-label Study Investigating the Safety and Pharmacokinetics 
of Administration of Subcutaneous Blinatumomab for the Treatment of 
Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma
Amgen Protocol Number (Product Name: Blinatumomab) 20140286
EudraCT number 2016-002034-76
NCT number 02961881
Clinical Study Sponsor:
Amgen Inc.
One Amgen Center Drive
Thousand Oaks, California 91320
United States
Phone: 1-805-447-1000
Fax: 1-805-480-4978
Key Sponsor Contact(s):
, MD
Clinical Research Medical Director
Phone:
Email:
Global Clinical Trial Manager
Phone:
E-mail: 
Date:
31 May 2016
Amendment 1:
14 September 2016
Amendment 2:
08 January 2017
Superseding Amendment 2:
14 February 2017
Amendment 3
30 March 2017
Amendment 4
11 August 2017
Amendment 5
15 February 2018
Amendment 6
17 January 2019
Superseding Amendment 6
06 February 2019
Superseding Amendment 6 v2
25 February 2019
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:  United States (US) sites, 1- 800-77-AMGEN, Canadian sites, 
1-866-50-AMGEN; for all other countries, please call the local toll-free Medical Information 
number provided by your monitor or Amgen’s general number in the US (1-805-447-1000).
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
Page 2 of 113
CONFIDENTIAL
Investigator’s Agreement
I have read the attached protocol entitled “A Phase 1b Open-label Study Investigating 
the Safety and Pharmacokinetics of Administration of Subcutaneous Blinatumomab for 
the Treatment of Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma”, dated
25 February 2019, and agree to abide by all provisions set forth therein.  
I agree to comply with the International Conference on 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)
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
Page 3 of 113
CONFIDENTIAL
Protocol Synopsis
Title:  A Phase 1b Open-label Study Investigating the Safety and Pharmacokinetics of 
Administration of Subcutaneous Blinatumomab for the Treatment of Relapsed/Refractory Indolent 
Non-Hodgkin’s Lymphoma
Study Phase:  1b
Indication:  Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma
Primary Objective:
To evaluate the safety and tolerability of subcutaneous (SC) blinatumomab dose 
administrations 
Secondary Objectives:  
To determine pharmacokinetics (PK) with continuous intravenous (cIV) and SC administrations
To estimate the maximum tolerated dose (MTD) tested for blinatumomab administered 
subcutaneously 
To determine the incidence of anti-blinatumomab antibody formation following SC administration 
To evaluate efficacy response following treatment with SC blinatumomab administration
Exploratory Objectives:
To determine the pharmacodynamic (PD) time profiles for B- and T-lymphocytes as well as 
cytokine profiles during SC administration
To evaluate efficacy response following treatment with SC blinatumomab administration using 
Lugano criteria if positron emission tomography-computed tomography (PET/CT) is used 
for evaluation (Appendix B)
Hypotheses:  
Blinatumomab administered through the SC route will demonstrate a tolerable safety-profile with 
serum concentrations comparable to those for which efficacy was shown with cIV administration 
in subjects with indolent relapsed/refractory Non-Hodgkin’s Lymphoma (NHL)
Primary Endpoint:  
Subject grade, incidence, and severity of dose limiting toxicities (DLTs) and adverse events
Secondary Endpoints:  
Blinatumomab PK parameters under cIV and SC administrations 
MTD
Incidence of anti-blinatumomab antibodies 
Overall response rate (ORR) (complete response [CR] partial response [PR]) as determined by 
best overall response using Cheson criteria (Appendix A)
Exploratory Endpoints:
PD parameters of B- and T-lymphocytes and cytokines following administration of SC 
blinatumomab
ORR (CR PR) as determined by best overall response using Lugano criteria (Appendix B)
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
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Study Design:  This is a global multi-center, Phase 1b open-label study investigating the safety 
and PK of blinatumomab administered subcutaneously for the treatment of relapsed/refractory 
indolent NHL.  The SC administration of blinatumomab will be tested for the first time in humans.  
Period 1 of the study will focus on the determination of PK, bioavailability, and safety profile of 
blinatumomab SC administration.  The PK and bioavailability data from Period 1 of the study will 
be used in conjunction with safety data (DLT) to determine the SC MTD.  The MTD or the 
maximum tested dose, if MTD is not reached, will be further tested in Period 2 in an expanded 
cohort.  Efficacy of blinatumomab administered subcutaneously will also be investigated in each 
period of the study.
Cycle 1/Period 1:
In Period 1, 3 or more separate dose cohorts of up to 6 DLT evaluable subjects each will be 
enrolled and undergo treatment as follows:

Subjects will undergo an initial cIV blinatumomab run-in period (weeks 1 to 3) followed by a 
12-hour treatment free period.

Subjects will then receive SC administration (week 4) followed by a treatment free period 
of 2 to not more than 3 days.

After the SC administration period, subjects should return to receive cIV treatment to 
complete 6 weeks of therapy (weeks 5 to 6).  
For all cohorts, the initial cIV dose of blinatumomab will be 9 μg/day for the first 7 days (to 
mitigate for potential cytokine release syndrome [CRS] and neurologic events associated with 
introduction to blinatumomab) which then will be escalated (dose-step) to 28 μg/day starting on 
day 8 through day 14 (week 2), and to 112 μg/day starting on day 15 until day 21 (week 3). 
After stopping cIV blinatumomab, there is a 12-hour treatment free period before starting 
SC blinatumomab.
SC blinatumomab starts after the 12-hour treatment free period and will be administered 
(week 4) as the following dose-cohort levels:  

Dose Cohort 1: 112 μg q12h × 5 days for a total of 9 doses (n 6)

Dose Cohort 2:  225 μg q12h × 5 days for a total of 9 doses (n 6)
(Note:  A total of 9 SC doses will be given for the q12h dosing, so intensive PK samples can 
be obtained on day shift to reduce errors).

Dose Cohort 3: 450 μg q24h × 5 days for a total of 5 doses (n 6)

Additional Dose Cohorts: Dose level and dosing frequency to be determined as 
described below
One or more dosing regimens (refer to Dosing Schema Figure 1) may be selected based 
on clinical findings including safety, tolerability, and PK results from previous cohorts;
and after Dose Level Review Team (DLRT) review and make recommendations for the next 
SC cohort dose and frequency.  The dose may be increased (by 1 dose level or between 
the dose of the previous cohort and the next higher dosing level in Figure 1 schema), kept 
at the same dose level or decreased by 1 or more dose levels.  The dose frequency chosen 
(q12h, q24h, q48h, q72h, q96h, or q7days) will be decided by the DLRT and will be based 
on the previous cohort PK data. 
Once the SC dosing is complete, a treatment free period of 2 to not more than 3 days 
between stopping SC and restarting cIV will be observed. Then the cIV blinatumomab 
dosing will resume at 112 μg/day (weeks 5 to 6) to complete 6 weeks of treatment.  
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
Page 5 of 113
CONFIDENTIAL
For each SC dose cohort, if 1 of the 6 DLT evaluable subjects experience a DLT during the SC 
administration DLT evaluation period then the dose will be determined to be tolerable and the 
DLRT will decide the next dose level to be initiated and the frequency of administration for 
the next cohort; see Section 6.2.1.2.2 for definition of the DLT evaluation period.  
For each SC dose cohort, if 2 of the 6 DLT evaluable subjects experience a DLT during the SC 
administration then dosing will stop for individual subjects who experience a DLT, a DLRT 
meeting will be conducted, and further steps will be determined, such as dose de-escalation or 
increasing dosing interval (Figure 1).  In addition, if subjects on this cohort have not 
reached the SC dosing, they will be allowed to stay on study but will finish cycle 1/period 1 
as cIV.
MTD will be defined as the highest dose level at which 1 of 6 subjects experience a DLT.  If no 
subject experiences a DLT, the MTD will be defined as the maximal dose tested.
For further details, see Section 6.2.1.2.1 and Section 6.2.1.2.3.
Cycle 1/Period 2: 
The aim of Period 2 will be to assess the MTD as derived from Period 1, or the maximum tested 
dose, if MTD has not been reached, for additional safety and preliminary efficacy data in an 
expanded cohort of up to 15 evaluable subjects receiving SC treatment only (no cIV run-in)
Figure 2.
Doses for Cycle 1/Period 2 will be derived based on PK, bioavailability, and safety data collected 
in Cycle 1/Period 1 and DLRT review and recommendations.  Subjects will receive sequentially 
the estimated SC doses equivalent to the 9 g/day cIV in week 1, SC doses equivalent to the 
28 g/day cIV starting in week 1 and continuing into week 2, and then the SC doses of the 
selected maximal dose and dosing interval from Cycle 1/Period 1 starting in week 2 (day 12) 
and continuing to complete a total of 6 weeks of blinatumomab (see Section 6.2.1.2.2 for 
definition of the DLT evaluation period for Period 2).
Sample Size:  Six DLT evaluable subjects will be enrolled at each SC dose level in 
Cycle 1/Period 1.  Subjects may be replaced.  This sample size is based on practical 
considerations and is consistent with conventional phase 1 oncology studies. If the true DLT rate 
is 10, there is a 89probability of observing 1 DLT and 11probability of observing 2 or 
more DLT in 6 subjects. If the true DLT rate is 30, the probability of observing 1 DLT 
decreases to 42and probability of observing 2 or more DLT increases to 58.
Up to 15 evaluable subjects will be enrolled into Cycle 1/Period 2 with the planned target 
treatment dose being the highest tolerable dose regimen or highest tested dose regimen based 
on DLRT’s recommendations. Continuous toxicity monitoring for early termination of the trial in 
Cycle 1/Period 2 will be performed.  Termination of Cycle 1/Period 2 will occur if the posterior 
probability that the DLT rate is greater than 25is at least 80.
Summary of Subject Eligibility Criteria:  
Age 18 years old at the time of informed consent
Subjects must have a histologically determined B cell NHL subtype as defined in the bullets 
below. In addition, they must have disease that is primary refractory after initial therapy or have 
relapsed disease.
Follicular Lymphoma I, II, IIIA
Marginal zone lymphoma (extranodal, nodal, or splenic).  Subjects with gastric 
mucosa-associated lymphoid tissue must have progressed after Helicobacter pylori therapy and 
radiation.  Subjects with splenic marginal zone lymphoma must have prior splenectomy.
Lymphoplasmocytic lymphoma
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
Page 6 of 113
CONFIDENTIAL
Mantle cell lymphoma ([MCL] with the exception of aggressive MCL, defined as Ki67 30, or 
blastoid histology)
Small lymphocytic lymphoma
Subjects without standard therapy alternatives, or contraindicated for standard therapy by 
investigator, or subjects unwilling to receive standard therapy.  The disease status must be 1 of 
the following:
Primary refractory (at least 1 prior line of therapy)
Relapsed within 1 year of first response
Responded to initial therapy for 1 year and relapsed after 2 or more lines of therapy, including 
an anti-CD20 monoclonal antibody
Measurable disease that has not been previously irradiated on PET-CT, or computed tomography 
(CT), of at least 1.5 cm within the last 21 days before the start of investigational product (IP)
treatment
For a full list of eligibility criteria, please refer to Section 4.1 through Section 4.1.2.
Investigational Product
Amgen Investigational Product Dosage and Administration: Blinatumomab will be 
administered as SC or cIV.  
Cycle 1/Period 1: Blinatumomab is administered as a cIV infusion, 9 μg/day cIV for the first 
7 days to mitigate for potential CRS and neurologic events associated with introduction to 
blinatumomab.  The blinatumomab will then be escalated (dose-step) to 28 μg/day cIV 
starting on day 8 through day 14 (week 2), and to 112 μg/day cIV starting on day 15 
(week 3), for 21 days of treatment. In addition, the blinatumomab dose of 112 μg/day cIV may 
continue for any number of days required to bridge cIV dosing so that SC dosing begins on a 
Monday (unless the study site can administer SC injections on the weekend).  There is then a
12-hour treatment free period that is followed by 5 days of SC dosing (week 4) for Dose 
Cohorts 1, 2, and 3.  The SC dose and frequency will be chosen by the DLRT for further 
cohorts (see Figure 1).  There is then at least 2 days to not more than 3 days of no 
investigational product, followed by a return to investigational product 112 μg/day cIV 
administration for 2 weeks (weeks 5 and 6) to complete a total of 6 weeks of therapy for a single 
cycle.  
(Note:  A total of 9 SC doses will be given for the q12h dosing, so intensive PK samples can be 
obtained on day shift to reduce errors).
Cycle 1/Period 2: Subjects will receive the estimated SC equivalent doses of the 2 lower cIV 
doses given in the run-in period of Cycle 1/Period 1 sequentially: the equivalent SC dose of
9 g/day cIV during week 1, the equivalent SC dose of 28 g/day cIV starting in week 1 and 
continuing into week 2, and then the SC MTD from Cycle 1/Period 1 (or the maximum tested 
dose if MTD is not reached) starting in week 2 at the dosing and frequency determined in 
Cycle 1/Period 1 for a total of 6 weeks of SC blinatumomab.
Optional Cycle 2 for Period 1: A subject may receive a second cycle of blinatumomab if, in the 
investigator`s opinion, the subject derives benefit from treatment.  The optional cycle 2 of 
blinatumomab will be dosed at 9 µg/day cIV for 7 days for days 1 through day 7, next the dose 
will be escalated (dose-step) to 28 µg/day cIV for 7 days starting on day 8 through day 14, and 
then advanced to 112 μg/day cIV for 28 days starting on day 15 through day 42.  
A treatment-free interval of 14 days will be observed after the completion of the first cycle 
of blinatumomab before starting the second cycle.
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
Page 7 of 113
CONFIDENTIAL
Optional Cycle 2 for Period 2:  A subject may receive a second cycle of blinatumomab 
administered SC if the subject derived clinical benefit (demonstrated on staging scans) 
from Cycle 1/Period 2 treatment.  
If no clinical benefit occurred with SC in Cycle 1/Period 2 then an optional Cycle 2/Period 2 
may still be given but will administered as a cIV infusion instead of SC.  If blinatumomab is 
administered as a cIV infusion it will be dosed at 9 µg/day cIV for 7 days for days 1 through 
day 7, next the dose will be escalated (dose-step) to 28 µg/day cIV for 7 days starting on 
day 8 through day 14, and then advanced to 112 μg/day cIV for 28 days starting on day 15 
through day 42.
A treatment-free interval of 14 days will be observed after the completion of the first cycle 
of blinatumomab before starting the second cycle.
Procedures:  At specified time points outlined in the Schedule of Assessments subjects will 
undergo the following procedures: collection of informed consent form, medical history/current 
medical conditions, demographics, Eastern Cooperative Oncology Group (ECOG) Performance 
Status, physical exam including neurologic examination, height, weight, medical and surgical 
histories, vital signs and temperature, PET-CT (per standard of care), CT scan (per standard of 
care), and bone marrow biopsy (per standard of care).  Subjects will provide samples for 
coagulation, hematology with differential, blood chemistry profiles, urinalysis, hepatitis serology, 
human immunodeficiency virus (HIV), anti-blinatumomab antibodies, and immunoglobulin G
(IgG).  Subjects will further provide samples for other specialty labs including cytokines, 
lymphocyte subsets, PK samples, and a serum or urine pregnancy test for women of childbearing 
potential.  Research staff will document the use of concomitant medications and all adverse 
events reported by the subject.  Approximately 30 days (7 days) after the last dose of 
blinatumomab, subjects will undergo a safety follow-up visit.  For a full list of study procedures, 
including the timing of each procedure, please refer to Section 7 and the Schedule of 
Assessments (Table 3, Table 4, Table 5, Table 6, and Table 7).  
Statistical Considerations:  The final analysis will occur when target enrollment is complete and 
all subjects either complete the study or withdraw from the study.
Descriptive statistics will be provided for demographics, safety, PK parameters, PD parameters, 
and biomarker data by dose, dose schedule, and time as appropriate. PK parameters will be 
estimated by non-compartmental analysis.  Descriptive statistics on continuous data will include 
means, medians, standard deviations and ranges, while categorical data will be summarized via 
the number and percentage of subjects in each category.
Safety data will be reviewed on an ongoing basis. Amgen, in consultation with the site 
investigator, will review in DLRT meetings all available accumulating data by cohort before
making dose escalation decisions.
Point estimates for response rates will be accompanied by confidence intervals (CIs). Subject 
listings with related collected parameters will also be provided.
For a full description of statistical analysis methods, please refer to Section 10.
Sponsor:  Amgen Inc.
Data Element Standards 
Version(s)/Date(s): 
Version 5.0, 20 March 2015
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
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CONFIDENTIAL
Study Design and Treatment Schemas
Figure 1.  Study Schema for Cycle 1/Period 1: cIV Run-in and SC Dose 
Abbreviations: cIV continuous intravenous; DLRT Dose Level Review Team; DLT dose limiting
toxicities; IP investigational product; PK = pharmacokinetic; SC subcutaneous; q12h every 12 hours; 
q24h = every 24 hours, q48h = every 48 hours, q72h = every 72 hours, q96h = every 96 hours, 
q7d = every 7 days
**SC dose may be increased (by 1 dose level or between the dose of previous cohort and next higher 
dosing level), kept at the same dose level or decreased by 1 or more dose levels, and the dose 
frequency chosen (q12h, q24h, q48h, q72h, q96h, or q7days) will be decided by the DLRT and will be 
based on the previous cohort PK data.
If 2/6 DLT, then an immediate DLRT review will be conducted to determine next steps
If < 1/6 DLT, then DLRT will be convened and next dose will be tested in a new cohort of subjects as 
outlined in the protocol
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
Page 9 of 113
CONFIDENTIAL
Figure 2.  Study Schema for Cycle 1/Period 2
N=15
9ug equivalent SC
week 1 with 
dosing frequency to 
be determined by 
Cycle1/Period1 PK
28ug equivalent SC
Week 1-2 with
dosing frequency to
be determined by
Cycle 1/Period 1 PK
MTD SC
weeks 2-6 with
dosing frequency to
be  determined by 
Cycle 1/Period 1 PK
Continuous toxicity monitoring
for early termination of the trial will be 
performed (refer to section 10.2)
Abbreviations:  MTD maximum tolerated dose; PK = pharmacokinetic; SC subcutaneous
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
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Study Glossary
Abbreviation or Term
Definition/Explanation
ADA
Anti-blinatumomab antibodies
ALL
acute lymphoblastic leukemia
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
anti-HCV positive
hepatitis C virus
AST
aspartate aminotransferase
AUC
area under the curve
BID
twice a day
CART
chimeric antigen receptor T-cell
CHOP
cyclophosphamide, doxorubicin, Oncovin (vincristine), and 
prednisone
CI
Confidence Interval
cIV
continuous intravenous
CNS
central nervous system
CR
complete response
CRF
Case Report Form
CRS
cytokine release syndrome
CSF
cerebrospinal fluid
Css
concentration of drug at steady state
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug induced liver injury 
DLBCL
Diffuse large B-cell lymphoma
DLRT
Dose Level Review Team
DLT
dose limiting toxicities
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
Electronic Source Data 
(eSource) 
source data captured initially into a permanent electronic record 
used for the reconstruction and evaluation of a trial
End of Follow-up
defined as when the last subject completes the last 
protocol-specified assessment in the study  
End of Study (end of trial) the time when the last subject is assessed or receives an 
intervention for evaluation in the study; the final analysis will occur at 
this time
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
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Abbreviation or Term
Definition/Explanation
End of Study for 
Individual Subject
defined as the last day that protocol-specified procedures are 
conducted for an individual subject
End of Treatment
defined as the last assessment for the protocol-specified treatment 
phase of the study for an individual subject
EOS
end of study
eSAE
electronic Serious Adverse Event
EU
European Union
Exposure-Response 
Analysis
mechanism-based modeling & simulation and statistical analyses 
based on individual pharmacokinetic [PK] exposure (eg, population 
pharmacokinetic modeling) and response, which may include 
biomarkers, pharmacodynamic (PD) effects, efficacy and safety 
endpoints.
FAS
full analysis set
GCP
Good Clinical Practice
HBsAg
hepatitis B virus
HIV
human immunodeficiency virus
HRT
hormonal replacement therapy
HSCT
hematopoietic c stem cell transplant
ICF
informed consent form
ICH
International Conference on Harmonisation
IFN-
interferon gamma
IgG
immunoglobulin G
INR
international normalized ratio
IP
investigational product
IPIM
Investigational Product Instruction Manual
IRB/IEC
institutional review board/independent ethics committee
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine hormonal-releasing system 
IV
Intravenous
MALT
Mucosa-associated lymphoid tissue
MCL
Mantle cell lymphoma
MTD
maximum tolerated dose
MZL
Marginal zone lymphoma
NASH
nonalcoholic Fatty Liver Disease including Steatohepatitis
NHL
Non-Hodgkin’s Lymphoma
ORR
Overall response rate
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
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Abbreviation or Term
Definition/Explanation
PD
Pharmacodynamic
PET-CT
Positron emission tomography–computed tomography
PK
pharmacokinetic
PR
partial response
PTT 
partial thromboplastin time
Q12h
every 12 hours
Q24h
every 24 hours
SC
Subcutaneous
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOC
System Organ Class
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 
product(s)/protocol required therapies is/are administered to the 
subject
TBL
total bilirubin
TLS
Tumor lysis syndrome
TNF-
tumor necrosis factor alpha
ULN
upper limit of normal
US
United States
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
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TABLE OF CONTENTS
Protocol Synopsis............................................................................................................3
Study Design and Treatment Schemas ...........................................................................8
Study Glossary..............................................................................................................10
1.
OBJECTIVES .......................................................................................................18
1.1
Primary .....................................................................................................18
1.2
Secondary.................................................................................................18
1.3
Exploratory................................................................................................18
2.
BACKGROUND AND RATIONALE.......................................................................18
2.1
Disease.....................................................................................................18
2.2
Amgen Investigational Product Background:  Blinatumomab.....................20
2.3
Dose Selection..........................................................................................20
2.3.1
Pharmacokinetics......................................................................20
2.4
Rationale...................................................................................................21
2.5
Immunogenicity.........................................................................................22
2.6
Rationale for SC vs cIV Route of Administration........................................22
2.7
Clinical Hypotheses...................................................................................22
3.
EXPERIMENTAL PLAN........................................................................................22
3.1
Study Design.............................................................................................22
3.1.1
Cycle 1/Period 1........................................................................23
3.1.2
Cycle 1/Period 2........................................................................25
3.2
Number of Sites ........................................................................................25
3.3
Number of Subjects...................................................................................25
3.4
Replacement of Subjects ..........................................................................26
3.4.1
Replacement Rules in Cycle 1/Period 1.....................................26
3.4.2
Replacement Rules in Cycle 1/Period 2.....................................26
3.5
Estimated Study Duration..........................................................................27
3.5.1
Study Duration for Subjects.......................................................27
3.5.2
End of Study..............................................................................27
4.
SUBJECT ELIGIBILITY ........................................................................................27
4.1
Inclusion and Exclusion Criteria ................................................................27
4.1.1
Inclusion Criteria........................................................................27
4.1.2
Exclusion Criteria ......................................................................28
5.
SUBJECT ENROLLMENT....................................................................................29
5.1
Treatment Assignment ..............................................................................30
6.
TREATMENT PROCEDURES..............................................................................31
6.1
Classification of Product............................................................................31
6.2
Investigational Product..............................................................................31
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
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6.2.1
Amgen Investigational Product Blinatumomab...........................31
6.2.1.1
Dosage, Administration, and Schedule....................31
6.2.1.2
Dose-cohort Study Escalation and 
Stopping Rules........................................................36
6.2.1.3
Premedication With Dexamethasone for 
Blinatumomab Treatment ........................................39
6.2.1.4
Dosage Adjustments, Delays, Rules for 
Withholding or Restarting, Permanent 
Discontinuation........................................................40
6.3
Hepatotoxicity Stopping and Rechallenge Rules .......................................47
6.3.1
Criteria for Permanent Discontinuation of 
Blinatumomab and Other Protocol-required Therapies 
Due to Potential Hepatotoxicity .................................................48
6.3.2
Criteria for Conditional Withholding of Blinatumomab 
and Other Protocol-required Therapies Due to 
Potential Hepatotoxicity.............................................................49
6.3.3
Criteria for Rechallenge of Blinatumomab and Other
Protocol-required Therapies After Potential 
Hepatotoxicity............................................................................49
6.4
Concomitant Therapy................................................................................50
6.5
Other Treatment Procedures.....................................................................50
6.5.1
Fever Management ...................................................................50
6.6
Medical Devices........................................................................................51
6.7
Product Complaints...................................................................................51
6.8
Excluded Treatments, Medical Devices, and/or Procedures 
During Study Period..................................................................................51
6.9
Contraceptive Requirements.....................................................................52
6.9.1
Female Subjects........................................................................52
6.9.2
Unacceptable Methods of Birth Control for Women 
Subjects ....................................................................................53
7.
STUDY PROCEDURES .......................................................................................53
7.1
Schedule of Assessments.........................................................................55
7.2
General Study Procedures........................................................................69
7.2.1
Screening Enrollment and/or Randomization.............................69
7.2.2
Rescreening ..............................................................................69
7.2.3
Treatment..................................................................................70
7.2.4
Safety Follow-up Visit(s)/End of Study Visit ...............................70
7.2.5
Early Termination Visit...............................................................70
7.3
Description of Study Procedures...............................................................70
7.3.1
Informed Consent......................................................................70
7.3.2
Medical History/Current Medical Condition................................71
7.3.3
Prior Therapies..........................................................................71
7.3.4
Demographic Data.....................................................................71
7.3.5
ECOG Performance Status Assessment ...................................71
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7.3.6
Physical Examination ................................................................71
7.3.7
Physical Measurements and Vital Signs....................................71
7.3.8
Neurological Examination..........................................................72
7.3.9
Adverse Events/Serious Adverse Events/ Disease 
Related Events..........................................................................72
7.3.10
PET-CT Scan and Interim CT Scan...........................................72
7.3.11
Magnetic Resonance Image......................................................73
7.3.12
Bone Marrow Biopsy .................................................................73
7.3.13
Lumbar Puncture to Examine Cerebrospinal Fluid.....................73
7.3.14
Laboratory Assessments ...........................................................74
7.3.15
Pharmacokinetic Samples .........................................................75
7.3.15.1
Cycle 1/Period 1......................................................76
7.3.15.2
Cycle 1/Period 2......................................................77
7.3.15.3
Optional Cycle 2/Period 2........................................77
7.3.16
Pharmacodynamic Samples......................................................78
7.3.16.1
Lymphocyte Subsets...............................................78
7.3.16.2
Cytokines ................................................................78
7.4
Antibody Testing Procedures ....................................................................78
7.5
Biomarker Development............................................................................78
7.6
Sample Storage and Destruction...............................................................79
8.
WITHDRAWAL FROM TREATMENT, PROCEDURES, AND STUDY..................80
8.1
Subjects’ Decision to Withdraw .................................................................80
8.2
Investigator or Sponsor Decision to Withdraw or Terminate 
Subjects’ Participation Prior to Study Completion......................................81
8.3
Reasons for Removal From Treatment or Study .......................................81
8.3.1
Reasons for Removal From Treatment......................................81
8.3.2
Reasons for Removal From Study.............................................81
9.
SAFETY DATA COLLECTION, RECORDING, AND REPORTING.......................82
9.1
Definition of Safety Events ........................................................................82
9.1.1
Disease Related Events ............................................................82
9.1.2
Adverse Events .........................................................................83
9.1.3
Serious Adverse Events ............................................................84
9.2
Safety Event Reporting Procedures ..........................................................84
9.2.1
Reporting Procedures for Disease Related Events....................84
9.2.2
Adverse Events .........................................................................85
9.2.2.1
Reporting Procedures for Adverse Events 
That do not Meet Serious Criteria............................85
9.2.2.2
Reporting Procedures for Serious Adverse 
Events.....................................................................86
9.2.2.3
Reporting Serious Adverse Events After 
the Protocol-required Reporting Period ...................87
9.3
Pregnancy and Lactation Reporting ..........................................................87
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10.
STATISTICAL CONSIDERATIONS ......................................................................88
10.1
Study Endpoints, Analysis Sets, and Covariates .......................................88
10.1.1
Study Endpoints ........................................................................88
10.1.1.1
Primary Endpoint.....................................................88
10.1.1.2
Secondary Endpoints ..............................................89
10.1.1.3
Exploratory Endpoints .............................................89
10.1.2
Analysis Sets.............................................................................89
10.1.2.1
Full Analysis Set......................................................89
10.1.2.2
Safety Analysis Set .................................................89
10.1.2.3
DLT Analysis Set.....................................................89
10.1.2.4
Pharmacokinetic Analyses Set................................89
10.1.2.5
Pharmacodynamic Analyses Set.............................90
10.1.3
Covariates and Subgroups ........................................................90
10.2
Sample Size Considerations .....................................................................90
10.3
Planned Analyses .....................................................................................91
10.3.1
Interim Analyses........................................................................91
10.3.2
Dose Level Review Team..........................................................91
10.3.3
Final Analysis ............................................................................92
10.4
Planned Methods of Analysis ....................................................................92
10.4.1
General Considerations.............................................................92
10.4.2
Secondary Efficacy Endpoints...................................................92
10.4.3
Safety Endpoints .......................................................................93
10.4.3.1
Adverse Events.......................................................93
11.
REGULATORY OBLIGATIONS............................................................................93
11.1
Informed Consent......................................................................................93
11.2
Institutional Review Board/Independent Ethics Committee........................94
11.3
Subject Confidentiality...............................................................................94
11.4
Investigator Signatory Obligations.............................................................95
12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS..................................................95
12.1
Protocol Amendments and Study Termination ..........................................95
12.2
Study Documentation and Archive ............................................................96
12.3
Study Monitoring and Data Collection .......................................................96
12.4
Investigator Responsibilities for Data Collection........................................97
12.5
Language..................................................................................................98
12.6
Publication Policy......................................................................................98
12.7
Compensation...........................................................................................99
13.
REFERENCES...................................................................................................100
14.
APPENDICES ....................................................................................................102
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List of Tables
Table 1.  Dexamethasone Pre-dose Treatment and for Events .....................................40
Table 2.  Treatment Interruptions and Restart ...............................................................43
Table 3.  Schedule of Assessments for Cycle 1/Period 1...............................................55
Table 4.  Cycle 1/Period 1 Investigational Product Dosing and PK 
Assessments for Week 4 and 5 ..............................................................58
Table 5.  Schedule of Assessments for Cycle 1/Period 2...............................................59
Table 6.  Subcutaneous Dosing Options for Cycle 1/Period 2........................................62
Table 7.  Schedule of Assessments for Optional Cycle 2...............................................67
Table 8.  Laboratory Analyte Listing ..............................................................................75
Table 9.  Disease-related Adverse Events by System Organ Class...............................82
Table 10.  Cycle 1/Period 2 Stopping Boundaries..........................................................91
Table 11.  Operating Characteristics .............................................................................91
List of Figures
Figure 1.  Study Schema for Cycle 1/Period 1:  cIV Run-in and SC Dose........................8
Figure 2.  Study Schema for Cycle 1/Period 2 .................................................................9
Figure 3.  Simulated Blinatumomab Concentration-time Profiles Under 
Continuous IV Infusion and Under Once (1a) or Twice (1b) 
Daily Subcutaneous Administrations.......................................................22
List of Appendices
Appendix A.  Modified Cheson Criteria for Evaluation of Extramedullary 
Disease ................................................................................................103
Appendix B.  Response Assessment Per the Lugano Classification............................104
Appendix C.  Eastern Cooperative Oncology Group (ECOG) Performance 
Status...................................................................................................105
Appendix D.  Additional Safety Assessment Information .............................................106
Appendix E.  Clinically Relevant Neurologic Events by High-level Group Term 
(HLGT) .................................................................................................108
Appendix F.  Sample Serious Adverse Event Report Form..........................................109
Appendix G.  Pregnancy and Lactation Notification Worksheets..................................112
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1.
OBJECTIVES
1.1
Primary

To evaluate the safety and tolerability of subcutaneous (SC) blinatumomab dose 
administrations 
1.2
Secondary

To determine pharmacokinetics (PK) with continuous intravenous (cIV) and SC 
administrations

To estimate the maximum tolerated dose (MTD) tested for blinatumomab 
administered subcutaneously 

To determine the incidence of anti-blinatumomab antibody formation following SC 
administration 

To evaluate efficacy response following treatment with SC blinatumomab 
administration
1.3
Exploratory

To determine the pharmacodynamic (PD) time profiles for B- and T-lymphocytes as 
well as cytokine profiles during SC administration  

To evaluate efficacy response following treatment with SC blinatumomab 
administration using Lugano criteria if positron emission tomography-computed 
tomography (PET/CT) is used for evaluation (Appendix B)
2.
BACKGROUND AND RATIONALE
2.1
Disease
Non-Hodgkin’s Lymphoma (NHL) represents the tenth most common cancer with a 
yearly incidence of approximately 15/100,000 in the developed world 
(GLOBOCAN 2012). Globally, almost 400,000 new cases of NHL are diagnosed each 
year; approximately 200,000 patients die of NHL per year, with approximately 40of 
them in developed countries (GLOBOCAN 2012). The median age at diagnosis is 
66 years of age (Howlader et al, 2016).
NHL is a heterogeneous set of malignancies with many histologic subtypes.  Various 
international classification systems have been merged into the World Health 
Organization classification (Harris et al, 1994).  For practical clinical purposes, NHL can 
be divided into indolent (low-grade) and aggressive (high-grade) lymphomas.  The main 
histological subtype of the indolent NHL is the follicular lymphoma, which accounts for 
approximately 20of all NHL (Gribben 2007).  Diffuse large B-cell lymphoma with a 
frequency of approximately 25among all NHL is the main variant of aggressive 
lymphomas, WHO classification 2008 (Swerdlow et al, 2008).  Most NHLs are B-cell 
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derived (90) and express common B-cell antigens such as CD19, CD20, and 
CD22 (Gribben 2007). 
In addition, to histological classification, several factors predict the prognosis and help 
guide therapy.  The anatomical localization of disease will influence prognosis and 
management in NHL.  The most commonly used staging system is the Ann Arbor 
classification.  Specifically for follicular lymphoma, important prognostic factors are the 
number of nodal areas, lactate dehydrogenase, age, stage, and hemoglobin 
concentrations.  These factors have been integrated into a “Follicular Lymphoma 
International Prognostic Index" (lPl), allowing risk/prognosis assessments for follicular 
lymphoma (Lister et al, 1989).
Management of NHL varies considerably, ranging from no initial therapy at all to 
multimodality therapy using radiotherapy, cytotoxic chemotherapy, and/or combinations 
of chemotherapy and immunotherapy.  Whereas most patients with limited disease may 
be cured, all indolent and up to 50of aggressive NHL patients with advanced disease, 
(Ann Arbor stage lll/lV) cannot be cured by conventional chemotherapy 
(Armitage et al, 1998).
Consequently, primary therapy is for most patients followed by additional therapies to 
manage first and later relapses. Duration of remission usually gets shorter, and most 
patients inevitably die from their disease.
In relapse, indolent NHL patients may be retreated with chemotherapy.  An alternative to 
chemotherapy for these patients is immunotherapy with the monoclonal antibody 
rituximab directed against CD20, which is increasingly used to manage relapsed stage 
lll/lV follicular lymphoma patients.  Rituximab has also been reported to improve the 
outcome of first line therapy when administered in combination with cyclophosphamide,
doxorubicin, Oncovin (vincristine), and prednisone ([CHOP] chemotherapy regimen) for 
the treatment of aggressive lymphoma (Gribben 2007).
Most patients with advanced stage indolent disease will succumb to their disease.  
Therefore, a high-unmet medical need exists to develop novel agents that will further 
improve the survival of NHL patients.  Current limitations of chemotherapy and the 
success of rituximab indicate that immunotherapies could be of significance.  Ongoing 
studies using chimeric antigen receptor T-cell therapies are being investigated, and have 
provided preliminary evidence of CD19 as an important potential target 
(Singh et al, 2016).
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2.2
Amgen Investigational Product Background: Blinatumomab
Blinatumomab (BLINCYTO, AMG 103, formerly also known as MT103 or 
bscCD19xCD3) is a member of a novel class of bispecific antibody constructs called 
BiTE, or “bispecific T-cell engagers” (Dreier et al, 2002, Schlereth et al, 2006).  
Blinatumomab is a BiTEantibody construct 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 B cells by a single blinatumomab-activated 
T-cell closely resembles a natural cytotoxic T-cell reaction.  In clinical studies, T-cell 
activation, B-cell depletion, and transient cytokine release have been observed in 
patients being evaluated.
Blinatumomab is approved in multiple regions for the treatment of Philadelphia 
chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic 
leukemia (ALL).
Detailed information on the nonclinical effects of blinatumomab, and its clinical effects in 
this patient population is provided in the current country-specific prescribing information 
for blinatumomab.  The European Union Summary of Product Characteristics provides 
detailed product information for investigators in the European Union and in regions 
where blinatumomab is not currently approved.  The United States (US) Prescribing 
Information provides detailed product information for investigators in the US.
Refer to the specific section of the Investigator’s Brochure for additional information 
related to the physical, chemical, and pharmaceutical properties and formulation(s).
2.3
Dose Selection
2.3.1
Pharmacokinetics
The PK of blinatumomab was assessed over a dose range from 5 to 90 μg/m2/day 
following cIV administration in subjects with NHL.  Mean concentration of drug at steady 
state values increased dose-proportionally over the dose range tested.  The estimated 
mean clearance, volume of distribution, and terminal half-life were 2.29 L/hour, 
4.84 L and 2.47 hours, respectively, in subjects with NHL (Study MT103-104
[Goebeler et al, 2016]).  Since body size (weight or body surface area [BSA]) was not a 
factor affecting the blinatumomab PK, a fixed dosing regimen, instead of BSA based 
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dosing, is appropriate for the treatment in adults.  The fixed dosing regimen has been 
tested in Study MT103-208 (Viardot et al, 2016) in patients with diffuse large B-cell 
lymphoma and showed comparable exposure levels as those with an equivalent BSA 
based regimen.
2.4
Rationale
The effect of blinatumomab in the treatment of NHL was tested in a dose escalation 
study (Study MT103-104 [Goebeler et al, 2016]).  A dose dependent clinical response 
was observed and objective clinical responses were seen starting at 
15 μg/m2/d (28 g/day) and peaked at 60 μg/m2/d (112 g/day).  Due to transient 
cytokine release after initiation of treatment, a step-dosing regimen was implemented to 
minimize cytokine related adverse events.  An effective step-dose regimen of 9 g/d 
(week 1)-28 g/d (week 2)-112 g/d (remaining weeks) following cIV infusion for 
8 weeks was established for the treatment of diffuse large B-cell lymphoma in 
study MT103-208 (Viardot et al, 2016).  In this study, the blinatumomab concentration 
levels following the cIV regimen will be used as a reference to guide dose selection of 
SC administration.  The target SC dose for the treatment of NHL is a dose that can 
achieve a similar exposure (area under the curve) as that of 112 g/d dose under cIV.  
To facilitate the SC dose selection, PK simulation was performed with the PK 
parameters (clearance and volume of distribution) generated from human studies under 
cIV and an assumed bioavailability of 0.25 in humans which was an approximate 
average of bioavailability in mouse (0.35), rat (0.16), monkey (0.21) and pig (0.30) under 
SC administration.  
The simulated PK profiles of cIV (9/28/112 g/d) and SC every day (112/450) and 
twice a day ([BID] 56/225 g/dose) are provided in Figure 3. Based on currently 
available information on bioavailability and exposure, 450 (or 225 g/BID) is the 
estimated SC equivalent dose to the cIV 112 g/d dose.
The assumption will be examined in Period 1 of this study following the PK assessment 
in the cIV run-in phase and then SC administration.  
The calculated bioavailability for SC administration, the PK profiles of SC as well as 
safety and tolerability data will be used to assess the doses recommended for the 
Period 2 of the study. 
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Figure 3.  Simulated Blinatumomab Concentration-time Profiles Under Continuous 
IV Infusion and Under Once (1a) or Twice (1b) Daily Subcutaneous 
Administrations
Abbreviations: BID twice a day; cIV continuous intravenous; Css concentration of drug at steady state; 
IVintravenous; SC subcutaneous; QD every day
2.5
Immunogenicity
Anti-blinatumomab antibodies (ADA) have been detected in a very limited number of 
adult patients with relapsed or refractory ALL treated with blinatumomab via cIV.  No 
anti-blinatumomab antibodies have been detected in subjects with NHL under cIV.  The 
incidence of anti-blinatumomab antibodies with SC administration will be examined in 
this study.  
2.6
Rationale for SC vs cIV Route of Administration
The SC delivery could simplify administration and improve convenience, and has been 
assessed for rituximab, veltuzumab, trastuzumab, and alemtuzumab in various cancer 
settings (Goldenberg, et al, 2010, Pivot, et al, 2013, Stilgenbauer, et al, 2009,
Shpilberg, et al, 2013).  The SC delivery could also reduce the incidence of severe 
administration related reactions and costs (De Cock, et al, 2013, Lundin, et al, 2002), as 
well as avoid the need for a central line, potentially decreasing the risk of infection.
2.7
Clinical Hypotheses
Blinatumomab administered through the SC route will demonstrate a tolerable 
safety-profile with serum concentrations comparable to those for which efficacy was 
shown with cIV administration in subjects with indolent relapsed/refractory NHL.
3.
EXPERIMENTAL PLAN
3.1
Study Design
The overall study design is described by study schemas in Figure 1 and Figure 2 at the 
end of the protocol synopsis section.
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This is a global multi-center, Phase 1b open-label study investigating the safety and PK 
of blinatumomab administered subcutaneously for the treatment of relapsed/refractory 
indolent NHL.  The SC administration of blinatumomab will be tested for the first time in 
humans.  
Approximately 30 subjects’ evaluable for dose limiting toxicities (DLT) will be enrolled in 
Period 1 (6 evaluable subjects in each dose-cohort).  The focus of this period is to 
determine the PK, bioavailability, and safety profile of blinatumomab SC administration.  
The PK and bioavailability data from Period 1 of the study will be used in conjunction 
with safety data (DLT) to determine the SC MTD.  The MTD or the maximum tested 
dose, if MTD is not reached, will be further tested in Period 2 in an expanded cohort of 
up to 15 additional evaluable subjects.  Efficacy of blinatumomab administered 
subcutaneously will also be investigated in each period of the study.
3.1.1
Cycle 1/Period 1
In Period 1, 3 or more separate dose cohorts of up to 6 DLT evaluable subjects each 
will be enrolled.  Subjects will undergo an initial cIV blinatumomab run-in period 
(weeks 1 to 3) followed by a 12-hour treatment free period, and then receive 
SC administration (week 4).  After a treatment free period of 2 to not more than 
3 days, subjects receive cIV treatment to complete 6 weeks of therapy (weeks 5 to 6)
Figure 1.  
For all cohorts, the initial cIV dose of blinatumomab will be 9 μg/day for the first 7 days 
(to mitigate for potential cytokine release syndrome [CRS] and neurologic events 
associated with introduction to blinatumomab) which then will be escalated (dose-step) 
to 28 μg/day starting on day 8 through day 14 (week 2), and to 112 μg/day starting on 
day 15 until day 21 (week 3). 
After stopping cIV blinatumomab, there is a 12-hour treatment free period before 
starting SC blinatumomab.
SC blinatumomab starts after the 12-hour treatment free period and will be 
administered (week 4) as the following dose-cohort levels:  

Dose Cohort 1: 112 μg q12h × 5 days (n 6) for a total of 9 doses

Dose Cohort 2:  225 μg q12h × 5 days (n 6) for a total of 9 doses
(Note:  A total of 9 SC doses will be given for the q12h dosing, so intensive PK 
samples can be obtained on day shift to reduce errors)
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
Dose Cohort 3: 450 μg q24h × 5 days (n = 6) for a total of 5 doses

Additional Dose Cohorts: Dose level and dosing frequency to be 
determined as described below
One or more dosing regimens may be selected based on clinical findings 
including safety, tolerability, and PK results from previous cohorts; after DLRT 
review, the DLRT may make recommendations for the next SC cohort dose and 
frequency. The dose may be increased (by 1 dose level or between the dose of
the previous cohort and the next higher dosing level in Figure 1 schema), kept at 
the same dose level or decreased by 1 or more dose levels.  The dose frequency 
chosen (q12h, q24h, q48h, q72h, q96h, or q7 days) will be decided by the DLRT 
and will be based on the previous cohort PK data (refer to dosing schema 
Figure 1).
Once the SC dosing is complete, a treatment free period of 2 to not more than 
3 days between stopping SC and restarting cIV will be observed. Then the cIV 
blinatumomab dosing will resume at 112 μg/day (weeks 5 to 6) to complete 
6 weeks of treatment.
For each SC dose cohort, if 1 of the 6 DLT evaluable subjects experience a DLT 
during the SC administration DLT evaluation period then the dose will be determined to 
be tolerable and the DLRT will decide the next dose level to be initiated and the 
frequency of administration for the next cohort; see Section 6.2.1.2.2 for definition of 
the DLT evaluation period.
For each SC dose cohort, if 2 of the 6 evaluable subjects experience a DLT during the 
SC administration then dosing will stop for individual subjects who experience a DLT, a 
DLRT meeting will be conducted, and further steps will be determined, such as dose 
de-escalation or increasing dosing interval (Figure 1). In addition, if subjects on 
this cohort have not reached the SC dosing, they will be allowed to stay on study 
but will finish cycle 1/period 1 as cIV.
MTD will be defined as the highest dose level at which 1 of 6 subjects experience a 
DLT.  If no subject experiences a DLT, the MTD will be defined as the maximal dose 
tested.
For further details see Section 6.2.1.2.1 and Section 6.2.1.2.3.
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3.1.2 
Cycle 1/Period 2 
The aim of Period 2 will be to assess the MTD as derived from Period 1, or the 
maximum tested dose, if MTD has not been reached, for additional safety and 
preliminary efficacy data in an expanded cohort of up to 15 evaluable subjects receiving 
SC treatment only (no cIV run-in) Figure 2.  
Doses for Cycle 1/Period 2 will be derived based on PK, bioavailability, and safety data 
collected in Cycle 1/Period 1 and DLRT review and recommendations.  Subjects will 
receive the estimated SC equivalent doses of the 2 lower cIV doses as given in the 
cIV blinatumomab run-in period sequentially:  2 doses of the equivalent SC dose 
to 9 µg/day of cIV during week 1, 3 doses of the equivalent SC dose to 28 μg/day 
cIV starting in week 1 and continuing into week 2, and then the SC MTD (or the 
maximum tested dose if MTD is not reached) and SC dosing interval as 
determined in Cycle 1/Period 1 starting in week 2 (day 12) and continuing to 
complete a total of 6 weeks of blinatumomab.  See Section 6.2.1.2.2 for definition 
of the DLT evaluation period for Period 2. 
Continuous toxicity monitoring for early termination of the trial in Cycle 1/Period 2 
will be performed.  Termination of Cycle 1/Period 2 will occur if the posterior 
probability that the DLT rate is greater than 25% given the cumulative data thus far 
is at least 80%. 
The study endpoints are defined in Section 10.1.1 and stopping rules are detailed in 
Section 10.2. 
3.2 
Number of Sites 
The study will be conducted at approximately 15 to 20 sites in the United States (US), 
Europe, and Australia. 
Sites that do not enroll subjects into an open cohort within 6 months of site initiation may 
be closed.   
3.3 
Number of Subjects 
Participants in this clinical investigation shall be referred to as “subjects”. 
Approximately 54 subjects will be enrolled in this study in order to ensure 
approximately 30 evaluable subjects in Period 1 and up to 15 evaluable subjects in 
Period 2 are treated with blinatumomab.  It is expected that approximately 20% of 
subjects will discontinue the study prematurely (ie, due to adverse event, subject 
request, requirement for alternative therapy) during the cIV run-in period 
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(Cycle 1/Period 1) or prior to receiving sufficient SC dosing (Cycle 1/Period 2 
weeks 1 to 3) and will need to be replaced per Section 3.4.  Refer to Section 10.2 for 
sample size considerations. 
3.4 
Replacement of Subjects 
Subjects enrolled may be replaced if they are not evaluable for DLT during the DLT 
observation period as described in Section 6.2.1.2.2. 
3.4.1 
Replacement Rules in Cycle 1/Period 1 
Subjects may be replaced for any of the following reasons: 
• 
failing to complete all 3 cIV dosing levels during cIV run-in (weeks 1 to 3) 
• 
failure to receive all doses (q48h, q72h, q96h, or q7d dosing), at least 4 of the 
5 doses (q24h dosing), or at least 8 of 9 doses (q12h dosing) during the SC 
treatment period (week 4) 
• 
withdrawal from study for DLT without having had PK assessments (subjects who 
withdraw due to DLT are evaluable from a safety standpoint, but may not be 
evaluable from a PK standpoint if they have not completed their PK blood draws) 
• 
subjects may be replaced if they miss the PK assessment time point and are unable 
to resume dosing and PK assessments 
o Note:  Subjects who miss a dose before any PK assessments will default to 
the day of the missed dose.  PK assessments will be performed per Table 4 
following the subject´s resumed dose of investigational product (IP).  For 
example, if a subject misses the dose on study day 2, the restart treatment 
day will be considered as study day 2 and all applicable assessments will be 
done per Schedule of Assessments (refer to Table 3 and Table 4 for further 
details) 
• 
for all subjects who miss PK samples, the PK scientist will evaluate the PK results for 
this subject, and determine if the subject needs to be replaced, or if the PK results 
are sufficient for analysis.  The DLRT will be informed of this decision to replace or 
not replace individual subjects at the time of the DLRT meeting.  
o subjects who do not complete PK assessments may continue on study, even 
if replaced 
3.4.2 
Replacement Rules in Cycle 1/Period 2 
Subjects may be replaced for any of the following reasons (except subjects removed for 
DLT that will never be replaced): 
• 
failure to receive at least 85% of the first 8 planned doses during the SC 
treatment period as outlined in Table 6 (this would include 5 doses of step 
dose run-in and 3 doses at MTD) 
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3.5
Estimated Study Duration
3.5.1
Study Duration for Subjects
For an individual subject, the length of participation includes a 14 day screening period, 
up to a 14 week treatment period (6 weeks for cycle 1 in Period 1 and Period 2 and 
6 weeks for the optional Cycle 2, separated by a 14 day treatment free interval), and a 
safety follow-up visit (30 days [7 days] after the last dose of study treatment). 
For subjects who complete the protocol from the date of first dose through optional 
Cycle 2, the entire duration of the study will take approximately 20 weeks to complete.  
However, individuals’ study duration will vary depending on administration of an optional
second cycle and tolerability of blinatumomab by an individual subject.
3.5.2
End of Study
End of Trial:  the time when the last subject is assessed or receives an intervention for 
evaluation in the study; the final analysis will occur at this time.
4.
SUBJECT ELIGIBILITY
Before any study-specific activities/procedure, the appropriate written informed consent 
must be obtained (see Section 11.1).  
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).  
4.1
Inclusion and Exclusion Criteria
4.1.1
Inclusion Criteria
101.
Subject has provided informed consent
102.
Age 18 years old at the time of informed consent
103.
Subjects must have a histologically determined B cell NHL subtype as defined in 
the bullets below.  In addition, they must have disease that is primary refractory 
after initial therapy or have relapsed disease. 

Follicular Lymphoma I, II, IIIA

Marginal zone lymphoma (extranodal, nodal, or splenic).  Subjects with gastric 
mucosa-associated lymphoid tissue must have progressed after Helicobacter 
pylori therapy and radiation.  Subjects with splenic marginal zone lymphoma must 
have prior splenectomy.

Lymphoplasmocytic lymphoma

Mantle cell lymphoma ([MCL] with the exception of aggressive MCL, defined as 
Ki67 30, or blastoid histology)

Small lymphocytic lymphoma
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104.
Subjects without standard therapy alternatives, or contraindicated for standard 
therapy by investigator, or subjects unwilling to receive standard therapy.  The 
disease status must be 1 of the following:

primary refractory (at least 1 prior line of therapy)

relapsed within 1 year of first response

responded to initial therapy for 1 year and relapsed after 2 or more lines of 
therapy, including an anti-CD20 monoclonal antibody
105.
Measurable disease that has not been previously irradiated on positron emission 
tomography–computed tomography (PET-CT), or computed tomography (CT), of 
at least 1.5 cm within the last 21 days before the start of IP treatment.
106.
Eastern Cooperative Oncology Group (ECOG) performance status 2 
(Appendix C).
107.
Life expectancy 3 months as determined by the treating physician.
108.
Subjects must have adequate organ and bone marrow function at screening as 
defined below:
Hematological:

peripheral neutrophils 500/L prior to start of treatment

hemoglobin 8 g/dL

platelets 50,000/L
Hepatic:

aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) 5 × upper 
limit of normal (ULN)

total bilirubin 1.5 × ULN
Renal:

creatinine clearance 50 mL/min (Cockcroft-Gault)
4.1.2
Exclusion Criteria
201.
Currently receiving treatment in another investigational device or drug study, or 
less than 30 days between ending treatment on another investigational device or 
drug study(ies) and start of IP treatment.  Other investigational procedures while 
participating in this study are excluded.
202.
Known hypersensitivity to immunoglobulins or any other component of the study 
drug.
203.
Subject likely to not be available to complete all protocol required study visits or 
procedures to the best of the subject and investigator’s knowledge. 
204.
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.
205.
Subjects who have had treatments with anti-cancer agents including rituximab or 
obinutuzumab and/or other monoclonal antibody or radioimmunotherapy within 
6 weeks prior to starting IP treatment.  
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206.
Autologous stem cell transplantation within 12 weeks prior to starting IP 
treatment or past history of allogeneic stem cell transplantation.
207.
Subjects who have received anti-CD 19 targeted therapies, chimeric antigen 
receptor T-cell or other cellular therapies for the treatment of their lymphoma.
208.
Subjects with suspected or known brain metastases should be excluded from this 
clinical study because of their poor prognosis and because they often develop 
progressive neurologic dysfunction that would confound the evaluation of 
neurologic and other adverse events.
209.
Infection with human immunodeficiency virus (HIV) or chronic infection with 
hepatitis B virus or hepatitis C virus.
210.
History of or clinically relevant central nervous system (CNS) pathology such as 
epilepsy, recurrent seizures, paresis, aphasia, apoplexia, severe brain injuries, 
cerebellar disease, organic brain syndrome, or psychosis.
211.
History of malignancy other than their lymphoma with the exception of:

Malignancy treated with curative intent and with no known active disease present 
for 3 years before enrollment and felt to be at low risk for recurrence by the 
treating physician

Adequately treated non-melanoma skin cancer or lentigo maligna without 
evidence of disease 

Adequately treated cervical carcinoma in situ without evidence of disease 

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.
212.
Uncontrolled intercurrent illness including, but not limited to, ongoing or 
uncontrolled systemic fungal, bacterial, viral, or other infection, symptomatic 
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study 
requirements.
213.
A female who is pregnant or breastfeeding or planning to become pregnant or 
breastfeed during treatment and for an additional 48 hours (Period 1) or 96 hours 
(Period 2), respectively, after the last dose of blinatumomab (Female subjects of 
childbearing potential should only be included in the study after a confirmed 
menstrual period and a negative highly sensitive urine or serum pregnancy test).
214.
A female of childbearing potential unwilling to use a highly effective method of 
contraception during treatment and for an additional 48 hours (Period 1) or 
96 hours (Period 2), respectively, after the last dose of blinatumomab.  Refer to 
Section 6.9 for additional contraceptive requirement information.
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 
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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). 
Subject must personally sign and date the IRB/IEC and Amgen approved informed 
consent form before the commencement of study-specific procedures.  Upon completion 
of the screening period the subject is evaluated by the investigator and providing the
subject continues to meet the inclusion/exclusion criteria, the subject is subsequently 
eligible to be enrolled in the study and assigned to a treatment regimen (dose cohort).
A subject is considered enrolled when the investigator decides that the subject has met 
all eligibility criteria.  The investigator is to document this decision and date, in the 
subject’s medical record and in/on the enrollment case report form (CRF).
Each subject who enters into the screening period for the study receives a unique 
subject identification number before any study-related activities/procedures are 
performed.  The subject identification number will be assigned manually.  This number 
will be used to identify the subject throughout the clinical study and must be used on all 
study documentation related to that subject.  A subject may be rescreened up to 
3 additional times during the study at the discretion of the investigator.
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.
There will be a 96-hour interval between the start of treatment of each subject entered 
on study.  See Section 6.2.1.4.2 for interruption of blinatumomab treatment/dose 
modification due to adverse events.
5.1
Treatment Assignment
This is an open-label study.  Subjects, investigators and the study team will all be aware 
of the assigned dose of blinatumomab.
An Amgen representative will notify the sites when a cohort is open to screen new 
subjects.  Once a site has confirmed eligibility of a screened subject, the site will be 
informed in writing about the applicable dose for the dose cohort the subject will be 
assigned to.
The treatment assignment date is to be documented in the subject’s medical record and
on the enrollment CRF.
Approved 
 
 


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6.
TREATMENT PROCEDURES
6.1
Classification of Product
The Amgen Investigational Product used in this study is blinatumomab.
The Investigational Product Instruction Manual (IPIM), a document external to this 
protocol, contains detailed information regarding the storage, preparation, destruction, 
and administration of blinatumomab. 
Other protocol-mandated medication (eg, dexamethasone used for pre-dose treatment 
or for treatment of adverse events) are commercially available and are not provided or 
reimbursed by Amgen (except if required by local regulation). The investigator will be 
responsible for obtaining supplies of these protocol-specified therapies.
6.2
Investigational Product
6.2.1
Amgen 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 a 4 mL single-use glass injection vials as a sterile, 
preservative-free, white to off-white, lyophilized powder for intravenous (IV)/SC 
administration, respectively, after reconstitution with sterile water for injection.
Blinatumomab for cIV administration is formulated with citric acid monohydrate, 
trehalose dihydrate, lysine hydrochloride, and polysorbate 80, pH 7.0. Each vial 
contains 38.5 g blinatumomab. 
Blinatumomab for SC administration is formulated with 10 mM potassium phosphate, 
4(w/v) mannitol, 2(w/v) sucrose, 1(w/v) sulfobutylether beta-cyclodextrin, 
0.01(w/v) polysorbate 80, pH 7.0. Each vial contains 1.0 mg blinatumomab.
6.2.1.1
Dosage, Administration, and Schedule
Blinatumomab will be administered as cIV via a central line (not peripheral) or SC.  
Exceptions for technical difficulties with the central line may be made after discussing 
with the Amgen medical monitor.
For SC administration, there is an allowed time window of 1 hour for the q12h, q24h,
q48h, q72h, q96h, and q7d dosing.
The dose, start and stop date/time, and lot number of the protocol-specified therapy are 
to be recorded on each subject’s CRF. 
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The dosing schedule is described by study schemas in Figure 1 and Figure 2 at the end 
of the protocol synopsis section.
6.2.1.1.1
Cycle 1/Period 1
Cycle 1/Period 1 will consist of blinatumomab administered as a cIV infusion for 21 days 
(weeks 1 to 3) of treatment and in addition, any number of days required to bridge cIV 
dosing so that SC dosing begins on a Monday (unless the study site can administer SC 
injections on the weekend), followed by a 12-hour treatment free period.
Then subjects will receive SC dosing in week 4 followed by a treatment free period 
of 2 to not more than 3 days, and then subjects return to cIV administration for 
2 weeks (weeks 5 to 6) to complete a total of 6 weeks of treatment.  
The initial dose of blinatumomab will be 9 μg/day cIV for the first 7 days (to mitigate for 
potential CRS and neurologic events associated with introduction to blinatumomab) and
then the dose will be escalated (dose-step) to 28 μg/day cIV starting on day 8 through 
day 14 (week 2), and to 112 μg/day cIV starting on day 15 through 21 (week 3).
If there are any interruptions in treatment that lead to the start day of SC dosing to be on 
a weekend day, then cIV dosing will be continued at the maximum dose and stopped 
12 hours before starting the SC injections, which can commence on a Monday if not 
logistically feasible to administer SC injections on a weekend day.
After completion of the initial cIV blinatumomab run-in period, there is a treatment free 
period of 12 hours, then SC blinatumomab will be administered daily for 5 days 
(week 4) for dose cohort 1, 2, and 3.  The SC dose and frequency will be chosen by 
the DLRT for further cohorts (see Figure 1).  After completing SC dosing there is 
at least 2 days to not more than 3 days of no investigational product, followed by 
a return to investigational product at 112 μg/day cIV administration for 2 weeks 
(weeks 5 and 6) to complete a total of 6 weeks of therapy.  (Note:  A total of 
9 SC doses will be given for the q12h dosing, so intensive PK samples can be obtained 
on day shift to reduce errors).
6.2.1.1.2
Cycle 1/Period 2
Subjects will receive the estimated SC equivalent doses of the 2 lower cIV doses as 
given in the cIV blinatumomab run-in period sequentially: 2 doses of the equivalent 
SC dose to 9 g/day of cIV during week 1, 3 doses of the equivalent SC dose to 
28 μg/day cIV starting in week 1 and continuing into week 2, and then the SC MTD 
(or the maximum tested dose if MTD is not reached) and SC dosing interval as 
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determined in Cycle 1/Period 1 starting in week 2 (day 12) and continuing to 
complete a total of 6 weeks of blinatumomab (Figure 2).
6.2.1.1.2.1
Special Case of SC Dosing Interruptions and Weekend Dose Holds
for Cycle 1/Period 1.
For dose cohorts 1, 2, and 3 the SC administration of blinatumomab will occur over 
5 days in Cycle 1/Period 1.  If administration at a study site is feasible on weekends, 
then SC administration may commence any day of the week.  If weekend administration 
of blinatumomab at a study site is not feasible, then SC administration should 
commence on a Monday so that the fifth day of dosing can be given on a Friday.
In instances where there is a dose interruption during the SC administration, and the site 
does not have the ability to restart dosing on a weekend day, the subject should have 
the dose held over the weekend and resume dosing the next available weekday. 
Premedication dexamethasone will be given as per protocol after an interruption 
(Table 1) of cIV and SC dosing.
6.2.1.1.3
Optional Cycle 2
Optional Cycle 2 for Period 1:  A subject may receive a second cycle of blinatumomab 
if, in the investigator`s opinion, the subject may derive benefit from the treatment.  The 
optional cycle 2 of blinatumomab will be dosed at 9 μg/day cIV for 7 days for days 1 
through day 7, next the dose will be escalated (dose-step) to 28 μg/day cIV for 7 days 
starting on day 8 through day 14, and then advanced to 112 μg/day cIV for 28 days 
starting on day 15 through day 42.  A treatment free interval of 14 days will be observed 
after the completion of the first cycle of blinatumomab before starting the second cycle.
Optional Cycle 2 for Period 2:  A subject may receive a second cycle of 
blinatumomab administered SC if the subject had clinical benefit on scans from 
treatment given SC in Cycle 1/Period 2 (Section 6.2.1.1.2).  
If no clinical benefit on scans after Cycle 1/Period 2, then optional Cycle 2 is 
administered as a cIV infusion.  If cIV is used, blinatumomab will be dosed at 
9 µg/day cIV for 7 days for days 1 through day 7, next the dose will be escalated 
(dose-step) to 28 µg/day cIV for 7 days starting on day 8 through day 14, and then 
advanced to 112 μg/day cIV for 28 days starting on day 15 through day 42.  A 
treatment free interval of 14 days will be observed after the completion of the first 
cycle of blinatumomab before starting the second cycle.
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6.2.1.1.4
Blinatumomab Inpatient Dosing
It is mandated in this study that subjects are hospitalized at least during the first 
72 hours at the start of cIV infusion (Cycle 1/Period 1, Optional Cycle 2/Period 1, and 
Optional Cycle 2/Period 2 if administered as a cIV infusion) as well as after any 
additional dose-step.  Hospitalization is also required during the first 48 hours after the 
return to cIV infusion after the SC dosing in Cycle 1/Period 1.  Subjects will remain 
hospitalized during the entire SC administration dosing in Cycle 1/Period 1.  
In Cycle 1/Period 2, subjects are hospitalized:  For subjects 1-5:  day 1 until 
completion of the second MTD dose PK being finished. Sites where outpatient PK 
cannot be obtained, for the third MTD SC dose, the subject needs to be 
hospitalized until completion of the third MTD dose PK.  Subjects 6-15:  are 
hospitalized on days 1-8 (discharge 8 hours after day 8, 28 µg/day equivalent SC 
dose is administered) and readmitted to the hospital on day 12 (prior to first MTD 
SC dose) until 8 hours after the second MTD SC dose is administered.  Sites 
where outpatient PK cannot be obtained, for third 28 ug/day equivalent SC dose 
and third MTD SC dose, the subject needs to be hospitalized until completion of 
the third MTD dose PK.
In Optional Cycle 2/Period 2, if given SC subjects are hospitalized on days 1-8 
(discharge 8 hours after day 8, 28 µg/day equivalent SC dose is administered) and 
readmitted to the hospital on day 12 (prior to first MTD SC dose) until 8 hours after 
the second MTD SC dose is administered.  The infusion bags will be changed (if IP is 
administered as a cIV infusion) and SC injections administered by trained site nursing 
personnel.  Close monitoring during the first 72 hours of treatment at each dose will be 
required because of the potential for adverse events.
6.2.1.1.5
Blinatumomab Outpatient Dosing and Home Health Care 
Administration for cIV and SC Dosing
If a subject is deemed stable by the investigator, the subject may continue blinatumomab 
(cIV [in all periods] or SC administration [in Cycle 1/Period 2 only]) as an outpatient. 
In the outpatient setting, the subject will return to the study site or the subject will be 
visited by a well-trained home health care service provider at specific intervals to change 
the infusion bag or for administration of the SC injection, as applicable.  The subject and 
the home health care provider will receive written instructions for storage of the IV bags 
and/or blinatumomab for SC administration as applicable. 
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The home health care provider will be trained on study-specific requirements, recording
of source documentation, and completion of the study delegation log (authorized by the 
investigator) must be completed before any study-related tasks are started.  A 
comprehensive list of all 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 provided in a home health care manual.  Following each 
visit, this information will be documented on the Ambulant/Home Care Services visit 
worksheet and forwarded to the investigator.  Any unexpected or unusual events as well 
as any deviations will be communicated promptly to the investigator.  In addition, the 
subject will visit the study site for assessments according to Table 3, Table 4, Table 5, 
Table 6, and Table 7.
In the event of drug interruptions refer to Section 6.2.1.4.1.
In case of an adverse event occurring in the outpatient setting, the subject or the home 
health care service provider should contact the investigator immediately at the study 
center for further instruction on management and the investigator will assess the 
adverse event.
6.2.1.1.6
Overdose
The daily blinatumomab cIV dose may be up to 10lower or higher in order to account 
for possible pump inaccuracies.  A dose of up to 10% higher than the intended dose 
may not require specific intervention. 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. If the overdose results in clinically apparent or symptomatic 
adverse events or additional adverse events, the subject should be followed carefully 
until all signs of toxicity are resolved and the adverse event/s should be 
recorded/reported per Section 9.
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In the SC route of administration, any dose above the planned dose will be considered 
an overdose.  In the event of any overdose, subjects should be observed and clinically 
evaluated for at least the dosing interval the subject was assigned without 
receiving any further doses of SC injection (eg, if subject assigned to q24h, to be 
evaluated for 24 hours).  After that period of time, if the subject has not developed any 
adverse events or serious adverse events, dosing may be resumed after consultation 
with the Amgen Medical Monitor.  If the subject has developed any adverse events or 
serious adverse events see dose interruption rules as outlined in Section 6.2.1.4. Any 
dose above the planned dose of blinatumomab for SC dose will be considered clinically 
important and classified as a serious adverse event under the criterion of “other 
medically important serious event” per Section 9.1.3.
6.2.1.2
Dose-cohort Study Escalation and Stopping Rules
6.2.1.2.1
Dose Level Review Team
The DLRT meeting will be held to review data, monitor safety, and make decisions on 
dose escalation/change, or changes in pre-medication.  The DLRT will be composed of 
the investigators or designees, and the following Amgen representatives: medical 
monitor, global safety officer or designee, clinical trial manager, biostatistician, PK 
scientist (optional), site investigator or designee, and other functional area 
representatives as appropriate.  A quorum as defined below must be in attendance for 
the DLRT.  The quorum is defined as 50of the participating investigators (defined 
as the number of investigators that had subjects enrolled on the cohort for that 
DLRT meeting) or their qualified designee (ie, sub-investigator or research nurse or 
study coordinator possessing written documentation [eg, e-mail] of the investigator`s 
vote), as well as 50of Amgen representatives listed above.  The medical monitor or 
designee must attend for the quorum to be reached.  The DLRT will be rescheduled if a 
quorum is not reached.  
The following members are responsible for DLRT decisions: investigators, Amgen 
medical monitor, and global safety officer or designee.  
The following decisions may be made by the DLRT:

dose escalation/de-escalation decisions 

changes in dosing frequency

expansion of a cohort

continuation, delay or termination of dosing
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All available study data, including demographics, investigational product administration, 
medical history, concomitant medications, adverse events, vital signs, laboratory data, 
and PK/PD information will be reviewed.  In addition to DLTs, all ≥ grade 3 toxicities not 
meeting DLT criteria will be reviewed and may be considered in DLRT decisions.  
Source data and queries do not need to be resolved before the DLRT.  Continuous 
toxicity monitoring for early termination of the trial in Cycle 1/Period 2 will be performed.  
All adverse events that occur during the DLT evaluation period will be reviewed and may 
be considered in DLRT decisions. 
6.2.1.2.2 
Dose Limiting Toxicity Rules 
Cycle 1/Period 1 
The DLT evaluation period includes the entire week 4 (7 days) which is the week that 
blinatumomab is administered SC during Cycle 1/Period 1 of the study.  To be 
evaluable for a DLT, subjects must have experienced a DLT within the DLT evaluation 
period.  In addition, if the investigator and/or sponsor removes the subject from the study 
due to a treatment-related toxicity during the DLT evaluation period, regardless of the 
grade of toxicity, this will be considered a DLT.  If a subject does not experience a DLT 
during the DLT evaluation period and does not receive all doses (q48h, q72h, q96h, or 
q7d dosing), at least 4 of the 5 doses (q24h dosing), or at least 8 of 9 doses 
(q12h dosing) of SC blinatumomab during Cycle 1/Period 1 of the study, the subject will 
not be considered DLT-evaluable and will be replaced as described in Section 3.4.1. 
If ≤ 1 of the 6 evaluable subjects in a dose SC cohort experience a DLT during the SC 
administration, then the dose will be determined to be tolerable and the next dose-cohort 
level will be initiated in a new dose-cohort of subjects after review by the DLRT.   
If ≥ 2 subjects of the 6 evaluable subjects in a SC dose cohort experience a DLT during 
SC administration then dosing will stop for individual subjects who experience a DLT, a 
DLRT meeting will be conducted, and further steps will be determined. 
Additionally, the DLRT will meet: 
• 
once dose-cohort 1 has completed subcutaneous dosing  
• 
once dose-cohorts 2 and 3 have completed subcutaneous dosing  
• 
once any additional cohorts complete dosing if additional dose-cohorts are tested 
to determine the MTD in Cycle 1/Period 1 
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Cycle 1/Period 2
For subjects who receive optional Cycle 2 after Cycle 1/Period 2 (SC dosing period), the 
DLT evaluation period includes the entire duration of SC administration in Cycle 1 and 
16 days following the last SC dose (56 days in total) or until the start of optional Cycle 2, 
whichever is longer, up to 30 days after the last SC dose of Cycle 1.
For subjects who do not receive optional Cycle 2, the DLT evaluation period includes the 
entire duration of SC administration and 30 days following the last SC dose (70 days in 
total).
Continuous monitoring for early termination of the trial will be performed (refer to 
Section 10.2).
6.2.1.2.3
Dose Limiting Toxicities
All toxicities will be graded using the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 (see Appendix D).  The occurrence of any of the following toxicities 
during the DLT evaluation period will be considered a DLT, if judged by the investigator 
to be related to the administration of blinatumomab:

Any treatment-related death

Any treatment-related toxicity, regardless of grade, that leads to a subject’s removal 
from the study by the investigator and/or sponsor

Persistent CTCAE grade 2 non-hematologic adverse events related to 
blinatumomab that are deemed intolerable by the subject or the treating physician 
and that do not respond to appropriate medical management within 5 days and lead 
to treatment discontinuation will be considered DLTs

Recurrent grade 2 seizures ie, brief generalized seizures

All grade 3 and 4 adverse events and laboratory abnormalities, which occur during 
the SC administration portion of the treatment period and which, in the opinion of the 
investigator, are at least possibly related to the investigational drug, are considered
as DLT with exceptions noted below: 
o
Laboratory parameters of grade 3 that responds to intervention/treatment 
interruption and resolves to grade 1 within 7 days
o
Grade 3 and 4 lymphopenia
o
Grade 3 fever or infection
o
Grade 3 events of CRS or tumor lysis syndrome that responds to
intervention/treatment interruption and resolves to grade 1 within 7 days
o
Grade 3 neurologic events that respond to intervention/treatment 
interruption and resolves to grade < 1 within 7 days
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6.2.1.3
Premedication With Dexamethasone for Blinatumomab Treatment
Mandatory premedication with dexamethasone is required before each cIV and SC 
treatment cycle and dose-step for the prevention of CRS events resulting from 
blinatumomab treatment: 

Dexamethasone 20 mg IV within 6 hours before the start of infusion/first injection 
on cycle day 1.  

Dexamethasone 20 mg IV within 6 hours before each dose-step

Dexamethasone premedication 20 mg IV within 6 hours prior to starting SC 
on Cycle 1 Day 22, and within 6 hours prior to resuming IV on Cycle 1 
Day 29 is mandatory (in Cycle 1/Period 1).

Dexamethasone premedication will also be required before the restarting 
blinatumomab after a dose interruption due to an adverse event.  See Table 1 for 
details.
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Table 1.  Dexamethasone Pre-dose Treatment and for Events
Treatment Phase
Target Subject (route of 
administration)
Dexamethasone Dose
Comments
Pre-dose 
Dexamethasone 
Prior to Each 
Treatment Cycle / 
Dose-Step
All subjects
Dexamethasone 20 mg 
IV within 6 hours before 
the start of infusion/first 
injection in each 
treatment cycle, and 
within 6 hours before the
dose-step
See Section 6.1
Cycle 1/Period 1
Day 22 prior to 
starting SC
Cycle 1/Period 1 
Day 29 prior to 
resuming cIV
Dexamethasone 20 mg 
IV within 6 hours prior 
to first SC dose Day 22 
and within 6 hours prior 
to resuming cIV on 
Day 29
See
Section 6.2.1.1.1
Infusion 
Interruption/Dose 
Modification Due 
to Adverse Event
Subjects with treatment 
interruption 4 hours 
(cIV)
Subjects with 2 missed 
doses on the q12h dosing 
regimen and 1 missed 
dose on the q24h, q48h, 
q72h, q96h, or q7d
dosing regimen (SC)
Dexamethasone 20 mg 
IV within 6 hours before 
the restart of treatment
See Section 6.1
and 6.2.1.4.2
In case of signs 
of CRS
Subjects with signs of 
CRS (cIV or SC)
Dexamethasone at a 
dose maximum 
3 × 8 mg/day for up to 
3 days.  Reduce
step-wise over 4 days.
See 
Section 6.2.1.4.2
In case of 
Neurologic 
Events
Subjects with central 
nervous system -related 
adverse event
(cIV or SC)
Dexamethasone at a 
maximum dose of 
24 mg/day × 3 days 
maximum.  Reduce 
step-wise over 4 days.
See 
Section 6.2.1.4.2
Abbreviations: cIV continuous intravenous, CRS cytokine release syndrome, IV intravenous, 
q12h every 12 hours; q24h every 24 hours; q48h = every 48 hours; q72h = every 72 hours; 
q96h = every 96 hours; q7d = every 7 days; SC subcutaneous
6.2.1.4
Dosage Adjustments, Delays, Rules for Withholding or Restarting, 
Permanent Discontinuation
6.2.1.4.1
Interruption of Blinatumomab cIV Administration or Missed Doses 
During SC Administration
If possible, during the cIV administration of blinatumomab administration should not be 
interrupted.  In case of blinatumomab interruption because of any technical or logistic 
reason, the interruption should be as short as possible and blinatumomab treatment 
should continue at the earliest time possible.  Any interruption longer than 1 hour should 
Approved 
 
 


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be documented.  If the interruption is longer than 4 hours, re-start of blinatumomab 
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 of the cIV 
or SC IP, in the hospital.  Premedication dexamethasone should be administered as 
described in Table 1.
In the event of drug interruptions of 4 hours in the cIV infusion, or if 2 doses are 
missed in the q12h SC dosing schedule or a single missed dose in the q24h, q48h, 
q72h, q96h, or q7d SC dosing schedule, the restart of IP should be performed in the 
hospital under the supervision of the investigator, with premedication dexamethasone as 
described in Table 1.  The subject should be observed overnight for possible side effects 
after the re-start of the cIV or SC IP.
6.2.1.4.2
Interruption of Blinatumomab Treatment/Dose Modification Due to 
Adverse Events
Common Terminology Criteria for Adverse Events (CTCAE) grade 4 non-laboratory 
adverse events at least possibly related to blinatumomab will require permanent 
discontinuation of blinatumomab.  For all CTCAE grade 3 laboratory events reflective 
of hepatotoxicity or CRS, refer to Sections 6.3 and  Table 2, respectively, for specific 
guidance for the interruption and discontinuation of therapy.  Subjects who have been 
dose reduced will have an option to receive the higher dose level once the adverse 
event has resolved to grade 1 or less for at least 7 days.  For interruptions or dose 
modifications because of neurologic events as defined in Appendix E (refer to Table 2).
If the interruption after an adverse event lasts no longer than 7 days, the same cycle 
should be continued.  An infusion interruption of more than 2 weeks because of an 
adverse event related to blinatumomab will lead to permanent discontinuation of 
treatment.  The infusion duration before and after an interruption should total 7 days at 
each dose level for cIV run-in and the SC treatment duration should be a total of 5 days 
for dose cohorts 1, 2, and 3 or for any additional cohorts at the SC dose and 
frequency determined by the DLRT during week 4 in Cycle 1/Period 1.  For
Cycle 1/Period 2 after a treatment interruption, treatment will resume on the same 
treatment day of the week that it was originally interrupted on (eg, if there was in 
interruption on day 3 of a cycle, day 3 of the cycle will be repeated with all applicable 
assessments at re-start).
For cIV infusion of IP, the lowest dose for restart is 9 μg/day if last dose given was 9 or 
28 μg/day.  The lowest dose for restart should be 28 μg/day cIV infusion if the last dose 
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given was 112 μg/day cIV infusion.  Restart following a dose interruption for cIV infusion 
and SC should be performed in the hospital, under supervision of the investigator and 
the subject should be hospitalized for 48 hours.
For a grade ≥3 neurologic adverse event occurring at initial dosing of 9 μg/day cIV in
Cycle1/Period 1 or 9 μg/day SC equivalent in Cycle 1/Period 2, permanently 
discontinue blinatumomab.
Administer premedication as described in Table 1.  The treatment time for each of the 
treatment cycles is approximately 6 weeks.
Restart cIV infusion should be performed with a 9/28/112 μg/day weekly dose escalation 
if last dose given was 9 or 28 μg/day.  If last dose given was 112 μg/day restart should 
be performed with a 28/112 μg/day dose escalation (dose escalation 1 week after 
restart).  
For SC dosing, the doses that have equivalent exposures to the cIV doses mentioned 
above should be used.
Restart and dose escalation for cIV infusion and SC should be performed in the hospital, 
under supervision of the investigator and the subject should be hospitalized for 48 hours.
In addition, to the events described above, the dose may be temporarily or permanently 
reduced to 9 μg/day cIV infusion (or the equivalent SC dose) if, by the investigator´s 
judgment, it is necessary for safety reasons.  After at least 7 days of dosing at 9 μg/day
cIV infusion (or the equivalent SC dose), the dose may be increased to 28 μg/day cIV 
infusion (or the equivalent SC dose) or treatment may be continued at the dose of 
9 μg/day cIV infusion (or the equivalent SC dose) after consultation with an Amgen 
medical monitor.  Likewise, if an event occurred at a dose of 112 g/ day cIV infusion or 
the SC MTD, the dose may be temporarily or permanently reduced to 28 μg/day cIV 
infusion (or the equivalent SC dose) and may be increased to 112 g/day cIV infusion
(or SC MTD) following the same guidance as described above.  This does not apply for 
neurologic events (refer to Table 2).
Detailed instructions for blinatumomab interruption and re-start instructions for CRS, 
neurotoxicity, hepatotoxicity, and other clinically relevant adverse events are detailed in 
Table 2.
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Table 2. Treatment Interruptions and Restart
Toxicity
Grade
Instructions for Treatment Interruptions and Restart
Neurologic Events
Grade 3
If grade 3 neurologic adverse event occurred at 9 µg/day cIV or 
9 ug/day SC equivalent without prior dose escalation

Permanently discontinue blinatumomab
If grade 3 neurologic adverse event occurred during 
cIV infusion 

Interrupt blinatumomab until grade 1 and administer 
corticosteroids (refer to Table 1)

A contrast-enhanced MRI of the brain should be performed 
before treatment may be resumed

Restart no less than 72 hours after the initial observation 
of the grade 3 event:
For cIV infusions:
o
If event occurred at 112 µg/day cIV 
infusion, resume cIV infusion at 28 µg/day
o
If event occurred at 28 g/day cIV infusion:  
resume cIV infusion at 9 µg/day
o
Escalate up 1 dose level after 7 days if 
toxicity does not reoccur.  Increase dose 
stepwise at 7-day intervals to 112 µg/day 
cIV infusion
             For SC week 4 Period 1/Cycle 1
o
Resume at 28 g/day cIV infusion.
o
Escalate up after 7 days if toxicity does not 
reoccur to 112 µg/day cIV infusion for 
7 days.
o
Hold cIV infusion for 12 hours if toxicity 
did not reoccur
o
Resume with the day SC that toxicity 
occurred at the dose of that cohort (ie, if 
toxicity occurred on day 23 then resume 
SC on day 23 of cycle and repeat all labs 
that are written for this day on Schedule of 
Assessments).
           For SC Period 2:
o
If event occurred at MTD SC, resume SC at 
28 µg/day equivalent
o
If event occurred at 28 µg/day SC equivalent, 
resume SC at 9 µg/day SC equivalent
o
Escalate up 1 dose level after 7 days if 
toxicity does not reoccur.  Increase dose 
stepwise at 7-day intervals to MTD SC
Permanently discontinue blinatumomab if: 

Initial grade 3 event does not improve to grade 1 
within 7 days, OR

Grade 3 event reoccurs at the lower dose level within 
7 days of re-initiation, OR

Initial Grade 3 event occurred at dose of 9 µg/day cIV 
or SC equivalent 9 ug/day without out prior dose 
escalation
Page 1 of 4
Abbreviations defined on last page of the table.
Approved 
 
 


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Table 2. Treatment Interruptions and Restart
Toxicity
Grade
Instructions for Treatment Interruptions and Restart
Neurologic Events
(continued)
Grade 4

Permanently discontinue blinatumomab
Seizure 

Interrupt blinatumomab and administer 
corticosteroids (refer to Table 1) and anti-seizure 
medication according to 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 blinatumomab if:
o
A second seizure occurs with re-initiation of 
blinatumomab at any dose
Cytokine release 
syndrome
Grade 3

Interrupt blinatumomab until grade 1 and administer 
corticosteroids (refer to Table 1).

Restart no less than 72 hours after the initial observation 
of the grade 3 event at the following dose levels:
For cIV infusions:

If event occurred at 112 g/day, resume cIV infusion at 
28 μg/day

If event occurred at dose of 9 g/day or 28 g/day, 
resume cIV infusion at 9 g/day

Escalate up 1 dose level after 7 days if toxicity does 
not reoccur.  Increase dose stepwise at 7-day intervals 
to target dose of 112 g/day if toxicity does not 
re-occur
       For SC week 4 Period 1/Cycle 1
o
Resume at 28 g/day cIV infusion.
o
Escalate up after 7 days if toxicity does not 
reoccur to 112 µg/day cIV infusion for 7 days.
o
Hold cIV infusion for 12 hours if toxicity did not 
reoccur
o
Resume with the day SC that toxicity occurred at 
the dose of that cohort (i.e if toxicity occurred on 
day 23 then resume SC on day 23 of cycle and 
repeat all labs that are written for this day on 
Schedule of Assessments).
       For Period 2 SC:
o
If event occurred at MTD SC, resume at 28 μg/day 
SC equivalent
o
If event occurred at SC dose equivalent to 
9 g/day or 28 g/day, resume SC at 9 g/day SC 
equivalent
o
Escalate up 1 dose level after 7 days if toxicity 
does not reoccur.  Increase dose stepwise at 
7-day intervals to MTD SC if toxicity does not 
re-occur
Page 2 of 4
Abbreviations defined on last page of the table.
Approved 
 
 


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Page 45 of 113
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Table 2. Treatment Interruptions and Restart
Toxicity
Grade
Instructions for Treatment Interruptions and Restart
Cytokine release 
syndrome
(continued)
Grade 4

Permanently discontinue blinatumomab 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 re-initiation, OR
o
Grade 3 CRS reoccurs at a dose of 9 μg/day cIV (or the 
equivalent SC dose) without prior step-dose 
escalation

Permanently discontinue blinatumomab
Elevated liver 
enzymes

Interrupt blinatumomab if any 1 of the following occurs:
o
TBL 3 × ULN at any time
o
ALP 8 × ULN at any time
o
AST or ALT 8 × ULN at any time
o
AST or ALT 5 × ULN but 8 × ULN for 2 weeks
o
AST or ALT 3 × ULN with clinical signs or symptoms 
that are consistent with hepatitis (eg, RUQ abdominal 
pain/tenderness, fever, nausea, vomiting, jaundice)

Permanently discontinue blinatumomab if:
o
TBL 2 × ULN OR INR 1.5 (for subjects not on 
anticoagulant therapy)
AND
o
AST or ALT 3 × ULN (when baseline was ULN)
AND
o
No other cause for the combination of the above 
laboratory abnormalities is immediately apparent
Refer to Section 6.3 for additional details
Other clinically 
relevant adverse 
events
Grade 3
o
Interrupt blinatumomab until grade 1
o
Restart no less than 72 hours after the initial 
observation of the grade 3 event at the following dose 
levels:
For cIV infusion
o
If event occurred at 112 g/day, resume cIV infusion at 
28 μg/day 
o
If event occurred at dose of 9 g/day or 28 g/day, 
resume cIV infusion at 9 g/day
o
Escalate up 1 dose level after 7 days if toxicity does 
not reoccur.  Increase dose stepwise at 7-day intervals 
to target dose of 112 g/day if toxicity does not 
re-occur
Page 3 of 4
Abbreviations defined on last page of the table.
Approved 
 
 


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Page 46 of 113
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Table 2. Treatment Interruptions and Restart
Toxicity
Grade
Instructions for Treatment Interruptions and Restart
Other clinically 
relevant adverse 
events (continued)
Grade 3
        For SC week 4 Period 1/Cycle 1
o
Resume at 28 g/day cIV infusion.
o
Escalate up after 7 days if toxicity does not reoccur 
to 112 µg/day cIV infusion for 7 days.
o
Hold cIV infusion for 12 hours if toxicity did not 
reoccur
o
Resume with the day SC that toxicity occurred at the 
dose of that cohort (i.e if toxicity occurred on day 23 
then resume SC on day 23 of cycle and repeat all 
labs that are written for this day on Schedule of 
Assessments).
         For SC Period 2:
o
If event occurred at MTD SC, resume SC at 
28 µg/day equivalent SC
o
If event occurred at 28 µg/day SC equivalent, 
resume SC at 9 µg/day SC equivalent
o
Escalate up 1 dose level after 7 days if 
toxicity does not reoccur.  Increase dose 
stepwise at 7-day intervals to MTD SC 

Permanently discontinue blinatumomab if:
o
Initial grade 3 event does not improve to 
grade 1 within 14 days, OR
o
Grade 3 event reoccurs at the lower dose 
level within 7 days of re-initiation, OR
o
Grade 3 event reoccurs at a dose of 
9 μg/day cIV (or the equivalent SC dose) 
without prior step-dose escalation
Grade 4
Permanently discontinue for non-laboratory adverse events at 
least possibly related to blinatumomab
Page 4 of 4
Abbreviations: ALP alkaline phosphatase; ALT alanine aminotransferase; AST aspartate 
aminotransferase; cIV continuous intravenous; CRS cytokine release syndrome; INR international 
normalized ratio; MRI magnetic resonance imaging; MTD = maximum tolerated dose; RUQ right upper 
quadrant; SC subcutaneous; TBL total bilirubin level; ULN upper limit of normal.
Biomarker samples, as described in Section 7.5, will also be collected for grade 
3 neurologic adverse events or grade 3 CRS that occur in all periods of the study at 
the start of the adverse event and at the time of resolution of the adverse event.
If 2 subjects within any Cycle1/Period 1 cohort experience a DLT, the remaining 
subjects enrolled in that cohort that have not reached the SC week 4 of 
Cycle 1/Period 1 will not receive any SC but can continue on cIV dosing to
complete 6 weeks of IV treatment.
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6.2.1.4.3
Criteria for Permanent Discontinuation of Blinatumomab
Treatment with blinatumomab should be permanently discontinued in the event of any of 
the following (see Section 8.3.1):

clinically relevant disease progression, relapse, non-response for subjects in 
period 1

subject or investigator not compliant with the study protocol

administration of relevant non-permitted concomitant medication(s) 

occurrence of an adverse event which makes discontinuation from treatment 
necessary due to protocol specified safety criteria or desirable in the investigator's 
and/or the subject's opinion

occurrence of one of the following (defined in Appendix E):
o
a second seizure that occurred with re-initiation of blinatumomab at any dose
o
a CTCAE grade 4 neurologic event
o
an initial grade 3 neurologic event that does not improve to grade 1 within
7 days
o
a grade 3 neurologic event that reoccurs at the lower dose level within 7 days 
of re-initiation
o
Initial grade 3 neurologic event that occurred at the 9 µg/day cIV or 
9 µg/day SC equivalent without prior dose escalation
o
grade 4 CRS

grade 3 CRS that reoccurs at the lower dose level within 7 days of re-initiation

initial grade 3 CRS that does not resolve to grade 1 within 7 days 

grade 3 CRS that reoccurs at a dose of 9 g/day cIV (or the equivalent SC dose) 
without prior step-dose escalation

elevated liver enzymes (meeting all of the criteria below):
o
total bilirubin (TBL) 2 × ULN or international normalized ratio (INR) 1.5 (for 
subjects not on anticoagulant therapy)
o
AST or ALT 3 × ULN (when baseline was ULN)
o
no other cause for the combination of the above laboratory abnormalities is 
immediately apparent

an infusion interruption of more than 14 days due to an adverse event related to 
blinatumomab (with the exception of delay in restart due to logistical difficulties, in 
which case the restart may be postponed for an additional 7 days)

any grade 4 non-laboratory adverse event at least possibly related to blinatumomab
6.3
Hepatotoxicity Stopping and Rechallenge Rules
Subjects with abnormal hepatic laboratory values (ie, alkaline phosphatase [ALP], AST, 
ALT, TBL) and/or INR and/or signs/symptoms of hepatitis (as described below) may 
meet the criteria for withholding or permanent discontinuation of Amgen investigational 
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product or other protocol-required therapies as specified in the Guidance for Industry 
Drug-Induced Liver Injury: Premarketing Clinical Evaluation, July 2009.
6.3.1
Criteria for Permanent Discontinuation of Blinatumomab and Other 
Protocol-required Therapies Due to Potential Hepatotoxicity
Blinatumomab and other protocol-required therapies should be discontinued 
permanently and the subject should be followed according to the recommendations in 
Appendix D (Additional Safety Assessment Information) for possible drug induced liver 
injury (DILI), if ALL of the criteria below are met:

TBL 2 × ULN or INR 1.5

AND increased AST or ALT from the relevant baseline value as specified below: 
Baseline AST or ALT value
AST or ALT elevation
ULN
3 × ULN

AND no other cause for the combination of the above laboratory abnormalities is 
immediately apparent; important alternative causes for elevated AST/ALT and/or 
TBL values include, but are not limited to:

hepatobiliary tract disease

viral hepatitis (eg, Hepatitis A/B/C/D/E, Epstein-Barr Virus, 
cytomegalovirus, Herpes Simplex Virus, Varicella, toxoplasmosis, and 
Parvovirus)

right sided heart failure, hypotension or any cause of hypoxia to the liver 
causing ischemia

exposure to hepatotoxic agents/drugs or hepatotoxins, including herbal 
and dietary supplements, plants and mushrooms  

heritable disorders causing impaired glucuronidation (eg, Gilbert’s 
Syndrome, Crigler-Najjar syndrome) and drugs that inhibit bilirubin 
glucuronidation (eg, indinavir, atazanavir)

alpha-one antitrypsin deficiency

alcoholic hepatitis

autoimmune hepatitis 

Wilson’s disease and hemochromatosis

nonalcoholic Fatty Liver Disease including Steatohepatitis (NASH) 

non-hepatic causes (eg, rhabdomylosis, hemolysis)

cytokine release syndrome
If an alternative cause for hepatotoxicity is identified or less stringent conditions 
developed than what are noted above, the investigator should determine (based on 
patient population and/or severity of the hepatotoxicity or event) if blinatumomab and 
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other protocol-required therapies should be withheld or permanently discontinued, as 
deemed appropriate for the safety of the subject. 
6.3.2
Criteria for Conditional Withholding of Blinatumomab and Other 
Protocol-required Therapies Due to Potential Hepatotoxicity
For subjects who do not meet the criteria for permanent discontinuation of blinatumomab 
outlined above and have no underlying liver disease, and eligibility criteria requiring 
normal transaminases and TBL at baseline or subjects with underlying liver disease and 
baseline abnormal transaminases, the following rules are recommended for withholding 
of blinatumomab and other protocol-required therapies:

Elevation of either AST or ALT according to the following schedule:
Baseline AST or ALT value
AST or ALT elevation 
Any
8 × ULN at any time
Any
5 × ULN but 8 × ULN for 2 weeks
Any
5 × ULN but 8 × ULN and unable to adhere to 
enhanced monitoring schedule
Any
3 × ULN with clinical signs or symptoms that are 
consistent with hepatitis (such as right upper quadrant 
pain/tenderness, fever, nausea, vomiting, jaundice).  

OR: TBL 3 × ULN at any time

OR: ALP 8 × ULN at any time
Blinatumomab and other protocol-required therapies, as appropriate should be withheld 
pending investigation into alternative causes of DILI.  If IP is withheld, the subject is to 
be followed according to recommendations in Appendix D for possible DILI.  
Rechallenge may be considered if an alternative cause for impaired liver tests (ALT, 
AST, ALP) and/or elevated TBL, is discovered and the laboratory abnormalities resolve 
to normal or baseline (Section 6.3.3).
6.3.3
Criteria for Rechallenge of Blinatumomab 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 
Section 6.2.1.4.3) should never be rechallenged.
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6.4
Concomitant Therapy
Throughout the study, investigators may prescribe any concomitant medications or 
treatments deemed necessary to provide adequate supportive care except for those 
listed in Section 6.8.
For concomitant therapies being taken for NHL and that assist in the evaluation of 
efficacy or safety endpoints, collect therapy name, indication, dose, unit, frequency, start 
date and stop date. 
For all other concomitant therapies, collect therapy name, indication, dose, unit, 
frequency, route, start date and stop date.  
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community 
standards of medical care.  All concomitant medication will be recorded on the CRF 
including all prescription, over-the-counter, herbal supplements, and IV medications and 
fluids.  Concomitant therapies are to be collected from signing of the informed consent 
form through the safety follow-up period.  For therapies used for the treatment of 
lymphoma, all data for medications and treatments will be recorded from the time of 
diagnosis of the lymphoma, not the signing of the informed consent form.  If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
may also be included on the CRF.
6.5
Other Treatment Procedures
6.5.1
Fever Management
Fevers may be managed per local clinical standard of care.  For symptomatic relief of 
fevers due to any cause (eg, infection, drug fever) the recommended first choices for 
fever management are paracetamol/acetaminophen and/or dexamethasone.  The 
dexamethasone dose should be reduced step-wise as soon as the fever is resolved.  If 
these are not sufficiently effective, pethidin/meperidine is recommended.  For 
pethidin/meperidine, adequate antiemetic prophylaxis should be administered.  The 
treating physician should also use their clinical judgment to determine the underlying 
cause of the fever and treatment.  For instance, in the case of fever due to infection one 
should consider the use of antibiotics and avoid the use of dexamethasone.
Approved 
 
 


Product:  Blinatumomab
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Date:  25 February 2019
Page 51 of 113
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6.6
Medical Devices
Blinatumomab (cIV) must be administered using infusion pumps approved for use by the 
appropriate regulatory authorities for the country in which the subject is undergoing 
treatment.
Blinatumomab infusion for solution will be prepared in bags for IV infusion and delivered 
through infusion lines that are both compatible with the IP as described in the IPIM.  The 
blinatumomab final solution for infusion should not come into contact with the pump at 
any time.
SC formulation dosing will be administered via standard, locally available plastic 
disposable syringe.
Additional details for the use of the above-mentioned medical devices are provided in 
the IPIM.
6.7
Product Complaints
A product complaint is any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug(s) or device(s) after it is released for distribution to market or 
clinic by either Amgen or by distributors and partners for whom Amgen manufactures the 
material. 
This includes any drug(s), device(s) or combination product(s) provisioned and/or 
repackaged /modified by Amgen.  Drug(s) or device(s) includes investigational product.
Any product complaint(s) associated with an investigational product(s) or 
non-investigational product(s) or device(s) supplied by Amgen are to be reported
according to the instructions provided in the IPIM.
6.8
Excluded Treatments, Medical Devices, and/or Procedures During 
Study Period
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this study:

antineoplastic systemic chemotherapy or biological therapy such as rituximab or 
obinutuzumab and/or other monoclonal antibody

immunotherapy not specified in this protocol such as anti-CD19 targeted therapies, 
chimeric antigen receptor T-cell or other cellular therapies
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
investigational agents other than blinatumomab

radiation therapy including radioimmunotherapy
Exception:  Palliative radiation therapy to a symptomatic solitary lesion may be 
considered.  The subject must have clear measurable disease outside the 
radiated field.  
6.9
Contraceptive Requirements
6.9.1
Female Subjects
A female is considered of childbearing potential unless she has undergone a
hysterectomy, bilateral salpingectomy, bilateral oophorectomy, or is postmenopausal.  
Postmenopausal is defined as:  

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  (A high follicle stimulating hormone level in the 
postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
[HRT].  However, in the absence of 12 months of amenorrhea, a single follicle 
stimulating hormone measurement is insufficient).

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study.  Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
Female subjects of childbearing potential must agree to practice sexual abstinence or 
use an acceptable method of effective contraception during the treatment and for an 
additional 48 hours after the last dose of cIV or 96 hours after the last dose of SC 
blinatumomab.  
Acceptable methods of contraception include:  

Combined (estrogen and progestogen) or Progestogen-only hormonal methods 
given via oral, intravaginal, transdermal, injectable, or implantable route

Intrauterine device (IUD)

Intrauterine hormonal-releasing system (IUS)

Bilateral tubal ligation/occlusion

Vasectomized partner (Provided that partner is the sole sexual partner of the 
female subject of childbearing potential and that the vasectomized partner has 
received medical assessment of the surgical success)
Approved 
 
 


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
Sexual abstinence (Defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatments.  The reliability of 
sexual abstinence must be evaluated in relation to the duration of the trial and 
the preferred and usual lifestyle of the subject.)

Double barrier method:  the male uses a condom and the female may choose 
either a cervical cap, diaphragm, or contraceptive sponge with spermicide 
(A female condom is not an option due to the risk of tearing when both partners 
use a condom.)
Female subjects of childbearing potential must receive pregnancy prevention counseling 
and be advised of the risk to fetus if they become pregnant during treatment and for an 
additional 48 hours after the last dose of cIV blinatumomab or 96 hours after the last 
dose of SC blinatumomab.
Additional medications given during treatment with blinatumomab may alter the 
contraceptive requirements.  These additional medications may require female subjects 
use highly effective methods of contraception and for an increased length of time.  In 
addition, male subjects may also be required to use contraception.  The investigator is to 
discuss these contraceptive changes with the subject.
If a female subject is suspected of being pregnant, the protocol-required therapies must 
be stopped immediately and may not be resumed until absence of pregnancy has been 
medically confirmed.  
6.9.2
Unacceptable Methods of Birth Control for Women Subjects
Birth control methods that are considered unacceptable in clinical trials include:  periodic 
abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method.
7.
STUDY PROCEDURES
Screening assessments and study procedures outlined in this section and in Table 3, 
Table 4, Table 5, Table 6, and Table 7 will be performed after obtaining a signed 
informed consent form.  
It is very important to attempt to perform study procedures and obtain samples at the 
precise timepoints stipulated below.  When it is not possible to perform the study visit at 
the exact time point, the visit may be performed within the acceptable visit window as 
defined in the visit-specific section below.
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 
Approved 
 
 


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Date:  25 February 2019
Page 54 of 113
CONFIDENTIAL
schedule.  Missed assessments at prior visits should not be duplicated at subsequent
visits.
Refer to the applicable supplemental laboratory manuals for detailed collection and 
handling procedures.
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
Page 55 of 113
CONFIDENTIAL
7.1
Schedule of Assessments
Table 3.  Schedule of Assessments for Cycle 1/Period 1
Screening
Treatment Period
Safety 
Follow-up a, b, c
EOS 
(7 days)
Study Part
cIV Run-in
Subcutaneous Administration
cIV to complete 
6 weeks of treatment
EOT 
(3 
days)
Cycle Day
-14 to -1
1
2
3
8
9
10
15
16
17
22
23
24
25
26
27
28
29
30
31
37
43
Cycle Week
1
2
3
4
5
6
GENERAL AND SAFETY ASSESSMENTS
Informed consent
X
Inclusion/exclusion 
criteria
X
Medical history/ current 
medical conditions
X
Demographics
X
ECOG Performance 
Status
X
X
Physical examination 
(including neurologic 
examination)d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizatione
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs, 
temperaturef
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse eventsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious adverse 
eventsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Disease related events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
LABORATORY ASSESSMENTS
Serum or urine 
pregnancy testh
X
Coagulationi
X
X
Hematology 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
Page 1 of 2
Footnote defined on next page of the table
 
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
Page 56 of 113
CONFIDENTIAL
Table 3.  Schedule of Assessments for Cycle 1/Period 1
Screening
Treatment Period
Safety 
Follow-upa, b, c
EOS 
(7 days)
Study Part
cIV Run-in
Subcutaneous Administration
cIV to complete 
6 weeks of treatment
EOT 
(3 
days)
Cycle Day
-14 to -1
1
2
3
8
9
10
15
16
17
22
23
24
25
26
27
28
29
30
31
37
43
Cycle Week
1
2
3
4
5
6
LABORATORY ASSESSMENTS (Continued)
Hepatitis serology, 
HIV
X
Anti-blinatumomab
antibody
Xp
Xp
Xp
X
IgG
X
X
X
Lumbar puncturej
X
Creatinine 
Clearancek
X
INVESTIGATIONAL PRODUCT DOSING
Blinatumomab
X
X
X
X
X
X
X
X
X
├───────────────see Table 4 below──────────────┤
BIOMARKER ASSESSMENTS
Cytokines
Xq
Xq
Lymphocyte subsetsl
X
X
PK ASSESSMENTS
Blinatumomab PK 
sample
Xr
Xr
Xr
├───────────────see Table 4 below──────────────┤
DISEASE ASSESSMENTS
PET-CT, CT, or 
contrast enhanced 
CTm
X
X
Bone marrow biopsy n, 
o
X
Xs
Page 2 of 2
Abbreviations: cIV continuous intravenous, CRS cytokine release syndrome, CTCAE Common Terminology Criteria for Adverse Events, CT computed tomography, 
ECOG Eastern Cooperative Oncology Group, EOT end of treatment, EOS end of study, HIV human immunodeficiency virus, IgG immunoglobulin G, INR international 
normalized ratio, IP investigational product, PET positron emission tomography, PK pharmacokinetic, PTT partial thromboplastin time, q12h every 12 hours, SC subcutaneous.
a If a subject discontinues the study the safety follow-up procedures should be conducted immediately.
b All subjects, including subjects who withdraw from the study early, should complete a safety follow-up visit 30 (7) days after the last dose of blinatumomab, or before hematopoietic stem 
cell transplant (HSCT) or any other non-protocol specified anti-tumor therapy, if applicable.
c Safety follow-up (EOS) should only be done following cycle 1 if treatment is ended after the 6 weeks of blinatumomab and no second cycle is planned to be administered.  If a second 
cycle is planned then obtain the EOS after cycle 2.
 
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d Physical examination will include weight.  Screening only: medical and surgical history, and height will also be obtained.  Physical examination should be performed before the start of 
cIV infusion or dose increase, or before the subcutaneous injection, respectively.
e Hospitalization during cIV administration in Period 1: at least 72 hours at the start of cIV and after each dose-step, as well as for at least 48 hours after the return to cIV infusion after 
the SC dosing in Cycle 1/Period 1. Hospitalization during subcutaneous administration: 5 days SC administration, and an additional 2 days drug free (7 days total).  NOTE: SC 
dosing should begin on a Monday (unless the study site can administer SC injections on the weekend).
f The investigator should monitor the subject's vital signs continuously every 4 hours (2 hours) during the first 12 hours after the start of each new treatment/dose-step.  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 most recumbent position possible.  The position selected for a subject should be the same throughout the study. Vital sign measurements will be repeated daily during the 
subject's hospitalization.
g Serious adverse events are collected from the time of signing informed consent form to the end of study and adverse events are collected after the first dose of IP.
h Serum or urine pregnancy test will be performed for all female subjects unless surgically sterile or 2 years postmenopausal.  Additional pregnancy testing may be performed at the 
investigators’ discretion or as required per local laws and regulations.
I Coagulation will include partial thromboplastin time (PTT), INR, and fibrinogen.
j Lumbar puncture is only needed for disease assessment per standard of care per investigator.  Lumbar puncture should be obtained for evaluation of seizures during blinatumomab 
treatment, if clinically stable, and a sample sent for blinatumomab PK.
k Creatinine clearance to be calculated by Cockcroft-Gault equation.
l Lymphocyte subsets for the study are listed above in SOA and are to be collected prior to administration of IP on days 1 and 22, however, additional samples will be collected for adverse 
events of CTCAE grade 3 neuro toxicity and CRS occurs throughout the study at the start and resolution of the event (refer to Section 7.3.16.1).
m Disease assessments are to be performed to establish staging and response per Cheson if disease assessment is by CT scans (Appendix A) and Lugano criteria if disease 
assessment includes PET/CT (Appendix B).  For PET-CT, CT, or contrast enhanced CT the same imaging modality should be used throughout the study for an individual subject.  
Disease assessment to occur: during screening; just prior to optional cycle 2 if given (attempt to obtain this study at least 2 weeks after stopping IP in cycle 1 and just prior to starting 
cycle 2); and the last disease assessment is 4 weeks after finishing the last dose of IP.  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.
n Bone marrow biopsy to be performed according to Cheson (Appendix A) and Lugano criteria (Appendix B [standard of care per investigator]). 
o Bone marrow biopsy performed within 21 days of the first dose of IP may be used in place of screening assessment to establish staging or response per Cheson (Appendix A) and Lugano 
criteria (Appendix B).
p Anti-blinatumomab antibody predose on day 1, before the administration of first SC dose (following 12 hour wash out from cIV), and predose at the re-start of cIV infusion (following the 
2 to 3 day washout). 
q Cytokine sample on days 1 and 22: predose and at the following time points postdose, 2 hours (15 minutes), 4 hours, 6 hours (30 minutes for both the 4 and 6 hour time 
points), and 12 hours (before the next injection in case of q12h dosing 1 hour). Additional samples will be collected for adverse events of CTCAE grade 3 neuro toxicity 
and CRS occurs throughout the study at the start and resolution of the event (Refer to Section 7.3.16.2).
r During cIV run-in, PK samples are collected any time during the day on the second day after the start of the 9 g/day, 28 g/day and 112 g/day doses, (obtain samples on 
days 2, 9, and 16, respectively).  During SC dosing, PK samples are collected per Table 4.  Refer Section 7.3.15 for detail, sampling window and handling if dose interruption 
occurred. Additional samples will be collected for adverse events of CTCAE grade 3 neuro toxicity and CRS occurs throughout the study at the start of the event, 24 hours
after the event, and at the resolution of the event (Refer to Section 7.3.15).
s Bone marrow biopsy only to be repeated with a response assessment (3 weeks after end of treatment as per standard of care) to establish staging or response per Cheson 
(Appendix A) and Lugano criteria (Appendix B).
 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20140286 
Date:  25 February 2019 
Page 58 of 113 
CONFIDENTIAL 
 
 
Table 4.  Cycle 1/Period 1 Investigational Product Dosing and PK Assessments for Week 4 and 5 
Study Part 
Subcutaneous Administration 
(Doses tested sequentially in separate cohorts) 
cIV to complete  
6 weeks of treatment 
Cycle Day 
22 
23 
24 
25 
26 
27 
28 
29 
30 
31 
37 
Cycle Week 
4 
 
5 
 
6 
q12h 
Blinatumomab 
Xb 
Xb 
Xb 
Xb 
Xb 
 
 
X 
X 
X 
X 
Blinatumomab PK samplea 
Xc 
 
 
 
Xc 
Xc 
Xc 
 
Xd 
 
 
q24h 
Blinatumomab 
Xb 
Xb 
Xb 
Xb 
Xb 
 
 
X 
X 
X 
X 
Blinatumomab PK samplea 
Xc 
 
 
 
Xc 
Xc 
Xc 
 
Xd 
 
 
q48h 
Blinatumomab 
Xb 
 
Xb 
 
Xb 
 
 
X 
X 
X 
X 
Blinatumomab PK samplea 
Xc 
 
 
 
Xc 
Xc 
Xc 
 
Xd 
 
 
q72h 
Blinatumomab 
Xb 
 
 
Xb 
 
 
 
X 
X 
X 
X 
Blinatumomab PK samplea 
Xe 
 
 
Xe 
Xe 
Xe 
Xe 
 
Xd 
 
 
q96h 
Blinatumomab 
Xb 
 
 
 
Xb 
 
 
X 
X 
X 
X 
Blinatumomab PK samplea 
Xc 
 
 
 
Xc 
Xc 
Xc 
 
Xd 
 
 
q7d 
Blinatumomab 
Xb 
 
 
 
 
 
 
X 
X 
X 
X 
Blinatumomab PK samplea 
Xf 
Xf 
Xf 
Xf 
Xf 
 
 
 
Xd 
 
 
Abbreviations:  cIV = continuous intravenous; CRS = cytokine release syndrome; CTCAE = Common Terminology Criteria for Adverse Events; PK = pharmacokinetic; 
q12h = every 12 hours; q24h = every 24 hours; q48h = every 48 hours; q72h = every 72 hours; q96h = every 96 hours; q7d = every 7 days; SC = subcutaneous 
a Additional PK samples will be collected for adverse events of CTCAE ≥ grade 3 neuro toxicity and CRS occur throughout the study at the start, 24 hours after the event and at 
the resolution of the event.  PK data will be collected for CTCAE ≥ grade 3 adverse events of CRS or neurotoxicity that occurs during SC administration.  Obtain the samples 
as close as possible to the start of the event, at approximately 24 hours after the event and at the end of the event when all symptoms are resolved.  Refer to 
Section 7.3.15.1. 
b If a subject has a dose interruption during the SC administration period and that dose needed to be provided on a weekend, then the dose will be held and dosing will resume on the next 
business day if the site is unable to administer SC dosing on weekends due to local feasibility challenges.  In that case, despite any extra days added due to treatment interruption in the 
cIV portion, day 22 still refers to the first day of SC administration. 
c During SC dosing, at q12h, q24h, q48h, and q96h, PK samples are collected for the first dose on day 22 (pre-dose, as well as 1 hour ± 15 minutes, 2 hours ± 15 minutes, 
4 hours ± 30 minutes, 6 hours ± 30 minutes, 8 ± 1 hours, and 12 ± 1 hour (before the next q12h dose if applicable)  and for the last dose on day 26 (pre-dose, as well as post-dose at 
1 hour ± 15 minutes, 2 hours ± 15 minutes, 4 hours ± 30 minutes, 6 hours ± 30 minutes, 8 ± 1 hours, 12 ± 1 hours, as well as 24 ± 2 hours (day 27), and 48 ± 2 hours (day 28).   
d In the return to cIV dosing following the 5 treatment days of SC administration, PK samples are collected at any time during the day on the second day (day 30) after resuming 112 µg/day 
cIV dose (day 29).  Refer Section 7.3.15.1 for detail, sampling window and handling if dose interruption occurred. 
e For the SC q72h dosing regimen, PK samples are collected for the first dose on day 22 (pre-dose, as well as 1 hour ± 15 minutes, 2 hours ± 15 minutes, 4 hours ± 30 minutes, 
6 hours ± 30 minutes, 8 ± 1 hours, and 12 ± 1 hour and for the last dose on day 25 (pre-dose, as well as post-dose at 1 hour ± 15 minutes, 2 hours ± 15 minutes, 
4 hours ± 30 minutes, 6 hours ± 30 minutes, 8 ± 1 hours, 12 ± 1 hours, as well as 24 ± 2 hours (day 26), 48 ± 2 hours (day 27), and 72 ± 2 hours (day 28).   
f For the SC q7d dosing regimen, PK samples are collected for the dose on day 22 (pre-dose, as well as 1 hour ± 15 minutes, 2 hours ± 15 minutes, 4 hours ± 30 minutes, 
6 hours ± 30 minutes, 8 ± 1 hours, and 12 ± 1 hour as well as 24 ± 2 hours (day 23), 48 ± 2 hours (day 24). 72 ± 2 hours (day 25) and 96 ± 2 hours (day 26).   
 
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
Page 59 of 113
CONFIDENTIAL
Table 5.  Schedule of Assessments for Cycle 1/Period 2
Screening
Treatment Period
Safety 
Follow-up 
a, b, c
EOS
(7 days)
Study Part
Period 2 Subcutaneous Administration
EOT 
(3 days)
Cycle Day
-14 to -1
1
2
3
8
9
10
15
16
17
22t
29t
36t
42
Cycle Week
1
2
3
4
5
6
GENERAL AND SAFETY ASSESSMENTS
Informed consent
X
Inclusion/exclusion criteria
X
Medical history/ current medical 
condition
X
Demographics
X
ECOG Performance Status
X
X
Physical examination 
(including neurological 
examination)d
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizatione
├────────────────see footnote e below───────────────┤
Vital signs, temperaturef
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse eventsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious adverse eventsg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Disease related events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
LABORATORY ASSESSMENTS
Serum or urine pregnancy testh
X
Coagulationi
X
X
Hematology 
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
Hepatitis serology, HIV
X
Page 1 of 2
Footnotes defined on next page of the table
 
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
Page 60 of 113
CONFIDENTIAL
Table 5.  Schedule of Assessments for Cycle 1/Period 2
Screening
Treatment Period
Safety 
Follow-up 
a, b, c
EOS
(7 days)
Study Part
Period 2 Subcutaneous Administration
EOT 
(3 days)
Cycle Day
-14 to -1
1
2
3
8
9
10
15
16
17
22t
29t
36t
42
Cycle Week
1
2
3
4
5
6
LABORATORY ASSESSMENTS (continued)
Anti-blinatumomab antibody
Xn
Xu
Xu
Xu
Xu
X
IgG
X
X
X
Lumbar puncturej
X
Creatinine Clearances
X
INVESTIGATIONAL PRODUCT DOSING
Blinatumomab
├──────────────────────────────see Table 6 below─────────────────────┤
BIOMARKER ASSESSMENTS
Cytokineso
├─────────────────────────see Table 6 below───────────────────┤
Lymphocyte subsetsp
├─────────────────────────see Table 6 below───────────────────┤
PK ASSESSMENTS
Blinatumomab PK sampleq
├─────────────────────────see Table 6 below───────────────────┤
DISEASE ASSESSMENTS
PET-CT, CT or contrast enhanced 
CTk
X
X
Bone marrow biopsyl, m
X
Xr
Page 2 of 2
Abbreviations: CT computed tomography, ECOG Eastern Cooperative Oncology Group, EOT end of treatment, EOS end of study, HIV human immunodeficiency virus, 
HSCT hematopoietic c stem cell transplant, IgG immunoglobulin G, INR international normalized ratio, IP investigational product, PET positron-emission tomography, 
PK pharmacokinetic, PTT partial thromboplastin time, SC subcutaneous.
a If a subject discontinues the study the safety follow-up procedures should be conducted immediately.
b All subjects, including subjects who withdraw from the study, should complete a safety follow-up visit 30 (7) days after the last dose of blinatumomab, or before HSCT or any other 
non-protocol specified anti-tumor therapy, if applicable.
c Safety follow-up (EOS) should only be done following cycle 1 if treatment is ended after the 6 weeks of blinatumomab and no second cycle is planned to be administered.  If a second 
cycle is planned then obtain the EOS after Cycle 2.
d Physical examination will include weight.  Screening only: medical and surgical history, and height will also be obtained. 
 
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  25 February 2019
Page 61 of 113
CONFIDENTIAL
e Hospitalization in Period 2: For subjects 1-5:  day 1 until completion of the second MTD dose PK being finished.  Sites where outpatient PK cannot be obtained, for third MTD 
SC dose, the subject needs to be hospitalized until completion of the third MTD dose PK.  Subjects 6-15:  are hospitalized on days 1-8 (discharge 8 hours after day 8, 
28 µg/day SC dose is administered) and readmitted to the hospital on day 12 (prior to first MTD SC dose) until 8 hours after the second MTD SC dose is administered.  Sites 
where outpatient PK cannot be obtained, for third 28 µg/day equivalent SC dose and third MTD SC dose, the subject needs to be hospitalized until completion of the third
MTD dose PK.
f The investigator should monitor the subject's vital signs continuously every 4 hours (2 hours) during the first 12 hours after the start of each new treatment/dose-step. 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 most recumbent position possible.  The position selected for a subject should be the same throughout the study.  Vital sign measurements will be repeated daily during the 
subject's hospitalization.
g Serious adverse events are collected from the time of signing informed consent form to the end of study and adverse events are collected after the first dose of IP.
h Serum or urine pregnancy test will be performed for all women subjects unless surgically sterile or 2 years postmenopausal.  Additional pregnancy testing may be performed at the 
investigator’s discretion or as required per local laws and regulations.
I Coagulation will include PTT, INR, and fibrinogen. 
j Lumbar puncture is only needed for disease assessment per standard of care per investigator.  Lumbar puncture should be obtained for evaluation of seizures that occur during 
blinatumomab treatment, if clinically stable, and a sample sent for blinatumomab PK.
k Disease assessments are to be performed as to establish staging and response per Cheson (Appendix A) and Lugano criteria (Appendix B).  For PET-CT, CT, or contrast enhanced CT 
the same imaging modality should be used throughout the study for an individual subject.  Disease assessment to occur: during screening; just prior to optional cycle 2 if given (attempt 
to obtain this study at least 2 weeks after stopping IP in cycle 1 and just prior to starting cycle 2); and the last disease assessment is 4 weeks after finishing the last dose of IP. 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. 
l Bone marrow biopsy to be performed according to Cheson (Appendix A) and Lugano criteria (Appendix B [standard of care per investigator]).
m Bone marrow assessment performed within 21 days of the first dose of IP may be used in place of screening assessment to establish staging or response per Cheson (Appendix A) and 
Lugano criteria (Appendix B).
n Anti-blinatumomab antibody on day 1 predose
o Cytokines will be obtained as outlined in the dosing option tables (Table 6); additional cytokine samples will also be collected for adverse events of CTCAE grade 3 of CRS 
or neurotoxicity if it occurs (Refer to Section 7.3.16.2).  Obtain the samples as close as possible to the start of the event and at resolution of the event (Refer to
Section 7.3.16.2).
p Lymphocyte subsets will be collected as outlined in the dosing option tables (Table 6) additional samples will be collected for adverse events of CTCAE grade 3 neuro toxicity at 
the start and resolution of the event (Refer to Section 7.3.16.1).
q The PK samples will be obtained as outlined in the dosing options table (Table 6). (Refer to Section 7.3.15.2 for sampling times, sampling window and handling for dose 
interruption).  PK data will also be collected in the events of CTCAE grade 3 adverse events of CRS or neurotoxicity that occurs during SC administration.  Obtain the samples as 
close as possible to the start of the event, at approximately 24 hours after the event, and at the end of the event when all symptoms are resolved (refer to Section 7.3.15.2).
r Bone marrow biopsy only to be repeated with a response assessment (3 weeks after end of treatment as per standard of care) to establish staging or response per Cheson (Appendix A) 
and Lugano criteria (Appendix B).
s Creatinine clearance to be calculated by Cockcroft-Gault equation.
t Assessments/Lab studies for Day 22, Day 29 and Day 36 (weeks 4, 5, and 6) will be obtained on the day of the first MTD dose given SC that week per interval option 
determined in Cycle 1/Period 1.  Week 4 assessments/labs are obtained Day 22 (for 48h dosing), Day 24 (for q72h dosing), Day 24 (for 96h dosing), Day 26 (for q7 day dosing); 
Week 5 assessments/labs are obtained Day 30 (for 48h dosing), Day 30 (for 72h dosing), Day 32 (for q96h dosing), Day 33 (for q7 day dosing); Week 6 assessments/labs are 
obtained Day 36 (for q 48h, 72h, 96h), Day 42 (for q7 day dosing).  This allows the assessments/labs to be obtained during clinic visit to receive SC blinatumomab.
u Anti-blinatumomab antibody will be obtained weekly starting week 3.  Please obtain this lab on the first date of the week where lab study assessments are obtained.  Please 
obtain weekly (weeks 3, 4, 5, and 6).
 
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Table 6.  Subcutaneous Dosing Options for Cycle 1/Period 2
The dosing option to follow in Cycle 1/Period 2 will be the dosing option and interval determined to be MTD in Cycle 1/Period 1.  
Below are the possible options for this study.
Week
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday
SC Dosing Option A:  q48h
Week 1
9 g/day SC 
equivalent 
PKa
Cytokine/
Lymphocyte 
subsets, 6h (30 
minutes)
Cytokine/
Lymphocyte 
subsets
24h (2h)
9 g/day SC 
equivalent 
PKa
28 g/day SC 
equivalent
PKa
Cytokine/
Lymphocyte 
subsets, 6h (30 
minutes)
Cytokine/
Lymphocyte 
subsets
24h (2h)
Cytokine/
Lymphocyte subsets
48h (2h)
Week 2
28 g/day SC 
equivalent
28 g/day SC 
equivalent
PKa
MTD 
PKa
Cytokine/
Lymphocyte 
subsets, 6h (30 
minutes)
Cytokine/
Lymphocyte 
subsets
24h (2h)
Cytokine/
Lymphocyte subsets
48h (2h) (prior to 
SC MTD dose)
MTD
PKa
Week 3
MTD 
PKa
MTD
MTD
Week 4
MTD
MTD
MTD
MTD
Week 5
MTD
MTD
MTD
Week 6
MTD
MTD
MTD
MTD
Page 1 of 4
Footnotes defined on last page of the table
 
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Table 6.  Subcutaneous Dosing Options for Cycle 1/Period 2
Week 
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday
SC Dosing Option B:  q72h
Week 1
9 g/day SC 
equivalent
PKa
Cytokine/
Lymphocyte 
subsets, 6h (30 
minutes)
Cytokine/
Lymphocyte 
subsets
24h (2h)
9 g/day SC 
equivalent
PKa
28 g/day SC 
equivalent
PKa
Cytokine/
Lymphocyte 
subsets, 6h (30 
minutes)
Cytokine/
Lymphocyte 
subsets
24h (2h)
Cytokine/
Lymphocyte
48h (2h)
Week 2
28 g/day SC 
equivalent
28 g/day SC 
equivalent
PKa
MTD
PKa
Cytokine/
Lymphocyte 
subsets, 6h (30 
minutes)
Cytokine/
Lymphocyte 
subsets
24h (2h)
Cytokine/
Lymphocyte subsets
48h (2h)
Week 3
MTD 
PKa
MTD
PKa
MTD
Week 4
MTD
MTD
Week 5
MTD
MTD
Week 6
MTD
MTD
MTD
Page 2 of 4
Footnotes defined on last page of the table
 
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CONFIDENTIAL
Table 6.  Subcutaneous Dosing Options for Cycle 1/Period 2
Week 
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday
SC Dosing Option C:  q96h
Week 1
9 g/day SC 
equivalent
PKa
Cytokine/
Lymphocyte 
subsets, 6h (30 
minutes)
Cytokine/
Lymphocyte 
subsets
24h (2h)
9 g/day SC 
equivalent
PKa
28 g/day SC 
equivalent
PKa
Cytokine/
Lymphocyte 
subsets, 6h (30 
minutes)
Cytokine/
Lymphocyte 
subsets
24h (2h)
Cytokine/
Lymphocyte subsets
48h (2h)
Week 2
28 g/day SC 
equivalent
28 g/day SC 
equivalent
PKa
MTD 
PKa
Cytokine/
Lymphocyte 
subsets, 6h (30 
minutes)
Cytokine/
Lymphocyte 
subsets
24h (2h)
Cytokine/
Lymphocyte subsets
48h (2h)
Week 3
MTD
PKa
MTD
PKa
Week 4
MTD
MTD
Week 5
MTD
Week 6
MTD
MTD
Page 3 of 4
Footnotes defined on last page of the table
 
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Table 6.  Subcutaneous Dosing Options for Cycle 1/Period 2
Week 
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday
SC Dosing Option D:  q7d
Week 1
9 g/day SC 
equivalent
PKa
Cytokine/
Lymphocyte subsets, 
6h (30 minutes)
Cytokine/
Lymphocyte 
subsets
24h (2h)
9 g/day SC 
equivalent
PKa
28 g/day SC 
equivalent
PKa
Cytokine/
Lymphocyte subsets, 
6h (30 minutes)
Cytokine/
Lymphocyte 
subsets
24h (2h)
Cytokine/
Lymphocyte subsets
48h (2h)
Week 2
28 g/day SC 
equivalent
28 g/day SC 
equivalent
PKa
MTD 
PKa
Cytokine/
Lymphocyte subsets, 
6h (30 minutes)
Cytokine/
Lymphocyte 
subsets
24h (2h)
Cytokine/
Lymphocyte subsets
48h (2h)
Week 3
MTD 
PKa
Week 4
MTD
PKa
Week 5
MTD
Week 6
MTD
Page 4 of 4
Abbreviations:  cIV continuous intravenous; B = baseline; h = hour; MTD = maximum tolerated dose; PK = pharmacokinetics; q12h = every 12 hours; 
q24h = every 24 hours, q48h = every 48 hours, q72h = every 72 hours, q96h = every 96 hours, q7d = every 7 days; SC = subcutaneous
a PK samples are collected for 9 g/day SC equivalent dose 1 (Monday-Day 1):  pre-dose, 1 hour 15 minutes, 2 hours 15 minutes, 4 hours 30 minutes, 
6 hours 30 minutes, 8 1 hours, and 12 1 hours, 24 1 hours
PK samples are collected for 9 g/day SC equivalent dose 2 (Wednesday-Day 3):  pre-dose, 1 hour 15 minutes, 2 hours 15 minutes, 
4 hours 30 minutes, 6 hours 30 minutes, 8 1 hours, and 12 1 hours, 24 1 hours 
PK samples are collected for 28 g/day SC equivalent dose 1 (Friday-Day 5): pre-dose, 1 hour 15 minutes, 2 hours 15 minutes, 4 hours 30 minutes, 
6 hours 30 minutes, 8 1 hours, and 12 1 hours, 24 1 hours, 48 1 hours
 
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PK samples are collected for 28 g/day SC equivalent dose 3 (Wednesday-Day 10): pre-dose, 1 hour 15 minutes, 2 hours 15 minutes, 
4 hours 30 minutes, 6 hours 30 minutes, 8 1 hours, and 12 1 hours, 24 1 hours
PK samples are collected for MTD dose #1 (Friday-day 12): pre-dose, 1 hour 15 minutes, 2 hours 15 minutes, 4 hours 30 minutes, 
6 hours 30 minutes, 8 1 hours, and 12 1 hours
PK samples are collected for MTD dose # 2 (as denoted in the schedules for the different options):  pre-dose, 1 hour 15 minutes, 2 hours 15 minutes, 
4 hours 30 minutes, 6 hours 30 minutes, 8 1 hours and 12 1 hours
PK samples are collected for MTD dose # 3 (as denoted in the schedules for the different options): pre-dose, 1 hour 15 minutes, 2 hours 15 minutes, 
4 hours 30 minutes, 6 hours 30 minutes, 8 1 hours, 12 1 hours, 24 hr 1 hours, and 48 hr 1 hour (this is pre-dose for q48h option)
 
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Table 7.  Schedule of Assessments for Optional Cycle 2
Treatment Period
Safety 
Follow-up a, 
b
EOS
(7days)
Study Part
Cycle 2
EOT
(3 days
)
Cycle Day
1m
2m
3m
8m
9m
12m
14m
15m
16m
19m
22n
29n
36n
43
Cycle Week
1
2
3
4
5
6
GENERAL AND SAFETY ASSESSMENTS
ECOG
X
X
Physical examination 
(including neurological 
examination)c
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizationd
X
X
X
X
X
X
X
X
X
X
Vital signs, temperaturee
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse eventsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serious adverse eventsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Disease related events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
LABORATORY ASSESSMENTSo
Serum or urine pregnancy testg
X
Coagulationh
X
X
Hematology 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
Anti-blinatumomab antibody
Xk
X
IgG
X
X
X
INVESTIGATIONAL PRODUCT DOSING
Blinatumomab
├─────────────────────refer to Section 6.2.1.1.3 for dosing instructions────────────────────┤
DISEASE ASSESSMENTS
PET-CT, CT or contrast enhanced 
CTi
X
X
Bone marrow biopsyj 
X
Xl
Footnotes defined on next page of the table
 
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Abbreviations: cIV continuous intravenous, CRS = cytokine release syndrome, CT computed tomography, CTCAE = Common Terminology Criteria for Adverse Events, 
ECOG Eastern Cooperative Oncology Group, EOT end of treatment, EOS end of study, HSCT hematopoietic c stem cell transplant, IgG immunoglobulin G, INR international 
normalized ratio, IP investigational product, MTD = maximum tolerated dose, PET positron-emission tomography, PK pharmacokinetic, PTT partial thromboplastin time,
q48h = every 48 hours, q72h = every 72 hours, q96h = every 96 hours, q7d = every 7 days, SC subcutaneous.
a If a subject discontinues the study the safety follow-up procedures should be conducted immediately.
b All subjects, including subjects who withdraw from the study, should complete a safety follow-up visit 30 (7) days after the last dose of blinatumomab, or before HSCT or any other 
non-protocol specified anti-tumor therapy, if applicable.
c Physical examination will include weight. 
d Hospitalization in Optional Cycle 2: For Period 1 and Period 2 (if given as a cIV infusion), hospitalize at least 3 days at the start of treatment, and for each dose step. In Period 2 if 
given SC, subjects are hospitalized on days 1-8 (discharge 8 hours after day 8, 28 g/day SC dose is administered) and readmitted to the hospital on day 12 (prior to first 
MTD SC dose) until 8 hours after the second MTD SC dose is administered.
e The investigator should monitor the subject's vital signs continuously every 4 hours (2 hours) during the first 12 hours after the start of each new treatment/dose.  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 most recumbent position possible.  The position selected for a subject should be the same throughout the study.  Vital sign measurements will be repeated daily during the subject's 
hospitalization.
f Serious adverse events are collected from the time of signing informed consent form to the end of study and adverse events are collected after the first dose of IP.
g Serum or urine pregnancy test, prior to starting IP on day 1, will be performed for all women subjects unless surgically sterile or 2 years postmenopausal.  Additional pregnancy testing 
may be performed at the investigator’s discretion or as required per local laws and regulations.
h Coagulation will include PTT, INR, and fibrinogen.
I Disease assessments are to be performed to establish staging and response per Cheson (Appendix A) and Lugano criteria (Appendix B).  For PET-CT, CT, or contrast enhanced CT the 
same imaging modality should be used throughout the study for an individual subject.  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. Obtain assessments prior to starting cycle 2 blinatumomab and also at the EOS safety follow-up.
j Bone marrow biopsy is not required if PET scan is negative and if not otherwise clinically necessary by investigator discretion. If bone marrow biopsy is needed, obtain just prior to 
cycle 2 and repeat at the EOS safety follow-up.
k Anti-blinatumomab antibody on day 1 pre-dose.
l Bone marrow biopsy only to be repeated with a response assessment (3 weeks after end of treatment as per standard of care) to establish staging or response per Cheson (Appendix A) 
and Lugano criteria (Appendix B).
m Assessments/Laboratory studies for optional cycle 2/Period 1 or option cycle 2/Period 2 if administered as cIV infusion should be obtained Days 1, 2 (week 1), 8, 9 (week 2), 
15, 16 (week 3), and days 22, 29, 36 and EOT D43 (3 days).  Assessments/Laboratory studies for optional cycle 2/period 2 if administered SC should be obtained on Days 1, 2,
and 3 (week 1), Days 8 and 12 (week 2) for q48h, q72h, q96h and q7 day dosing options; Only obtain Day 14 (week 2) for q48h dosing option, Only obtain Day 15 (week 3) for 
q72h dosing option; Only obtain Day 16 (week 3) for q 48h and q96H dosing option; Only obtain Day 19 (week 3) for q7day dosing option. All dosing options will have the EOT 
D43 (3 days) assessments/laboratory studies. 
n Assessments/Lab studies for optional cycle 2/period 2 for Day 22, Day 29 and Day 36 (weeks 4, 5, and 6) will be obtained on the day of the first MTD dose given SC that week 
per interval option determined in Cycle 1/Period 1. Week 4 assessments/labs are obtained Day 22 (for 48h dosing), Day 24 (for q72h dosing), Day 24 (for 96h dosing), Day 26 
(for q7 day dosing); Week 5 assessments/labs are obtained Day 30 (for 48h dosing), Day 30 (for 72h dosing), day 32 (for q96h dosing), Day 33 (for q7 day dosing); Week 6 
assessments/labs are obtained Day 36 (for q 48h, 72h, 96h), Day 43 (for q7 day dosing).  This allows the assessments/labs to be obtained during clinic visit to receive SC 
blinatumomab. 
o Pharmacokinetic, cytokine and lymphocyte subset samples will only be obtained in Optional Cycle 2 for CTCAE grade 3 adverse events of CRS or neurotoxicity.  PK will be 
collected as close as possible to the start of the event, at approximately 24 hours after the event, and at the end of the event when all symptoms are resolved.  Lymphocyte 
subsets and cytokines will be collected as close as possible to the start of the event and at resolution of the event. Refer to Section 7.3.15.3.
 
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7.2
General Study Procedures
A description for each phase of the study is provided in this section.  Refer to the CRF 
completion guidelines for data collection requirements and documentation of study 
assessments/procedures.
Confirmation that the most current IRB/IEC approved written informed consent form has 
been signed should occur before any study-specific procedures are performed.  All 
subjects who are enrolled and receive blinatumomab or undergo study-specific 
procedures should be reconsented with any updated versions of IRB/IEC approved 
informed consents during study participation as applicable and per institutional 
guidelines.
7.2.1
Screening Enrollment and/or Randomization
Informed consent must be obtained before completing any study-specific 
procedures. Procedures that are part of standard of care are not considered 
study-specific procedures and may be performed before the informed consent and used 
to determine eligibility, but must be done within 2 weeks to treatment start (unless 
specified otherwise), as described in the eligibility criteria. 
After written informed consent has been obtained, subjects will be screened to assess 
eligibility for study participation.  The screening period is up to 14 days. If a subject has 
not met all eligibility criteria at the end of the 14-day window, the subject will be 
registered as a screen failure. Subjects who screen fail may be eligible to rescreen 
3 additional times per Section 7.2.2.
All screening procedures except PET-CT, CT, and bone marrow biopsy must be 
performed within 14 days of day 1 (equals start of treatment with study drug), unless 
otherwise noted.  PET-CT, CT, and bone marrow biopsy assessments can be done 
within 21 days of the first dose of IP.  Subjects who meet the eligibility criteria will be 
eligible to be enrolled in the study.
7.2.2
Rescreening
Subjects who are unable to complete or meet eligibility at the initial screening will be 
permitted to rescreen up to 3 additional times, provided study recruitment has not 
closed. Upon signing a new informed consent form, a new 14-day screening window will 
begin. Subjects will retain the same subject identification number assigned at the 
original screening.
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After reconsenting, all screening procedures, excluding PET-CT, CT, and bone marrow 
biopsy, must be repeated unless the procedure was performed within 2 weeks before 
the treatment start.  The PET-CT, CT, and bone marrow biopsy need to be performed 
within 21 days of the first dose of IP prior to treatment start.
7.2.3
Treatment
Procedures will be completed during the treatment period from  each treatment cycle 
(day 1 to day 43 of Cycle 1/Period 1, day 1 to day 43 Cycle 1/Period 2, and day 1 to 
day 43 of cycle 2) at the times designated in the Schedule of Assessments (Table 3,
Table 4, Table 5, Table 6, and Table 7).
Subjects satisfying eligibility requirements will be enrolled into the treatment period and 
should receive the first dose of blinatumomab on day 1 of the study.  All subsequent 
study visits will be scheduled based on the day 1 date.  
7.2.4
Safety Follow-up Visit(s)/End of Study Visit
Approximately 30 days (7 days) after their last dose of blinatumomab, subjects will 
complete a EOS/safety follow-up visit (Table 3, Table 5, and Table 7).  If hematopoietic 
stem cell transplant (HSCT) or any other non-protocol specified anti-tumor therapy will 
be administered after blinatumomab, the end of study visit should be conducted before 
these alternative treatments are administered.
7.2.5
Early Termination Visit
If a subject withdraws informed consent from the study, safety follow-up procedures 
should be conducted immediately if possible (Table 3, Table 5, and Table 7).
7.3
Description of 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 receive 
protocol-specified therapy or specified treatment should be re-consented with any 
updated versions of IRB/EC approved informed consents during study participation as 
applicable and per institutional guidelines.
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7.3.2
Medical History/Current Medical Condition
The investigator or designee will collect a complete medical and surgical history from
5 years before the screening through to the time of informed consent. Medical history 
will include information on the subject’s concurrent medical conditions. Record all 
findings on the medical history CRF.
Relevant medical history, including previous chemotherapy/immunotherapy or 
radiotherapy, antecedent hematologic or oncologic disease, other diseases/symptoms 
such as fatigue, bleeding, and infection (resolved and ongoing) will be 
collected. Lymphoma history must date back to the initial diagnosis and any response 
duration must be recorded. The current toxicity grade will be collected for each condition 
that has not resolved.
7.3.3
Prior Therapies
For prior therapies being taken for relapsed/refractory indolent NHL, collect therapy 
name, indication, dose, unit, frequency, start date and stop date. 
For all other prior therapies, collect therapy name, indication, dose, unit, frequency, 
route, start date and stop date.  
7.3.4
Demographic Data
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.  
Additionally, demographic data will be used to study the impact on biomarkers variability
and PK of blinatumomab.  
7.3.5
ECOG Performance Status Assessment
ECOG performance status assessment will be performed using the ECOG score
(Appendix C).
7.3.6
Physical Examination
Physical examination will be completed as per standard of care as outlined in the 
Schedule of Assessments (Table 3, Table 5, and Table 7). Physical examination 
findings at screening will include medical and surgical history and will be recorded on the 
medical history CRF.  Any new findings on physical examination during the course of the 
study will be considered adverse events.
7.3.7
Physical Measurements and Vital Signs
Height in centimeters and weight in kilograms should be measured without shoes.  
Height will only be performed at screening in cycle 1.
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The following measurements for vital signs must be performed: systolic/diastolic blood 
pressure, heart rate, respiratory rate, and temperature.  The investigator should monitor 
the subject's vital signs continuously every 4 hours (2 hours) during the first 12 hours 
after the start of each new treatment/dose-step.  Vital sign measurements will be 
repeated daily during the subject's hospitalization.  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 
most recumbent position possible.  The position selected for a subject should be the 
same throughout the study and documented on the vital signs CRF.  The temperature 
location selected for a subject should be the same throughout the study and 
documented on the vital signs CRF.  If abnormalities are found and they are considered 
an adverse event, record on the adverse event summary page.
7.3.8
Neurological Examination
A neurological examination will be performed as outlined in the Schedule of 
Assessments (Table 3, Table 5, and Table 7).  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).  If 
they are present at screening, then they will be considered as medical history.  Any new 
findings on neurologic examination during the study will be considered adverse events.
7.3.9
Adverse Events/Serious Adverse Events/ Disease Related Events
Adverse events observed by the investigator or reported by the subject will be collected 
at all study visits starting with the first IP administration.
Serious adverse events are collected from the time of signing the informed consent form 
to the end of the study. 
Disease Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease (Table 9).  Refer to Section 9.1.1 for 
further information. 
7.3.10
PET-CT Scan and Interim CT Scan
PET-CT (head to thigh), CT (head/neck, thorax, and pelvic/abdomen), or contrast 
enhanced CT (head/neck, thorax and pelvic/abdomen as clinically indicated and 
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evaluated per Appendix A [Cheson et al, 2007] and Appendix B [Cheson et al, 2014]) 
should be performed within 21 days of the first dose of IP and during the Safety 
Follow-up visit (2 to 4 weeks after the end of therapy for cycle 1). In the case where a 
second cycle is administered, the assessment has to be done prior to the start of the 
next cycle to assess the evolution of disease (as close to 2 weeks after the last dose of 
IP cycle 1, but before starting cycle 2).  Additional PET-CT or CT follow up following the 
optional second cycle of treatment should be performed during the Safety Follow-up visit 
(2 to 4 weeks after the end of therapy for cycle 2).  The same imaging modality should 
be used throughout the study for an individual subject. 
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.
7.3.11
Magnetic Resonance Image
Magnetic Resonance Image Scan of the brain with contrast is recommended as part of 
the evaluation of the etiology of a grade 3 seizure or neurologic event that occurs 
during IP infusion. The magnetic resonance image is obtained if there are no 
contraindications to the procedure.
7.3.12
Bone Marrow Biopsy
Bone marrow biopsies should be performed within 21 days of start of IP treatment and 
3 to 4 weeks after the end of treatment (may occur with the Safety Follow-up visit), if 
required for staging or response assessment.  Bone marrow biopsies are recommended 
to be unilateral and the samples must be 2.5 cm (total biopsy length) as per standard 
of care if required for staging and for evaluation of disease response/progression.
Refer to Appendix A (Cheson et al, 2007) and Appendix B (Cheson et al, 2014)
recommendations for staging and response assessments.  
No central radiographic or bone marrow reads will be performed.  
7.3.13
Lumbar Puncture to Examine Cerebrospinal Fluid
A lumbar puncture will be performed at screening if concern of CNS lymphoma 
involvement as outlined in the Schedule of Assessments or during treatment period if 
subject has a seizure.  Cerebrospinal fluid (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 and may include PK for 
blinatumomab. The lumbar puncture is obtained if there are no contraindications to the 
procedure.
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7.3.14
Laboratory Assessments
The analytes for all laboratory tests used throughout this study are listed in Table 8.  
Chemistry, coagulation tests, hematology, urinalysis, hepatitis serology, HIV, 
immunoglobulin G (IgG), and pregnancy confirmation will be performed locally.  
Anti-blinatumomab antibody samples, PK samples, cytokines, and lymphocyte subsets 
will be evaluated centrally.
Amgen or the central laboratories will supply containers for sample collection, 
preparation, packaging, and shipping.  Detailed instructions for sample collection, 
processing, and shipping are provided in the central laboratory manual and/or 
Amgen-provided training materials.  The date and time of sample collection will be 
recorded in the source documents at the site. 
During cIV administration, blood draws should not be done via the 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 8 outlines the specific analytes that will be assessed during the study at time 
points outlined in the Schedule of Assessments (Table 3, Table 5, and Table 7).
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Table 8.  Laboratory Analyte Listing
Local Lab 
Chemistry
Sodium
Potassium
Chloride
Total 
protein
Albumin
Calcium
Magnesium
Phosphorus
Glucose
BUN or 
Urea
Creatinine
Uric acid
Alk phos
LDH
AST 
(SGOT)
ALT 
(SGPT)
C-reactive 
protein
Lipase
Amylase
Bilirubin 
(total)
GGT
Local Lab 
Coagulation
PTT
INR
Fibrinogen
Local Lab 
Urinalysis
Blood
Protein
Glucose
Local Lab 
Hematology
Hemoglobin
Hematocrit
Reticulocytes
Platelets
WBC
RBC
Differential
• Neutrophils
• Bands/stabs
• Eosinophils
• Basophils
• Lymphocytes
• Monocytes
Local Lab
Other Labs
IgG
HIV
Hepatitis B 
surface 
antigen
Hepatitis B 
core 
antibody
Hepatitis C 
virus 
antibody
Urine or 
serum 
pregnancy 
test
Bone 
marrow 
biopsya
Lumbar 
puncturea
Central Lab 
Other Labs
Anti-blinatumomab 
antibodies
Lymphocyte 
subsets
Cytokines 
PK 
Abbreviations: ALK phos alkaline phosphatase; ALT alanine transaminase; AST aspartate
transaminase; BUN blood urease nitrogen; GGT gamma-glutamyl transferase; HIV human 
immunodeficiency virus; IgG Immunoglobulin G; INR international normalized ratio; LDH lactic 
dehydrogenase; PK pharmacokinetic; RBC red blood count; SGOT Serum glutamic oxaloacetic 
transaminase; SGPT Serum glutamic pyruvic transaminase; WBC white blood count.
a Bone marrow and lumbar puncture only required if concerns of disease presence per investigator 
judgement.  A sample of CSF if obtained for grade 3 or higher neurologic event will be obtained for 
blinatumomab PK (central lab) and other local labs (refer to Section 7.3.13).
7.3.15
Pharmacokinetic Samples
Serum samples will be collected during the blinatumomab treatment in all subjects to 
measure blinatumomab serum concentration by a validated bioassay.  Blood samples
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for PK are outlined in the Schedule of Assessments (Table 3 and Table 5).  Details are 
provided below: 
7.3.15.1 
Cycle 1/Period 1 
During cIV run-in, PK samples are collected at any time during the day on the second 
day after the start of the 9 µg/day, 28 µg/day, and 112 µg/day doses, (ie, PK samples 
are obtained on day 2, day 9, and day 16, respectively).  
During SC dosing, PK samples are collected for:  
For SC dosing at q12h, q24h q48h and q96h: 
• 
PK samples are collected for the first dose on day 22 (pre-dose, as well as 
1 hour ± 15 minutes, 2 hours ± 15 minutes, 4 hours ± 30 minutes, 
6 hours ± 30 minutes, 8 ± 1 hours, and 12 ± 1 hours (before the next q12h dose 
if applicable) and for the last dose on day 26 (pre-dose, as well as post-dose at 
1 hour ± 15 minutes, 2 hours ± 15 minutes, 4 hours ± 30 minutes, 
6 hours ± 30 minutes, 8 ± 1 hours, 12 ± 1 hours, as well as 24 ± 2 hours 
(day 27), and 48 ± 2 hours (day 28).  (Refer to Table 3 and Table 4). 
For SC dosing at q72 hours: 
• 
PK samples are collected for the first dose on day 22 (pre-dose, as well as 
1 hour ± 15 minutes, 2 hours ± 15 minutes, 4 hours ± 30 minutes, 
6 hours ± 30 minutes, 8 ± 1 hours, and 12 ± 1 hour and for the last dose on 
day 25 (pre-dose, as well as post-dose at 1 hour ± 15 minutes, 
2 hours ± 15 minutes, 4 hours ± 30 minutes, 6 hours ± 30 minutes, 8 ± 1 hours, 
12 ± 1 hours, as well as 24 ± 2 hours (day 26), 48 ± 2 hours (day 27), and 
72 ± 2 hours (day 28) (Refer to Table 3 and Table 4) 
For the SC dosing at q7days: 
• 
PK samples are collected for the dose on day 22 (pre-dose, as well as 1 hour 
± 15 minutes, 2 hours ± 15 minutes, 4 hours ± 30 minutes, 6 hours ± 
30 minutes, 8 ± 1 hours, 12 ± 1 hour as well as 24 ± 2 hours (day 23), 48 ± 
2 hours (day 24), 72 ± 2 hours (day 25) and 96 ± 2 hours (day 26). (Refer to 
Table 3 and Table 4) 
In the return to cIV dosing following the 5 treatment days of SC administration, PK 
samples are collected any time during the day on the second day (day 30) after 
resuming 112 µg/day dose on day 29.  See Table 3 and Table 4 for further details.  In 
addition to the above listed PK samples, PK data will also be collected for adverse 
events of CTCAE ≥ grade 3 of CRS or neurotoxicity.  Obtain the samples as close 
as possible to the start of the event, at approximately 24 hours after the event and 
at the end of the event when all symptoms are resolved. 
PK samples should be drawn peripherally during cIV dosing period. 
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7.3.15.2 
Cycle 1/Period 2 
• 
PK samples are collected for 9 µg/day SC equivalent dose 1 (Monday-Day 1):  
pre-dose, 1 hour ± 15 minutes, 2 hours ± 15 minutes, 4 hours ± 30 minutes, 
6 hours ± 30 minutes, 8 ± 1 hours, and 12 ± 1 hours, 24 ± 1 hours 
• 
PK samples are collected for 9 µg/day SC equivalent dose 2 
(Wednesday-Day 3):  pre-dose, 1 hour ± 15 minutes, 2 hours ± 15 minutes, 
4 hours ± 30 minutes, 6 hours ± 30 minutes, 8 ± 1 hours, and 12 ± 1 hours, 
24 ± 1 hours  
• 
PK samples are collected for 28 µg/day SC equivalent dose 1 (Friday-Day 5): 
pre-dose, 1 hour ± 15 minutes, 2 hours ± 15 minutes, 4 hours ± 30 minutes, 
6 hours ± 30 minutes, 8 ± 1 hours, and 12 ± 1 hours, 24 ± 1 hours, 48 ± 1 hours 
• 
PK samples are collected for 28 µg/day SC equivalent dose 3 
(Wednesday-Day 10):  pre-dose, 1 hour ± 15 minutes, 2 hours ± 15 minutes, 
4 hours ± 30 minutes, 6 hours ± 30 minutes, 8 ± 1 hours, and 12 ± 1 hours, 
24 ± 1 hours 
• 
PK samples are collected for MTD dose #1 (Friday-day 12):  pre-dose, 
1 hour ± 15 minutes, 2 hours ± 15 minutes, 4 hours ± 30 minutes, 
6 hours ± 30 minutes, 8 ± 1 hours, and 12 ± 1 hours  
• 
PK samples are collected for MTD dose # 2 (as denoted in the schedules for 
the different options): pre-dose, 1 hour ± 15 minutes, 2 hours ± 15 minutes, 
4 hours ± 30 minutes, 6 hours ± 30 minutes, 8 ± 1 hours and 12 ± 1 hours  
• 
PK samples are collected for MTD dose # 3 (as denoted in the schedules for 
the different options): pre-dose, 1 hour ± 15 minutes, 2 hours ± 15 minutes, 
4 hours ± 30 minutes, 6 hours ± 30 minutes, 8 ± 1 hours, 12 ± 1 hours, 
24 hr ± 1 hours, and 48 hr ± 1 hours (this is to be obtained pre-dose for q48h 
option) 
See Table 6 for further details.  
If doses were interrupted in any days associated with PK sampling, the PK sample 
collection day will be delayed accordingly until the resumed dose is given. 
In addition, PK data will also be collected in the events of CTCAE ≥ grade 3 adverse 
events of CRS or neurotoxicity that occurs during SC administration.  Obtain the 
samples as close as possible to the start of the event, at approximately 24 hours 
after the event, and at the end of the event when all symptoms are resolved. 
7.3.15.3 
Optional Cycle 2/Period 2 
Pharmacokinetic, cytokine and lymphocyte subset samples will only be obtained 
in Optional Cycle 2 for CTCAE ≥ grade 3 adverse events of CRS or neurotoxicity.  
PK will be collected as close as possible to the start of the event, at approximately 
24 hours after the event, and at the end of the event when all symptoms are 
resolved.  Lymphocyte subsets and cytokines will be collected as close as 
possible to the start of the event and at resolution of the event. 
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7.3.16
Pharmacodynamic Samples
7.3.16.1
Lymphocyte Subsets
Lymphocyte subsets will be measured by flow cytometry for quantification of different 
markers (eg, T cells: CD3, CD4, CD8; B cells: CD19).  The sampling time points are 
outlined in the Schedule of Assessments (Table 3, Table 5, Table 6, and Table 7).  In 
addition, lymphocyte subsets will also be collected for adverse events of CTCAE 
grade 3 of CRS or neurotoxicity that occurs during SC administration.  Obtain 
the samples as close as possible to the start of the event and at resolution of the 
event.
7.3.16.2
Cytokines
Cytokine samples (IL-6, IL-10, IL 12, interferon gamma [IFN-], and tumor necrosis factor 
alpha) will be measured by the commercially available FACS based BDTM Cytometric 
Bead Array system.  Blood samples will be collected at the time points outlined in the 
Schedule of Assessments (Table 3, Table 5, Table 6, and Table 7).  In addition, 
cytokine data will also be collected for adverse events of CTCAE grade 3 of CRS 
or neurotoxicity that occurs during SC administration.  Obtain the samples as 
close as possible to the start of the event and at resolution of the event.
7.4
Antibody Testing Procedures
Blood sample(s) will be collected at time points as outlined in the Table 3, Table 5, and 
Table 7 for the measurement of anti-blinatumomab binding antibodies.  Samples testing 
positive for binding antibodies will also be tested for neutralizing antibodies and may be 
further characterized for quantity/titer, isotype, affinity and presence of immune 
complexes.  Additional blood samples may be obtained to rule out anti-blinatumomab 
antibodies during the study.  Subjects who test positive for anti-blinatumomab 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.
7.5
Biomarker Development
Blood samples will be collected to monitor changes in lymphocytes (B-cell and T-cell 
populations) and cytokines in peripheral blood.
In addition, biomarker data as described above will also be collected for CTCAE 
grade 3 adverse events of CRS or neurotoxicity that occurs throughout the study both 
at the start and resolution of the event.
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7.6
Sample Storage and Destruction
Any blood biomarker, PK sample collected according to the Schedule of Assessments 
(Table 3, Table 4, Table 5, Table 6, and Table 7) 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 before the 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 may do additional testing on 
remaining samples (ie, residual and back-up) to investigate and better understand the 
relapsed/refractory indolent NHL, the dose response and/or prediction of response to 
blinatumomab, as required, 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 pharmacogenetic, 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 identification number so that any 
remaining sample types (eg, blood, tumor) samples and any other components from the 
cells can be located and destroyed. Samples will be destroyed once all protocol-defined 
procedures are completed. However, information collected from samples before 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 (or a legally acceptable representative) can decline to continue receiving 
investigational product and/or other protocol-required therapies or procedures at any 
time during the study but continue participation in the study.  A legally acceptable 
representative is an individual or other body authorized under applicable law to consent, 
on behalf of a prospective subject, to the subject’s participation in the clinical study.  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 3, Table 4, Table 5, Table 6, and Table 7) 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 3, Table 4, Table 5, Table 6, and Table 7) 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, publicly available data 
can be included after withdrawal of consent.  The investigator is to discuss with the 
subject appropriate procedures for withdrawal from the study.  
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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 before the study completion.  
Subjects may be eligible for continued treatment with Amgen investigational product(s)
and/or other protocol-required therapies by a separate protocol or as provided for by the 
local country’s regulatory mechanism, based on parameters consistent with 
Section 12.1.
8.3
Reasons for Removal From Treatment or Study
8.3.1
Reasons for Removal From Treatment
Reasons for removal from protocol-required IP(s) or procedural assessments include 
any of the following:

Protocol-specified criteria: a DLT during the DLT evaluation period (see 
Section 6.2.1.2.3), neurological event as described in Section 6.2.1.4.3 and 
Appendix E

Subject request 

Safety concern:

due to an adverse event

pregnancy

ineligibility determined

protocol deviation

non-compliance 

requirement for alternative therapy (including transplant),

Death

Lost to follow-up

Decision by sponsor (other than subject request or safety concern, lost to follow)

Disease progression (eg, clinically relevant disease progression, relapse or 
non-response) for subjects in Period 1
8.3.2
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
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As part of the study, sites may be asked to conduct searches of public records, such as 
those establishing survival status, if available, to obtain survival data for any subject for 
whom the survival status is not known.  
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 eg, disease progression (Table 9).  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.
If the outcome of the underlying disease is worse than that which would normally be 
expected for the subject, or if the investigator believes there is a causal relationship 
between the IP(s)/study treatment protocol required therapies and disease worsening, 
this must be reported as an adverse event or a serious adverse event.  Table 9 outlines 
the expected Disease-Related Events by System Organ Class.
Table 9.  Disease-related Adverse Events by System Organ Class
System Organ Class
Preferred Terms
Blood and lymphatic system disorders
lymphadenopathy
General disorders and administration
site conditions
Disease progression
fatigue
Investigations
Weight decreased 
Skin and subcutaneous tissue 
disorders
Night sweats
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Disease Related Events that would qualify as an Adverse Event or Serious Adverse 
Event:

An event based on the underlying disease that is worse than expected as 
assessed by the investigator for the subject’s condition or if the investigator
believes there is a causal relationship between the investigational 
product(s)/study treatment/protocol-required therapies and disease worsening, 
this must be reported as an Adverse Event or Serious Adverse Event.
9.1.2
Adverse Events
An adverse event is defined as any untoward medical occurrence in a clinical trial 
subject.  The event does not necessarily have a causal relationship with study treatment.  
The investigator is responsible for ensuring that any adverse events observed by the 
investigator or reported by the subject are recorded in the subject’s medical record.  
The definition of adverse events includes worsening of a pre-existing medical condition.  
Worsening indicates that the pre-existing medical condition or underlying disease 
(eg, diabetes, migraine headaches, gout) has increased in severity, frequency, and/or 
duration more than would be expected, and/or has an association with a significantly 
worse outcome than expected.  A pre-existing condition that has not worsened more 
than anticipated (ie, more than usual fluctuation of disease) during the study or involves 
an intervention such as elective cosmetic surgery or a medical procedure while on study,
is not considered an adverse event.  
If the severity of an adverse event changes from the date of onset to the date of 
resolution, record as a single event with the worst severity on the Event CRF.
For situations when an adverse event or serious adverse event is due to the underlying 
lymphoma, 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, relapsed/refractory indolent NHL).
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 use error or from intentional misuse of the device.
The investigator’s clinical judgment is used to determine whether a subject is to be 
removed from treatment due to an adverse event.  In the event a subject, or subject’s 
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legally acceptable representative requests to withdraw from protocol-required therapies
or the study due to an adverse event, refer to Section 8.1 for additional instructions on 
the procedures recommended for safe withdrawal from protocol-required therapies or 
the study.  
9.1.3
Serious Adverse Events
A serious adverse event is defined as an adverse event that meets at least 1 of the 
following serious criteria (unless it meets the definition of a Disease Related Event as 
defined in Section 9.1.1):

fatal

life threatening (places the subject at immediate risk of death)

requires in-patient hospitalization or prolongation of existing hospitalization

results in persistent or significant disability/incapacity

congenital anomaly/birth defect

other medically important serious event
A disease related event blood and lymphatic system disorders or investigations are to be 
reported as a serious adverse event if:

the subject’s pre-existing condition becomes worse than what the investigator would 
consider typical for a patient with the same underlying condition, or

if the investigator believes a causal relationship exists between the investigational 
medicinal product(s)/protocol-required therapies and the event, 

and the event meets at least 1 of the serious criteria.
An adverse event would meet the criterion of “requires hospitalization”, if the event 
necessitated an admission to a health care facility (eg, overnight stay).  
If an investigator considers an event to be clinically important, but it does not meet any 
of the serious criteria, the event could be classified as a serious adverse event under the 
criterion of “other medically important serious event”.  Examples of such events could 
include allergic bronchospasm, convulsions, blood dyscrasias, DILI (see Appendix D 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 the first dose of investigational 
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medicinal product(s)/study treatment/protocol-required therapies through the safety 
follow-up visit and are recorded on the Event CRF as a Disease Related Event.  
Disease Related Events assessed by the investigator to be more severe than expected 
and/or related to the investigational medicinal product(s)/study 
treatment/protocol-required therapies, and determined to be serious, must be recorded 
on the Event eCRF as Serious Adverse Events.  
Additionally, the investigator is required to report a fatal Disease Related Event on the 
Event eCRF.  
9.2.2
Adverse Events
9.2.2.1
Reporting Procedures for Adverse Events That do not Meet Serious 
Criteria
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject that occur after first dose of IP through 30 days 
after the last dose of study treatment or the safety follow-up visit (whichever is later) 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 blinatumomab or protocol required medication or 
medical device, and

Action taken.
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 Adverse Event 
Summary CRF.
The adverse event grading scale used will be the Amgen adverse event standard 
grading score; CTCAE. The grading scale used in this study is described in
Appendix D.  
The investigator must assess whether the adverse event is possibly related to 
blinatumomab.  This relationship is indicated by a “yes” or “no” response to the question:  
Is there a reasonable possibility that the event may have been caused by the 
Investigational Medicinal Product?
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The investigator must assess whether the adverse event is possibly related to any 
study-mandated activity (eg, administration of investigational product, protocol-required 
therapies, device(s) and/or procedure (including any screening procedure(s)).  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 investigational product, 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.  Laboratory value changes that require intervention 
(eg, treatment, hospitalization, or adjustment in current therapy) 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 all be recorded 
as adverse events.  The laboratory abnormality and any signs/symptoms should be 
graded according to their own CTCAE criteria. 
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 the safety follow-up period 30 days after the last dose of 
protocol-specified therapies are recorded in the subject’s medical record and are 
submitted to Amgen.  All serious adverse events must be submitted to Amgen within 
24 hours following the investigator’s knowledge of the event via the Event CRF.  
If the electronic data capture (EDC) system is unavailable to the site staff to report the 
serious adverse event, the information is to be reported to Amgen via an electronic 
Serious Adverse Event (eSAE) Contingency Report Form within 24 hours of the 
investigator’s knowledge of the event.  See Appendix F for a sample of the Serious 
Adverse Event Worksheet/eSAE Contingency Report Form.  
The investigator must assess whether the serious adverse event is possibly related to 
the blinatumomab. 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?
The investigator is expected to follow reported serious adverse events until stabilization 
or reversibility. 
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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.
The investigator is to notify the appropriate IRB/IEC of serious adverse events occurring 
at the site and other adverse event reports received from Amgen, in accordance with 
local regulatory requirements and procedures.
9.2.2.3
Reporting Serious Adverse Events After the Protocol-required 
Reporting Period
There is no requirement to monitor study subjects for serious adverse events following 
the protocol-required reporting period or after end of study.  However, these serious 
adverse events can be reported to Amgen.  In some countries (eg, European Union 
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. 
9.3
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.
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In addition to reporting any pregnancies occurring during the study, investigators should 
monitor for pregnancies that occur after the last dose of blinatumomab through 48 hours 
after the last dose of cIV blinatumomab or 96 hours after the last dose of SC 
blinatumomab for both male and female subjects.
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 G).  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 cIV blinatumomab or 96 hours 
after the last dose of SC blinatumomab.
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 G).  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

Subject grade, incidence and severity of DLTs and adverse events
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10.1.1.2
Secondary Endpoints

Blinatumomab PK parameters under cIV and SC administrations 

MTD

Incidence of anti-blinatumomab antibodies 

ORR (complete response [CR] partial response [PR]) as determined by best 
overall response using Cheson criteria (Appendix A)
10.1.1.3
Exploratory Endpoints

PD parameters of B- and T-lymphocytes and cytokines following administration 
of SC blinatumomab

ORR (CR PR) as determined by best overall response using Lugano criteria
(Appendix B)
10.1.2
Analysis Sets
The statistical analysis will be based on the following study populations.  Subjects will be 
summarized separately by the planned dose cohorts.
The analysis of all endpoints, unless noted otherwise, will be conducted on the Full 
Analysis Set.
The analysis of DLTs will be restricted to DLT-evaluable subjects.
10.1.2.1
Full Analysis Set
All subjects who receive blinatumomab are included in the full analysis set.  This 
definition is in line with the intent-to-treat principle in single-arm open-label studies. 
10.1.2.2
Safety Analysis Set
For each part of the study, the safety analysis set will be the same as the full analysis 
set. 
10.1.2.3
DLT Analysis Set
All subjects who are DLT-evaluable are included in this analysis set as defined in 
Section 6.2.1.2.2. 
10.1.2.4
Pharmacokinetic Analyses Set
All subjects who received any blinatumomab and had at least one PK sample collected 
will be included in the PK analysis set.  These subjects will be evaluated for PK unless 
significant protocol deviations affect the data analysis or if key dosing, dosing 
interruption, or sampling information is missing. 
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10.1.2.5 
Pharmacodynamic Analyses Set 
All subjects who had cytokine and/or lymphocyte subset samples collected at any time 
during the study will be included in the PD analysis set. 
10.1.3 
Covariates and Subgroups 
The relationship of the certain baseline covariates to endpoints will be explored if 
appropriate.  Biomarker data may be incorporated in additional exploratory subgroup or 
multivariate analyses.  The analyses of biomarkers may be performed after collection of 
all samples during the conduct of the study and therefore may be reported after the final 
analysis. 
10.2 
Sample Size Considerations 
Approximately 54 evaluable subjects will be enrolled in the study.   
Six evaluable subjects will be enrolled at each SC dose level in Cycle 1/Period 1.  
Subjects may be replaced (replacement rules outlined in Section 3.4).  This sample size 
is based on practical considerations and is consistent with conventional 
phase 1 oncology studies.  If the true DLT rate is 10%, there is an 89% probability of 
observing ≤ 1 DLT and 11% probability of observing 2 or more DLT in 6 subjects.  If the 
true DLT rate is 30%, the probability of observing ≤ 1 DLT decreases to 42% and 
probability of observing 2 or more DLT increases to 58%.  
Up to 15 evaluable subjects will be enrolled into Cycle 1/Period 2 with the planned target 
treatment dose being the highest tolerable dose regimen or highest tested dose regimen 
based on DLRT’s recommendations.  Continuous toxicity monitoring for early termination 
of the trial in Cycle 1/Period 2 will be performed.  Termination of the study in Cycle 
1/Period 2 will occur if the posterior probability that the DLT rate greater than 25%, given 
the cumulative data thus far is at least 80%.  Starting with the fifth subject treated in 
Cycle 1/Period 2, stopping may occur any time.  The stopping boundaries assume a 
prior beta distribution of (0.50, 1.50) and a batch size of 1 (starting with the fifth subject 
treated) are presented in Table 10 and the operating characteristics are given in 
Table 10.  The operating characteristics in Table 10 provide the probability of stopping 
the trial early for given hypothetical true DLT rates whereas the stopping criteria in 
Table 10 are based on situations where the empirical evidence would result in a 
posterior probability ≥ 80% that the true DLT rate is ≥ 25% (Thall et al, 1995).  
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Table 10.  Cycle 1/Period 2 Stopping Boundaries
Cumulative Number of Subjects
Stop Study if This Many Subjects Have a 
Dose-limiting Toxicity
5 - 6
3
7 - 10
4
11 - 13
5
14
6
15
Study Period 2 is complete at 15
Note: Study may stop with fewer than 5 subjects if 3 or more subjects with DLTs have been 
observed
Abbreviation:  DLT = dose limiting toxicities
Table 11.  Operating Characteristics
True Rate of Dose-Limiting 
Toxicities
Probability of Stopping Early
Average Sample Size
20
17
13.7
25
30
12.7
30
45
11.6
40
72
9.3
50
90
7.3
60
98
6.1
10.3
Planned Analyses
10.3.1
Interim Analyses
Safety data will be reviewed on an ongoing basis.  Amgen, in consultation with the site 
investigator, will review in DLRT meetings all available accumulating data by multiple 
subject cohort before making dosing decisions.  Adverse events and DLTs observed in 
all subjects will be evaluated continually and will be fully integrated into all DLRT 
meeting and considered in all enrollment and dosing decisions.
DLRT meeting will be held to review data, monitor safety, and make dosing decisions.  
10.3.2
Dose Level Review Team
The DLRT will consist of the Amgen medical monitor, global safety officer or designee, 
clinical trial manager, biostatistician, PK scientist (optional), site investigator or designee,
and other functional area representatives as appropriate.  Refer to Section 6.2.1.2.1 for 
more information on the scope of the DLRT.
All DLRT requirements are outlined in Section 6.2.1.2.1.  A DLRT Charter will not be 
used.
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10.3.3
Final Analysis
The final analysis will be triggered when target enrollment is complete and all subjects 
complete the study or withdraw from the study.
10.4
Planned Methods of Analysis
10.4.1
General Considerations
A clinical study report will be generated for the final analysis.  All documented 
parameters will be adequately evaluated.  The data will be summarized overall, and by 
assigned dose cohort using suitable descriptive measures.  Individual data will be listed. 
The DLT findings during Period 1 will be tabulated. 
Descriptive statistics for demographic, safety, PK parameters, and biomarker data will be 
summarized by dose, dose schedule, and time as appropriate.  The PK parameters will 
be estimated with non-compartmental analysis.  For categorical variables, the number 
and percentage of subjects in each category will be summarized.  Continuous variables 
will be summarized by n, mean, standard deviation, median, Q1 (25th percentile), 
Q3 (75th percentile), minimum, and maximum values.
Point estimates for efficacy endpoint incidences will be accompanied by 2-sided 
95exact binomial confidence intervals (CIs) (Clopper CJ, Pearson ES, 1934).  
When data are summarized by time, the values recorded against the scheduled time 
points listed in the protocol will be used.  When assessing minimum/maximum increases 
or decrease over the study, all assessments including unscheduled assessments will be 
used.  In general, data listings will be sorted by dose, subject, and time.
10.4.2
Secondary Efficacy Endpoints
The efficacy endpoint of the study is ORR (CRPR) after blinatumomab treatment based 
on Chesons’ 2007 criteria (Appendix A).  The analysis is based on the response 
evaluation recorded in the CRF for subjects in the full analysis set.  Subjects will be 
considered as non-responders if there is no response assessment available.  The rate 
will be estimated along with its 95exact confidence Interval.  Subject listings with 
related collected parameters will also be provided.
Summary of other best responses status by each response category will be also 
provided.
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10.4.3
Safety Endpoints
Unless otherwise specified, statistical analyses on safety endpoints will be done using 
subjects from the full analysis set, which includes subjects that are enrolled and received 
at least 1 dose of blinatumomab.
10.4.3.1
Adverse Events
Subject incidence of all treatment-emergent adverse events will be tabulated by system 
organ class and preferred term.  The number and percentage of subjects reporting 
adverse events will be evaluated overall and by dose level and will also be tabulated by 
relationship to study drug.
Tables of fatal adverse events, serious adverse events, adverse events leading to 
withdrawal from investigational product or other protocol-required therapies, and 
significant treatment-emergent adverse events will also be provided.
Subject incidence of disease related events and fatal disease related events will be 
tabulated by system organ class and 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 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.
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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.
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.  Refer to ICH GCP 
guideline, Section 4.8.9.
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.  
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
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 
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, 
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 before the 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. 
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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.
12.2
Study Documentation and Archive
The investigator is to maintain a list of appropriately qualified persons to whom he/she 
has delegated study duties.  All persons authorized to make entries and/or corrections 
on CRFs will be included on the Amgen Delegation of Authority Form.
Source documents are original documents, data, and records from which the subject’s 
CRF data are obtained.  These include but are not limited to hospital records, clinical 
and office charts, laboratory and pharmacy records, diaries, microfiches, radiographs, 
and correspondence.
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation, suitable for 
inspection at any time by representatives from Amgen and/or applicable regulatory 
authorities.  
Elements to include:

Subject files containing completed CRFs, informed consent forms, and subject 
identification list

Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of prestudy documentation, and all correspondence to and from the 
IRB/IEC and Amgen

Investigational product-related correspondence including Proof of Receipts 
(POR), Investigational Product Accountability Record(s), Return of Investigational 
Product for Destruction Form(s), Final Investigational Product Reconciliation 
Statement, as applicable.

Non-investigational product(s) and or medical device(s) 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, 
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upon request, inspecting the various records of the clinical study (eg, CRFs and other 
pertinent data) provided that subject confidentiality is respected.
The Clinical Monitor is responsible for verifying the CRFs at regular intervals throughout 
the study to verify adherence to the protocol; completeness, accuracy, and consistency 
of the data; and adherence to local regulations on the conduct of clinical research.  The
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 
investigator inspected or reviewed the data on the CRF, the data queries, and 
agrees with the content.
12.4
Investigator Responsibilities for Data Collection
The investigator is responsible for complying with the requirements for all assessments 
and data collection (including subject’s not receiving protocol-required therapies) as 
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stipulated in the protocol for each subject in the study.  For subjects who withdraw 
before the completion of all protocol-required visits and are unable or unwilling to 
continue the Schedule of Assessments (Table 3, Table 4, Table 5, Table 6, and 
Table 7), the investigator can search publicly available records [where permitted]) to 
ascertain survival status.  This ensures that the data set(s) produced as an outcome of 
the study is/are as comprehensive as possible.  
12.5
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.

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.
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
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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lymphomas: clinical features of the nature histologic subtypes. Non-Hodgkin's 
Lymphoma Classification Project. J Clin Onc. 1998;16:2780-2795.
Cheson B, Pfistner B, Juweid M, et al. Revised response criteria for malignant 
lymphoma. Jour of Clin Oncol 2007;25(5):579-586.
Cheson B, Fisher R, Barrington, S, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: The Lugano 
Classification. Jour of Clin Oncol 2014;32(27):3059-3068. 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika. 1934;26(4):404-413.
De Cock E, Kritikou P, et al. Time savings with rituximab subcutaneous (SC) injection vs 
rituximab intravenous (IV) infusion: final analysis from a time-and-motion study in
8 countries. Blood 2013;122:abstr 1742.
Dreier T, Lorenczewski G, Brandl C et al.: Extremely potent, rapid and co-stimulation 
independent cytotoxic T-cell response against lymphoma cells catalyzed by a 
single-chain bispecific antibody. I nt J Cancer 2002; 100 :690-697.
GLOBOCAN, 2012.
Goldenberg DM, Morschhauser F, Tao S, et al. Veltuzumab (humanized 
anti-CD20 monoclonal antibody): characterization, current clinical results, and future 
prospects. Leuk Lymphoma 2010;51:747–755.
Goebeler ME, Knop S, Viardot A, et al. Bispecific T-Cell Engager (BiTE) Antibody 
Construct Blinatumomab for the Treatment of Patients With Relapsed/Refractory 
Non-Hodgkin Lymphoma: Final Results From a Phase I Study. J Clin Oncol. 
2016;34:1104-1111.
Gribben J. How do I treat Lymphoma. Blood 2007;109,(11). Abstract;4617-4626.
Harris N, Jaffe E, Wegener WA, et al. A revised European-American classification of 
lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 
1994;84:1361-92.
Howlader N, Noone AM, et al. SEER Cancer Statistics Review, 1975-2013, National 
Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2013/, based on 
November 2015 SEER data submission, posted to the SEER web site, April 2016.
International Committee of Medical Journal Editors, Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals: Writing and Editing for Biomedical 
Publication. 2013. http://www.icmje.org/.
Lister TA, Crowther D, et al. Report of a committee convened to discuss the evaluation 
and staging of patients with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 
1989, 7:1630-1636.
Lundin J, Kimby E, Bjorkholm M, et al. Phase II trial of subcutaneous anti-CD52 
monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with 
B-cell chouronic lymphocytic leukemia (B-CLL). Blood 2002;100:768–773.
Pivot X, Gligorov J, Muller V, et al. Preference for subcutaneous or intravenous 
administration of trastuzumab in patients with HER2-positive early breast cancer 
(PrefHer): an open-label randomised study. Lancet Oncol 2013;14:962–970.
Approved 
 
 


Product:  Blinatumomab
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Date:  25 February 2019
Page 101 of 113
CONFIDENTIAL
Schlereth B, Quadt C, Dreier T et al.: T-cell activation and B-cell depletion in 
chimpanzees treated with a bispecific anti-CD19/ anti-CID3 single chain antibody 
construct. Cancer Immunol Immunother 2006;55:503-514.
Singh N, Frey NV, Grupp S, Maude S. CAR T Cell Therapy in Acute Lymphoblastic 
Leukemia and Potential for Chronic Lymphocytic Leukemia.  Curr. Treat. Options in 
Oncol. 2016: 17:28.
Stilgenbauer S, Zenz T, Winkler D, et al. Subcutaneous alemtuzumab in 
fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic 
marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia 
Study Group. J Clin Oncol 2009;27:3994–4001.
Shpilberg O, Jackisch C. Subcutaneous administration of rituximab (MabThera) and 
trastuzumab (Herceptin) using hyaluronidase. Br J Cancer 2013;109:1556–61.
Swerdlow SH, Campo E, Harris NL, et al. World Health Organization Classification of 
Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon 2008.
Thall PF, Simon RM, and Estey EH.  Bayesion sequential monitoring designs for 
single-arm clinical trials with multiple outcomes.  Stat. Med.  1995;14(4):357-379.
Viardot A, Goebeler M, Hess G, et al. Phase 2 study of the bispecific T-cell engager 
(BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma”. 
Blood. 2016; 127:1410-1416.
Approved 
 
 


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Date:  25 February 2019
Page 102 of 113
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14.
APPENDICES
Approved 
 
 


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Appendix A.  Modified Cheson Criteria for Evaluation of Extramedullary Disease
Response
Definition
Nodal Masses
Spleen, Liver
Bone Marrow
CR
Disappearance of all 
evidence of disease
(a) FDG-avid or PET positive prior to therapy; 
mass of any size permitted if PET negative 
(b) Variably FDG-avid or PET negative; regression 
to normal size on CT
Not palpable, nodules 
disappeared
Infiltrate cleared on repeat biopsy; if 
indeterminate by morphology, 
immunohistochemistry should be 
negative
PR
Regression of 
measurable disease 
and no new sites
≥ 50% decrease in SPD of up to 6 largest 
dominant masses; no increase in size of other 
nodes 
(a) FDG-avid or PET positive prior to therapy; one 
or more PET positive at previously involved 
site 
(b) Variably FDG-avid or PET negative; regression 
on CT
≥ 50% decrease in SPD of 
nodules (for single nodule in 
greatest transverse diameter); no 
increase in size of liver or spleen
Irrelevant if positive prior to therapy; 
cell type should be specified
SD
Failure to attain 
CR/PR or PD

FDG-avid or PET positive prior to therapy; 
PET positive at prior sites of disease and no 
new sites on CT or PET

Variably FDG-avid or PET negative; no 
change in size of previous lesions on CT
Relapsed 
disease or PD
Any new lesion or 
increase by ≥ 50% of 
previously involved 
sites from nadir
Appearance of a new lesion(s) > 1.5 cm in any 
axis, ≥ 50% increase in SPD of more than one 
node, or ≥ 50% increase in longest diameter of 
a previously identifed node > 1 cm in short axis
Lesions PET positive if FDG-avid lymphoma or 
PET positive prior to therapy
> 50% increase from nadir in the 
SPD of any previous lesions
New or recurrent involvement
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR, partial remission; SPD, sum of the 
product of the diameters; SD, stable disease; PD, progressive disease.
Approved 
 
 


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Date:  25 February 2019
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Appendix B.  Response Assessment Per the Lugano Classification
Source:  Cheson et al, 2014
Approved 
 
 


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Date:  25 February 2019 
Page 105 of 113 
CONFIDENTIAL 
 
 
Appendix C.  Eastern Cooperative Oncology Group (ECOG) Performance Status 
Grade 
Descriptions 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (eg, light housework, office work). 
2 
Ambulatory and capable of all 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 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. 
Approved 
 
 


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Appendix D.  Additional Safety Assessment Information
Refer to the NCI 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 DILI, cases of concurrent AST/ALT and 
TBL and/or INR elevation according to the criteria specified in Section 6.3 require the 
following:

The event is to be reported to Amgen as a serious adverse event within 1 working 
day of discovery or notification of the event (ie, before additional etiologic 
investigations have been concluded)

The appropriate CRF (eg, Event CRF) that captures information necessary to 
facilitate the evaluation of treatment-emergent liver abnormalities are 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 9.2.2.2.
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 
Sections 6.3.2 and 6.3.3 or who experience AST or ALT elevations 3 × ULN are to
undergo a period of “close observation” until abnormalities return to normal or to the 
subject’s baseline levels.  
Assessments that are to be performed during this period include: 

Repeat AST, ALT, ALP, bilirubin (total and direct), and INR within 24 hours 

In cases of TBL 2 × ULN or INR 1.5, retesting of liver tests, BIL (total and direct), 
and INR is to be performed every 24 hours until laboratory abnormalities improve
Testing frequency of the above laboratory tests may decrease if the abnormalities 
stabilize or the investigational product(s) or protocol-required therapies has/have been 
discontinued AND the subject is asymptomatic.
Approved 
 
 


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
Initiate investigation of alternative causes for elevated AST or ALT and/or elevated 
TBL:  

Obtain complete blood count  with differential to assess for eosinophilia

Obtain serum total immunoglobulin IgG, Anti-nuclear antibody (ANA), Anti 
Smooth Muscle Antibody, and Liver Kidney Microsomal antibody 1 (LKM1) to 
assess for autoimmune hepatitis

Obtain serum acetaminophen (paracetamol) levels

Obtain 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

Obtain viral serologies

Obtain CPK, haptoglobin, LDH, and peripheral blood smear

Perform appropriate liver imaging if clinically indicated

Obtain appropriate blood sampling for pharmacokinetic analysis if this has not 
already been collected 

Obtain hepatology consult (liver biopsy may be considered in consultation with an 
hepatologist)

Follow the subject and the laboratory tests (ALT, AST, TBL, INR) until all laboratory 
abnormalities return to baseline or normal or considered stable by the investigator.  
The “close observation period” is to continue for a minimum of 4 weeks after 
discontinuation of all investigational product(s) and protocol-required therapies.
The potential DILI event and additional information such as medical history, concomitant 
medications and laboratory results must be captured in the corresponding CRFs.
Approved 
 
 


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Date:  25 February 2019
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Appendix E.  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
Deliria (including confusion)
Dementia and amnestic conditions
Disturbances in thinking and perception
Psychiatric disorders NEC
Schizophrenia and other psychotic disorders
Approved 
 
 


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Appendix F.  Sample Serious Adverse Event Report Form
Approved 
 
 


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Approved 
 
 


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Approved 
 
 


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Date:  25 February 2019
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CONFIDENTIAL
Appendix G.  Pregnancy and Lactation Notification Worksheets
Approved 
 
 


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Date:  25 February 2019
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CONFIDENTIAL
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20140286 
Date:  25 February 2019 
Page 1 of 84 
CONFIDENTIAL 
 
 
Amendment 6 
Protocol Title:  A Phase 1b Open-label Study Investigating the Safety and 
Pharmacokinetics of Administration of Subcutaneous Blinatumomab for the 
Treatment of Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma 
 
Amgen Protocol Number 20140286 
EudraCT number 2016-002034-76 
NCT number 02961881 
 
Amendment 6 Date: 
17 January 2019 
Superseding Amendment 6  
06 February 2019 
Superseding Amendment 6 
v2 
25 February 2019 
Rationale: 
The purpose of this protocol amendment is to: 
• 
Expand the primary objective to include additional SC dosing frequency intervals 
based on PK and safety data by deleting q12h and qd dosing frequency in the 
objective 
• 
Add potential for additional dose cohorts in Period 1 beyond Cohorts 1-3 to explore 
different SC dosing regimens (doses and intervals) during Cycle 1 Week 4 
o Expand the SC dosing frequency options to include longer intervals of q48h, 
q72h, q96h, q7d, in addition to the pre-existing q12h and q24h options 
o Expand the SC dose range to 169-900 µg including intermediate dose options 
• 
Expand Schedule of Assessments to define dosing schedule, PK sampling, 
biomarker sampling and hospitalization requirements for the additional SC 
frequencies (Period 2) 
• 
Increase the number of subjects to accommodate potential for 2 additional cohorts in 
Period 1, and to allow for up to 20% replacement rate of subjects who prematurely 
discontinue in either Period  
• 
Clarify that the DLRT will decide on choice of SC dosing regimen for each cohort 
based off review of clinical, safety, tolerability and PK data from previous cohorts, 
and to define boundaries for dose and frequency choices  
• 
Extend the premedication dexamethasone administration window from within 1 hour 
prior to up to 6 hours prior to first dose/dose-step, and to clarify that dexamethasone 
requirements also apply prior to first dose SC and prior to resuming cIV in 
Cycle 1/Period 1 Weeks 4 and 5 respectively 
• 
Update the subject replacement rules for Cycle 1/Period 2 
• 
Clarify DLRT Investigator quorum includes PI’s that enrolled subjects on cohort. 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20140286 
Date:  25 February 2019 
Page 2 of 84 
CONFIDENTIAL 
 
 
• 
The DLRT will decide the change in dosing frequency based on results of 
pharmacokinetics from previous cohorts. 
• 
Modify DLT criteria to exclude all Grade 3 and 4 lymphopenia.  Grade 4 lymphopenia 
is known to occur from therapies used to treat 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 does resolve after therapy is 
completed.   
• 
Modify DLT to exclude Grade 3 neurological events that resolve within 7 days.   
o This is based on that Grade 3 neurologic events are known to occur with cIV 
blinatumomab and resolve within 7 days in most cases.  After resolution of the 
neurologic event the blinatumomab can be restarted at the next lower dose level 
and if the event doesn’t occur again then the dose can be escalated to the target 
dose.   
o There are now 12 patients that have been treated with SC blinatumomab and 
have tolerated the dose which has similar pharmacokinetics to the target dose of 
112 ug/day cIV.   One subject had Grade 3 neurotoxicity after the third SC dose 
that resolved after 24 hours.  One subject had Grade 3 neurotoxicity in cIV Run 
In at 112 ug/day cIV that resolved on holding the infusion.  The subject 
proceeded to SC and tolerated this well without reoccurrence of the grade 3 
neurotoxicity.   
• 
Revise toxicity management, treatment interruptions and re-start table, including 
capacity to rechallenge with SC in the event of Grade 3 neurological event that 
resolves within 7 days 
• 
Add contingent treatment management instructions for remaining subjects enrolled in 
any Period 1/Cycle 1 cohort in the scenario that preceding subjects in that cohort 
experience a DLT and the cohort is terminated. 
• 
Modify optional Cycle 2 in Period 2 to allow SC if the subject had clinical benefit in 
Cycle 1, if no benefit they could receive cIV.  
• 
Clarify that post-Cycle 1 and post-Cycle 2 disease assessment PET-CT/CT scans 
should be performed within 2-4 weeks post last dose  
• 
Increase contraception and lactation reporting and washout period post last dose of 
SC from 48 hours up to 96 hours in the Safety section and under Exclusion Criteria, 
based on review of actual Period 1 PK data 
• 
Make editorial and administrative changes for grammatical reasons as well as for 
internal consistency within the protocol. 
Additional errors were identified and rectified in the superseding amendment, and 
administrative errors were corrected: 
• 
incorporate superseding revisions to Table 7 (Schedule of Assessments for Optional 
Cycle 2) to correct typographical errors in cycle day and footnote “m”  
• 
to correct the wording of footnote “m”. 
A date error was identified and rectified in Superseding Amendment 3 Version 2.0: 
• 
Date in the header was changed from 17 January 2019 to 25 February 2019 
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  06 February 2019
Page 1 of 84
CONFIDENTIAL
Amendment 6
Protocol Title:  A Phase 1b Open-label Study Investigating the Safety and 
Pharmacokinetics of Administration of Subcutaneous Blinatumomab for the 
Treatment of Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma
Amgen Protocol Number 20140286
EudraCT number 2016-002034-76
NCT number 02961881
Amendment 6 Date:
17 January 2019
Superseding Amendment 6 
06 February 2019
Rationale:
The purpose of this protocol amendment is to:

Expand the primary objective to include additional SC dosing frequency intervals 
based on PK and safety data by deleting q12h and qd dosing frequency in the 
objective

Add potential for additional dose cohorts in Period 1 beyond Cohorts 1-3 to explore 
different SC dosing regimens (doses and intervals) during Cycle 1 Week 4
o
Expand the SC dosing frequency options to include longer intervals of q48h, 
q72h, q96h, q7d, in addition to the pre-existing q12h and q24h options
o
Expand the SC dose range to 169-900 µg including intermediate dose options

Expand Schedule of Assessments to define dosing schedule, PK sampling, 
biomarker sampling and hospitalization requirements for the additional SC 
frequencies (Period 2)

Increase the number of subjects to accommodate potential for 2 additional cohorts in 
Period 1, and to allow for up to 20% replacement rate of subjects who prematurely 
discontinue in either Period 

Clarify that the DLRT will decide on choice of SC dosing regimen for each cohort 
based off review of clinical, safety, tolerability and PK data from previous cohorts, 
and to define boundaries for dose and frequency choices 

Extend the premedication dexamethasone administration window from within 1 hour 
prior to up to 6 hours prior to first dose/dose-step, and to clarify that dexamethasone 
requirements also apply prior to first dose SC and prior to resuming cIV in 
Cycle 1/Period 1 Weeks 4 and 5 respectively

Update the subject replacement rules for Cycle 1/Period 2

Clarify DLRT Investigator quorum includes PI’s that enrolled subjects on cohort.

The DLRT will decide the change in dosing frequency based on results of 
pharmacokinetics from previous cohorts.
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20140286 
Date:  17 January 2019 
Page 1 of 84 
CONFIDENTIAL 
 
 
Amendment 6 
Protocol Title:  A Phase 1b Open-label Study Investigating the Safety and 
Pharmacokinetics of Administration of Subcutaneous Blinatumomab for the 
Treatment of Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma 
 
Amgen Protocol Number 20140286 
EudraCT number 2016-002034-76 
NCT number 02961881 
 
Amendment 6 Date: 
17 January 2019 
Rationale: 
The purpose of this protocol amendment is to: 
• 
Expand the primary objective to include additional SC dosing frequency intervals 
based on PK and safety data by deleting q12h and qd dosing frequency in the 
objective 
• 
Add potential for additional dose cohorts in Period 1 beyond Cohorts 1-3 to explore 
different SC dosing regimens (doses and intervals) during Cycle 1 Week 4 
o Expand the SC dosing frequency options to include longer intervals of q48h, 
q72h, q96h, q7d, in addition to the pre-existing q12h and q24h options 
o Expand the SC dose range to 169-900 µg including intermediate dose options 
• 
Expand Schedule of Assessments to define dosing schedule, PK sampling, 
biomarker sampling and hospitalization requirements for the additional SC 
frequencies (Period 2) 
• 
Increase the number of subjects to accommodate potential for 2 additional cohorts in 
Period 1, and to allow for up to 20% replacement rate of subjects who prematurely 
discontinue in either Period  
• 
Clarify that the DLRT will decide on choice of SC dosing regimen for each cohort 
based off review of clinical, safety, tolerability and PK data from previous cohorts, 
and to define boundaries for dose and frequency choices  
• 
Extend the premedication dexamethasone administration window from within 1 hour 
prior to up to 6 hours prior to first dose/dose-step, and to clarify that dexamethasone 
requirements also apply prior to first dose SC and prior to resuming cIV in 
Cycle 1/Period 1 Weeks 4 and 5 respectively 
• 
Update the subject replacement rules for Cycle 1/Period 2 
• 
Clarify DLRT Investigator quorum includes PI’s that enrolled subjects on cohort. 
• 
The DLRT will decide the change in dosing frequency based on results of 
pharmacokinetics from previous cohorts. 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20140286 
Date:  17 January 2019 
Page 2 of 84 
CONFIDENTIAL 
 
 
• 
Modify DLT criteria to exclude all Grade 3 and 4 lymphopenia.  Grade 4 lymphopenia 
is known to occur from therapies used to treat 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 does resolve after therapy is 
completed.   
• 
Modify DLT to exclude Grade 3 neurological events that resolve within 7 days.   
o This is based on that Grade 3 neurologic events are known to occur with cIV 
blinatumomab and resolve within 7 days in most cases.  After resolution of the 
neurologic event the blinatumomab can be restarted at the next lower dose level 
and if the event doesn’t occur again then the dose can be escalated to the target 
dose.   
o There are now 12 patients that have been treated with SC blinatumomab and 
have tolerated the dose which has similar pharmacokinetics to the target dose of 
112 ug/day cIV.   One subject had Grade 3 neurotoxicity after the third SC dose 
that resolved after 24 hours.  One subject had Grade 3 neurotoxicity in cIV Run 
In at 112 ug/day cIV that resolved on holding the infusion.  The subject 
proceeded to SC and tolerated this well without reoccurrence of the grade 3 
neurotoxicity.   
• 
Revise toxicity management, treatment interruptions and re-start table, including 
capacity to rechallenge with SC in the event of Grade 3 neurological event that 
resolves within 7 days 
• 
Add contingent treatment management instructions for remaining subjects enrolled in 
any Period 1/Cycle 1 cohort in the scenario that preceding subjects in that cohort 
experience a DLT and the cohort is terminated. 
• 
Modify optional Cycle 2 in Period 2 to allow SC if the subject had clinical benefit in 
Cycle 1, if no benefit they could receive cIV.  
• 
Clarify that post-Cycle 1 and post-Cycle 2 disease assessment PET-CT/CT scans 
should be performed within 2-4 weeks post last dose  
• 
Increase contraception and lactation reporting and washout period post last dose of 
SC from 48 hours up to 96 hours in the Safety section and under Exclusion Criteria, 
based on review of actual Period 1 PK data 
• 
Make editorial and administrative changes for grammatical reasons as well as for 
internal consistency within the protocol. 
 
Approved 
 
 


Product:  Blinatumomab
Protocol Number:  20140286
Date:  15 February 2018
Page 1 of 8
CONFIDENTIAL
Amendment 5
Protocol Title:  A Phase 1b Open-label Study Investigating the Safety and 
Pharmacokinetics of Administration of Subcutaneous Blinatumomab for the 
Treatment of Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma
Amgen Protocol Number 20140286
EudraCT number 2016-002034-76
NCT number 02961881
Amendment 5 Date:
15 February 2018
Rationale:
The purpose of this protocol amendment is to:

Change Optional Cycle 2 dosing to step-dosing (9/28/112 μg/day) to mitigate grade 3 
neurologic event

Clarify that cohorts receiving every 12 hours (q12h) subcutaneous (SC) dosing, will 
receive 9 doses of SC to allow for intensive pharmacokinetic (PK) sampling to occur 
on day shift 

Clarification in ‘Table 2.  Treatment Interruptions and Restart’ instructions for grade 3
neurologic events for:
o
continuous intravenous (cIV) given after SC is completed in Cycle 1/Period 1, and 
o
cIV infusion in Optional Cycle 2 

Clarification in Table 2 for ‘Other clinically relevant adverse events’ to permanently 
discontinue blinatumomab for non-laboratory adverse events at least possibly related 
to blinatumomab to make consistent with wording in text of section 6.2.1.4.2

Added creatinine clearance to screening section in SOA for cycle 1/period 1 and 
cycle 1/period 2

Address administrative, typographical, and formatting changes within the protocol.
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20140286 
Date:  11 August 2017 
Page 1 of 4 
CONFIDENTIAL 
 
Amendment 4 
Protocol Title:  A Phase 1b Open-label Study Investigating the Safety and 
Pharmacokinetics of Administration of Subcutaneous Blinatumomab for the 
Treatment of Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma 
 
Amgen Protocol Number 20140286 
EudraCT number 2016-002034-76 
NCT number 02961881 
 
Amendment Date: 
11 August 2017 
 
Rationale: 
The purpose of this protocol amendment is to: 
• 
Remove typographical error in exclusion criterion 211 that was inadvertently 
introduced within the previous amendment. 
• 
Correctly align inclusion criterion 105 with screening procedures and timeframe to 
in-text descriptions of the protocol. 
• 
Address administrative, typographical, and formatting changes within the protocol. 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20140286 
Date:  30 March 2017 
Page 1 of 4 
CONFIDENTIAL 
Amendment 3 
Protocol Title:  A Phase 1b Open-label Study Investigating the Safety and 
Pharmacokinetics of Administration of Subcutaneous Blinatumomab for the 
Treatment of Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma
Amgen Protocol Number Blinatumomab 20140286
EudraCT number 2016Ǧ002034Ǧ76
Amendment Date:
30 March 2017
Rationale: 
This protocol is being amended to remove “legally acceptable representative” from the 
protocol per the US central IRB.  It is being removed due to the fact that this is a phase 
1 protocol.  The protocol is also being amended to make updates to Section 5 (Subject 
Enrollment) language regarding the 96-hour interval between start of blinatumomab 
treatment for each subject. 


Product:  Blinatumomab 
Protocol Number:  20140286 
Date:  08 January 2017 
Page 1 of 23 
 
Amendment 2 
Protocol Title:  A Phase 1b Open-label Study Investigating the Safety and 
Pharmacokinetics of Administration of Subcutaneous Blinatumomab for the 
Treatment of Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma 
 
Amgen Protocol Number (Product Name: Blinatumomab) 20140286 
 
Amendment Date: 
08 January 2017 
Rationale: 
This protocol is being amended as a result of discussions with the US Food and Drug 
Administration (FDA). 
The changes reflect the following key modifications: 
• 
Inclusion criterion 103, clarified to be eligible subjects must have a histologically 
determined B cell non-Hodgkin’s lymphoma (NHL) subtype as defined in the 
bulleted list and must have disease that is primary refractory after initial therapy 
or have relapsed disease. 
• 
Inclusion criterion 104, clarified that the subject’s disease status for eligibility in 
the study. 
• 
Dose-limiting toxicity (DLT) rules were clarified to more precisely define what the 
DLT evaluable period is for each subcutaneous (SC) period (Periods 1 and 2) of 
the study and to clarify how many doses a subject must receive in order to be 
considered DLT-evaluable if the subject did not have a DLT.  
• 
Clarified the definition of a DLT and better define what is considered an adverse 
event in the study. 
• 
Added a table to help the investigator better understand what to do when there is 
an interruption of blinatumomab and dose modification because of an adverse 
event and the criteria for rechallenge. 
• 
Added amylase to the list of chemistries to monitor for pancreatitis to be 
consistent with the acute lymphoblastic leukemia (ALL) label.  
• 
Revised the table for disease-related adverse events to include only adverse 
events that are directly related to the underlying disease.  
• 
Revised the language for laboratory adverse events to include the requirement 
that laboratory abnormalities that require intervention be recorded as adverse 
events. 
• 
Revised Figure 4 to show continuous monitoring. 
• 
Clarified the stopping rules for Cycle 1/Period 2. 
• 
Clarified that up to 15 additional subjects may be enrolled in the Period 2 
expanded cohort to allow for flexibility in stopping the study. 
• 
Administration, typographical and formatting changes were made throughout the 
protocol. 
CONFIDENTIAL 
 
 
Approved 
 
 


Product:  Blinatumomab 
Protocol Number:  20140286 
Date:  14 September 2016 
Page 1 of 67 
CONFIDENTIAL 
 
 
Amendment 1 
Protocol Title:  A Phase 1b Open-label Study Investigating the Safety and 
Pharmacokinetics of Administration of Subcutaneous Blinatumomab for the 
Treatment of Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma 
 
Amgen Protocol Number (Blinatumomab) 20140286 
 
 
Amendment Date: 
14 September 2016 
Rationale: 
• 
To align the protocol safety section with the blinatumomab lymphoma program.   
• 
To established safety guidelines for CRS and Neurologic adverse events so that all 
subjects will be treated across the program in the same manner.   
• 
Disease related adverse events by system organ class table was also updated and 
aligns with the other lymphoma protocols  
• 
Updated the Schedule of Assessments to include monitoring of hematology, 
chemistry, and a tumor evaluation prior to optional cycle 2  
• 
Editorial changes for clarification and consistency throughout the protocol 

SAP_001.pdf: 
Product:  Blinatumomab
Statistical Analysis Plan:  20140286
Date:  21 May 2019
Page 1
STATISTICAL ANALYSIS PLAN
A Phase 1b Open-label Study Investigating the Safety and Pharmacokinetics of 
Administration of Subcutaneous Blinatumomab for the Treatment of 
Relapsed/Refractory Indolent Non-Hodgkin’s Lymphoma
Protocol Number:
20140286
Version:
2.0
Date:
21 May 2019
Authors:
 
 from Global Biostatistical Science
, Clinical Pharmacology
NCT Number: NCT02961881
This NCT number has been applied to the document
for the purposes of posting on clinicaltrials.gov


Product:  Blinatumomab
Statistical Analysis Plan:  20140286
Date:  21 May 2019
Page 2
Version Number
Date
(DDMMMYYYY)
Summary of Changes, 
including rationale for changes
Original (v1.0)
03May2017
Amendment 1 (v2.0)
21May2019
1. SAP is updated as per protocol 
amendment 6.
2. Section 6 Definitions of Best 
Overall Response is updated for 
assessment timepoint during 
Safety Follow-up visit.
3. Section 6 DLT evaluable 
definition, Optional Cycle2 are 
updates as per protocol
4. Section 8.1.1.1 Dose Level 
Review Team and 8.1.1.2 Dose 
Limiting toxicity rules are updated 
as per protocol amendment 6
5. Section 10.5.1 ,Analysis for DRE 
included.
6. Section 10.6.1 Analyses of 
Secondary Efficacy Endpoints is 
updated.
7. Table 4, 5, and 6 Schedule of 
assessment for cycle 1 and cycle 
2 are removed.
8. Appendix D updated to include
PROC FREQ code for Clopper 
Pearson method to find 95 % CI.
9. Section 6  TEAE definition is 
updated to “A treatment emergent 
adverse event refers to the 
adverse event that starts on or 
after first dose of blinatumomab 
through 30 days after the last 
dose of blinatumomab.
10. Section 10.5.1 Adverse Event is 
updated to include "Similar 
summaries will be repeated for 
EOIs. Time to onset and duration 
of selected EOIs (infection and 
neurologic events) may also be 
summarized.”


Product:  Blinatumomab
Statistical Analysis Plan:  20140286
Date:  21 May 2019
Page 3
Table of Contents
Table of Abbreviations.....................................................................................................6
1.
Introduction.............................................................................................................7
2.
Objectives...............................................................................................................7
2.1
Primary Objective........................................................................................7
2.2 
Secondary Objectives .................................................................................7
2.3
Exploratory Objective..................................................................................7
3.
Study Overview ......................................................................................................7
3.1
Study Design...............................................................................................7
3.1.1
Cycle 1/Period 1..........................................................................8
3.1.2
Cycle 1/Period 2..........................................................................9
3.1.3
Safety Monitoring ......................................................................10
3.1.4
Study Schema...........................................................................11
3.2
Sample Size..............................................................................................12
4.
Study Endpoints and Covariates...........................................................................13
4.1
Study Endpoints........................................................................................13
4.1.1
Primary Endpoint.......................................................................13
4.1.2
Secondary Endpoints ................................................................13
4.1.3
Exploratory Endpoint .................................................................13
4.2
Planned Covariates...................................................................................13
5.
Hypotheses and/or Estimations ............................................................................13
6.
Definitions.............................................................................................................13
7.
Analysis Subsets ..................................................................................................18
7.1
Full Analysis Set........................................................................................18
7.2
Safety Analysis Set ...................................................................................18
7.3
DLT Analysis Set.......................................................................................18
7.4
Pharmacokinetic Analysis Set ...................................................................18
7.5
Pharmacodynamic Analysis Set................................................................18
8.
Interim Analysis and Early Stopping Guidelines....................................................19
8.1
Interim Analysis.........................................................................................19
8.1.1
Dose-cohort Study Escalation and Stopping Rules....................19
8.1.1.1
Dose Level Review Team........................................19
8.1.1.2
Dose Limiting Toxicity Rules ...................................20
9.
Data Screening and Acceptance...........................................................................21
9.1
General Principles.....................................................................................21
9.2
Data Handling and Electronic Transfer of Data..........................................21
9.3
Handling of Missing and Incomplete Data .................................................21
9.4
Detection of Bias.......................................................................................21


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Date:  21 May 2019
Page 4
9.5
Outliers .....................................................................................................21
9.6
Distributional Characteristics.....................................................................21
9.7
Validation of Statistical Analyses...............................................................21
10.
Statistical Methods of Analysis..............................................................................22
10.1
General Principles.....................................................................................22
10.2
Subject Accountability ...............................................................................22
10.3
Important Protocol Deviations ...................................................................23
10.4
Demographic and Baseline Characteristics...............................................23
10.5
Safety Analyses ........................................................................................23
10.5.1
Adverse Events .........................................................................23
10.5.1.1
Dose Limiting Toxicities...........................................24
10.5.2
Laboratory Test Results.............................................................24
10.5.2.1
Chemistry, Hematology and Coagulation ................24
10.5.2.2
Urinalysis ................................................................25
10.5.3
Vital Signs .................................................................................25
10.5.4
Eastern Cooperative Oncology Group (ECOG) 
Performance Status...................................................................25
10.5.5
Antibody Formation ...................................................................25
10.5.6
Exposure to Investigational Product ..........................................26
10.5.7
Exposure to Concomitant Medication ........................................26
10.6
Efficacy Analyses......................................................................................26
10.6.1
Analyses of Secondary Efficacy Endpoint(s)..............................26
10.6.2
Analyses of Exploratory Endpoints ............................................26
10.7
Pharmacokinetic Analysis .........................................................................27
10.8
Pharmacodynamic Analysis ......................................................................28
11.
Changes From Protocol-specified Analyses..........................................................28
12.
Literature Citations / References...........................................................................29
13.
Prioritization of Analyses.......................................................................................30
14.
Data Not Covered by This Plan.............................................................................30
15.
Appendices...........................................................................................................31
List of Tables
Table 1.  Cycle 1/Period 2 Stopping Boundaries............................................................10
Table 2.  Operating Characteristics ...............................................................................10
Table 3.  Disease-related Adverse Events by System Organ Class...............................15
List of Figures
Figure 1.  Study Schema for Cycle 1/Period 1: cIV Run-in and SC Dose.......................11
Figure 2.  Study Schema for Cycle 1/Period 2 ...............................................................12


Product:  Blinatumomab
Statistical Analysis Plan:  20140286
Date:  21 May 2019
Page 5
List of Appendices
Appendix A.  Technical Detail and Supplemental Information Regarding 
Statistical Procedures.............................................................................32
Appendix B.  Modified Cheson Criteria for Evaluation of Extramedullary 
Disease ..................................................................................................34
Appendix C.  Response Assessment Per the Lugano Classification..............................35
Appendix D.  Code Fragments.......................................................................................36
Appendix E.  Reference Values/Toxicity Grades ...........................................................37
Appendix F.  DLRT Output List......................................................................................38


Product:  Blinatumomab
Statistical Analysis Plan:  20140286
Date:  21 May 2019
Page 6
Table of Abbreviations
Abbreviation or Term
Definition/Explanation
cIV
Continuous Intravenous
CR
Complete Response
CRF
Case Report Form
CRS
Cytokine Release Syndrome
CTCAE
Common Terminology Criteria for Adverse Events
DLRT
Dose Level Review Team
DLT
Dose Limiting Toxicities
ECOG
Eastern Cooperative Oncology Group
EOS
End of Study
FAS
Full Analysis Set
FL
Follicular Lymphoma I, II, IIIA
ICH
International Conference on Harmonisation
IP
Investigational Product
IV
Intravenous
MCL
Mantle cell lymphoma
MTD
Maximum Tolerated Dose
NHL
Non-Hodgkin’s Lymphoma
ORR
Overall response rate
PD
Pharmacodynamic
PK
Pharmacokinetic
PR
Partial Response
q12h
Every 12 hours
q24h
Every 24 hours
SAP
Statistical Analysis Plan
SC
Subcutaneous
SOC
System Organ Class
WBC
White Blood Cells
WHO
World Health Organization


Product:  Blinatumomab
Statistical Analysis Plan:  20140286
Date:  21 May 2019
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 for study 20140286 Blinatumomab, 
Superseding Amendment 6 V2 dated 25Feb2019. The scope of this plan includes the 
interim analysis and the final analysis that are planned and will be executed by the 
Biostatistics department or designee unless otherwise specified eg, pharmacokinetic 
(PK) analysis will be provided by Clinical Pharmacology, Modeling and Simulation 
(CPMS) department.
2.
Objectives
2.1
Primary Objective

To evaluate the safety and tolerability of subcutaneous (SC) blinatumomab dose
administrations.
2.2
Secondary Objectives

To determine pharmacokinetics (PK) with continuous intravenous (cIV) and SC 
administrations

To estimate the maximum tolerated dose (MTD) tested for blinatumomab 
administered subcutaneously 

To determine the incidence of  anti-blinatumomab antibody formation following 
SC administration 

To evaluate efficacy response following treatment with SC blinatumomab 
administration
2.3
Exploratory Objective

To determine the pharmacodynamics (PD) time profiles for B- and T-lymphocytes 
as well as cytokine profiles during SC administration.

To evaluate efficacy response following treatment with SC blinatumomab 
administration using Lugano criteria if positron emission tomography-computed 
tomography (PET/CT) is used for evaluation (Appendix B)
3.
Study Overview
3.1
Study Design
This is a global multi-center, Phase 1b open-label study investigating the safety and PK 
of blinatumomab administered subcutaneously for the treatment of relapsed/refractory 
indolent NHL. The SC administration of blinatumomab will be tested for the first time in 
humans.  
Period 1 of the study will focus on the determination of PK, bioavailability, and safety 
profile of blinatumomab SC administration. The PK and bioavailability data from Period 
1 of the study will be used in conjunction with safety data (DLT) to determine the SC 


Product:  Blinatumomab
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Date:  21 May 2019
Page 8
MTD. The MTD or the maximum tested dose, if MTD is not reached, will be further 
tested in Period 2 in an expanded cohort. Efficacy of blinatumomab administered 
subcutaneously will also be investigated in each period of the study.
3.1.1
Cycle 1/Period 1
In Period 1, 3 or more separate dose cohorts of up to 6 DLT evaluable subjects each will 
be enrolled and undergo treatment as follows:

Subjects will undergo an initial cIV blinatumomab run-in period (weeks 1 to 3) 
followed by a 12-hour treatment free period.

Subjects will then receive SC administration (week 4) followed by a treatment free 
period of 2 to not more than 3 days.

After the SC administration period, subjects should return to receive cIV treatment to
complete 6 weeks of therapy (weeks 5 to 6).
For all cohorts, the initial cIV dose of blinatumomab will be 9 μg/day for the first 7 days 
(to mitigate for potential cytokine release syndrome [CRS] and neurologic events 
associated with introduction to blinatumomab) which then will be escalated (dose-step) 
to 28 μg/day starting on day 8 through day 14 (week 2), and to 112 μg/day starting on 
day 15 until day 21 (week 3). 
After stopping cIV blinatumomab, there is a 12-hour treatment free period before starting
SC blinatumomab. SC blinatumomab starts after the 12-hour treatment free period and 
will be administered (week 4) as the following dose-cohort levels:

Dose Cohort 1: 112 μg q12h × 5 days for a total of 9 doses (n= 6)

Dose Cohort 2: 225 μg q12h × 5 days for a total of 9 doses (n = 6)
(Note: A total of 9 SC doses will be given for the q12h dosing, so intensive PK samples 
can be obtained on day shift to reduce errors).

Dose Cohort 3: 450 μg q24h × 5 days for a total of 5 doses (n = 6)

Additional Dose Cohorts: Dose level and dosing frequency to be determined as
described below
One or more dosing regimens (refer to Dosing Schema Figure 1 in protocol) may be 
selected based on clinical findings including safety, tolerability, and PK results from 
previous cohorts; and after Dose Level Review Team (DLRT) review and make 
recommendations for the next SC cohort dose and frequency. The dose may be 
increased (by 1 dose level or between the dose of the previous cohort and the next 
higher dosing level in Figure 1 schema in protocol), kept at the same dose level or 
decreased by 1 or more dose levels. The dose frequency chosen (q12h, q24h, q48h, 


Product:  Blinatumomab
Statistical Analysis Plan:  20140286
Date:  21 May 2019
Page 9
q72h, q96h, or q7days) will be decided by the DLRT and will be based on the previous 
cohort PK data.
Once the SC dosing is complete, a treatment free period of 2 to not more than 3 days
between stopping SC and restarting cIV will be observed. Then the cIV blinatumomab
dosing will resume at 112 μg/day (weeks 5 to 6) to complete 6 weeks of treatment.
For each SC dose cohort, if ≤ 1 of the 6 DLT evaluable subjects experience a DLT 
during the SC administration DLT evaluation period then the dose will be determined to 
be tolerable and the DLRT will decide the next dose level to be initiated and the 
frequency of administration for the next cohort; see Section 6.2.1.2.2 in protocol for 
definition of the DLT evaluation period.
For each SC dose cohort, if ≥2 of the 6 DLT evaluable subjects experience a DLT 
during the SC administration then dosing will stop for individual subjects who experience 
a DLT, a DLRT meeting will be conducted, and further steps will be determined, such as 
dose de-escalation or increasing dosing interval (Figure 1 in protocol ). In addition, if 
subjects on this cohort have not reached the SC dosing, they will be allowed to stay on 
study but will finish cycle 1/period 1 as cIV.
MTD will be defined as the highest dose level at which ≤ 1 of 6 subjects experience a 
DLT.If no subject experiences a DLT, the MTD will be defined as the maximal dose 
tested.
For further details, see Section 6.2.1.2.1 and Section 6.2.1.2.3 of protocol.
3.1.2
Cycle 1/Period 2
The aim of Period 2 will be to assess the MTD as derived from Period 1, or the 
maximum tested dose, if MTD has not been reached, for additional safety and 
preliminary efficacy data in an expanded cohort of up to 15 evaluable subjects receiving 
SC treatment only (no cIV run-in).  
Doses for Cycle 1/Period 2 will be derived based on PK, bioavailability, and safety data
collected in Cycle 1/Period 1 and DLRT review and recommendations. Subjects will
receive sequentially the estimated SC doses equivalent to the 9 µg/day cIV in week 1, 
SC doses equivalent to the 28 µg/day cIV starting in week 1 and continuing into week 2, 
and then the SC doses of the selected maximal dose and dosing interval from Cycle 
1/Period 1 starting in week 2 (day 12) and continuing to complete a total of 6 weeks of 
blinatumomab (see Section 6.2.1.2.2 in protocol for definition of the DLT evaluation 
period for Period 2).


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3.1.3
Safety Monitoring
Safety monitoring will be implemented using continuous toxicity monitoring for early 
termination of the trial in Cycle 1/Period 2. Termination of study Cycle 1/Period 2 will 
occur if the posterior probability that the DLT rate is greater than 25, given the 
cumulative data thus far, is at least 80. Starting with the fifth subject treated in 
Cycle 1/Period 2, stopping may occur at any time.
The stopping boundaries assume a prior beta distribution of (0.50, 1.50) and a batch 
size of 1 (starting with the fifth subject treated) are presented in Table 1 and the 
operating characteristics are given in Table 2. The operating characteristics in Table 2
provide the probability of stopping the trial early for given hypothetical true DLT (please 
see section 6 for more details) rates whereas the stopping criteria in Table 1 are based
on situations where the empirical evidence would result in a posterior probability 80
that the true DLT rate is 25(Thall et al, 1995).
Table 1.  Cycle 1/Period 2 Stopping Boundaries
Cumulative Number of Subjects
Stop Study if This Many Subjects Have a 
Dose-limiting Toxicity
5 - 6
3
7 - 10
4
11 - 13
5
14
6
15
Study Period 2 is complete at 15
Note: Study may stop with fewer than 5 subjects if 3 or more subjects with DLTs have been observed
Table 2.  Operating Characteristics
True Rate of Dose-Limiting 
Toxicities
Probability of Stopping Early
Average Sample Size
20
17
13.7
25
30
12.7
30
45
11.6
40
72
9.3
50
90
7.3
60
98
6.1


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3.1.4
Study Schema
Figure 1.  Study Schema for Cycle 1/Period 1: cIV Run-in and SC Dose
Abbreviations:  cIV continuous intravenous; DLRT Dose Level Review Team; DLT dose limiting 
toxicities; IP investigational product; PK = pharmacokinetic; SC subcutaneous; q12h every 12 hours; 
q24h = every 24 hours, q48h = every 48 hours, q72h = every 72 hours, q96h = every 96 hours, q7d = every 
7 days
**SC dose may be increased (by 1 dose level or between the dose of previous cohort and next higher 
dosing level), kept at the same dose level or decreased by 1 or more dose levels, and the dose frequency 
chosen (q12h, q24h, q48h, q72h, q96h, or q7days) will be decided by the DLRT and will be based on the 
previous cohort PK data.
If 2/6 DLT, then an immediate DLRT review will be conducted to determine next steps
If < 1/6 DLT, then DLRT will be convened and next dose will be tested in a new cohort of subjects as 
outlined in the protocol


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Figure 2.  Study Schema for Cycle 1/Period 2
N=15
9ug equivalent SC
week 1 with 
dosing frequency to 
be determined by 
Cycle1/Period1 PK
28ug equivalent SC
Week 1-2 with
dosing frequency to
be determined by
Cycle 1/Period 1 PK
MTD SC
weeks 2-6 with
dosing frequency to
be  determined by 
Cycle 1/Period 1 PK
Continuous toxicity monitoring
for early termination of the trial will be 
performed (refer to section 10.2)
Abbreviations:  MTD =maximum tolerated dose; PK = pharmacokinetic; SC = subcutaneous
3.2
Sample Size
Approximately 54 subjects will be enrolled in this study in order to ensure approximately 
30 evaluable subjects in Period 1 and up to 15 evaluable subjects in Period 2 are treated 
with blinatumomab.Subjects may be replaced (replacement rules outlined in protocol 
Section 3.4). This sample size is based on practical considerations and is consistent 
with conventional phase 1 oncology studies. If the true DLT rate is 10, there is a 89
probability of observing 1 DLT and 11probability of observing 2 or more DLT in 
6 subjects.  If the true DLT rate is 30, the probability of observing 1 DLT decreases 
to 42and probability of observing 2 or more DLT increases to 58.  
Up to 15 evaluable subjects will be enrolled into Cycle1/Period 2 with the planned target 
treatment dose being the highest tolerable dose regimen or highest tested dose regimen 
based on the DLRT’s recommendations. There will be interim look at the cumulative 
data in this period and based on the toxicity observed, early termination of the trial in 
Cycle 1/Period 2 will occur. For example, with 14 subjects receiving AMG 103 SC doses 
in Cycle 1/Period 1, there is a 17chance of early termination if the true DLT rate is 


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Date:  21 May 2019
Page 13
20and with a true DLT rate of 30increases the chance of early termination to 45
when the sample size is 12. Early termination rules are detailed in section Table 2.
4.
Study Endpoints and Covariates
4.1
Study Endpoints
4.1.1
Primary Endpoint

Subject grade, incidence, and severity of dose limiting toxicities (DLTs) and 
adverse events
4.1.2
Secondary Endpoints  

Blinatumomab PK parameters under cIV and SC administrations 

MTD

Incidence of anti-blinatumomab antibodies 

Overall response rate (ORR) (complete response [CR] partial response [PR]) 
as determined by best overall response ORR using Cheson criteria (see 
Appendix B)
4.1.3
Exploratory Endpoint

PD parameters of B- and T-lymphocytes and cytokines following administration 
of SC blinatumomab

ORR (CR PR) as determined by best overall response using Lugano criteria
(see Appendix C)
4.2
Planned Covariates
The relationship of the certain baseline covariates to endpoints will be explored if
appropriate. Biomarker data may be incorporated in additional exploratory subgroup or
multivariate analyses.  The analyses of biomarkers may be performed after collection of
all samples during the conduct of the study and therefore may be reported after the final
analysis.
5.
Hypotheses and/or Estimations
No formal statistical hypothesis will be tested. 
The clinical hypothesis is that blinatumomab administered through the SC route will 
demonstrate a tolerable safety-profile with serum concentrations comparable to those for 
which efficacy was shown with cIV administration in subjects with indolent 
relapsed/refractory Non-Hodgkin’s Lymphoma (NHL).
6.
Definitions
Age at Enrollment
Subject age at enrollment will be collected in years in the clinical database.


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Baseline
For the analysis of all endpoints, baseline will be defined as the value measured on 
day 1 of the first cycle of blinatumomab.. If a day 1 value is not available, the most 
recent value before the day of the start of any protocol-specified therapy may be used.
Best Overall Response
Best overall response for a subject is determined as ORR (CRPR) using Cheson 
(Appendix B) and Lugano criteria (Appendix C) during the Safety Follow-up visit (2 to 
4 weeks after the end of therapy for cycle 1). In the case where a second cycle is 
administered, the assessment has to be done prior to the start of the next cycle to 
assess the evolution of disease (as close to 2 weeks after the last dose of IP cycle 1, but 
before starting cycle 2). 
Change From Baseline
Change from Baseline is the arithmetic difference between post-Baseline and Baseline 
values.
Disease Related Events
Disease Related Events are events (serious or non-serious) anticipated to occur in the 
study population due to the underlying disease eg, disease progression (Table 3).  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.
If the outcome of the underlying disease is worse than that which would normally be 
expected for the subject, or if the investigator believes there is a causal relationship 
between the IP(s)/study treatment protocol required therapies and disease worsening, 
this must be reported as an adverse event or a serious adverse event. Table 3 outlines 
the expected Disease-Related Events by System Organ Class (SOC).


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Table 3.  Disease-related Adverse Events by System Organ Class
System Organ Class (SOC)
Preferred Terms
Blood and lymphatic system disorders
Lymphadenopathy
General disorders and administration site conditions
Disease progression
Fatigue
Investigations
Weight decreased
Skin and subcutaneous tissue disorder
Night sweats
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.
DLT Evaluable
Period 1:
To be evaluable for DLT, subjects must meet one of the following criteria: 
o
Cohort I and II: received treatment for or at least 8 of the 9 doses or 
experienced a DLT at any time while receiving blinatumomab. 
o
Cohort III: treated at least 4 of the 5 doses or experienced a DLT at any 
time while receiving the target dose of blinatumomab.
If a subject does not experience a DLT during the DLT evaluation period and does not 
receive all doses (q48h, q72h, q96h, or q7d dosing), at least 4 of the 5 doses (q24h 
dosing) or at least 8 of the 9 doses (q12h dosing) of subcutaneous Blinatumomab and 
taken off study for reasons other than toxicity the subject will not be considered 
DLT-evaluable and will be replaced as described in Protocol Section 3.4.1.
Period 2:
To be evaluable for DLT, subjects must meet one of the following criteria:
o
If only cycle 1 is given : experienced a DLT during the entire duration of 
the SC administrations and 30 days after the last SC dose or treated with 
blinatumomab targeted dose for 5 days. 
o
If cycle 2 is given: experienced a DLT during the entire duration of the SC 
administrations and 16 days following the last SC dose or until the start of 
cycle 2 (whichever is longer), up to 30 days after the last SC dose or 
treated with blinatumomab at 112 μg/day cIV for 42 days.


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Dose Limiting Toxicity (DLT)
The occurrence of any of the toxicities mentioned in the section 6.2.1.2.3 of the protocol 
will be considered a DLT, if judged by the investigator to be related to administration of 
blinatumomab.
ECOG Performance Status Assessment
ECOG performance status assessment will be performed using the ECOG score. For 
more details please refer appendix C in Protocol.
End of Study for Individual Subject
End of IP Administration for subjects who had blinatumomab is defined as the date the 
decision was made to end IP as recorded on the End of IP CRF page.
End of Treatment
Defined as the last assessment for the protocol-specified treatment phase of the study 
for an individual subject.
End of Follow-up
Defined as the date that the last subject completes the last protocol-specified 
assessment in the study.
Enrollment Date
Enrollment Date is defined as the date of enrollment collected on the CRF.
Subject Level End of Study (EOS) Date
End of study for each subject is defined as the date the subject last completed a 
protocol-specified procedure. The date will be recorded on the End of Study CRF page. 
Investigational Product
The term ‘investigational product’ is used in reference to blinatumomab.
Last Dose Date of Investigational Product 
This is the stop date of the last dose of blinatumomab administration reported on the 
Investigational Product Administration CRF.


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Maximum Tolerated Dose (MTD)
MTD will be defined as the highest dose level at which 1 of 6 subjects experience a 
DLT. If no subject experiences a DLT, the MTD will be defined as the maximal dose 
tested.
Optional Cycle 2
A subject may receive a second cycle of blinatumomab administered SC if the subject 
derived clinical benefit (demonstrated on staging scans) from Cycle 1/Period 2 
treatment. If no clinical benefit occurred with SC in Cycle 1/Period 2 then an optional 
Cycle 2/Period 2 may still be given but will administered as a cIV infusion instead of SC.  
If blinatumomab is administered as a cIV infusion it will be dosed at 9 µg/day cIV for 
7 days for days 1 through day 7, next the dose will be escalated (dose step) to 28 µg/day 
cIV for 7 days starting on day 8 through day 14, and then advanced to 112 μg/day cIV 
for 28 days starting on day 15 through day 42.
Percent Change From Baseline
Percent change from Baseline is the arithmetic difference between post-Baseline and 
Baseline divided by Baseline values times 100.
Screened
A subject is considered in screening once a consent form has been signed.
Study Day 1
Study day 1 is defined as the first day of administration of the investigational product 
after enrollment. The day prior to Study Day 1 is considered Day -1. 
Study Day
Post study day 1:
study day(date - date of Study Day 1) 1
Pre study day 1:
study day(date – date of Study Day 1)
Study Duration
For an individual subject, the length of participation includes a 14 day screening period, 
up to a 14 week treatment period (6 weeks for cycle 1 in Period 1 and Period 2 and 
6 weeks for the optional Cycle 2, separated by a 14 day treatment free interval ), and a 
safety follow-up visit (30 days [7 days] after the last dose of study treatment). 


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For subjects who complete the protocol from the date of first dose through optional 
Cycle 2, the entire duration of the study will take approximately 20 weeks to complete.  
However, individual study duration will vary depending on administration of a second 
cycle and tolerability of blinatumomab by an individual subject.
Treatment emergent adverse events (TEAEs)
A treatment emergent adverse event refers to the adverse event that starts on or after 
first dose of blinatumomab through 30 days after the last dose of blinatumomab. It is 
indicated by the flag whether an event start before first dose of blinatumomab on the 
Event CRF page. This reporting window also applies to treatment-emergent serious 
adverse events (SAEs).
7.
Analysis Subsets
The analysis of all endpoints, unless noted otherwise, will be conducted on the Full
Analysis Set defined in Section 7.1.
7.1
Full Analysis Set
All subjects who receive blinatumomab are included in the full analysis set (FAS).  This 
definition is in line with the intent-to-treat (ITT) principle in single-arm open-label studies.
For the dose escalation part of the study subjects will be analyzed according to the initial 
blinatumomab dose received. For the dose expansion, subjects will be analyzed 
according to the dose selected for this part of the study.
7.2
Safety Analysis Set
For each part of the study, the safety analysis set will be the same as the FAS. All  other 
analysis sets will be a subset of FAS.
7.3
DLT Analysis Set
All subjects who are DLT-evaluable are included in this analysis set as defined 
in section 8.1.1.2
7.4
Pharmacokinetic Analysis Set
All subjects who received any blinatumomab and had at least one PK sample collected 
will be included in the PK analysis set. These subjects will be evaluated for PK unless 
significant protocol deviations affect the data analysis or if key dosing, dosing 
interruption, or sampling information is missing.
7.5
Pharmacodynamic Analysis Set 
All subjects who had cytokine and/or lymphocyte subset samples collected at baseline or 
any time during the study will be included in the PD analysis set.


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8.
Interim Analysis and Early Stopping Guidelines
8.1
Interim Analysis
Safety data will be reviewed on an ongoing basis using an as-is database snapshot.  
Amgen, in consultation with the site investigator, will review in DLRT meetings all 
available accumulating data by multiple subject cohort before making dosing decisions.  
Adverse events and DLTs observed in all subjects will be evaluated continually and will 
be fully integrated into all DLRT meetings and considered in all enrollment and dosing 
decisions.
DLRT meetings will be held to review data, monitor safety, and make dosing decisions.
8.1.1
Dose-cohort Study Escalation and Stopping Rules
8.1.1.1
Dose Level Review Team
The DLRT meeting will be held to review data, monitor safety, and make decisions on 
dose escalation/change, or changes in pre-medication.  The DLRT will be composed of 
the investigators or designees, and the following Amgen representatives: medical 
monitor, global safety officer or designee, clinical study manager, biostatistician, PK 
scientist (optional), and other functional area representatives as appropriate.  A quorum 
as defined below must be in attendance for the DLRT.  The quorum is defined as 50
of the participating investigators (defined as the number of investigators that had 
subjects enrolled on the cohort for that DLRT meeting) or their qualified designee (ie, 
sub-investigator or research nurse or study coordinator possessing written 
documentation [eg, e-mail] of the investigator`s vote), as well as 50of Amgen 
representatives listed above.  The medical monitor or designee must attend for the 
quorum to be reached.  The DLRT will be rescheduled if a quorum is not reached.  
The following members are responsible for DLRT decisions: investigators, Amgen 
medical monitor, and global safety officer or designee.  
The following decisions may be made by the DLRT:

dose escalation/de-escalation decisions 

changes in dosing frequency

expansion of a cohort

continuation, delay or termination of dosing
All available study data, including demographics, investigational product administration, 
medical history, concomitant medications, adverse events, vital signs, laboratory data, 
and PK/PD information will be reviewed.  In addition to DLTs, all grade 3 toxicities not 


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meeting DLT criteria will be reviewed and may be considered in DLRT decisions.  
Source data and queries do not need to be resolved before the DLRT.  Continuous 
toxicity monitoring for early termination of the trial in Cycle 1/Period 2 will be performed. 
All adverse events that occur the DLT window will be reviewed and may be considered 
in DLRT decisions.
8.1.1.2
Dose Limiting Toxicity Rules
Cycle 1/Period 1
The DLT evaluation period includes the entire week 4 (7 days) which is the week that 
blinatumomab is administered SC during Cycle 1/Period 1 of the study. To be evaluable 
subjects need to fulfill the criteria described in section 6. 
If 1 of the 6 evaluable subjects in a dose SC cohort experience a DLT during the SC 
administration, then the dose will be determined to be tolerable and the next dose-cohort 
level will be initiated in a new dose-cohort of subjects after review by the DLRT.
If 2 subjects of the 6 evaluable subjects in a SC dose cohort experience a DLT during 
SC administration then dosing will stop for individual subjects who experience a DLT, a 
DLRT meeting will be conducted, and further steps will be determined.
Additionally, the DLRT will meet:

once dose-cohort 1 has completed subcutaneous dosing 

once dose-cohorts 2 and 3 have completed subcutaneous dosing 

once any additional cohorts complete dosing if additional dose-cohorts are 
tested to determine the MTD in Cycle 1/Period 1
Cycle 1/Period 2
For subjects who receive optional Cycle 2 (cIV dosing period) after Cycle 1/Period 2 (SC 
dosing period), the DLT evaluation period includes the entire duration of SC 
administration in Cycle 1 and 16 days following the last SC dose (56 days in total) or 
until the start of optional Cycle 2, whichever is longer, up to 30 days after the last SC 
dose of Cycle 1. For subjects who do not receive optional Cycle 2, the DLT evaluation 
period includes the entire duration of SC administration and 30 days following the last 
SC dose (70 days in total).Continuous monitoring for early termination of the trial will be 
performed by DLRT(refer to Section 3.1.3 and Section 8.1.1.).


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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.
9.2
Data Handling and Electronic Transfer of Data
Amgen’s Clinical Data Management (CDM) department will provide all data to be used in 
the planned analyses. The database will be subject to edit checks outlined in the Clinical 
Data Management Plan (DMP). See details of this section in the DMP.
9.3
Handling of Missing and Incomplete Data
The following imputation of missing values will be done:

Incomplete adverse event and concomitant medication dates will be imputed as
per Appendix A

No data imputation for PK and biomarker data.
9.4
Detection of Bias
Lack of protocol compliance and the potential for biased statistical analyses will be 
examined by assessing the incidence of important protocol deviations. The clinical study 
team will identify and document the criteria for important protocol deviations following 
Amgen SOP.
9.5
Outliers
Details of detecting outliers can be found in the DMP or other data management 
document. In addition, outliers may be identified via the use of descriptive statistics. All 
confirmed outlier data will be included in the analyses presented in this statistical 
analysis plan unless there is sufficient scientific justification to exclude them.
9.6
Distributional Characteristics
Where appropriate, the assumptions underlying the proposed statistical methodologies 
will be assessed. Data distribution will be explored, if required, data transformations or 
alternative non-parametric methods of analyses will be utilized.  
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.  


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The production environment for statistical analyses consists of Amgen-supported 
versions of statistical analysis software; for example, the SAS System version 9.4.
10.
Statistical Methods of Analysis
10.1
General Principles
Descriptive statistics will be provided for selected demographics, safety, immunogenicity,
PK, PD, and biomarker data. Descriptive statistics on continuous measurements will
include means, medians, standard deviations, and ranges, while categorical data will be
summarized using frequency counts and percentages. Data will be summarized by dose 
cohort and by time as appropriate. Graphical summaries of the data may also be 
presented. When data are summarized by time, the scheduled time points listed in the 
protocol will be used).  For statistical analyses comparing change from baseline, only 
subjects with both baseline and at least one post-baseline assessment will be included. 
When assessing minimum/maximum increases or decreases over the study, all 
assessments, including unscheduled assessments will be used.
The final analysis will be triggered when target enrolment is complete, and all subjects
complete the study or withdraw from the study. The data will be analyzed once they 
have been entered, cleaned, and locked.
10.2
Subject Accountability
The number and percent of subjects who were screened, enrolled, received at least one 
dose of blinatumomab, completed investigational product, discontinued from 
investigational product (including reasons for discontinuing),completed study, 
discontinued the study (including reasons for discontinuing) will be summarized overall 
and by dose cohort. 
Key study dates for the first subject enrolled, last subject enrolled, and last subject’s end 
of study will be presented.
A subject listing and summary noting inclusion in each analysis subset will be provided 
for all subjects enrolled.  A subject listing noting, reason for discontinuation of treatment, 
and reason for discontinuing the study will be provided.  A list of subjects screened but 
not enrolled (screen failures) will be provided.


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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. If a snapshot is being taken during the study rather than a database lock 
at the end of the study, categories should be 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. The final IPD list is used to produce the list of subjects with 
IPDs. In addition, a separate listing of all inclusion and exclusion deviations will be 
provided.
10.4
Demographic and Baseline Characteristics
Demographic (ie, age, age groups [18-64, 65-74, 75-84 and 85], sex, race, ethnicity)
and baseline characteristics will be summarized by dose cohort and overall using 
descriptive statistics. If multiple races have been reported for a subject, the subject will 
be categorized as multiple race as well as by the combination of race.
The baseline characteristics to be summarized include:

Height

Weight

NHL Subtype: FL, Marginal zone lymphoma, Lymphoplasmocytic lymphoma, 
MCL and Small lymphocytic lymphoma

Line of Previous Therapies: 1st line, 2nd line, 3rd line, 4th line and Other
A listing of Non-Hodgkins Lymphoma Medical History will be provided.
10.5
Safety Analyses
Unless otherwise specified, statistical analyses on safety endpoints will be done using 
subjects from the full analysis set, which includes subjects that are enrolled and received 
at least 1 dose of blinatumomab.
10.5.1
Adverse Events
The Medical Dictionary for Regulatory Activities (MedDRA) version 19.0 or later will be 
used to code all adverse events to a system organ class and a preferred term. 
The severity of each adverse event will be graded using CTCAE version 4.0 criteria.
Subject incidence of treatment emergent events and treatment related treatment 
emergent events will further be summarized by worst severity grade.


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Subject incidence of all treatment emergent, serious treatment emergent, treatment
related, serious treatment related, those leading to withdrawal of investigational product
or other protocol-required therapies, and fatal adverse events will further be tabulated by 
system organ class and preferred term for each dose cohort in descending order of 
frequency. The above adverse event tables will include disease related events and will
not be created if two or fewer subjects in the study experience the adverse event. Similar 
summaries will be repeated for EOIs. Time to onset and duration of selected EOIs 
(infection and neurologic events) may also be summarized.
Subject incidence of disease related events and fatal disease related events will be 
tabulated by system organ class and preferred term for each dose cohort. All DREs and 
fatal DREs would be tabulated by system organ class and preferred term separately.
DREs should be included with AEs in any submission datasets, integrated summaries 
and in CTD reporting.
Tables with AEs as above will be produced for period 1 for SC and cIV dosing 
separately.Listings of any on-study deaths, including early withdrawals due to adverse 
events will be provided should they occur.
10.5.1.1
Dose Limiting Toxicities
The analysis of dose limiting toxicities (DLT) will be based on the DLT Analysis Set 
defined in Section 7.3. A listing and summary of the subject incidence of dose limiting 
toxicities (DLT) during period 1 will be provided should they occur.
10.5.2
Laboratory Test Results
10.5.2.1
Chemistry, Hematology and Coagulation
Individual chemistry, hematology and coagulation laboratory data will be listed and may 
also be plotted for selected parameters. Values outside the normal laboratory reference 
ranges will be flagged as high or low on the listings. CTCAE grades will also be 
highlighted where appropriate. Unscheduled assessments will be incorporated in the 
laboratory analyses where possible.
The number and percentage of subjects experiencing treatment emergent laboratory 
toxicities with worst post dose CTCAE grades of 1, 2, 3 and 4 will be presented. 
The direction of the laboratory worsening will be denoted. The summary will be 
presented for all laboratory parameters for which at least one subject experienced a 
treatment emergent toxicity with a worst grade 3.


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Additionally, the number and percentage of subjects experiencing 1, 2, 3 and 
4 worsening CTCAE grade shifts from baseline will be presented. The direction of the 
laboratory worsening will again be denoted.
Shifts tables indicating the change between the baseline and the maximum post dose 
CTCAE grades for an increased value, and the maximum post dose grade for a 
decreased value will be provided for selected laboratory parameters of interest.
A listing of CTCAE grade 3 or higher laboratory toxicities will be provided. This listing will
include all laboratory data for the subject and laboratory parameter of interest in order to 
provide proper context. A flag will indicate the grade 3 or higher toxicity.
Summaries of the absolute value and/or changes from baseline at each scheduled 
assessment will be provided for selected laboratory parameters of interest.
A summary of the change from baseline to the post dose maximum, time to post-dose
maximum, change from baseline to the post dose minimum, and the time to the post 
dose minimum may also be provided for selected parameters of interest.
10.5.2.2
Urinalysis
Individual urinalysis data will be listed.
Blood, protein and glucose will be graded in the following manner: 0’0 or Trace’, 
1’1’, 2’2’, 3’3’, 4’4’. The number and percent of subjects by worst post-dose 
levels will be presented for blood, protein and glucose in the urine).
10.5.3
Vital Signs
Vital signs data will be reviewed for each subject. Depending on the size and scope of 
the changes, the analyses of vital signs may include summary statistics over time and/or 
changes from baseline over time by dose cohort.
10.5.4
Eastern Cooperative Oncology Group (ECOG) Performance Status
ECOG performance status scores will be summarized at each assessed time point. The 
change in scores from screening to safety follow-up (end of study) or last post-baseline 
value (if safety follow-up is not available) will also be summarized.
10.5.5
Antibody Formation
The presence of anti-blinatumomab binding antibodies will be assessed using a 
validated assay. The incidence of anti-blinatumomab antibodies will be listed for each 
subject.  The number and percentage of subjects who have developed 


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anti-blinatumomab antibodies (binding and if positive, neutralizing) at any time, at 
baseline and during post-baseline visits will be summarized by dose cohort.
10.5.6
Exposure to Investigational Product
Descriptive statistics will be produced to describe the exposure to investigational product 
by dosing schedule for cIV and SC separately. The number of cycles, number of doses 
of investigational product and the total dose in μg will be summarized.
Details for each blinatumomab administration will be listed for every subject. In addition,
a listing of the unique manufacturing lot numbers, and a listing of the subjects 
administered each manufacturing lot number will be provided.
10.5.7
Exposure to Concomitant Medication
All medication will be coded using the WHO drug dictionary. A subject listing of all prior 
and concomitant medications will be presented.
10.6
Efficacy Analyses
Statistical analyses of efficacy endpoints will be considered secondary. Efficacy data will 
be conducted on the Full Analysis Set. 
10.6.1
Analyses of Secondary Efficacy Endpoint(s)
The efficacy endpoint of the study is ORR (CRPR) after blinatumomab treatment based 
on Chesons’ 2007 criteria (Appendix B).  The analysis is based on the response 
evaluation recorded in the CRF for subjects in the full analysis set.  Subjects will be 
considered as non-responders if there is no response assessment available.  The rate 
will be estimated along with its 95Clopper-Pearson exact confidence interval by dose 
group and overall.  Subject listings with related collected parameters will also be 
provided.
Summary of other best responses status by each response category will be also 
provided. The number and percentage of subjects with a disease response of complete 
response (CR), partial response (PR), stable disease (SD) or progressive disease (PD)
will be presented for the dose escalation and/or expansion parts of the study. 
Subject listings with related collected parameters will also be provided.
10.6.2
Analyses of Exploratory Endpoints
Overall Response Rate (CR+PR) after blinatumomab treatment based on Lugano 
criteria (Appendix C) will be presented using the same methods as the secondary ORR 
endpoint.


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Graphical summaries of changes from baseline over time in biomarker levels may be 
provided. Association between baseline levels or presence of tumor biomarkers will be 
explored graphically for ORR and PD effects.
10.7
Pharmacokinetic Analysis
The PK analysis will be based on the PK analysis set described in section 7.4. 
Blinatumomab serum concentration-time data will be used to determine the PK 
parameters under cIV and subcutaneous administration, respectively, using
non-compartmental methods and will be listed for individual subjects. All concentration 
values below the quantifiable limits were set to zero before pharmacokinetic analysis. 
Actual dose and actual sampling time will be used for PK analysis. Summary statistics, 
including mean, standard deviation, median (range), geometric mean and CVof 
geometric mean will be computed for each pharmacokinetic parameter and grouped by 
dose, period  and route of administration. Individual concentration-time data will be 
tabulated and presented graphically. Mean concentration-time profiles for each dose will 
be provided.
The following PK parameters will be estimated:

The steady state serum concentration (Css) under continuous IV infusion 
(cIV), summarized as the observed concentrations collected after 
5 half-lives after the start of the IV infusion of each dose (ie, 9, 28 and 
112 µg/day). 

Systemic clearance (CL) following cIV; calculated as CL=R0/Css; where 
R0 is the infusion rate (µg/hr) and Css is the average Css. Both R0 and 
Css were dose-normalized to 112 µg/day for this calculation. 

The maximum observed blinatumomab concentration (Cmax) after 
subcutaneous administration 

The time (tmax) at which Cmax occurred after subcutaneous administration

The area under the concentration-time curve (AUC) after the first and the 
last subcutaneous doses for a dosing interval (AUC); estimated using 
the linear trapezoidal method; where is a dosing interval (eg, 12 hr or 
24 hr)

Cmin, defined as trough concentration at 12 hrs for q12h regimen or at 
24 hrs for q24h regimen after subcutaneous administration 

The apparent clearance (CL/F) after subcutaneous dosing; calculated as 
CL/F = Dosesc / AUC-ss (at steady state)

The volume of distribution based on terminal phase (Vz/F) after 
subcutaneous administration; calculated as Vz/F=CL/F / λz, where λz was 
the first-order rate constant estimated via linear regression of the terminal 
log-linear decay phase as determined from the noncompartmental 
analysis


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
Terminal half-life (t1/2,z) after subcutaneous administration; calculated as 
t1/2,z = ln(2) / λz

Accumulation ratio after subcutaneous administration, calculated as the 
ratio of AUC(last dose) / AUC (first dose) 

Bioavailability (F); calculated as F =  (CL * AUC-ss) / Dosesc
10.8
Pharmacodynamic Analysis
Time profiles of pharmacodynamic markers (eg, T-cell, B-cell, cytokines) may be 
provided if data are sufficient. Mean (SD) peak (eg, cytokine) or trough concentrations
(eg, B-cells) of pharmacodynamic markers will be summarized with descriptive statistics 
by dose level, cohort and route of administration. Time to reach peak or trough 
concentrations of pharmacodynamic markers may be summarized by dose, cohort and 
route of administration.
11.
Changes From Protocol-specified Analyses
There are no changes to the protocol-specified analyses.  


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12.
Literature Citations / References
Cheson B, Pfistner B, Juweid M, et al. Revised response criteria for malignant
lymphoma. Jour of Clin Oncol 2007;25(5):579-586.
Cheson B, Fisher R, Barrington, S, et al. Recommendations for initial evaluation,staging, 
and response assessment of Hodgkin and non-Hodgkin lymphoma: The 
LuganoClassification. Jour of Clin Oncol 2014;32(27):3059-3068.
Clopper CJ, Person ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika. 1934;26:404-413.
Thall PF, Simon RM, and Estey EH. Bayesion sequential monitoring designs for 
single-arm clinical trials with multiple outcomes. Stat. Med. 1995 Feb 28; 14(4):357-79.


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13.
Prioritization of Analyses
There is no prioritization of analyses.
14.
Data Not Covered by This Plan
Exploratory data not included in this plan may be analyzed at a later date or may be 
analyzed by a different Amgen Department.


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15.
Appendices


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Appendix A.  Technical Detail and Supplemental Information Regarding Statistical 
Procedures
Imputation Rules for Partial or Missing Stop Dates
If the month and year are present, impute the last day of the month.  If only the year is 
present, impute December 31 of that year.  If the stop date is entirely missing, assume 
the event or medication is ongoing.  If a partial or complete stop date is present and the 
‘ongoing’ or ‘continuing’ box is checked, then it will be assumed that the AE or conmed 
stopped and the stop date will be imputed, if partial.  
If the month and year are present, impute the last day of the month.  If only the year is 
present, impute December 31 of that year.  If the stop date is entirely missing, assume 
the event or medication is ongoing.  If a partial or complete stop date is present and the 
‘ongoing’ or ‘continuing’ box is checked, then it will be assumed that the AE or conmed 
stopped and the stop date will be imputed, if partial.
Stop Date
Complete: 
yyyymmdd
Partial: yyyymm
Partial: yyyy
Missing
Start 
Date
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


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Note: 

For subjects who were never treated (first dose date is missing), partial start dates 
will be set to the first day of the partial month.

If the start date imputation leads to a start date that is after the stop date, then do not 
impute the start date


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Appendix B.  Modified Cheson Criteria for Evaluation of Extramedullary Disease
Response
Definition
Nodal Masses
Spleen, Liver
Bone Marrow
CR
Disappearance of all 
evidence of disease
(a) FDG-avid or PET positive prior to therapy; 
mass of any size permitted if PET negative 
(b) Variably FDG-avid or PET negative; regression 
to normal size on CT
Not palpable, nodules 
disappeared
Infiltrate cleared on repeat biopsy; if 
indeterminate by morphology, 
immunohistochemistry should be 
negative
PR
Regression of 
measurable disease 
and no new sites
≥ 50% decrease in SPD of up to 6 largest 
dominant masses; no increase in size of other 
nodes 
(a) FDG-avid or PET positive prior to therapy; one 
or more PET positive at previously involved 
site 
(b) Variably FDG-avid or PET negative; regression 
on CT
≥ 50% decrease in SPD of 
nodules (for single nodule in 
greatest transverse diameter); no 
increase in size of liver or spleen
Irrelevant if positive prior to therapy; 
cell type should be specified
SD
Failure to attain 
CR/PR or PD

FDG-avid or PET positive prior to therapy; 
PET positive at prior sites of disease and no 
new sites on CT or PET

Variably FDG-avid or PET negative; no 
change in size of previous lesions on CT
Relapsed 
disease or PD
Any new lesion or 
increase by ≥ 50% of 
previously involved 
sites from nadir
Appearance of a new lesion(s) > 1.5 cm in any 
axis, ≥ 50% increase in SPD of more than one 
node, or ≥ 50% increase in longest diameter of 
a previously identifed node > 1 cm in short axis
Lesions PET positive if FDG-avid lymphoma or 
PET positive prior to therapy
> 50% increase from nadir in the 
SPD of any previous lesions
New or recurrent involvement
Abbreviations: CR, complete remission; FDG, [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR, partial remission; SPD, sum of the 
product of the diameters; SD, stable disease; PD, progressive disease.


Product:  Blinatumomab
Statistical Analysis Plan:  20140286
Date: 21 May 2019
Page 35
Appendix C.  Response Assessment Per the Lugano Classification


Product:  Blinatumomab
Statistical Analysis Plan:  20140286
Date: 21 May 2019
Page 36
Appendix D.  Code Fragments
Provisional Code Fragments for calculating a confidence interval using the Clopper 
Pearson Method. The following example SAS code will be utilized for the response rate 
analysis providing the proportion of subjects responding to treatment with corresponding 
95confidence intervals.
proc freq data=<dataset> ;
   tables <response variable> / binomial (exact) alpha=.05;
run;


Product:  Blinatumomab
Statistical Analysis Plan:  20140286
Date: 21 May 2019
Page 37
Appendix E.  Reference Values/Toxicity Grades
The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be used
and is available at the following location:
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm


Product:  Blinatumomab
Statistical Analysis Plan:  20140286
Date: 21 May 2019
Page 38
Appendix F.  DLRT Output List
Following analyses will be done by Biostatistical Science group and the output will be
sent to Clinical Study Manager by a pre-defined timeline. In addition to the following list 
PK data is essential for the DLRT decision making which will be provided from PK group. 
Also, if available Antibody, Cytokine and Lymphocyte subset data will also be presented
in DLRT.
Listings:
For each cohort, following data listings will be provided in an Excel spreadsheet where 
each listing will be included in a separate worksheet.
1. Subject demographics
2. Date, time, dose of investigational product administration
3. Vital signs
4. Reported adverse events (AEs)
5. Safety laboratory data (Chemistry, Hematology, Urinalysis, Coagulation )
6. Medical history
7. Concomitant medications
8. Prior therapy data
Figures:
Following line plots will be presented for each individual subject:
1. Line plot of vital signs by time course
2. Line plot of all safety labs (Chemistry, Hematology, Urinalysis) by time course